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1. High School and College Biology: A Multi-Level Model of the Effects of High School Courses on Introductory Course Performance

Author: Loehr, John F., Almarode, John T., Tai, Robert H., and Sadler, Philip M.
Abstract: In a climate where increasing numbers of students are encouraged to pursue post-secondary education, the level of preparedness students have for college-level coursework is not far from the minds of all educators, especially high school teachers. Specifically within the biological sciences, introductory biology classes often serve as the gatekeeper or a pre-requisite for subsequent coursework in those fields and pre-professional programmes (eg pre-medicine or pre-veterinarian). Thus, how helpful high school science and mathematics experiences are in preparing students for their introductory biology classes is important and relevant for teachers, science educators and policy makers alike. This quantitative study looked at the association between students' high school science and mathematics experiences with introductory college biology performance. Using a nationally representative sample of US students ("n" = 2667) enrolled in 33 introductory college biology courses, a multi-level statistical model was developed to analyse the association between high school educational experiences and the final course grade in introductory biology courses. Advanced high school science and mathematics coursework, an emphasis on a deep conceptual understanding of biology concepts and a prior knowledge of concepts addressed in well-structured laboratory investigations are all positively associated with students' achievement in introductory college biology. (Contains 1 table.)
Published: 2012
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2. Bats, Barnacles, and Bread Mold: An 'Organism Day' Laboratory for General Biology.

Author: Loehr, Karen A.
Abstract: Describes a laboratory exercise in which students select and identify an organism, study it as it interacts within its environment, collect further information through library research, and bring the organism (alive, preserved, or photographed) to lab for a five-minute presentation. (JN)
Published: 1983

3. Recurrent chromosomal translocations in sarcomas create a megacomplex that mislocalizes NuA4/TIP60 to Polycomb target loci

Author: Deepthi Sudarshan, Nikita Avvakumov, Marie-Eve Lalonde, Nader Alerasool, Charles Joly-Beauparlant, Karine Jacquet, Amel Mameri, Jean-Philippe Lambert, Justine Rousseau, Catherine Lachance, Eric Paquet, Lara Herrmann, Samarth Thonta Setty, Jeremy Loehr, Marcus Q. Bernardini, Marjan Rouzbahman, Anne-Claude Gingras, Benoit Coulombe, Arnaud Droit, Mikko Taipale, Yannick Doyon, and Jacques Côté
Subjects: Sarcoma, Endometrial Stromal, Polycomb-Group Proteins, Chromosomal translocation, macromolecular substances, Biology, medicine.disease_cause, Translocation, Genetic, Histones, Histone H3, medicine, Genetics, Humans, Polycomb Repressive Complex 2, Sarcoma, Methylation, Fusion protein, Chromatin, Endometrial Neoplasms, DNA-Binding Proteins, Histone, biology.protein, Female, PRC2, Carcinogenesis, Developmental Biology
Abstract: Chromosomal translocations frequently promote carcinogenesis by producing gain-of-function fusion proteins. Recent studies have identified highly recurrent chromosomal translocations in patients with Endometrial Stromal Sarcomas (ESS) and Ossifying FibroMyxoid Tumors (OFMT) leading to an in-frame fusion of PHF1 (PCL1) to six different subunits of the NuA4/TIP60 complex. While NuA4/TIP60 is a co-activator that acetylates chromatin and loads the H2A.Z histone variant, PHF1 is part of the Polycomb repressive complex 2 (PRC2) linked to transcriptional repression of key developmental genes through methylation of histone H3 on lysine 27. In this study, we characterize the fusion protein produced by the EPC1-PHF1 translocation. The chimeric protein assembles a mega-complex harboring both NuA4/TIP60 and PRC2 activities and leads to mislocalization of chromatin marks in the genome. These are linked to aberrant gene expression, in particular over an entire topologically-associated domain including part of the HOXD cluster. Furthermore, we show that JAZF1, implicated with PRC2 components in the most frequent translocations in ESS, is a potent transcription activator that physically associates with NuA4/TIP60. Altogether, these results indicate that most chromosomal translocations linked to these sarcomas employ the same molecular oncogenic mechanism through a physical merge of NuA4/TIP60 and PRC2 complexes leading to mislocalization of histone marks and aberrant polycomb target gene expression. HighlightsO_LIRecurrent oncogenic chromosomal translocations fuse Polycomb-like-1 (PHF1) with different subunits of the NuA4/TIP60 complex C_LIO_LITranslocation produces a mega-complex containing NuA4/TIP60 and PRC2 activities C_LIO_LITranslocation leads to mistargeting of histone marks throughout the genome and changes in gene expression C_LIO_LILoss of H3K27me3 and gain of H4ac on HOXD cluster are restricted to a topologically-associated domain (TAD) C_LIO_LIA highly recurrent JAZF1-SUZ12 translocation uses the same mechanism merging NuA4/TIP60 with PRC2 C_LI
Published: 2022
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4. Severe homocysteinemia in two givosiran-treated porphyria patients: is free heme deficiency the culprit?

Author: Elfriede Schuhmann, Brigitte Molitor, Heike Torkler, Christian Loehr, Maria K. Beykirch, Zahra Obermeier, Michael Klein, and Petro E. Petrides
Subjects: Male, 0301 basic medicine, Acetylgalactosamine, Pyrrolidines, Fulminant, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Homocysteine, Heme, biology, High-Throughput Nucleotide Sequencing, Heme arginate, Hematology, General Medicine, Colitis, Hydroxymethylbilane Synthase, 030220 oncology & carcinogenesis, Original Article, Female, 5-Aminolevulinate Synthetase, N-homocysteinylation, Adult, medicine.medical_specialty, Hyperhomocysteinemia, Acute porphyria, Arginine, Models, Biological, Drug Hypersensitivity, 03 medical and health sciences, Free heme, Colon, Sigmoid, Internal medicine, medicine, Humans, Severe homocysteinemia, ∂-ALA-Synthase 1, Adverse effect, Givosiran, business.industry, medicine.disease, Fibrosis, 030104 developmental biology, Porphyria, Pancreatitis, chemistry, Porphyria, Acute Intermittent, Methylenetetrahydrofolate reductase, Hepatocytes, biology.protein, Controlled Clinical Trials as Topic, business
Abstract: Givosiran is a novel approach to treat patients with acute intermittent porphyrias (AIP) by silencing of ∂-ALA-synthase 1, the first enzyme of heme biosynthesis in the liver. We included two patients in the Envision study who responded clinically well to this treatment. However, in both patients, therapy had to be discontinued because of severe adverse effects: One patient (A) developed local injection reactions which continued to spread all over her body with increasing number of injections and eventually caused a severe systemic allergic reaction. Patient B was hospitalized because of a fulminant pancreatitis. Searching for possible causes, we also measured the patients plasma homocysteine (Hcy) levels in fluoride-containing collection tubes: by LC–MS/MS unexpectedly, plasma Hcy levels were 100 and 200 in patient A and between 100 and 400 μmol/l in patient B. Searching for germline mutations in 10 genes that are relevant for homocysteine metabolism only revealed hetero- and homozygous polymorphisms in the MTHFR gene. Alternatively, an acquired inhibition of cystathionine-beta-synthase which is important for homocysteine metabolism could explain the plasma homocysteine increase. This enzyme is heme-dependent: when we gave heme arginate to our patients, Hcy levels rapidly dropped. Hence, we conclude that inhibition of ∂-ALA-synthase 1 by givosiran causes a drop of free heme in the hepatocyte and therefore the excessive increase of plasma homocysteine. Hyperhomocysteinemia may contribute to the adverse effects seen in givosiran-treated patients which may be due to protein-N-homocysteinylation.
Published: 2021
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5. Genomic Analysis of Circulating Tumor DNA in 3,334 Patients with Advanced Prostate Cancer Identifies Targetable BRCA Alterations and AR Resistance Mechanisms

Author: Andrew Simmons, Charles J. Ryan, Simon Chowdhury, Bernard Fendler, Jon Chung, Wassim Abida, Ryon Graf, Hanna Tukachinsky, Jeffrey S. Ross, Andrea Loehr, Tony Golsorkhi, Karim Fizazi, Jeffrey M. Venstrom, Russell Madison, Lucas Dennis, Samantha Morley, Ole Gjoerup, Geoffrey R. Oxnard, Brian M. Alexander, Lei Zhong, Eric Allan Severson, and Simon Paul Watkins
Subjects: 0301 basic medicine, Cancer Research, biology, business.industry, Concordance, medicine.disease, Germline, Androgen receptor, 03 medical and health sciences, Exon, Prostate cancer, 030104 developmental biology, 0302 clinical medicine, Oncology, Circulating tumor DNA, Polyclonal antibodies, 030220 oncology & carcinogenesis, Cancer research, biology.protein, medicine, business, CHEK2
Abstract: Purpose: Comprehensive genomic profiling (CGP) is of increasing value for patients with metastatic castration-resistant prostate cancer (mCRPC). mCRPC tends to metastasize to bone, making tissue biopsies challenging to obtain. We hypothesized CGP of cell-free circulating tumor DNA (ctDNA) could offer a minimally invasive alternative to detect targetable genomic alterations (GA) that inform clinical care. Experimental Design: Using plasma from 3,334 patients with mCRPC (including 1,674 screening samples from TRITON2/3), we evaluated the landscape of GAs detected in ctDNA and assessed concordance with tissue-based CGP. Results: A total of 3,129 patients (94%) had detectable ctDNA with a median ctDNA fraction of 7.5%; BRCA1/2 was mutated in 295 (8.8%). In concordance analysis, 72 of 837 patients had BRCA1/2 mutations detected in tissue, 67 (93%) of which were also identified using ctDNA, including 100% of predicted germline variants. ctDNA harbored some BRCA1/2 alterations not identified by tissue testing, and ctDNA was enriched in therapy resistance alterations, as well as possible clonal hematopoiesis mutations (e.g., in ATM and CHEK2). Potential androgen receptor resistance alterations were detected in 940 of 2,213 patients (42%), including amplifications, polyclonal and compound mutations, rearrangements, and novel deletions in exon 8. Conclusions: Genomic analysis of ctDNA from patients with mCRPC recapitulates the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of BRCA1/2 mutations, but more acquired resistance alterations detected in ctDNA. CGP of ctDNA is a compelling clinical complement to tissue CGP, with reflex to tissue CGP if negative for actionable variants. See related commentary by Hawkey and Armstrong, p. 2961
Published: 2021
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6. Fluorescent dATP for DNA Synthesis In Vivo

Author: Evelyn Lattmann, Ting Deng, Nathan W. Luedtke, Alex Hajnal, Stephan C.F. Neuhauss, Morten O Loehr, and Verena N. Schreier
Subjects: 0301 basic medicine, DNA synthesis, biology, 010405 organic chemistry, Chemistry, Kinetics, DNA replication, General Medicine, biology.organism_classification, 01 natural sciences, Biochemistry, 0104 chemical sciences, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, In vivo, Biophysics, Molecular Medicine, Cyanine, Zebrafish, Nucleoside, DNA
Abstract: Fluorescent nucleoside triphosphates are powerful probes of DNA synthesis, but their potential use in living animals has been previously underexplored. Here, we report the synthesis and characterization of 7-deaza-(1,2,3-triazole)-2'-deoxyadenosine-5'-triphosphate (dATP) derivatives of tetramethyl rhodamine ("TAMRA-dATP"), cyanine ("Cy3-dATP"), and boron-dipyrromethene ("BODIPY-dATP"). Upon microinjection into live zebrafish embryos, all three compounds were incorporated into the DNA of dividing cells; however, their impact on embryonic toxicity was highly variable, depending on the exact structure of the dye. TAMRA-EdATP exhibited superior characteristics in terms of its high brightness, low toxicity, and rapid incorporation and depletion kinetics in both a vertebrate (zebrafish) and a nematode (Caenorhabditis elegans). TAMRA-EdATP allows for unprecedented, real-time visualization of DNA replication and chromosome segregation in vivo.
Published: 2020
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7. High-Level Inactivity Despite Favorable Environmental Conditions in the Rock-Dwelling Dwarf Tortoise Chersobius boulengeri

Author: Toby Keswick, Merle A.D.E. Reijnders, Victor J. T. Loehr, and Iris M. Zweers
Subjects: education.field_of_study, Herbivore, Tortoise, biology, Ecology, Population, Foraging, biology.organism_classification, Arid, Predation, Ectotherm, Animal Science and Zoology, Homopus, education, Ecology, Evolution, Behavior and Systematics
Abstract: In arid regions with summer rainfall, herbivorous reptiles are able to acquire water and fresh food in the presence of high environmental temperatures that can promote ectotherm activity. However, extremely high temperatures and below average rainfall may also limit foraging opportunities due to risks of overheating and predation while gathering scarce food. Karoo Dwarf Tortoises (Chersobius boulengeri) inhabit an arid region in South Africa where most rains fall around austral summer (October–May). We used focal-animal observations and instantaneous recording to assess their behavioral patterns. Despite relatively high rainfall and available plant growth, Karoo Dwarf Tortoises spent approximately 80–90% of their time in retreats. Whereas activity (behavior outside retreats) in the spring was unrelated to time of the day, possibly due to moderate ambient temperatures, activity in the summer was restricted to the afternoon and evening, when tortoises walked and scanned for food and retreats, and fed only 11 min/d on average. In summer, body temperature of tortoises within retreats was positively associated with retreat temperatures, but tortoises appeared to thermoregulate using bodily postures and possibly other means. We suggest that Karoo Dwarf Tortoises mitigate predation risks by maintaining a low level of activity and thermoregulating within retreats. The short feeding time of Karoo Dwarf Tortoises compared to other tortoise taxa may result in slow growth and reproductive rates, which might in turn affect population resilience and conservation needs of this endangered species.
Published: 2021
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8. Beaver creates early successional hotspots for water beetles

Author: John Loehr, Wenfei Liao, Juliette van der Schoor, Petri Nummi, Wetland Ecology Group, Department of Forest Sciences, Forest Ecology and Management, Ecosystems and Environment Research Programme, Lammi Biological Station, and Biological stations
Subjects: 0106 biological sciences, Beaver, ECOSYSTEM ENGINEER, Biodiversity, DIVERSITY, Wetland, Conservation, 010603 evolutionary biology, 01 natural sciences, Ecosystem engineer, INVERTEBRATES, biology.animal, FISH ASSEMBLAGES, 14. Life underwater, Water beetle, HABITAT, DISTURBANCE, Restoration ecology, Ecology, Evolution, Behavior and Systematics, Nature and Landscape Conservation, Castor canadensis, geography.geographical_feature_category, Ecology, biology, DYTISCIDAE, 010604 marine biology & hydrobiology, SPECIES RICHNESS, CASTOR-CANADENSIS, Landscape heterogeneity, Aquatic insect, 15. Life on land, biology.organism_classification, Geography, 13. Climate action, 1181 Ecology, evolutionary biology, Species richness, Facilitation, LANDSCAPES
Abstract: Correction to: Beaver creates early successional hotspots for water beetles. Biodivers Conserv (2021). https://doi.org/10.1007/s10531-021-02230-7 Published 03 July 2021 Beavers (Castor spp.) are ecosystem engineers that induce local disturbance and ecological succession, which turns terrestrial into aquatic ecosystems and creates habitat heterogeneity in a landscape. Beavers have been proposed as a tool for biodiversity conservation and ecosystem restoration. So far, most research has compared biodiversity in beaver wetlands and non-beaver wetlands, but few studies have explored how beaver-created succession affects specific taxa. In this study, we investigated how water beetles responded to different successional stages of wetlands in a beaver-disturbed landscape at Evo in southern Finland. We sampled water beetles with 1-L activity traps in 20 ponds, including: 5 new beaver ponds, 5 old beaver ponds, 5 former beaver ponds, and 5 never engineered ponds. We found that beaver wetlands had higher species richness and abundance than non-beaver wetlands, and that new beaver wetlands could support higher species richness (321%) and abundance (671%) of water beetles compared to old beaver wetlands. We think that higher water beetle diversity in new beaver ponds has resulted from habitat amelioration (available lentic water, shallow shores, aquatic vegetation, and low fish abundance) and food source enhancement (an increase of both dead and live prey) created by beaver dams and floods. We conclude that using beavers as a tool, or imitating their way of flooding, can be beneficial in wetland restoration if beaver population densities are monitored to ensure the availability of newly colonizable sites.
Published: 2021

9. Design, Synthesis and Evaluation of WD-repeat containing protein 5 (WDR5) degraders

Author: N. Berner, Magda Szewczyk, B. Kuester, J. Weckesser, Martin Eilers, Andreas Kraemer, Christoph A. Sotriffer, Volker Doetsch, Bikash Adhikari, Frank Loehr, Stephanie Heinzlmeir, Dalia Barsyte-Lovejoy, A. Doelle, Mathias Diebold, Elmar Wolf, J. Gerbel, Lena M. Berger, Stefan Knapp, and Cheryl H. Arrowsmith
Subjects: Scaffold protein, Histone, biology, Chemistry, WD Repeat-Containing Protein 5, Histone methyltransferase, biology.protein, WDR5, Gene, Transcription factor, Function (biology), Cell biology
Abstract: Histone H3K4 methylation serves as post-translational hallmark of actively transcribed genes and is introduced by histone methyltransferases (HMT) and its regulatory scaffolding proteins. One of these is the WD-repeat containing protein 5 (WDR5) that has also been associated with controlling long non-coding RNAs and transcription factors including MYC. The wide influence of dysfunctional HMTs complexes and the typically upregulated MYC levels in diverse tumor types suggested WDR5 as an attractive drug target. Indeed, protein-protein interface inhibitors for two protein interaction interfaces on WDR5 have been developed. While such compounds only inhibit a subset of WDR5 interactions, chemically induced proteasomal degradation of WDR5 might represent an elegant way to target all oncogenic function. This study presents the design, synthesis and evaluation of two diverse WDR5 degrader series based on two WIN site binding scaffolds and shows that linker nature and length strongly influence degradation efficacy.
Published: 2021
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10. Health assessment of wild speckled dwarf tortoises, Chersobius signatus

Author: Giacomo Rossi, Francesco C. Origgi, Maira Napoleoni, Stefania Perrucci, Gianni Perugini, Livio Galosi, Vincenzo Cuteri, Victor J. T. Loehr, Adolfo Maria Tambella, Nicholas Aconiti Mandolini, and Annarita Attili
Subjects: Male, Veterinary medicine, Tortoise, 040301 veterinary sciences, media_common.quotation_subject, Population, Health assessment, Chersobius [Homopus] signatus, Reptile, Tortoise, Wildlife, Reptile, Wildlife, 0403 veterinary science, South Africa, 03 medical and health sciences, Health assessment, Animals, Parasite hosting, Ciliophora, Homopus, Ornithodoros, education, Eggs per gram, Feces, Chersobius [Homopus] signatus, media_common, 0303 health sciences, education.field_of_study, lcsh:Veterinary medicine, Bacteria, General Veterinary, biology, 630 Agriculture, 030306 microbiology, Antinematodal Agents, Fungi, Fenbendazole, 04 agricultural and veterinary sciences, General Medicine, Oxyurida Infections, biology.organism_classification, Coccidia, Tick Infestations, Turtles, lcsh:SF600-1100, Population study, 590 Animals (Zoology), Female, Reproduction, Research Article
Abstract: Background In free-ranging reptile populations, bacterial, fungal, viral and parasitic pathogens may affect hosts through impairment in movements, thermoregulation, reproduction, survival, and population dynamics. The speckled dwarf tortoise (Chersobius [Homopus] signatus) is a threatened species that is mostly restricted to the Succulent Karoo biome in South Africa, and little information on pathogens of this species is available yet. We derived baseline parameters for five males and five females that were captured to genetically enhance a conservation breeding program in Europe. Upon collection of the tortoises, ticks were removed and identified. Immediately upon arrival in Europe, ocular, nasal, oral and cloacal swabs were taken for viral, bacteriological and mycological examinations. Fecal samples were collected before and 1 month after fenbendazole treatment, and analyzed for parasites. A panel of PCR, aiming to detect herpesviruses, adenoviruses and iridoviruses, was carried out. Results Samples were negative for viruses, while bacteriological examination yielded detectable growth in 82.5% of the swabs with a mean load of 16 × 107 ± 61 × 108 colony forming units (CFU) per swab, representing 34 bacterial species. Cloacal and oral swabs yielded higher detectable growth loads than nasal and ocular swabs, but no differences between sexes were observed. Fungi and yeasts (mean load 5 × 103 ± 13 × 103 CFU/swab) were detected in 25% of the swabs. All pre-treatment fecal samples were positive for oxyurid eggs, ranging from 200 to 2400 eggs per gram of feces, whereas after the treatment a significantly reduced egg count (90–100% reduction) was found in seven out of 10 individuals. One remaining individual showed 29% reduction, and two others had increased egg counts. In five tortoises, Nycthocterus spp. and coccidian oocysts were also identified. Soft ticks were identified as Ornithodoros savignyi. Conclusions Our baseline data from clinically healthy individuals will help future studies to interpret prevalences of microorganisms in speckled dwarf tortoise populations. The study population did not appear immediately threatened by current parasite presence.
Published: 2021
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11. Fluorescent dATP for DNA Synthesis In Vivo

Author: Schreier, Verena N, Loehr, Morten O, Deng, Ting, Lattmann, Evelyn, Hajnal, Alex, Neuhauss, Stephan C F, Luedtke, Nathan W, University of Zurich, and Luedtke, Nathan W
Subjects: 1303 Biochemistry, 1313 Molecular Medicine, 570 Life sciences, biology, 10124 Institute of Molecular Life Sciences
Published: 2020

12. A Genetically Engineered Mouse Model of Malignant Testicular Germ Cell Tumors

Author: Amy M. Lyndaker, Amanda R Loehr, Timothy M. Pierpont, and Robert S. Weiss
Subjects: 0301 basic medicine, endocrine system, biology, DNA damage, business.industry, Cancer, Disease, medicine.disease, medicine.disease_cause, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Cancer stem cell, 030220 oncology & carcinogenesis, Genetically Engineered Mouse, medicine, Cancer research, biology.protein, PTEN, KRAS, business, Testicular cancer
Abstract: Testicular germ cell tumors (TGCTs) are among the most curable solid cancers and are typically highly responsive to conventional DNA-damaging chemotherapies, even in patients with metastatic disease. It has therefore been of great interest to understand the basis for the unique chemosensitivity of these cancers, which is linked to the DNA damage sensitivity of their cancer stem cells. TGCTs have been difficult to study in the mouse, however, since most of the existing mouse models develop benign teratomas that are unlike the malignant TGCTs that afflict most testicular cancer patients. We describe here methods for generating a TGCT mouse model that closely resembles the malignant, metastatic disease observed in men with testicular cancer, and additionally include methods for analyzing the cancer stems cells and responses to chemotherapeutics in these murine TGCTs.
Published: 2020
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13. Female-biased sex ratios in urban centers create a 'fertility trap' in post-war Finland

Author: Robert Lynch, Jenni E. Pettay, Virpi Lummaa, John Loehr, Biological stations, and Lammi Biological Station
Subjects: 0106 biological sciences, SELECTION, Natural experiment, media_common.quotation_subject, Fertility, urbanization, Biology, migration, ECOLOGY, 010603 evolutionary biology, 01 natural sciences, reproduction, 03 medical and health sciences, 5. Gender equality, Urbanization, Mating, mate choice, dispersal, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, media_common, fertility, 0303 health sciences, AcademicSubjects/SCI01330, 1. No poverty, WOMEN, Original Articles, sex ratio, Mate choice, 1181 Ecology, evolutionary biology, Biological dispersal, Animal Science and Zoology, Rural area, Sex ratio, Demography
Abstract: Because sex ratios are a key factor regulating mating success and subsequent fitness both across and within species, there is widespread interest in how population-wide sex ratio imbalances affect marriage markets and the formation of families in human societies. Although most modern cities have more women than men and suffer from low fertility rates, the effects of female-biased sex ratios have garnered less attention than male-biased ratios. Here, we analyze how sex ratios are linked to marriages, reproductive histories, dispersal, and urbanization by taking advantage of a natural experiment in which an entire population was forcibly displaced during World War II to other local Finnish populations of varying sizes and sex ratios. Using a discrete time-event generalized linear mixed-effects model, and including factors that change across time, such as annual sex ratio, we show how sex ratios, reproduction, and migration are connected in a female-dominated environment. Young childless women migrated toward urban centers where work was available to women, and away from male-biased rural areas. In such areas where there were more females, women were less likely to start reproduction. Despite this constraint, women showed little flexibility in mate choice, with no evidence for an increase in partner age difference in female-biased areas. We propose that together these behaviors and conditions combine to generate an “urban fertility trap” which may have important consequences for our understanding of the fertility dynamics of today including the current fertility decline across the developed world., We investigate how the local sex ratios (number of men for each woman) affected women’s decisions to marry, reproduce, and disperse after the Second World War in Finland in a population of forced migrants. We find that women in urban areas were less likely to start families when the sex ratio was more female-biased, and women were more likely to move away from rural to urban areas, presumably to pursue opportunities created from urbanization. Together, these behaviors and conditions combine to generate an “urban fertility trap” which may have important consequences for understanding the fertility decline among current urbanizing populations.
Published: 2020

14. Reproductive investments of a small, arid zone tortoise Chersobius signatus : Follicle and egg development

Author: Brian T. Henen, Margaretha D. Hofmeyr, and Victor J. T. Loehr
Subjects: 0106 biological sciences, Winter rainfall, Tortoise, business.industry, 010607 zoology, Zoology, Cell Biology, Biology, biology.organism_classification, 010603 evolutionary biology, 01 natural sciences, Follicle, Animal Science and Zoology, Ultrasonography, Homopus, business, Ecology, Evolution, Behavior and Systematics, Arid zone
Published: 2018
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15. Correction to: Beaver creates early successional hotspots for water beetles

Author: Wenfei Liao, Juliette van der Schoor, John Loehr, and Petri Nummi
Subjects: 0106 biological sciences, Beaver, Ecology, biology, 010604 marine biology & hydrobiology, Ecology (disciplines), Biodiversity, 010603 evolutionary biology, 01 natural sciences, Geography, biology.animal, Ecology, Evolution, Behavior and Systematics, Nature and Landscape Conservation
Published: 2021
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16. Foraging decisions of North American beaver (Castor canadensis) are shaped by energy constraints and predation risk

Author: John Loehr, Janne Sundell, Julien A. Salandre, and Rahel Beil
Subjects: 0106 biological sciences, Shore, Castor canadensis, Beaver, geography, geography.geographical_feature_category, biology, Ecology, 010604 marine biology & hydrobiology, Foraging, Betula pubescens, biology.organism_classification, 010603 evolutionary biology, 01 natural sciences, Predation, Animal ecology, biology.animal, Animal Science and Zoology, Predator, Ecology, Evolution, Behavior and Systematics
Abstract: Foraging herbivores have to trade-off between energy requirements and predator avoidance. We aimed to study the relative roles of these factors in beavers (Castor canadensis) when foraging on land. We hypothesized that beavers were able to assess the risk of predation by using two main cues: the distance from the water and the presence or absence of predator odors. First, we studied the food selection of beavers in relation to distance from the water in natural settings. The transects were made at beaver ponds, and the diameter, species, and distance from the shore of intact and beaver-cut trees were recorded. Secondly, we placed rows of aspen sticks (Populus tremula) perpendicular to the shore around beaver ponds, and treated each row with a neutral, alien, or wolf odor. We found that aspen, downy birch (Betula pubescens), and speckled alder (Alnus incana) were the preferred tree species. More of these species were cut close to the shore, and cut trees were smaller further away from the shore, except in the case of aspen. In the experiment, most of the aspen sticks were taken close to the shore. As predicted, beavers took less aspen sticks in rows treated with wolf odor than water. As the predator odor did not affect the foraging distance from the shore, it is likely that our observation that foraging was the most intense close to shore is due to energetic constraints. However, predation risk probably affects the decision whether to forage on the land in the first place.
Published: 2017
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17. Unexpected decline in a population of speckled tortoises

Author: Victor J. T. Loehr
Subjects: 0106 biological sciences, education.field_of_study, Ecology, Tortoise, 010604 marine biology & hydrobiology, Population, Biology, biology.organism_classification, 010603 evolutionary biology, 01 natural sciences, Predation, Homopus signatus, Population decline, Population model, General Earth and Planetary Sciences, education, Ecology, Evolution, Behavior and Systematics, Semelparity and iteroparity, Sex ratio, Nature and Landscape Conservation, General Environmental Science
Abstract: Long-lived, iteroparous species exhibit various mechanisms to overcome temporary unfavorable conditions and promote adult survival and population persistence. Consequently, populations may appear relatively stable while subtle and slow-progressing threats cause their decline. The speckled tortoise (Homopus signatus) is a long-lived, iteroparous species in South Africa that is thought to be secure in areas that meet the species’ known requirements. To verify its stability, I monitored a dense speckled tortoise population, integrating 2 mark-recapture studies (2000–2004 and 2012–2015) in long-term joint live and dead encounters and POPAN population models. From 2000 to 2015, the study site remained fenced, ungrazed, and was not modified in any way, yet the size-class frequency distribution, sex ratio, and abundance of speckled tortoises drastically changed. Population numbers decreased 66%, mainly because of the disappearance of juveniles and males. Modeling results identified a reduction in the number of entrants into the population (via births and immigration) as the likely cause of population changes, whereas apparent survival remained high. Observations, in part anecdotal, of increasing numbers of pied crows (Corvus albus) on the study site suggest that increased predation on speckled tortoise hatchlings contributed to the population decline. Examination of rainfall data for 1990–2015 did not reveal evidence of aridification in the study area, a documented cause of reduced reproduction in speckled tortoises. The results of this study caution against the assumption that areas in the range of the speckled tortoise that meet its known requirements can maintain healthy populations. © 2017 The Wildlife Society
Published: 2017
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18. Monitoring of ticks and tick-borne pathogens through a nationwide research station network in Finland

Author: Janne Sundell, Jari Ylönen, Jani J. Sormunen, Tero Klemola, Noora Haavisto, Hannu Ylönen, Silja Vuorenmaa, Tony Cederberg, Hanna Halonen, Tommi Andersson, Jaana Bäck, Jasmin Inkinen, Tuukka Petäjä, John Loehr, Niko Kulha, Maija Laaksonen, Eero J. Vesterinen, Niko Tanski, Martin Snickars, Satu Mäkelä, Ella-Maria Vesilahti, Pauliina Pajala, Jari Hänninen, Antti Uotila, Riku Paavola, Katja Mäkinen, Joanna Norkko, Anna I. E. Puisto, Ella Sippola, Jouni Aspi, Viikki Plant Science Centre (ViPS), Department of Forest Sciences, Forest Ecology and Management, Ecosystem processes (INAR Forest Sciences), Institute for Atmospheric and Earth System Research (INAR), Biological stations, Tvärminne Zoological Station, Boreal forest dynamics and biodiversity research group, Lammi Biological Station, Department of Physics, and Hyytiälän metsäasema
Subjects: 0301 basic medicine, virukset, Population Dynamics, monitorointi, Ixodes persulcatus, puutiaiset, ACARI, medicine.disease_cause, BURGDORFERI SENSU-LATO, DISEASE, bakteerit, Ticks, 0302 clinical medicine, INFECTION, POPULATION, Finland, 11832 Microbiology and virology, Tick-borne pathogens, biology, longitudinal study, levinneisyys, PREVALENCE, Infectious Diseases, taudinaiheuttajat, 1181 Ecology, evolutionary biology, Epidemiological Monitoring, tick-borne pathogens, Bartonella-bakteerit, Seasons, Longitudinal study, Nymph, Ixodes ricinus, Monitoring, Borrelia valaisiana, 030231 tropical medicine, Zoology, Babesia, LYME BORRELIOSIS, Borrelia miyamotoi, pitkittäistutkimus, Tick, Borrelia afzelii, Microbiology, ticks, Encephalitis Viruses, Tick-Borne, 03 medical and health sciences, COINFECTIONS, parasitic diseases, Gram-Negative Bacteria, medicine, Animals, Borrelia burgdorferi, Ixodes, IXODES-RICINUS TICKS, biology.organism_classification, bacterial infections and mycoses, punkit, Borrelia-bakteerit, monitoring, 030104 developmental biology, Nationwide, itiöeläimet, Insect Science, Parasitology, Borrelia garinii, nationwide, CANDIDATUS NEOEHRLICHIA MIKURENSIS
Abstract: In 2015 a long-term, nationwide tick and tick-borne pathogen (TBP) monitoring project was started by the Finnish Tick Project and the Finnish Research Station network (RESTAT), with the goal of producing temporally and geographically extensive data regarding exophilic ticks in Finland. In the current study, we present results from the first four years of this collaboration. Ticks were collected by cloth dragging from 11 research stations across Finland in May September 2015-2018 (2012-2018 in Seili). Collected ticks were screened for twelve different pathogens by qPCR: Borrelia afzelii, Borrelia garinii, Borrelia valaisiana, Borrelia burgdorferi sensu stricto, Borrelia miyamotoi, Babesia spp., Anaplasma phagocytophilum, Rickettsia spp., Candidatus Neoehrlichia mikurensis, Francisella tularensis, Bartonella spp. and tick-borne encephalitis virus (TBEV). Altogether 15 067 Ixodes ricinus and 46 Ixodes persulcatus were collected during 68 km of dragging. Field collections revealed different seasonal activity patterns for the two species. The activity of I. persulcatus adults (only one nymph detected) was unimodal, with activity only in May July, whereas Ixodes ricinus was active from May to September, with activity peaks in September (nymphs) or July August (adults). Overall, tick densities were higher during the latter years of the study. Borrelia burgdorferi sensu lato were the most common pathogens detected, with 48.9 +/- 8.4% (95% Cl) of adults and 25.3 +/- 4.4% of nymphs carrying the bacteria. No samples positive for F. tularensis, Bartonella or TBEV were detected. This collaboration project involving the extensive Finnish Research Station network has ensured enduring and spatially extensive, long-term tick data collection to the foreseeable future.
Published: 2020

19. Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants

Author: Namrata Gupta, Peter Durda, Elizabeth C. Oelsner, Martha L. Daviglus, Martin D. Tobin, James G. Wilson, Liana K. Preudhomme, Laura R. Loehr, Ingo Ruczinski, Pallavi Balte, Ramachandran S. Vasan, R. Graham Barr, Phuwanat Sakornsakolpat, Stephanie J. London, Robert M. Reed, Elaine Cornell, Josée Dupuis, Dandi Qiao, Dmitry Prokopenko, Russell P. Tracy, Alanna C. Morrison, Robert C. Kaplan, Cathy C. Laurie, Sina A. Gharib, Donna M. Muzny, Kent D. Taylor, Cecelia A. Laurie, Wonji Kim, Stephen S. Rich, Brian E. Cade, Kristin M. Burkart, Tamar Sofer, George T. O'Connor, Chiara Batini, Louise V. Wain, Leslie A. Lange, Ani Manichaikul, Susan Redline, Yanlin Ma, Bruce M. Psaty, Xutong Zhao, Yongmei Liu, Chaojie Yang, Edwin K. Silverman, David J. Vandenberg, Deborah A. Nickerson, George J. Papanicolaou, Bing Yu, L. Adrienne Cupples, Kathleen C. Barnes, François Aguet, Silva Kasela, Stacey Gabriel, Kristin G. Ardlie, Xiuqing Guo, Gonçalo R. Abecasis, Shannon Dugan-Perez, Harshavardhan Doddapaneni, Jerome I. Rotter, Ginger A. Metcalf, W. Craig Johnson, Michelle Daya, Nick Shrine, Sarah A Gagliano Taliun, Traci M. Bartz, Jiwon Lee, Deepti Jain, Tuuli Lappalainen, and Michael H. Cho
Subjects: 0301 basic medicine, Male, TOPMed Lung Working Group, General Physics and Astronomy, Genome-wide association study, Genome-wide association studies, Pulmonary function testing, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Polymorphism (computer science), 80 and over, 2.1 Biological and endogenous factors, DNA sequencing, Aetiology, lcsh:Science, Lung, Genetics, African Americans, Aged, 80 and over, COPD, education.field_of_study, Multidisciplinary, Chronic obstructive pulmonary disease, Intracellular Signaling Peptides and Proteins, Single Nucleotide, Middle Aged, Biobank, Protein Inhibitors of Activated STAT, 030220 oncology & carcinogenesis, Respiratory, Respiratory Physiological Phenomena, Small Ubiquitin-Related Modifier Proteins, Female, Biotechnology, Adult, Chronic Obstructive, Chronic Obstructive Pulmonary Disease, Science, Population, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, and over, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, Pulmonary Disease, 03 medical and health sciences, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, medicine, Humans, Genetic Predisposition to Disease, Polymorphism, education, Aged, Whole genome sequencing, Whole Genome Sequencing, Human Genome, Calcium-Binding Proteins, General Chemistry, Precision medicine, medicine.disease, respiratory tract diseases, Black or African American, 030104 developmental biology, Good Health and Well Being, Genetic Loci, Feasibility Studies, lcsh:Q, 2.4 Surveillance and distribution, Follow-Up Studies, Genome-Wide Association Study
Abstract: Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry., Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality. Here, the authors analyse whole genome sequence data and find new loci associated with lung function and COPD.
Published: 2020

20. Rucaparib in Men with Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration

Author: Jingsong Zhang, Simon Paul Watkins, Charles J. Ryan, Nicholas J. Vogelzang, David Campbell, Simon Chowdhury, Darrin Despain, Cora N. Sternberg, Andrea Loehr, Richard Martin Bambury, Gedske Daugaard, Josep M. Piulats, Wassim Abida, Karim Fizazi, Alan H. Bryce, Brieuc Sautois, Jeremy Shapiro, Andrew Simmons, Laurence Eliot Miles Krieger, Axel S. Merseburger, Eric Voog, Tony Golsorkhi, Melanie Dowson, Celestia S. Higano, Ray McDermott, Akash Patnaik, and Axel Heidenreich
Subjects: 0301 basic medicine, Male, Cancer Research, 2019-20 coronavirus outbreak, Indoles, endocrine system diseases, Castration resistant, Poly(ADP-ribose) Polymerase Inhibitors, Genitourinary Cancer, 03 medical and health sciences, chemistry.chemical_compound, Prostate cancer, 0302 clinical medicine, Germline mutation, Clinical Trials, Phase II as Topic, RAPID COMMUNICATIONS, Medicine, Humans, Progression-free survival, Neoplasm Metastasis, Rucaparib, Polymerase, Germ-Line Mutation, Aged, Aged, 80 and over, BRCA2 Protein, biology, business.industry, BRCA1 Protein, Editorials, Middle Aged, medicine.disease, Progression-Free Survival, Prostatic Neoplasms, Castration-Resistant, 030104 developmental biology, Oncology, chemistry, Gene Alteration, 030220 oncology & carcinogenesis, biology.protein, Cancer research, business
Abstract: PURPOSE BRCA1 or BRCA2 ( BRCA) alterations are common in men with metastatic castration-resistant prostate cancer (mCRPC) and may confer sensitivity to poly(ADP-ribose) polymerase inhibitors. We present results from patients with mCRPC associated with a BRCA alteration treated with rucaparib 600 mg twice daily in the phase II TRITON2 study. METHODS We enrolled patients who progressed after one to two lines of next-generation androgen receptor–directed therapy and one taxane-based chemotherapy for mCRPC. Efficacy and safety populations included patients with a deleterious BRCA alteration who received ≥ 1 dose of rucaparib. Key efficacy end points were objective response rate (ORR; per RECIST/Prostate Cancer Clinical Trials Working Group 3 in patients with measurable disease as assessed by blinded, independent radiology review and by investigators) and locally assessed prostate-specific antigen (PSA) response (≥ 50% decrease from baseline) rate. RESULTS Efficacy and safety populations included 115 patients with a BRCA alteration with or without measurable disease. Confirmed ORRs per independent radiology review and investigator assessment were 43.5% (95% CI, 31.0% to 56.7%; 27 of 62 patients) and 50.8% (95% CI, 38.1% to 63.4%; 33 of 65 patients), respectively. The confirmed PSA response rate was 54.8% (95% CI, 45.2% to 64.1%; 63 of 115 patients). ORRs were similar for patients with a germline or somatic BRCA alteration and for patients with a BRCA1 or BRCA2 alteration, while a higher PSA response rate was observed in patients with a BRCA2 alteration. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (25.2%; 29 of 115 patients). CONCLUSION Rucaparib has antitumor activity in patients with mCRPC and a deleterious BRCA alteration, but with a manageable safety profile consistent with that reported in other solid tumor types.
Published: 2020
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21. Germline genome protection: implications for gamete quality and germ cell tumorigenesis

Author: Amanda R Loehr, Robert S. Weiss, Jordana C. Bloom, and John C. Schimenti
Subjects: endocrine system, DNA repair, Somatic cell, Urology, Endocrinology, Diabetes and Metabolism, Testicular Germ Cell Tumor, Embryonic Germ Cells, Biology, medicine.disease_cause, Article, Germline, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Testicular Neoplasms, medicine, Animals, Humans, Induced pluripotent stem cell, 030219 obstetrics & reproductive medicine, Neoplasms, Germ Cell and Embryonal, Cell cycle, medicine.anatomical_structure, Reproductive Medicine, Drug Resistance, Neoplasm, Cancer research, Carcinogenesis, Germ cell, DNA Damage
Abstract: BACKGROUND Germ cells have a unique and critical role as the conduit for hereditary information and therefore employ multiple strategies to protect genomic integrity and avoid mutations. Unlike somatic cells, which often respond to DNA damage by arresting the cell cycle and conducting DNA repair, germ cells as well as long-lived pluripotent stem cells typically avoid the use of error-prone repair mechanisms and favor apoptosis, reducing the risk of genetic alterations. Testicular germ cell tumors, the most common cancers of young men, arise from pre-natal germ cells. OBJECTIVES To summarize the current understanding of DNA damage response mechanisms in pre-meiotic germ cells and to discuss how they impact both the origins of testicular germ cell tumors and their remarkable responsiveness to genotoxic chemotherapy. MATERIALS AND METHODS We conducted a review of literature gathered from PubMed regarding the DNA damage response properties of testicular germ cell tumors and the germ cells from which they arise, as well as the influence of these mechanisms on therapeutic responses by testicular germ cell tumors. RESULTS AND DISCUSSION This review provides a comprehensive evaluation of how the developmental origins of male germ cells and their inherent germ cell-like DNA damage response directly impact the development and therapeutic sensitivity of testicular germ cell tumors. CONCLUSIONS The DNA damage response of germ cells directly impacts the development and therapeutic sensitivity of testicular germ cell tumors. Recent advances in the study of primordial germ cells, post-natal mitotically dividing germ cells, and pluripotent stem cells will allow for new investigations into the initiation, progression, and treatment of testicular germ cell tumors.
Published: 2019
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22. Association of co-occurring gene alterations and clinical activity of rucaparib in patients with BRCA1 or BRCA2 mutated (BRCA+) metastatic castration-resistant prostate cancer (mCRPC)

Author: Raymond S. McDermott, Nicholas J. Vogelzang, Akash Patnaik, Axel S. Merseburger, Eric Voog, Richard Martin Bambury, Tony Golsorkhi, Darrin Despain, Melanie Dowson, Karim Fizazi, Alan H. Bryce, Jeremy Shapiro, Brieuc Sautois, Simon Chowdhury, Jingsong Zhang, Andrea Loehr, Wassim Abida, Josep M. Piulats, David Campbell, and Charles J. Ryan
Subjects: Oncology, Cancer Research, medicine.medical_specialty, biology, business.industry, Poly ADP ribose polymerase, Castration resistant, medicine.disease, Prostate cancer, chemistry.chemical_compound, chemistry, Co occurring, Internal medicine, medicine, biology.protein, In patient, Rucaparib, business, Gene, Polymerase
Abstract: 80 Background: The poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib was granted accelerated approval by the US Food and Drug Administration for patients with BRCA+ mCRPC based on results from the phase 2 TRITON2 study (NCT02952534). The TP53 tumor suppressor gene is among the most frequently mutated genes in human cancers, including mCRPC, and alterations in TP53, PTEN, and RB1 are associated with poor prognosis in patients with prostate cancer and other tumor types. We present data on co-occurring alterations in patients with BRCA+ mCRPC treated with rucaparib in TRITON2. Methods: Patients had progressed on 1–2 lines of androgen receptor-directed therapy and 1 taxane-based chemotherapy and were treated with rucaparib 600 mg BID. Tissue and/or cell-free DNA extracted from plasma samples were profiled comprehensively for genomic alterations using Foundation Medicine, Inc., next-generation sequencing assays. Objective response rate (ORR) was assessed per modified Response Evaluation Criteria in Solid Tumors and Prostate Cancer Working Group 3 criteria by independent radiologic review of patients with measurable disease. Prostate-specific antigen (PSA) response rate (≥50% decrease from baseline) was assessed in all patients. Results: Tissue and/or plasma samples were available for 114/115 patients with BRCA+ mCRPC (visit cutoff date: Dec. 23, 2019). Among patients with BRCA+ mCRPC who had samples available for comprehensive genomic profiling, 36.8% (42/114) had a co-occurring alteration in TP53. Deleterious alterations in PTEN were observed in 34.2% (39/114) of patients, 44% (17/39) of which were homozygous deletions of PTEN. RB1 loss was observed in 12.3% (14/114) of patients and was seen more frequently in patients with measurable disease (18.0%, 11/61) than in patients with non-measurable disease (5.7%, 3/53). Although patients with and without TP53 mutations had generally similar baseline demographics and disease characteristics, visceral disease was more prevalent in patients with TP53 mutations (54.8%; 23/42) than in those without them (29.2%; 21/72). Similar ORR and PSA response rates were seen in patients with BRCA+ mCRPC with or without TP53 mutation, with a non-significant trend towards lower response rates in patients with co-occurring TP53 alterations. Conclusions: Results from TRITON2 showed antitumor activity for rucaparib in patients with BRCA+ mCRPC associated with or without co-occurring alterations in TP53. Demographics and additional efficacy analyses in genomic subgroups with co-occurring alterations in TP53, PTEN, and RB1 will be reported. Clinical trial information: NCT02952534. [Table: see text]
Published: 2021
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23. Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations

Author: Camelia M. Monoranu, Andreas von Deimling, Albert J. Becker, Joerg Felsberg, Jens Schittenhelm, Martina Deckert, Marco Prinz, Rolf Buslei, Till Acker, Katharina Heß, Ute Pohl, Volker Hovestadt, Wolf Mueller, Patricia Kohlhof, Dorothee Gramatzki, Muin S. A. Tuffaha, Amulya NageswaraRao, Andrey Korshunov, Benjamin Brokinkel, Daniel Schrimpf, David T.W. Jones, Annekathrin Reinhardt, Ulrich W. Thomale, Werner Paulus, Ekkehard Hewer, Christian Koelsche, Christian Mawrin, Damian Stichel, Ori Staszewski, Wolfgang Wick, David E. Reuss, Almuth F. Kessler, Caterina Giannini, Annika K. Wefers, Michael Platten, Martin Sill, Daniel Hänggi, Kristin Huang, Christian Hartmann, Adriana Olar, David Capper, Volkmar Hans, Andreas Unterberg, Zane Jaunmuktane, Sebastian Brandner, Nuno Miguel Nunes, Christel Herold-Mende, Felix Sahm, Uri Tabori, Guido Reifenberger, Arend Koch, Mario Loehr, Michael Weller, Hildegard Dohmen, Stefan M. Pfister, Fausto J. Rodriguez, Reinhardt A., Stichel D., Schrimpf D., Sahm F., Korshunov A., Reuss D.E., Koelsche C., Huang K., Wefers A.K., Hovestadt V., Sill M., Gramatzki D., Felsberg J., Reifenberger G., Koch A., Thomale U.-W., Becker A., Hans V.H., Prinz M., Staszewski O., Acker T., Dohmen H., Hartmann C., Mueller W., Tuffaha M.S.A., Paulus W., Hess K., Brokinkel B., Schittenhelm J., Monoranu C.-M., Kessler A.F., Loehr M., Buslei R., Deckert M., Mawrin C., Kohlhof P., Hewer E., Olar A., Rodriguez F.J., Giannini C., NageswaraRao A.A., Tabori U., Nunes N.M., Weller M., Pohl U., Jaunmuktane Z., Brandner S., Unterberg A., Hanggi D., Platten M., Pfister S.M., Wick W., Herold-Mende C., Jones D.T.W., von Deimling A., and Capper D.
Subjects: 0301 basic medicine, Male, Medizin, Kaplan-Meier Estimate, Mitogen-Activated Protein Kinase Kinase, Histones, 0302 clinical medicine, CDKN2A, Retrospective Studie, Age Factor, 610 Medicine & health, Child, DNA Modification Methylases, Aged, 80 and over, Pilocytic astrocytoma, Brain Neoplasms, DNA Repair Enzyme, Age Factors, CDKN2A/B, Middle Aged, Molecular characterization, Isocitrate Dehydrogenase, Histone, ATRX, Child, Preschool, DNA methylation, Female, MGMT, Human, Signal Transduction, Adult, X-linked Nuclear Protein, IDH1, Adolescent, Panel sequencing, Biology, Astrocytoma, Pathology and Forensic Medicine, BRAF, DNA copy number alteration, Brain Neoplasm, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, Glioma, DNA Modification Methylase, medicine, Humans, Gene, neoplasms, Cyclin-Dependent Kinase Inhibitor p16, Retrospective Studies, Pilocytic astrocytoma with anaplasia, Aged, Mitogen-Activated Protein Kinase Kinases, Tumor Suppressor Protein, Methylation profile based classification, Tumor Suppressor Proteins, Infant, DNA Methylation, medicine.disease, Anaplastic pilocytic astrocytoma, 030104 developmental biology, DNA Repair Enzymes, FGFR1, NF1, Mutation, Cancer research, 570 Life sciences, biology, Neurology (clinical), 030217 neurology & neurosurgery, Anaplastic astrocytoma
Abstract: Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding(t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.
Published: 2018
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24. Eliminating Nox2 reactive oxygen species production protects dystrophic skeletal muscle from pathological calcium influx assessedin vivoby manganese-enhanced magnetic resonance imaging

Author: Gary R. Stinnett, George G. Rodney, Robia G. Pautler, Wesley T. Roten, Mayra Hernández-Rivera, Lon J. Wilson, and James A. Loehr
Subjects: chemistry.chemical_classification, Reactive oxygen species, Sarcolemma, biology, Physiology, Duchenne muscular dystrophy, Skeletal muscle, chemistry.chemical_element, Inflammation, Calcium, medicine.disease, 030218 nuclear medicine & medical imaging, Cell biology, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, chemistry, Biochemistry, In vivo, medicine, biology.protein, medicine.symptom, Dystrophin, 030217 neurology & neurosurgery
Abstract: Key points Inhibiting Nox2 reactive oxygen species (ROS) production reduced in vivo calcium influx in dystrophic muscle. The lack of Nox2 ROS production protected against decreased in vivo muscle function in dystrophic mice. Manganese-enhanced magnetic resonance imaging (MEMRI) was able to detect alterations in basal calcium levels in skeletal muscle and differentiate disease status. Administration of Mn2+ did not affect muscle function or the health of the animal, and Mn2+ was cleared from skeletal muscle rapidly. We conclude that MEMRI may be a viable, non-invasive technique to monitor molecular alterations in disease progression and evaluate the effectiveness of potential therapies for Duchenne muscular dystrophy. Abstract Duchenne muscular dystrophy (DMD) is an X-linked progressive degenerative disease resulting from a mutation in the gene that encodes dystrophin, leading to decreased muscle mechanical stability and force production. Increased Nox2 reactive oxygen species (ROS) production and sarcolemmal Ca2+ influx are early indicators of disease pathology, and eliminating Nox2 ROS production reduces aberrant Ca2+ influx in young mdx mice, a model of DMD. Various imaging modalities have been used to study dystrophic muscle in vivo; however, they are based upon alterations in muscle morphology or inflammation. Manganese has been used for indirect monitoring of calcium influx across the sarcolemma and may allow detection of molecular alterations in disease progression in vivo using manganese-enhanced magnetic resonance imaging (MEMRI). Therefore, we hypothesized that eliminating Nox2 ROS production would decrease calcium influx in adult mdx mice and that MEMRI would be able to monitor and differentiate disease status in dystrophic muscle. Both in vitro and in vivo data demonstrate that eliminating Nox2 ROS protected against aberrant Ca2+ influx and improved muscle function in dystrophic muscle. MEMRI was able to differentiate between different pathological states in vivo, with no long-term effects on animal health or muscle function. We conclude that MEMRI is a viable, non-invasive technique to differentiate disease status and might provide a means to monitor and evaluate the effectiveness of potential therapies in dystrophic muscle.
Published: 2016
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25. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author: Peter Kovacs, Alan F. Wright, Stephen Turner, Michèle M. Sale, Siim Sõber, Janoš Terzić, Elin Org, Richard S. Cooper, Alena Stančáková, Jerome I. Rotter, W. H. Linda Kao, Albert Hofman, Andrew B. Singleton, Florian Kronenberg, Jianjun Liu, Nicole L. Glazer, Christopher W. Knouff, Jennifer L. Bragg-Gresham, Juha Karjalainen, Li Ching Chang, Benjamin J. Wright, Jacqueline C.M. Witteman, Martin G. Larson, Klaus Stark, Richard J. Rodeheffer, Sharon L.R. Kardia, Douglas M. Ruderfer, Sheila Ulivi, Madhumathi Rao, Andrew A. Hicks, Eva Brand, Viviane Nicaud, Stephen G. Ball, Anna Köttgen, Germaine C. Verwoert, Anders Hamsten, Nick Shrine, Uwe Völker, Stefan Kloiber, Stephen Hancock, Emelia J. Benjamin, Bok Ghee Han, Kenneth Rice, Mark Woodward, Veronique Vitart, Karl Andersen, Nicholas J. Wareham, Robert Roberts, Maja Barbalić, David Couper, Yukinori Okada, André G. Uitterlinden, Sekar Kathiresan, Leo-Pekka Lyytikäinen, Pankaj Arora, Tatijana Zemunik, David S. Siscovick, Simonetta Guarrera, Dawn M. Waterworth, Tatjana Stojakovic, Braxton D. Mitchell, Devin Absher, Carmen A. Peralta, Mika Kivimäki, Xueling Sim, Norihiro Kato, Philippe Froguel, Keith L. Keene, Donna K. Arnett, Naoyuki Kamatani, Tazeen H. Jafar, Idris Guessous, Gunnar Jacobs, Michael M. Hoffmann, Kari Stefansson, Christian Hengstenberg, Tomonori Okamura, Inga Prokopenko, Christina Willenborg, Peter S. Braund, Rainer Rettig, Francesco U.S. Mattace-Raso, Vikal Tripathy, F. Gerald R. Fowkes, Laura R. Loehr, Harry Campbell, Margherita Cavalieri, Olle Melander, Hao Mei, I. Mateo Leach, Nicholette D. Palmer, Eva Albrecht, Naoharu Iwai, Stefan Martin Brand, Toshiko Tanaka, Jackie A. Cooper, Omri Gottesman, Manuela Uda, Angelo Scuteri, Aroon D. Hingorani, Cristiano Fava, Yusuke Nakamura, Jiang He, Min Jin Go, Serge Hercberg, Wendy L. McArdle, Philipp S. Wild, Florian Ernst, Paul Mitchell, Wolfgang Koenig, Caroline S. Fox, S. J.Cathy Fann, Janine F. Felix, Anna F. Dominiczak, Mike A. Nalls, Erik Ingelsson, Mario A. Morken, Susana Eyheramendy, Christopher Newton-Cheh, Igor Rudan, D. G. Vinay, Christopher P. Nelson, Ervin R. Fox, Xiuqing Guo, Jing Hua Zhao, Rick Twee-Hee Ong, Margaret M. Redfield, Oscar H. Franco, Yongmei Liu, Fulvio Ricceri, Mark A. Hlatky, Bernhard Paulweber, Mingyao Li, Themistocles L. Assimes, Karl Winkler, Inês Barroso, Sylvia E. Rosas, M Walker, Richard W Morris, Bo Hedblad, Hakon Hakonarson, Sonny Dandona, Peter H. Whincup, Martin Adam, Vilmundur Gudnason, Daniel Ackermann, Qiong Yang, Cuno S. P. M. Uiterwaal, Paul M. Ridker, George Davey Smith, Li Chen, C. Sinning, Terri L. Young, Jer-Yuarn Wu, Walter Palmas, Will Longstreth, Joe Devaney, Pavel Hamet, Xiaofeng Zhu, Fredrik Nyberg, Wilfried Renner, Anuj Goel, L. Adrienne Cupples, Nish Chaturvedi, Iftikhar J. Kullo, Nicholas D. Hastie, Aude Saint-Pierre, Panos Deloukas, Smita R. Kulkarni, Eric Boerwinkle, Wolfram Goessling, Gian Andri Thun, Eric J.G. Sijbrands, Shih-Jen Hwang, Carole Proust, Hirotsugu Ueshima, Kristian Hveem, Pierre Meneton, Joshua C. Denny, Olivier Devuyst, Kerri L. Wiggins, Ming-Huei Chen, Robert W. Lawrence, Robert L. Wilensky, Andre Franke, Nicole Soranzo, Simon Heath, Margot Haun, Karlhans Endlich, David Altshuler, Harald Grallert, Laurence Tiret, Luigi Ferrucci, Caroline Hayward, Sudha Seshadri, Bénédicte Stengel, Lynne E. Wagenknecht, John Attia, Andreas Ziegler, Renate B. Schnabel, Stefan Schreiber, Santosh Dahgam, Kurt Lohman, Christian M. Shaffer, Barbara Ludwig, Katalin Susztak, Chien-Hsiun Chen, Michele K. Evans, Paolo Vineis, Guo Li, Thomas J. Wang, Meena Kumari, Heather M. Stringham, Bruce M. Psaty, Norman Klopp, Halit Ongen, Ben A. Oostra, Stefan Coassin, Petra Bruse, Wei-Min Chen, Unnur Thorsteinsdottir, Charles N. Rotimi, Robert J. Carroll, Muredach P. Reilly, Niek Verweij, Dena G. Hernandez, Amy J. Swift, Barbara Kollerits, Hyung Lae Kim, Cristian Pattaro, Ivana Kolcic, Ronit Katz, John M. C. 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R., Fortmann, Stephen, Go, Alan, Hlatky, Mark, Iribarren, Carlo, Knowles, Joshua, Myers, Richard, Quertermous, Thoma, Sidney, Steven, Risch, Neil, Tang, Hua, Blankenberg, Stefan, Schnabel, Renate, Sinning, Christoph, Lackner, Karl J., Tiret, Laurence, Nicaud, Viviane, Cambien, Francoi, Bickel, Christoph, Rupprecht, Hans J., Perret, Claire, Proust, Carole, Münzel, Thomas F., Barbalic, Maja, Chen, Ida Yii Der, Demissie Banjaw, Serkalem, Folsom, Aaron, Lumley, Thoma, Marciante, Kristin, Taylor, Kent D., Volcik, Kelly, Gretarsdottir, Solveig, Gulcher, Jeffrey R., Kong, Augustine, Stefansson, Kari, Thorgeirsson, Gudmundur, Andersen, Karl, Fischer, Marcu, Grosshennig, Anika, Linsel Nitschke, Patrick, Stark, Klau, Schreiber, Stefan, Aherrahrou, Zouhair, Bruse, Petra, Doering, Angela, Klopp, Norman, Diemert, Patrick, Loley, Christina, Medack, Anja, Nahrstedt, Janja, Peters, Annette, Wagner, Arnika K., Willenborg, Christina, Böhm, Bernhard O., Dobnig, Harald, Grammer, Tanja B., Hoffmann, Michael M., Meinitzer, Andrea, Winkelmann, Bernhard R., Pilz, Stefan, Renner, Wilfried, Scharnagl, Hubert, Stojakovic, Tatjana, Tomaschitz, Andrea, Winkler, Karl, Guiducci, Candace, Burtt, Noel, Gabriel, Stacey B., Dandona, Sonny, Jarinova, Olga, Qu, Liming, Wilensky, Robert, Matthai, William, Hakonarson, Hakon H., Devaney, Joe, Burnett, Mary Susan, Pichard, Augusto D., Kent, Kenneth M., Satler, Lowell, Lindsay, Joseph M., Waksman, Ron, Knouff, Christopher W., Waterworth, Dawn M., Walker, Max C., Epstein, Stephen E., Rader, Daniel J., Nelson, Christopher P., Wright, Benjamin J., Balmforth, Anthony J., Ball, Stephen G., Loehr, Laura R., Rosamond, Wayne D., Benjamin, Emelia, Haritunians, Talin, Couper, David, Murabito, Joanne, Wang, Ying A., Stricker, Bruno H., Chang, Patricia P., Willerson, James T., Felix, Stephan B., Watzinger, Norbert, Aragam, Jayashri, Zweiker, Robert, Lind, Lar, Rodeheffer, Richard J., Greiser, Karin Halina, Deckers, Jaap W., Stritzke, Jan, Ingelsson, Erik, Kullo, Iftikhar, Haerting, Johanne, Reffelmann, Thorsten, Redfield, Margaret M., Werdan, Karl, Mitchell, Gary F., Arnett, Donna K., Gottdiener, John S., Blettner, Maria, Friedrich, Nele, Kovacs, Peter, Wild, Philipp S., Froguel, Philippe, Rettig, Rainer, Mägi, Reedik, Biffar, Reiner, Schmidt, Reinhold, Middelberg, Rita P. S., Carroll, Robert J., Penninx, Brenda W., Scott, Rodney J., Katz, Ronit, Sedaghat, Sanaz, Wild, Sarah H., Kardia, Sharon L. R., Ulivi, Sheila, Hwang, Shih Jen, Enroth, Stefan, Kloiber, Stefan, Trompet, Stella, Stengel, Benedicte, Hancock, Stephen J., Turner, Stephen T., Rosas, Sylvia E., Stracke, Sylvia, Harris, Tamara B., Zeller, Tanja, Zemunik, Tatijana, Lehtimäki, Terho, Illig, Thoma, Aspelund, Thor, Nikopensius, Tiit, Esko, Tonu, Tanaka, Toshiko, Gyllensten, Ulf, Völker, Uwe, Emilsson, Valur, Vitart, Veronique, Aalto, Ville, Gudnason, Vilmundur, Chouraki, Vincent, Chen, Wei Min, Igl, Wilmar, März, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Loos, Ruth J. F., Liu, Yongmei, Snieder, Harold, Pramstaller, Peter P., Parsa, Afshin, O'Connell, Jeffrey R., Susztak, Katalin, Hamet, Pavel, Tremblay, Johanne, De Boer, Ian H., Böger, Carsten A., Goessling, Wolfram, Chasman, Daniel I., Köttgen, Anna, Kao, W. H. Linda, Fox, Caroline S., RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Biochemie, RS: FHML MaCSBio, Ehret, Georg Benedikt, Guessous, Idris, Gaspoz, Jean-Michel, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Polymer Chemistry and Bioengineering, Value, Affordability and Sustainability (VALUE), Stem Cell Aging Leukemia and Lymphoma (SALL), Epidemiology, Public Health, Internal Medicine, Clinical Genetics, Erasmus MC other, Genetic Identification, ICBP Consortium, AGEN Consortium, CHARGe-Heart Failure Group, ECHOGen Consortium, CARDIOGRAM, Abecasis, GR., Adair, LS., Alexander, M., Altshuler, D., Amin, N., Arking, DE., Arora, P., Aulchenko, Y., Bakker, SJ., Bandinelli, S., Barroso, I., Beckmann, JS., Beilby, JP., Bergman, RN., Bergmann, S., Bis, JC., Boehnke, M., Bonnycastle, LL., Bornstein, SR., Bots, ML., Bragg-Gresham, JL., Brand, SM., Brand, E., Braund, PS., Brown, MJ., Burton, PR., Casas, JP., Caulfield, MJ., Chakravarti, A., Chambers, JC., Chandak, GR., Chang, YP., Charchar, FJ., Chaturvedi, N., Shin Cho, Y., Clarke, R., Collins, FS., Collins, R., Connell, JM., Cooper, JA., Cooper, MN., Cooper, RS., Corsi, AM., Dörr, M., Dahgam, S., Danesh, J., Davey Smith, G., Day, IN., Deloukas, P., Denniff, M., Dominiczak, AF., Dong, Y., Doumatey, A., Elliott, P., Elosua, R., Erdmann, J., Eyheramendy, S., Farrall, M., Fava, C., Forrester, T., Fowkes, FG., Fox, ER., Frayling, TM., Galan, P., Ganesh, SK., Garcia, M., Gaunt, TR., Glazer, NL., Go, MJ., Goel, A., Grässler, J., Grobbee, DE., Groop, L., Guarrera, S., Guo, X., Hadley, D., Hamsten, A., Han, BG., Hardy, R., Hartikainen, AL., Heath, S., Heckbert, SR., Hedblad, B., Hercberg, S., Hernandez, D., Hicks, AA., Hilton, G., Hingorani, AD., Bolton, JA., Hopewell, JC., Howard, P., Humphries, SE., Hunt, SC., Hveem, K., Ikram, MA., Islam, M., Iwai, N., Jarvelin, MR., Jackson, AU., Jafar, TH., Janipalli, CS., Johnson, T., Kathiresan, S., Khaw, KT., Kim, HL., Kinra, S., Kita, Y., Kivimaki, M., Kooner, JS., Kumar, MJ., Kuh, D., Kulkarni, SR., Kumari, M., Kuusisto, J., Kuznetsova, T., Laakso, M., Laan, M., Laitinen, J., Lakatta, EG., Langefeld, CD., Larson, MG., Lathrop, M., Lawlor, DA., Lawrence, RW., Lee, JY., Lee, NR., Levy, D., Li, Y., Longstreth, WT., Luan£££Jian'an£££ J., Lucas, G., Ludwig, B., Mangino, M., Mani, KR., Marmot, MG., Mattace-Raso, FU., Matullo, G., McArdle, WL., McKenzie, CA., Meitinger, T., Melander, O., Meneton, P., Meschia, JF., Miki, T., Milaneschi, Y., Mohlke, KL., Mooser, V., Morken, MA., Morris, RW., Mosley, TH., Najjar, S., Narisu, N., Newton-Cheh, C., Nguyen, KD., Nilsson, P., Nyberg, F., O'Donnell, CJ., Ogihara, T., Ohkubo, T., Okamura, T., Ong, RT., Ongen, H., Onland-Moret, NC., O'Reilly, PF., Org, E., Orru, M., Palmas, W., Palmen, J., Palmer, LJ., Palmer, ND., Parker, AN., Peden, JF., Peltonen, L., Perola, M., Pihur, V., Platou, CG., Plump, A., Prabhakaran, D., Psaty, BM., Raffel, LJ., Rao, DC., Rasheed, A., Ricceri, F., Rice, KM., Rosengren, A., Rotter, JI., Rudock, ME., Sõber, S., Salako, T., Saleheen, D., Salomaa, V., Samani, NJ., Schwartz, SM., Schwarz, PE., Scott, LJ., Scott, J., Scuteri, A., Sehmi, JS., Seielstad, M., Seshadri, S., Sharma, P., Shaw-Hawkins, S., Shi, G., Shrine, NR., Sijbrands, EJ., Sim, X., Singleton, A., Sjögren, M., Smith, NL., Soler Artigas, M., Spector, TD., Staessen, JA., Stancakova, A., Steinle, NI., Strachan, DP., Stringham, HM., Sun, YV., Swift, AJ., Tabara, Y., Tai, ES., Talmud, PJ., Taylor, A., Terzic, J., Thelle, DS., Tobin, MD., Tomaszewski, M., Tripathy, V., Tuomilehto, J., Tzoulaki, I., Uda, M., Ueshima, H., Uiterwaal, CS., Umemura, S., van der Harst, P., van der Schouw YT., van Gilst WH., Vartiainen, E., Vasan, RS., Veldre, G., Verwoert, GC., Viigimaa, M., Vinay, DG., Vineis, P., Voight, BF., Vollenweider, P., Wagenknecht, LE., Wain, LV., Wang, X., Wang, TJ., Wareham, NJ., Watkins, H., Weder, AB., Whincup, PH., Wiggins, KL., Witteman, JC., Wong, A., Wu, Y., Yajnik, CS., Yao, J., Young, JH., Zelenika, D., Zhai, G., Zhang, W., Zhang, F., Zhao, JH., Zhu, H., Zhu, X., Zitting, P., Zukowska-Szczechowska, E., Okada, Y., Wu, JY., Gu, D., Takeuchi, F., Takahashi, A., Maeda, S., Tsunoda, T., Chen, P., Lim, SC., Wong, TY., Liu, J., Young, TL., Aung, T., Teo, YY., Kim, YJ., Kang, D., Chen, CH., Tsai, FJ., Chang, LC., Fann, SJ., Mei, H., Hixson, JE., Chen, S., Katsuya, T., Isono, M., Albrecht, E., Yamamoto, K., Kubo, M., Nakamura, Y., Kamatani, N., Kato, N., He, J., Chen, YT., Tanaka, T., Reilly, MP., Schunkert, H., Assimes, TL., Hall, A., Hengstenberg, C., König, IR., Laaksonen, R., McPherson, R., Thompson, JR., Thorsteinsdottir, U., Ziegler, A., Absher, D., Chen, L., Cupples, LA., Halperin, E., Li, M., Musunuru, K., Preuss, M., Schillert, A., Thorleifsson, G., Wells, GA., Holm, H., Roberts, R., Stewart, AF., Fortmann, S., Go, A., Hlatky, M., Iribarren, C., Knowles, J., Myers, R., Quertermous, T., Sidney, S., Risch, N., Tang, H., Blankenberg, S., Schnabel, R., Sinning, C., Lackner, KJ., Tiret, L., Nicaud, V., Cambien, F., Bickel, C., Rupprecht, HJ., Perret, C., Proust, C., Münzel, TF., Barbalic, M., Chen, IY., Demissie-Banjaw, S., Folsom, A., Lumley, T., Marciante, K., Taylor, KD., Volcik, K., Gretarsdottir, S., Gulcher, JR., Kong, A., Stefansson, K., Thorgeirsson, G., Andersen, K., Fischer, M., Grosshennig, A., Linsel-Nitschke, P., Stark, K., Schreiber, S., Aherrahrou, Z., Bruse, P., Doering, A., Klopp, N., Diemert, P., Loley, C., Medack, A., Nahrstedt, J., Peters, A., Wagner, AK., Willenborg, C., Böhm, BO., Dobnig, H., Grammer, TB., Hoffmann, MM., Meinitzer, A., Winkelmann, BR., Pilz, S., Renner, W., Scharnagl, H., Stojakovic, T., Tomaschitz, A., Winkler, K., Guiducci, C., Burtt, N., Gabriel, SB., Dandona, S., Jarinova, O., Qu, L., Wilensky, R., Matthai, W., Hakonarson, HH., Devaney, J., Burnett, MS., Pichard, AD., Kent, KM., Satler, L., Lindsay, JM., Waksman, R., Knouff, CW., Waterworth, DM., Walker, MC., Epstein, SE., Rader, DJ., Nelson, CP., Wright, BJ., Balmforth, AJ., Ball, SG., Loehr, LR., Rosamond, WD., Benjamin, E., Haritunians, T., Couper, D., Murabito, J., Wang, YA., Stricker, BH., Chang, PP., Willerson, JT., Felix, SB., Watzinger, N., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, RJ., Greiser, KH., Deckers, JW., Stritzke, J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, MM., Werdan, K., Mitchell, GF., Arnett, DK., Gottdiener, JS., Blettner, M., and Friedrich, N.
Subjects: 0301 basic medicine, Nephrology, Genetics and Molecular Biology (all), estimated glomerular filtration rate, estimated glomerular filtration rate, chronic kidney disease, genetic determinants, General Physics and Astronomy, Kidney development, Genome-wide association study, Biochemistry, Settore MED/14 - NEFROLOGIA, Renal Insufficiency, Chronic, Genetics, AGEN Consortium, ddc:616, education.field_of_study, Kidney, Stage renal-disease, Multidisciplinary, Genome-wide association, CHARGe-Heart Failure Group, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Renal Insufficiency, Chronic, Genetic Predisposition to Disease, Biochemistry, Genetics and Molecular Biology (all), Chemistry (all), Physics and Astronomy (all), Metaanalysis, Renal Insufficiency, Chronic/genetics, Biological sciences, Serum creatinine, medicine.anatomical_structure, Efficient, Ronyons -- Fisiologia, Hypertension, ICBP Consortium, Transmembrane transporter activity, genetic association, loci, kidney function, CARDIOGRAM, Human, medicine.medical_specialty, Science, Population, Renal function, ECHOGen Consortium, Replication, Biology, Environment, Research Support, General Biochemistry, Genetics and Molecular Biology, N.I.H, genetic determinants, 03 medical and health sciences, GENOME-WIDE ASSOCIATION, FALSE DISCOVERY RATES, STAGE RENAL-DISEASE, SERUM CREATININE, METAANALYSIS, VARIANTS, INDIVIDUALS, POPULATION, RISK, HYPERTENSION, Kidney function, Research Support, N.I.H., Extramural, Internal medicine, MD Multidisciplinary, medicine, Journal Article, eGFRcrea, eGFRcys, ddc:610, Genetik, Mortality, education, ddc:613, urogenital system, Individuals, Extramural, General Chemistry, ta3121, medicine.disease, R1, 030104 developmental biology, 570 Life sciences, biology, Genètica, chronic kidney disease, Kidney disease, Meta-Analysis
Abstract: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.
Published: 2016
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26. JMJD6 participates in the maintenance of ribosomal DNA integrity in response to DNA damage

Author: Jérémie Fages, Yvan Canitrot, Jeremy Loehr, Suk-Min Jang, Didier Trouche, Jonathan Humbert, Jean-Philippe Lambert, Catherine Chailleux, Jacques Côté, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Faculté de médecine de l'Université Laval [Québec] (ULaval), Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Jumonji Domain-Containing Histone Demethylases, Cancer Research, Nucleolus, [SDV]Life Sciences [q-bio], Cellular homeostasis, Cell Cycle Proteins, QH426-470, Biochemistry, Histones, chemistry.chemical_compound, 0302 clinical medicine, Transcription (biology), Small interfering RNAs, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Staining, 0303 health sciences, Radiation, Physics, Cell Staining, Nuclear Proteins, 3. Good health, Cell biology, Nucleic acids, 030220 oncology & carcinogenesis, Physical Sciences, Cellular Structures and Organelles, Research Article, Protein Binding, DNA repair, DNA damage, DNA transcription, Biology, Research and Analysis Methods, Non-Homologous End Joining, 03 medical and health sciences, Tandem repeat, Cell Line, Tumor, DNA-binding proteins, Genetics, Humans, Non-coding RNA, Molecular Biology, Ribosomal DNA, Ecology, Evolution, Behavior and Systematics, Nuclear Physics, 030304 developmental biology, Cell Nucleus, Biology and life sciences, Proteins, DNA, Cell Biology, Phosphoproteins, Gene regulation, HEK293 Cells, chemistry, Specimen Preparation and Treatment, RNA, Ribosomal, Ionizing Radiation, RNA, Gene expression, Homologous recombination, 030217 neurology & neurosurgery
Abstract: Ribosomal DNA (rDNA) is the most transcribed genomic region and contains hundreds of tandem repeats. Maintaining these rDNA repeats as well as the level of rDNA transcription is essential for cellular homeostasis. DNA damages generated in rDNA need to be efficiently and accurately repaired and rDNA repeats instability has been reported in cancer, aging and neurological diseases. Here, we describe that the histone demethylase JMJD6 is rapidly recruited to nucleolar DNA damage and is crucial for the relocalisation of rDNA in nucleolar caps. Yet, JMJD6 is dispensable for rDNA transcription inhibition. Mass spectrometry analysis revealed that JMJD6 interacts with the nucleolar protein Treacle and modulates its interaction with NBS1. Moreover, cells deficient for JMJD6 show increased sensitivity to nucleolar DNA damage as well as loss and rearrangements of rDNA repeats upon irradiation. Altogether our data reveal that rDNA transcription inhibition is uncoupled from rDNA relocalisation into nucleolar caps and that JMJD6 is required for rDNA stability through its role in nucleolar caps formation., Author summary Ribosomal DNA is composed of repeated sequences and is the most transcribed genomic region. Transcription of rDNA is essential for cellular homeostasis and cell proliferation. Numerous pathologies such as cancer and neurological disorders are associated with defective rDNA repeats maintenance. The mechanisms involved in the control of rDNA integrity involve major DNA repair pathways such as Non-Homologous End Joining and Homologous Recombination. However, how they are controlled and orchestrated is poorly understood. Here, we identified JMJD6 as a new member of the maintenance of rDNA integrity. We observed that JMJD6 controls the recruitment of NBS1 in the nucleolus in order to lead to the proper management of rDNA damages
Published: 2020
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27. Cytotoxic T Cells and their Activation Status are Independent Prognostic Markers in Meningiomas

Author: Gerhard Jungwirth, Steffen Dettling, Andreas Unterberg, Matthias Simon, Ralf Ketter, Amir Abdollahi, Andreas von Deimling, Christine Jungk, Konstaninos Gousias, Steffi Urbschat, Andreas Mock, Rolf Warta, Carmen Rapp, Christian Senft, Melissa Schmidt, Niels Grabe, Katrin Lamszus, Fang Liu, Mario Loehr, Felix Sahm, Klaus Zweckberger, Anna Theresa Ull, Christel Herold-Mende, Saskia Roesch, Almuth F. Kessler, Juergen Debus, and Manfred Westphal
Subjects: 0301 basic medicine, Oncology, Adult, Male, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, CD3, Population, chemical and pharmacologic phenomena, Immunofluorescence, Lymphocyte Activation, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Lymphocytes, Tumor-Infiltrating, Internal medicine, Biomarkers, Tumor, Meningeal Neoplasms, Medicine, Cytotoxic T cell, Humans, education, Aged, Aged, 80 and over, education.field_of_study, medicine.diagnostic_test, biology, business.industry, Confounding, FOXP3, hemic and immune systems, Immunotherapy, Middle Aged, Prognosis, Survival Rate, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Female, Neoplasm Recurrence, Local, business, Meningioma, CD8, T-Lymphocytes, Cytotoxic
Abstract: Purpose: Clinically aggressive meningiomas (MGMs) are rare but treatment-resistant tumors in need for more effective therapies. Because tumor-infiltrating T lymphocytes (TILs) are essential for successful immunotherapy, we assessed TIL numbers and their activation status in primary (p-) and recurrent (r-) meningiomas and their impact on survival. Experimental Design: Presence of TILs was analyzed in 202 clinically well-annotated cases (n = 123 pMGMs and n = 79 rMGMs) focusing on higher-grade meningiomas [n = 97 World Health Organization (WHO) °II, n = 62 WHO°III]. TILs were quantified by a semiautomated analysis on whole-tissue sections stained by multicolor immunofluorescence for CD3, CD8, FOXP3, and programmed cell death protein 1 (PD-1). Results: Median T-cell infiltration accounted for 0.59% TILs per total cell count. Although there were no significant WHO°-dependent changes regarding helper (CD3+CD8−FOXP3−) and cytotoxic (CD3+CD8+FOXP3−) TILs in pMGMs, higher number of cytotoxic TILs were associated with an improved progression-free survival (PFS) independent of prognostic confounders. rMGMs were characterized by lower numbers of TILs in general, helper, and cytotoxic TILs. The additional analysis of their activation status revealed that a proportion of PD-1+CD8+ TILs within the TIL population was significantly decreased with higher WHO grade and in rMGMs. Furthermore, lower proportions of PD-1+CD8+ TILs were associated with inferior PFS in multivariate analyses, arguing for PD-1 as activation rather than exhaustion marker. Conclusions: We identified higher numbers of CD3+CD8+FOXP3− TILs and proportions of PD-1–expressing CD3+CD8+FOXP3− TILs as novel biomarkers for better survival. These findings might facilitate the selection of patients who may benefit from immunotherapy and argue in favor of an intervention in primary rather than recurrent tumors.
Published: 2019

28. Versatile and robust genome editing with Streptococcus thermophilus CRISPR1-Cas9

Author: Yannick Doyon, Sylvain Moineau, Minja Velimirovic, Sophie Carter, Daniel Agudelo, Sébastien Lévesque, Jeremy Loehr, Alexis Duringer, Adeline Goulet, Jean-François Rivest, Denis Cyr, Mathieu Laplante, Mathilde Mouchiroud, Paula J. Waters, Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Faculty of Medicine, Université Laval, Québec, QC, Canada., CHUS – Centre Hospitalier Universitaire de Sherbrooke [Sherbrooke, QC, Canada], Université Laval, centre de recherche sur le cancer, Québec, Canada, Département de Biochimie, Microbiologie et Bioinformatique [Québec, Canada], Université Laval [Québec] (ULaval)-Pavillon Charles-Eugène-Marchand [Québec, Canada] (CHM), Groupe de Recherche en Écologie Buccale (GREB) and Félix d’Hérelle Reference Center for Bacterial Viruses, Faculté de Médecine Dentaire, Université Laval [Québec] (ULaval), Architecture et fonction des macromolécules biologiques (AFMB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), ANR-18-CE11-0016,PHARE,Vengeance de phages: analyses structurales et fonctionnelles de protéines anti CRISPR-Cas9(2018), Laboratoire d'ingénierie des systèmes macromoléculaires (LISM), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0303 health sciences, Streptococcus thermophilus, biology, Cas9, [SDV]Life Sciences [q-bio], Computational biology, biology.organism_classification, Genome, Phenotype, Viral vector, 03 medical and health sciences, Protospacer adjacent motif, chemistry.chemical_compound, 0302 clinical medicine, chemistry, Genome editing, Genetics, 030217 neurology & neurosurgery, Genetics (clinical), Cytosine, 030304 developmental biology
Abstract: Targeting definite genomic locations using CRISPR-Cas systems requires a set of enzymes with unique protospacer adjacent motif (PAM) compatibilities. To expand this repertoire, we engineered nucleases, cytosine base editors, and adenine base editors from the archetypal Streptococcus thermophilus CRISPR1-Cas9 (St1Cas9) system. We found that St1Cas9 strain variants enable targeting to five distinct A-rich PAMs and provide structural basis for their specificities. The small size of this ortholog enables expression of the holoenzyme from a single adeno-associated viral vector for in vivo editing applications. Delivery of St1Cas9 to the neonatal liver efficiently rewired metabolic pathways, leading to phenotypic rescue in a mouse model of hereditary tyrosinemia. These robust enzymes expand and complement current editing platforms available for tailoring mammalian genomes.
Published: 2018
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29. An sRNA and Cold Shock Protein Homolog-Based Feedforward Loop Post-transcriptionally Controls Cell Cycle Master Regulator CtrA

Author: Marta Robledo, Jan-Philip Schlüter, Lars O. Loehr, Uwe Linne, Stefan P. Albaum, José I. Jiménez-Zurdo, Anke Becker, and Ministerio de Economía y Competitividad (España)
Subjects: 0301 basic medicine, Microbiology (medical), Riboregulator, Small RNA, Cellular differentiation, 030106 microbiology, lcsh:QR1-502, RNA-binding protein, Microbiology, post-transcriptional control, lcsh:Microbiology, 03 medical and health sciences, CtrA, Post-transcriptional regulation, Original Research, biology, RNA binding, Cell cycle, Cold-shock domain, proteins, Cell biology, 030104 developmental biology, Chaperone (protein), biology.protein, non-coding RNAs, cell cycle, RNA binding proteins, Sinorhizobium meliloti
Abstract: Adjustment of cell cycle progression is crucial for bacterial survival and adaptation under adverse conditions. However, the understanding of modulation of cell cycle control in response to environmental changes is rather incomplete. In a-proteobacteria, the broadly conserved cell cycle master regulator CtrA underlies multiple levels of control, including coupling of cell cycle and cell differentiation. CtrA levels are known to be tightly controlled through diverse transcriptional and post-translational mechanisms. Here, small RNA (sRNA)-mediated post-transcriptional regulation is uncovered as an additional level of CtrA fine-tuning. Computational predictions as well as transcriptome and proteome studies consistently suggested targeting of ctrA and the putative cold shock chaperone cspA5 mRNAs by the trans-encoded sRNA (trans-sRNA) GspR (formerly SmelC775) in several Sinorhizobium species. GspR strongly accumulated in the stationary growth phase, especially in minimal medium (MM) cultures. Lack of the gspR locus confers a fitness disadvantage in competition with the wild type, while its overproduction hampers cell growth, suggesting that this riboregulator interferes with cell cycle progression. An eGFP-based reporter in vivo assay, involving wild-type and mutant sRNA and mRNA pairs, experimentally confirmed GspR-dependent post-transcriptional down-regulation of ctrA and cspA5 expression, which most likely occurs through base-pairing to the respective mRNA. The energetically favored secondary structure of GspR is predicted to comprise three stem-loop domains, with stem-loop 1 and stem-loop 3 targeting ctrA and cspA5 mRNA, respectively. Moreover, this work reports evidence for post-transcriptional control of ctrA by CspA5. Thus, this regulation and GspR-mediated post-transcriptional repression of ctrA and cspA5 expression constitute a coherent feed-forward loop, which may enhance the negative effect of GspR on CtrA levels. This novel regulatory circuit involving the riboregulator GspR, CtrA, and a cold shock chaperone may contribute to fine-tuning of ctrA expression., This research was supported by funding from the LOEWE Program of the state of Hesse (SYNMIKRO) to AB and MR, the German Network for Bioinformatics Infrastructure (de.NBI, BMBF-funded project “Bielefeld-Gießen Center for Microbial Bioinformatics – BiGi,” Grant No. 031A533) to SPA, the German Research Foundation (CRC/TR 174 and INST 160/536-1 FUGG) to AB, and the Spanish Ministerio de Economía y Competitividad ERDF-cofinanced grant BFU2013-48282-C2-2-P to JJ-Z and Program of “Formación Post-doctoral” contract to MR.
Published: 2018
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30. Wide variation in carapacial scute patterns in a natural population of speckled tortoises,Homopus signatus

Author: Victor J. T. Loehr
Subjects: 0106 biological sciences, education.field_of_study, animal structures, Tortoise, Range (biology), Ecology, Population, 010607 zoology, Biology, biology.organism_classification, 010603 evolutionary biology, 01 natural sciences, Intraspecific competition, Homopus signatus, Natural population growth, Animal Science and Zoology, Carapace, Scute, education, Ecology, Evolution, Behavior and Systematics
Abstract: The arrangement of scutes on the carapaces of extant chelonians is very similar among species, but intraspecific deviations from typical scute patterns are common. Because intraspecific variation may relate to inbreeding depression, unfavourable egg incubation conditions and the presence of environmental pollutants, investigations of carapacial scute patterns in natural populations can enhance insight into the ecologies and survival challenges of chelonians. A population of the tortoise Homopus signatus, inhabiting an arid range with substantial annual rainfall variation, was sampled to record carapacial scute patterns. The typical pattern of H. signatus consisted of five vertebral scutes, four pairs of costal scutes, a cervical and a supracaudal scute, and 12 pairs of marginal scutes. Although it was expected that size classes (i.e. representing tortoises born in different years) and sexes would have different percentages deviations from the typical scute pattern as a result of different egg incu...
Published: 2016
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31. Magnetic guidance of the magnetotactic bacterium Magnetospirillum gryphiswaldense

Author: Dirk Schüler, Thomas M. Fischer, Daniel Pfeiffer, and Johannes Loehr
Subjects: 0301 basic medicine, Magnetic moment, biology, Field line, Magnetic Phenomena, Movement, Magnetosome, General Chemistry, equipment and supplies, Condensed Matter Physics, biology.organism_classification, Magnetic field, 03 medical and health sciences, Magnetic Fields, 030104 developmental biology, Nuclear magnetic resonance, Earth's magnetic field, Flagella, Chemical physics, Magnetotactic bacterium, Magnetospirillum, human activities
Abstract: Magnetospirillum gryphiswaldense is a magnetotactic bacterium with a permanent magnetic moment capable of swimming using two bipolarly located flagella. In their natural environment these bacteria swim along the field lines of the homogeneous geomagnetic field in a typical run and reversal pattern and thereby create non-differentiable trajectories with sharp edges. In the current work we nevertheless achieve stable guidance along curved lines of mechanical instability by using a heterogeneous magnetic field of a garnet film. The successful guidance of the bacteria depends on the right balance between motility and the magnetic moment of the magnetosome chain.
Published: 2016
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32. Small Vernal Home Ranges in the Namaqualand Speckled Tortoise,Homopus signatus

Author: Victor J. T. Loehr
Subjects: Herbivore, geography, geography.geographical_feature_category, Winter rainfall, biology, Tortoise, Ecology, Home range, biology.organism_classification, Arid, Homopus signatus, Spring (hydrology), Animal Science and Zoology, Ecology, Evolution, Behavior and Systematics, Primary productivity
Abstract: In some herbivores, home range size is correlated negatively with the primary productivity of their environments. Although the South African Succulent Karoo is arid, it receives relatively predictable winter rainfall and therefore relatively predictable primary production toward the following spring. Lush springs may alternate with occasional drought years. Over five spring seasons with variable rainfall patterns, I studied home range size in 21 male and 31 female Namaqualand Speckled Tortoises (Homopus signatus) in the Succulent Karoo using opportunistic sightings, thread-trailing, and radio telemetry. In addition, daily movement distances were determined for 8 males and 28 females with the use of thread-trailing over three spring seasons. The average home range size for H. signatus was 3,470 m2, much smaller than home ranges for tortoises in other arid regions. Home range size did not differ between the sexes, but was negatively correlated with rainfall. Daily movement distances were also simil...
Published: 2015
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33. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure

Author: Wain, Louise V., Verwoert, Germaine C., O'Reilly, Paul F., Shi, Gang, Johnson, Toby, Johnson, Andrew D., Bochud, Murielle, Rice, Kenneth M., Henneman, Peter, Smith, Albert V., Ehret, Georg B., Amin, Najaf, Larson, Martin G., Mooser, Vincent, Hadley, David, Dörr, Marcus, Bis, Joshua C, Aspelund, Thor, Esko, Tõnu, Janssens, A Cecile J. W., Zhao, Jing Hua, Heath, Simon, Laan, Maris, Fu, Jingyuan, Pistis, Giorgio, Luan, Jian'An, Arora, Pankaj, Lucas, Gavin, Pirastu, Nicola, Pichler, Irene, Jackson, Anne U., Webster, Rebecca J., Zhang, Feng, Peden, John F., Schmidt, Helena, Tanaka, Toshiko, Campbell, Harry, Igl, Wilmar, Milaneschi, Yuri, Hottenga, Jouke-Jan, Vitart, Veronique, Chasman, Daniel I., Trompet, Stella, Bragg-Gresham, Jennifer L., Alizadeh, Behrooz Z., Chambers, John C., Guo, Xiuqing, Lehtimäki, Terho, Kühnel, Brigitte, Lopez, Lorna M., Polašek, Ozren, Boban, Mladen, Nelson, Christopher P., Morrison, Alanna C., Pihur, Vasyl, Ganesh, Santhi K., Hofman, Albert, Kundu, Suman, Mattace-Raso, Francesco U. S., Rivadeneira, Fernando, Sijbrands, Eric J. G., Uitterlinden, Andre G., Hwang, Shih-Jen, Vasan, Ramachandran S., Wang, Thomas J., Bergmann, Sven, Vollenweider, Peter, Waeber, Gérard, Laitinen, Jaana, Pouta, Anneli, Zitting, Paavo, McArdle, Wendy L., Kroemer, Heyo K., Völker, Uwe, Völzke, Henry, Glazer, Nicole L., Taylor, Kent D., Harris, Tamara B., Alavere, Helene, Haller, Toomas, Keis, Aime, Tammesoo, Mari-Liis, Aulchenko, Yurii, Barroso, In S., Khaw, Kay-Tee, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Eyheramendy, Susana, Org, Elin, Sõber, Siim, Lu, Xiaowen, Nolte, Ilja M., Penninx, Brenda W., Corre, Tanguy, Masciullo, Corrado, Sala, Cinzia, Groop, Leif, Voight, Benjamin F, Melander, Olle, O'Donnell, Christopher J, Salomaa, Veikko, D'Adamo, Adamo Pio, Fabretto, Antonella, Faletra, Flavio, Ulivi, Sheila, Del Greco M, Fabiola, Facheris, Maurizio, Collins, Francis S., Bergman, Richard N., Beilby, John P., Hung, Joseph, Musk, A William, Mangino, Massimo, Shin, So-Youn, Soranzo, Nicole, Watkins, Hugh, Goel, Anuj, Hamsten, Anders, Gider, Pierre, Loitfelder, Marisa, Zeginigg, Marion, Hernandez, Dena, Najjar, Samer S., Navarro, Pau, Wild, Sarah H., Corsi, Anna Maria, Singleton, Andrew, De Geus, Eco J. C., Willemsen, Gonneke, Parker, Alex N., Rose, Lynda M., Buckley, Brendan, Stott, David, Orru, Marco, Uda, Manuela, Van Der Klauw, Melanie M., Zhang, Weihua, Li, Xinzhong, Scott, James, Chen, Yii-Der Ida, Burke, Gregory L, Kähönen, Mika, Viikari, Jorma, Döring, Angela, Meitinger, Thomas, Davies, Gail, Starr, John M., Emilsson, Valur, Plump, Andrew, Lindeman, Jan H., Hoen, Peter A. C. T., König, Inke R., Felix, Janine F., Clarke, Robert, Hopewell, Jemma C., Ongen, Halit, Breteler, Monique, Debette, Stéphanie, Destefano, Anita L., Fornage, Myriam, Mitchell, Gary F., Smith, Nicholas L., Holm, Hilma, Stefansson, Kari, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Samani, Nilesh J., Preuss, Michael, Rudan, Igor, Hayward, Caroline, Deary, Ian J., Wichmann, H-Erich, Raitakari, Olli T., Palmas, Walter, Kooner, Jaspal S., Stolk, Ronald P., Jukema, J Wouter, Wright, Alan F., Boomsma, Dorret I., Bandinelli, Stefania, Gyllensten, Ulf B., Wilson, James F., Ferrucci, Luigi, Schmidt, Reinhold, Farrall, Martin, Spector, Tim D., Palmer, Lyle J., Tuomilehto, Jaakko, Pfeufer, Arne, Gasparini, Paolo, Siscovick, David, Altshuler, David, Loos, Ruth J. F., Toniolo, Daniela, Snieder, Harold, Gieger, Christian, Meneton, Pierre, Wareham, Nicholas J., Oostra, Ben A., Metspalu, Andres, Launer, Lenore, Rettig, Rainer, Strachan, David P., Beckmann, Jacques S., Witteman, Jacqueline C. M., Erdmann, Jeanette, Van Dijk, Ko Willems, Boerwinkle, Eric, Boehnke, Michael, Ridker, Paul M., Jarvelin, Marjo-Riitta, Chakravarti, Aravinda, Abecasis, Goncalo R., Gudnason, Vilmundur, Newton-Cheh, Christopher, Levy, Daniel, Munroe, Patricia B., Psaty, Bruce M., Caulfield, Mark J., Rao, Dabeeru C., Tobin, Martin D., Elliott, Paul, Van Duijn, Cornelia M. McEniery CM, Wilkinson IB, Cockcroft JR, O'Shaughnessy KM, Newhouse SJ, Yasmin, Smith AV, Eiriksdottir G, Launer LJ, Sigurdsson S, Aspelund T, Gudnason V, De Bacquer D, Rietzschel ER, De Backer GG, Van Bortel L, De Buyzere ML, Segers P, Bekaert S, Gillebert TC, De Meyer T, Ferrucci L, Tanaka T, Johnson AD, Levy D, Benjamin EJ, Mitchell GF, Vita JA, Larson MG, Hamburg NM, Vasan RS, Isaacs A, Schut AF, Oostra BA, van Duijn CM, van Rijn MJ, Sie MP, Newman AB, Herrington DM, Andrews JS, Ding J, Sutton-Tyrrell KC, Harris TB, Howard TD, Liu Y, Parsa A, Shuldiner AR, McArdle PF, Gibson Q, Post WS, Dehghan A, Hofman A, Uitterlinden AG, Sijbrands EJ, Rivadeneira F, Mattace-Raso FU, Verwoert GC, Witteman JC, Scuteri A, Lakatta EG, Jewell E, Abecasis GR, Tarasov KV, Uda M, Najjar SS, Sanna S, Attwood T, Belz S, Braund P, Cambien F, Cooper J, Crisp-Hihn A, Deloukas P, Foad N, Eardman J, Goodall AH, Gracey J, Gray E, Gulde S, Gwilliams R, Heimerl S, Hengstenberg C, Jolley J, Krishnan U, Linsel-Nitschke P, Lloyd-Jones H, Lugauer I, Lundmark P, Maouche S, Moore JS, Muir D, Murray E, Nelson CP, Neudert J, Niblett D, O'Leary K, Ouwehand WH, Pollard H, Rankin A, Rice CM, Sager H, Samani NJ, Sambrook J, Schmitz G, Scholz M, Schroeder L, Schunkert H, Syvannen AC, Wallace C, Kathiresan S, Reilly MP, Erdmann J, Assimes TL, Boerwinkle E, Hall A, König IR, Laaksonen R, McPherson R, Thompson JR, Thorsteinsdottir U, Ziegler A, Absher D, Chen L, Cupples LA, Halperin E, Li M, Musunuru K, Preuss M, Schillert A, Thorleifsson G, Voight BF, Wells GA, Assime TL, Holm H, Roberts R, Stewart AF, Fortmann S, Go A, Hlatky M, Iribarren C, Knowles J, Myers R, Quertermous T, Sidney S, Risch N, Tang H, Blankenberg S, Zeller T, Wild P, Schnabel R, Sinning C, Lackner K, Tiret L, Nicaud V, Bickel C, Rupprecht HJ, Perret C, Proust C, Münzel T, Barbalic M, Bis J, Chen IY, Cupples L, Demissie-Banjaw S, Folsom A, Glazer N, Harris T, Heckbert S, Lumley T, Marciante K, Morrison A, O' Donnell CJ, Psaty BM, Rice K, Rotter JI, Siscovick DS, Smith N, Smith A, Taylor KD, van Duijn C, Volcik K, Whitteman J, Ramachandran V, Uitterlinden A, Gretarsdottir S, Gulcher JR, Kong A, Stefansson K, Thorgeirsson G, Andersen K, Fischer M, Grosshennig A, Lieb W, Stark K, Schreiber S, Wichmann HE, Aherrahrou Z, Bruse P, Doering A, Illig T, Klopp N, Loley C, Medack A, Meisinger C, Meitinger T, Nahrstedt J, Peters A, Wagner AK, Willenborg C, Böhm BO, Dobnig H, Grammer TB, Hoffmann MM, Kleber M, März W, Meinitzer A, Winkelmann BR, Pilz S, Renner W, Scharnagl H, Stojakovic T, Tomaschitz A, Winkler K, Guiducci C, Burtt N, Gabriel SB, O'Donnell CJ, Elosua R, Peltonen L, Salomaa V, Schwartz SM, Melander O, Altshuler D, Dandona S, Jarinova O, Qu L, Wilensky R, Matthai W, Hakonarson HH, Devaney J, Burnett MS, Pichard AD, Kent KM, Satler L, Lindsay JM, Waksman R, Knouff CW, Waterworth DM, Walker MC, Mooser V, Epstein SE, Rader DJ, Braund PS, Wright BJ, Balmforth AJ, Ball SG, Hall AS, Smith NL, Felix JF, Morrison AC, Demissie S, Glazer NL, Loehr LR, Rosamond WD, Bis JC, Folsom AR, Benjamin E, Aulchenko YS, Haritunians T, Couper D, Murabito J, Yang YA, Stricker BH, Gottdiener JS, Chang PP, Wang TJ, Rice KM, Heckbert SR, Fox ER, Willerson JT, Köttgen A, Pattaro C, Böger CA, Fuchsberger C, Olden M, Gao X, Yang Q, O'Connell JR, Schmidt H, Ketkar S, Hwang SJ, Teumer A, Paré G, Atkinson EJ, Lohman K, Cornelis MC, Probst-Hensch NM, Kronenberg F, Tönjes A, Hayward C, Rampersaud E, Mitchell BD, Arking DE, Struchalin M, Cavalieri M, Singleton A, Giallauria F, Metter J, de Boer IH, Siscovick D, Zillikens MC, Feitosa M, Province M, de Andrade M, Turner ST, Wild PS, Schnabel RB, Wilde S, Munzel TF, Leak TS, Koenig W, Zgaga L, Zemunik T, Kolcic I, Minelli C, Hu FB, Johansson A, Igl W, Zaboli G, Wild SH, Wright AF, Campbell H, Ellinghaus D, Imboden M, Nitsch D, Brandstätter A, Kollerits B, Kedenko L, Mägi R, Stumvoll M, Kovacs P, Boban M, Campbell S, Endlich K, Völzke H, Kroemer HK, Nauck M, Völker U, Polasek O, Vitart V, Badola S, Parker AN, Ridker PM, Kardia SL, Curhan GC, Franke A, Rochat T, Paulweber B, Prokopenko I, Wang W, Coresh J, Schmidt R, Shlipak MG, Borecki I, Krämer BK, Rudan I, Gyllensten U, Wilson JF, Pramstaller PP, Rettig R, Hastie N, Chasman DI, Kao WH, Heid IM, Fox CS, Felix SB, Watzinger N, Homuth G, Aragam J, Dörr M, Zweiker R, Lind L, Rodeheffer RJ, Greiser KH, Deckers JW, Stritzke J, Lackner KJ, Ingelsson E, Kullo I, Haerting J, Reffelmann T, Redfield MM, Werdan K, Arnett DK, Blettner M, Friedrich N, Chambers JC, Zhang W, Lord GM, van der Harst P, Lawlor DA, Sehmi JS, Gale DP, Wass MN, Ahmadi KR, Bakker SJ, Beckmann J, Bilo HJ, Bochud M, Brown MJ, Caulfield MJ, Connell JM, Cook HT, Cotlarciuc I, Davey Smith G, de Silva R, Deng G, Devuyst O, Dikkeschei LD, Dimkovic N, Dockrell M, Dominiczak A, Ebrahim S, Eggermann T, Farrall M, Floege J, Forouhi NG, Gansevoort RT, Han X, Hedblad B, Homan van der Heide JJ, Hepkema BG, Hernandez-Fuentes M, Hypponen E, Johnson T, de Jong PE, Kleefstra N, Lagou V, Lapsley M, Li Y, Loos RJ, Luan J, Luttropp K, Maréchal C, Munroe PB, Nordfors L, Penninx BW, Perucha E, Pouta A, Roderick PJ, Ruokonen A, Schalling M, Schlessinger D, Schlieper G, Seelen MA, Sjögren M, Smit JH, Snieder H, Soranzo N, Spector TD, Stenvinkel P, Sternberg MJ, Swaminathan R, Ubink-Veltmaat LJ, Vollenweider P, Waterworth D, Zerres K, Waeber G, Wareham NJ, Maxwell PH, McCarthy MI, Jarvelin MR, Lightstone L, Scott J, Navis G, Elliott P, Kooner JS., Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), University of Leicester, Department of Genetics [Leicester], Erasmus University Rotterdam, Netherlands Genomics Initiative, Department of Epidemiology and Biostatistics, School of Public Health, Zahedan University of Medical Sciences, Washington University in Saint Louis (WUSTL), Queen Mary University of London (QMUL), National Heart, Lung and Blood Institute, Partenaires INRAE, Centre Hospitalier Universitaire Vaudois (CHUV), Université de Lausanne = University of Lausanne (UNIL), Department of Biostatistics [Oslo], Institute of Basic Medical Sciences [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Leiden University Medical Center (LUMC), Universiteit Leiden, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland [Reykjavik], Johns Hopkins University, School of Medicine, Hôpitaux Universitaires de Genève (HUG), Department of Epidemiology, The Netherlands Cancer Institute, Department of Mathematics, Boston University [Boston] (BU), GlaxoSmithKline, Division of Community Health Sciences, St. George's, University of South Florida [Tampa] (USF), Universität Greifswald - University of Greifswald, University of Washington [Seattle], University of Tartu, Institute of Molecular and Cell Biology, Medical Research Council, Institut de Génomique, Centre National de Génotypage, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University Medical Center Groningen, Department of Genetics, University Medical Center Groningen [Groningen] (UMCG), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Massachusetts General Hospital [Boston], Centro de Regulación Genómica (CRG), Universitat Pompeu Fabra [Barcelona] (UPF), Università degli studi di Trieste = University of Trieste, Universität zu Lübeck = University of Lübeck [Lübeck], Department of Biostatistics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, The University of Western Australia (UWA), Department of Twin Research and Genetic Epidemiology, King's College London, London, University of Oxford, Medical University Graz, National Institute on Aging, Centre for population Health Sciences, University of Edinburgh, Uppsala University, Vrije Universiteit Amsterdam [Amsterdam] (VU), Western General Hospital, Harvard Medical School [Boston] (HMS), Brigham and Women's Hospital [Boston], University of Michigan System, University of Groningen, Ealing Hospital, School of Public Health - Department of Epidemiology and Biostatistics, Imperial College London, Medical Genetics Institute, Cedars-Sinai Medical Center, University of Tampere, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Split, The University of Texas Health Science Center at Houston (UTHealth), Johns Hopkins University (JHU), Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Swiss Institute of Bioinformatics [Lausanne] (SIB), Finnish Institute of Occupational Health, National Institute of Health and Welfare, University of Oulu, Lapland Central Hospital, University of Bristol [Bristol], Institute for Community Medicine, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), US National Institutes of Health, National Heart, Lung, and Blood Institute, European, Epidemiology, Internal Medicine, Public Health, Clinical Genetics, Université de Lausanne (UNIL), LeidenUniversity Medical Centre, University of Iceland, Università degli studi di Trieste, Universität zu Lübeck [Lübeck], University of Western Australia, University of Oxford [Oxford], VU University Amsterdam, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Human genetics, Psychiatry, EMGO - Mental health, NCA - Anxiety & Depression, Epidemiology and Data Science, Medical Research Council (MRC), Louise V., Wain, Germaine C., Verwoert, Paul F., O'Reilly, Gang, Shi, Toby, Johnson, Andrew D., Johnson, Murielle, Bochud, Kenneth M., Rice, Peter, Henneman, Albert V., Smith, Georg B., Ehret, Najaf, Amin, Martin G., Larson, Vincent, Mooser, David, Hadley, Marcus, Dörr, Joshua C., Bi, Thor, Aspelund, Tõnu, Esko, A. Cecile J. W., Janssen, Jing Hua, Zhao, Simon, Heath, Maris, Laan, Jingyuan, Fu, Giorgio, Pisti, Jian'An, Luan, Pankaj, Arora, Gavin, Luca, Pirastu, Nicola, Irene, Pichler, Anne U., Jackson, Rebecca J., Webster, Feng, Zhang, John F., Peden, Helena, Schmidt, Toshiko, Tanaka, Harry, Campbell, Wilmar, Igl, Yuri, Milaneschi, Jouke Jan, Hottenga, Veronique, Vitart, Daniel I., Chasman, Stella, Trompet, Jennifer L., Bragg Gresham, Behrooz Z., Alizadeh, John C., Chamber, Xiuqing, Guo, Terho, Lehtimäki, Brigitte, Kühnel, Lorna M., Lopez, Ozren, Polašek, Mladen, Boban, Christopher P., Nelson, Alanna C., Morrison, Vasyl, Pihur, Santhi K., Ganesh, Albert, Hofman, Suman, Kundu, Francesco U. S., Mattace Raso, Fernando, Rivadeneira, Eric J. G., Sijbrand, Andre G., Uitterlinden, Shih Jen, Hwang, Ramachandran S., Vasan, Thomas J., Wang, Sven, Bergmann, Peter, Vollenweider, Gérard, Waeber, Jaana, Laitinen, Anneli, Pouta, Paavo, Zitting, Wendy L., Mcardle, Heyo K., Kroemer, Uwe, Völker, Henry, Völzke, Nicole L., Glazer, Kent D., Taylor, Tamara B., Harri, Helene, Alavere, Toomas, Haller, Aime, Kei, Mari Liis, Tammesoo, Yurii, Aulchenko, Inês, Barroso, Kay Tee, Khaw, Pilar, Galan, Serge, Hercberg, Mark, Lathrop, Susana, Eyheramendy, Elin, Org, Siim, Sõber, Xiaowen, Lu, Ilja M., Nolte, Brenda W., Penninx, Tanguy, Corre, Corrado, Masciullo, Cinzia, Sala, Leif, Groop, Benjamin F., Voight, Olle, Melander, Christopher J., O'Donnell, Veikko, Salomaa, D'Adamo, ADAMO PIO, Antonella, Fabretto, Flavio, Faletra, Sheila, Ulivi, Fabiola Del Greco, M, Maurizio, Facheri, Francis S., Collin, Richard N., Bergman, John P., Beilby, Joseph, Hung, A., William Musk, Massimo, Mangino, So Youn, Shin, Nicole, Soranzo, Hugh, Watkin, Anuj, Goel, Anders, Hamsten, Pierre, Gider, Marisa, Loitfelder, Marion, Zeginigg, Dena, Hernandez, Samer S., Najjar, Pau, Navarro, Sarah H., Wild, Anna Maria, Corsi, Andrew, Singleton, Eco J. C., de Geu, Gonneke, Willemsen, Alex N., Parker, Lynda M., Rose, Brendan, Buckley, David, Stott, Marco, Orru, Manuela, Uda, Melanie M., van der Klauw, Weihua, Zhang, Xinzhong, Li, James, Scott, Yii Der Ida, Chen, Gregory L., Burke, Mika, Kähönen, Jorma, Viikari, Angela, Döring, Thomas, Meitinger, Gail, Davie, John M., Starr, Valur, Emilsson, Andrew, Plump, Jan H., Lindeman, Peter A. C., 't Hoen, Inke R., König, Janine F., Felix, Robert, Clarke, Jemma C., Hopewell, Halit, Ongen, Monique, Breteler, Stéphanie, Debette, Anita L., Destefano, Myriam, Fornage, Gary F., Mitchell, Nicholas L., Smith, Hilma, Holm, Kari, Stefansson, Gudmar, Thorleifsson, Unnur, Thorsteinsdottir, Nilesh J., Samani, Michael, Preu, Igor, Rudan, Caroline, Hayward, Ian J., Deary, H., Erich Wichmann, Olli T., Raitakari, Walter, Palma, Jaspal S., Kooner, Ronald P., Stolk, J., Wouter Jukema, Alan F., Wright, Dorret I., Boomsma, Stefania, Bandinelli, Ulf B., Gyllensten, James F., Wilson, Luigi, Ferrucci, Reinhold, Schmidt, Martin, Farrall, Tim D., Spector, Lyle J., Palmer, Jaakko, Tuomilehto, Arne, Pfeufer, Gasparini, Paolo, David, Siscovick, David, Altshuler, Ruth J. F., Loo, Daniela, Toniolo, Harold, Snieder, Christian, Gieger, Pierre, Meneton, Nicholas J., Wareham, Ben A., Oostra, Andres, Metspalu, Lenore, Launer, Rainer, Rettig, David P., Strachan, Jacques S., Beckmann, Jacqueline C. M., Witteman, Jeanette, Erdmann, Ko Willems van, Dijk, Eric, Boerwinkle, Michael, Boehnke, Paul M., Ridker, Marjo Riitta, Jarvelin, Aravinda, Chakravarti, Goncalo R., Abecasi, Vilmundur, Gudnason, Christopher Newton, Cheh, Daniel, Levy, Patricia B., Munroe, Bruce M., Psaty, Mark J., Caulfield, Dabeeru C., Rao, Martin D., Tobin, Paul, Elliott, Cornelia M., van Duijn, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, Wain, Louise V., Verwoert, Germaine C., O'Reilly, Paul F., Shi, Gang, Johnson, Toby, Johnson, Andrew D., Bochud, Murielle, Rice, Kenneth M., Henneman, Peter, Smith, Albert V., Ehret, Georg B., Amin, Najaf, Larson, Martin G., Mooser, Vincent, Hadley, David, Dörr, Marcu, Bis, Joshua C, Aspelund, Thor, Esko, Tõnu, Janssens, A Cecile J. W., Zhao, Jing Hua, Heath, Simon, Laan, Mari, Fu, Jingyuan, Pistis, Giorgio, Luan, Jian'An, Arora, Pankaj, Lucas, Gavin, Pichler, Irene, Jackson, Anne U., Webster, Rebecca J., Zhang, Feng, Peden, John F., Schmidt, Helena, Tanaka, Toshiko, Campbell, Harry, Igl, Wilmar, Milaneschi, Yuri, Hottenga, Jouke-Jan, Vitart, Veronique, Chasman, Daniel I., Trompet, Stella, Bragg-Gresham, Jennifer L., Alizadeh, Behrooz Z., Chambers, John C., Guo, Xiuqing, Lehtimäki, Terho, Kühnel, Brigitte, Lopez, Lorna M., Polašek, Ozren, Boban, Mladen, Nelson, Christopher P., Morrison, Alanna C., Pihur, Vasyl, Ganesh, Santhi K., Hofman, Albert, Kundu, Suman, Mattace-Raso, Francesco U. S., Rivadeneira, Fernando, Sijbrands, Eric J. 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Aragam, J, Dörr, M, Zweiker, R, Lind, L, Rodeheffer, Rj, Greiser, Kh, Deckers, Jw, Stritzke, J, Lackner, Kj, Ingelsson, E, Kullo, I, Haerting, J, Reffelmann, T, Redfield, Mm, Werdan, K, Arnett, Dk, Blettner, M, Friedrich, N, Chambers, Jc, Zhang, W, Lord, Gm, van der Harst, P, Lawlor, Da, Sehmi, J, Gale, Dp, Wass, Mn, Ahmadi, Kr, Bakker, Sj, Beckmann, J, Bilo, Hj, Bochud, M, Brown, Mj, Caulfield, Mj, Connell, Jm, Cook, Ht, Cotlarciuc, I, Davey Smith, G, de Silva, R, Deng, G, Devuyst, O, Dikkeschei, Ld, Dimkovic, N, Dockrell, M, Dominiczak, A, Ebrahim, S, Eggermann, T, Farrall, M, Floege, J, Forouhi, Ng, Gansevoort, Rt, Han, X, Hedblad, B, Homan van der Heide, Jj, Hepkema, Bg, Hernandez-Fuentes, M, Hypponen, E, Johnson, T, de Jong, Pe, Kleefstra, N, Lagou, V, Lapsley, M, Li, Y, Loos, Rj, Luan, J, Luttropp, K, Maréchal, C, Munroe, Pb, Nordfors, L, Penninx, Bw, Perucha, E, Pouta, A, Roderick, Pj, Ruokonen, A, Schalling, M, Schlessinger, D, Schlieper, G, Seelen, Ma, Sjögren, M, Smit, Jh, Snieder, H, Soranzo, N, Spector, Td, Stenvinkel, P, Sternberg, Mj, Swaminathan, R, Ubink-Veltmaat, Lj, Vollenweider, P, Waterworth, D, Zerres, K, Waeber, G, Wareham, Nj, Maxwell, Ph, Mccarthy, Mi, Jarvelin, Mr, Lightstone, L, Scott, J, Navis, G, Elliott, P, and Kooner, Js.
Subjects: Netherlands Twin Register (NTR), Linkage disequilibrium, pulse pressure, mean arterial pressure, genome-wide, [SDV]Life Sciences [q-bio], Genome-wide association study, BLOOD-PRESSURE, Blood Pressure, 030204 cardiovascular system & hematology, Linkage Disequilibrium, 0302 clinical medicine, RELEVANCE, CardioGram, Medicine and Health Sciences, Genetics & Heredity, ddc:616, Genetics, 0303 health sciences, Genome-wide association, 11 Medical And Health Sciences, Arteries, ADRENERGIC-RECEPTOR TRAFFICKING, Pulse pressure, EchoGen consortium, Hypertension, HEART-FAILURE, arterial pressure, Case-Control Studie, Life Sciences & Biomedicine, Human, circulatory and respiratory physiology, medicine.medical_specialty, Mean arterial pressure, Arterie, AortaGen Consortium, Cardiogenics consortium, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, Follow-Up Studie, 03 medical and health sciences, Internal medicine, medicine, Humans, cardiovascular diseases, METAANALYSIS, 030304 developmental biology, Genetic association, Science & Technology, HYPERTENSION, MORTALITY, Case-control study, CARDIOVASCULAR-DISEASE RISK, 06 Biological Sciences, GENE, MICE, Endocrinology, Blood pressure, CKDGen consortium, Genetic Loci, Case-Control Studies, KidneyGen consortium, CHARGE Consortium Heart Failure Working Group, LifeLines Cohort Study, Developmental Biology, Follow-Up Studies, Genome-Wide Association Study
Abstract: Les affiliations des 100 premiers auteurs sont renseignées dans la notice. Les affiliations des autres auteurs sont disponibles à la fin de la publication.; International audience; Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans(1-3). We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 x 10(-8) to P = 2.3 x 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
Published: 2016
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34. Thermoregulatory challenges in the habitat of the world's smallest tortoise, Chersobius signatus

Author: Victor J. T. Loehr
Subjects: 030110 physiology, 0106 biological sciences, 0301 basic medicine, Hibernation, Operative temperature, Tortoise, Physiology, Acclimatization, Biology, 010603 evolutionary biology, 01 natural sciences, Biochemistry, Body Temperature, 03 medical and health sciences, Temperate climate, Animals, Homopus, Ecosystem, Ecology, Feeding Behavior, Thermoregulation, biology.organism_classification, Turtles, Habitat, Ectotherm, General Agricultural and Biological Sciences, Locomotion, Developmental Biology
Abstract: Ectotherms have various means of dealing with low environmental temperatures, but relatively few species have been rigorously investigated. Consequently, we have little information to predict how ectotherm populations might respond to global temperature changes. Tortoises from temperate and subtropical regions often overcome periodically cool conditions by hibernation, but speckled dwarf tortoises (Chersobius signatus) need to remain active to exploit ephemeral resources in their arid winter-rainfall habitat. This study investigated how dwarf tortoises cope with low temperatures in winter and spring, by measuring thermal habitat quality and thermoregulation based on differently-sized operative temperature models in sun, shade, and in deep crevices. Investigations continued in summer and autumn to obtain a year-round picture of thermoregulatory challenges. Although large models (i.e., larger than dwarf tortoises) were expected to have lower operative temperatures than smaller models, due to the former's larger thermal inertia, all model sizes had similar temperatures. Hence, the species’ small body size does not appear constrained by obtainable body temperatures in cool seasons. Nevertheless, low operative temperatures in winter posed a challenge for the tortoises, which reached their field-preferred body temperature for an average of only 0.8−0.9 h per day. Moreover, a low thermoregulation effectiveness suggested that tortoises traded-off physiological benefits of favourable body temperatures against predation risk. Spring and autumn provided higher temperatures, but summer caused the greatest thermoregulatory challenge. Although summer body temperatures were closer to field-preferred body temperature than in any other season, tortoises required rock crevices to avoid overheating. The small size of dwarf tortoises might help them utilise crevices. In summer, maximum operative temperatures in crevices were similar to field-preferred body temperature, indicating that an increase in environmental temperatures might be detrimental to dwarf tortoises. In light of projected temperature rises, future studies should assess if dwarf tortoises can cope with higher environmental temperatures in summer.
Published: 2017

35. Author response: Extensive alternative splicing transitions during postnatal skeletal muscle development are required for calcium handling functions

Author: Zheng Xia, George G. Rodney, James A. Loehr, Thomas A. Cooper, Amy E. Brinegar, and Wei Li
Subjects: medicine.anatomical_structure, Calcium handling, Alternative splicing, medicine, Skeletal muscle, Biology, Cell biology
Published: 2017
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36. Growth of the Namaqualand speckled padloper, Homopus signatus signatus (Reptilia: Testudinidae)

Author: Victor J. T. Loehr
Subjects: Homopus signatus, Winter rainfall, Tortoise, biology, Zoology, tortoises, Homopus, ecology, growth, Animal Science and Zoology, Carapace, Homopus, Body size, biology.organism_classification, Sexual difference
Abstract: Growth was calculated for the world’s smallest tortoise species, Homopus signatus signatus, by comparing body size data gathered in spring 2000, 2001 and 2002. Sexual differences could not be identified, but mean growth was significantly lower in 2000/01 than in 2001/02, possibly due to higher winter rainfall preceding the second period. Variation in growth rates was highest in juveniles. Growth decreased with increasing straight carapace length, resulting in a preliminary estimate of 11 years for females to reach sexual maturity.Key words: tortoises, Homopus, ecology, growth.
Published: 2017

37. Circulating ceruloplasmin, ceruloplasmin-associated genes, and the incidence of atrial fibrillation in the Atherosclerosis Risk in Communities Study

Author: Ron C. Hoogeveen, Elsayed Z. Soliman, Laura R. Loehr, Antonio P. Arenas de Larriva, Faye L. Norby, Alvaro Alonso, Dan E. Arking, and Lin Y. Chen
Subjects: Male, medicine.medical_specialty, Single-nucleotide polymorphism, 030204 cardiovascular system & hematology, Lower risk, Gastroenterology, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Atrial Fibrillation, medicine, Humans, 030212 general & internal medicine, Genetic Association Studies, Aged, biology, Proportional hazards model, business.industry, Incidence (epidemiology), Incidence, Hazard ratio, Ceruloplasmin, Atrial fibrillation, Middle Aged, medicine.disease, Atherosclerosis, Confidence interval, Single nucleotide polymorphism, Endocrinology, Oxidative stress, biology.protein, Female, Independent Living, Cardiology and Cardiovascular Medicine, business, Biomarkers
Abstract: Background Ceruloplasmin (CP) may promote structural changes in the atrium making it more arrhythmogenic. We assessed the associations between CP, CP-associated genetic variants, and incident atrial fibrillation (AF) in the Atherosclerosis Risk in Communities (ARIC) study. Methods and results We studied 10,059 men and women without prevalent AF aged 53 to 75years in 1996–1998 and followed through 2012. Circulating CP was measured in stored blood samples obtained in 1996–1998. Polymorphisms rs11708215 and rs13072552, previously associated with CP concentrations, were measured in 10,059 and 8829 participants respectively. AF was ascertained from study electrocardiograms, hospital discharge codes, and death certificates. Multivariable Cox models were run to study the association between circulating CP, CP-associated polymorphisms, and the incidence of AF. Over 10.5years of mean follow-up, 1357 cases of AF were identified. After adjusting for traditional risk factors and biomarkers, higher levels of circulating CP were associated with incident AF (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.11, 1.61 comparing top to bottom quartiles). Both rs11708215 and rs13072552 were significantly associated with CP levels. Presence of the CP-increasing alleles in rs11708215 and rs13072552, however, were significantly associated with lower risk of AF in whites (HR 0.84, 95%CI 0.76, 0.94, p =0.002 and HR 0.83; 95%CI 0.69, 0.99, p =0.043 respectively per CP-increasing allele in the final adjusted model) but not in African Americans. Conclusions Even though higher CP concentrations were associated with increased AF risk, genetic variants associated with higher CP decreased the risk of AF in whites. Our results suggest that circulating CP levels may not be causally related to risk of incident AF.
Published: 2017

38. Extensive alternative splicing transitions during postnatal skeletal muscle development are required for calcium handling functions

Author: Thomas A. Cooper, James A. Loehr, Amy E. Brinegar, Wei Li, Zheng Xia, and George G. Rodney
Subjects: 0301 basic medicine, Gene isoform, QH301-705.5, Science, Biology, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, alternative splicing, 0302 clinical medicine, None, Gene expression, medicine, Animals, skeletal muscle, Biology (General), Muscle, Skeletal, calcineurin, 030304 developmental biology, 0303 health sciences, NFATC Transcription Factors, General Immunology and Microbiology, Nfat, Gene Expression Profiling, General Neuroscience, Alternative splicing, Skeletal muscle, NFAT, Cell Biology, General Medicine, Cell biology, Calcineurin, postnatal development, Developmental Biology and Stem Cells, 030104 developmental biology, medicine.anatomical_structure, Muscle relaxation, Animals, Newborn, RNA splicing, Medicine, Calcium, C2C12, 030217 neurology & neurosurgery, Research Article
Abstract: Postnatal development of skeletal muscle is a highly dynamic period of tissue remodeling. Here we used RNA-seq to identify transcriptome changes from late embryonic to adult mouse muscle and demonstrate that alternative splicing developmental transitions impact muscle physiology. The first two weeks after birth are particularly dynamic for differential gene expression and AS transitions, and calciumhandling functions are significantly enriched among genes that undergo alternative splicing. We focused on the postnatal splicing transitions of three calcineurin A genes, calcium-dependent phosphatases that regulate multiple aspects of muscle biology. Redirected splicing of calcineurin A to the fetal isoforms in adult muscle and in differentiated C2C12 slows the timing of muscle relaxation, promotes nuclear localization of calcineurin targets Nfatc3 and Nfatc2, and affects expression of Nfatc transcription targets. The results demonstrate a previously unknown specificity of calcineurin isoforms as well as the broader impact of AS during muscle postnatal development.
Published: 2017
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39. Genome-wide association analysis identifies six new loci associated with forced vital capacity

Author: Wenbo Tang, Stephen B. Kritchevsky, Ian P. Hall, Alexessander Couto Alves, Henry Völzke, Kim de Jong, Sina A. Gharib, Louise V. Wain, Adaikalavan Ramasamy, John M. Starr, Tatijana Zemunik, André G. Uitterlinden, Isabelle Pin, A. Bill Musk, Lina Zgaga, Ernst Omenaas, Mi Kyeong Lee, Nadia N. Hansel, Lewis J. Smith, Dana B. Hancock, Anne Viljanen, Anneli Pouta, Erik Melén, Nora Franceschini, Susan Campbell, Alicja R. Rudnicka, Melissa E. Garcia, Jemma B. Wilk, Igor Rudan, John Beilby, Fernando Rivadeneira, Gudny Eiriksdottir, Lenore J. Launer, Kristin M. Burkart, Ozren Polasek, Pieter S. Hiemstra, Regina Hampel, Jerome I. Rotter, Markku Heliövaara, Harald Grallert, Tim D. Spector, Andrew P. Morris, Jennifer E. Huffman, Pau Navarro, Jing Hua Zhao, Robert A. Scott, Bruno H. Stricker, Christopher Oldmeadow, Yeon-Mok Oh, Christian Gieger, Tove Fall, Caroline Hayward, Rodney J. Scott, Mika Kähönen, Vilmundur Gudnason, Guy Brusselle, Stefan Karrasch, Anne B. Newman, Alan James, Ida Surakka, Peter K. Joshi, R. Graham Barr, Fien Verhamme, Alexander Teumer, Ulf Gyllensten, Joohon Sung, Marjolein J. Peters, Ryan L. Minster, Kirsi H. Pietiläinen, Ian J. Deary, Lorna M. Lopez, Matthias Wjst, Myriam Fornage, Susan Redline, Wei Gao, Taina Rantanen, David J. Lederer, Gail Davies, Mary K. Wojczynski, Kari E. North, Beate Koch, Guo Li, George T. O'Connor, Blair H. Smith, Harry Campbell, Wendy B. White, Juha Pekkanen, Eva Albrecht, Sven Gläser, Joyce B. J. van Meurs, Stephen S. Rich, Wendy L. McArdle, Deborah Jarvis, Ani Manichaikul, Pirro G. Hysi, Christopher J Hammond, Erik Ingelsson, Albert V. Smith, John Attia, O. Dale Williams, Tamara B. Harris, Susan R. Heckbert, Josée Dupuis, Bruce M. Psaty, Åsa Johansson, Xin-Qun Wang, Samuli Ripatti, Woo Jin Kim, Patricia A. Cassano, H. Marike Boezen, David J. Porteous, Esteban G. Burchard, Kurt Lohman, Ivana Kolcic, Lies Lahousse, James F. Wilson, Dirkje S. Postma, Holly Trochet, Nicholas J. Wareham, Ana Viñuela, María Soler Artigas, Lars Lind, Jennie Hui, Bharat Thyagarajan, Judith M. Vonk, Marcy F. Petrini, Bonnie R. Joubert, Marjo-Riitta Järvelin, Xiangjun Gu, Claudia Flexeder, Generation Scotland, Sarah H. Wild, Nicholas D. Hastie, Thomas Lumley, Veronique Vitart, Laura R. Loehr, Joachim Heinrich, Yongmei Liu, Akshay Sood, Tess D. Pottinger, Alan F. Wright, Albert Hofman, Rajesh Kumar, Cisca Wijmenga, Elizabeth G. Holliday, Ian Sayers, David P. Strachan, Martin D. Tobin, Stefan Enroth, Thor Aspelund, Leslie A. Lange, Qing Duan, Daan W. Loth, Ken R. Bracke, Nathan C. Gaddis, David Couper, Stephanie J. London, Alanna C. Morrison, Holger Schulz, Jaakko Kaprio, Life Course Epidemiology (LCE), Groningen Research Institute for Asthma and COPD (GRIAC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Otorhinolaryngology and Head and Neck Surgery, Psychiatry, Epidemiology, Public Health, and Internal Medicine
Subjects: Spirometry, Lung Diseases, Vital capacity, Quantitative Trait Loci, Vital Capacity, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, DISEASE, Pulmonary function testing, Cohort Studies, FEV1/FVC ratio, Idiopathic pulmonary fibrosis, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, Forced Expiratory Volume, Databases, Genetic, Genetics, medicine, Humans, Restrictive lung disease, Lung volumes, Genetic Predisposition to Disease, lung, spriometry, SNP, gene, GENE-EXPRESSION, medicine.diagnostic_test, Genome, Human, HERITABILITY, HEALTHY TWIN, MORTALITY, ta3141, respiratory system, medicine.disease, Prognosis, 3. Good health, Respiratory Function Tests, respiratory tract diseases, FAMILY, LUNG-FUNCTION, Genetic Loci, Immunology, CELLS, IDIOPATHIC PULMONARY-FIBROSIS, TRAITS, Follow-Up Studies, Genome-Wide Association Study
Abstract: Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P
Published: 2014
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40. Abstract 727: Comprehensive genomic profiling of >1000 plasma and tumor tissue samples from metastatic castration-resistant prostate cancer (mCRPC) patients gives insight into targeted treatment strategies

Author: Tony Golsorkhi, Jeremy Shapiro, Wassim Abida, Andrea Loehr, Josep M. Piulats, Ray McDermott, Peter Ostler, Simon Chowdhury, Foad Green, Arif Hussain, Ivor John Percent, Jingsong Zhang, Simon Paul Watkins, Alison Reid, David Campbell, Dominique Spaeth, and Andrew Simmons
Subjects: 0301 basic medicine, Cancer Research, medicine.drug_class, Frameshift mutation, 03 medical and health sciences, chemistry.chemical_compound, Prostate cancer, 0302 clinical medicine, Germline mutation, Prostate, Medicine, PTEN, Rucaparib, Taxane, biology, business.industry, Androgen, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Oncology, chemistry, 030220 oncology & carcinogenesis, biology.protein, Cancer research, business
Abstract: Background: The phase 2 TRITON2 (NCT02952534) study is evaluating the poly(ADP-ribose) polymerase inhibitor rucaparib in mCRPC patients with a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM, or 1 of 12 other DNA damage repair (DDR) genes who have progressed on prior androgen receptor-directed therapy and 1 taxane-based therapy. Here we present results from central genomic screening of plasma and tissue samples for TRITON2. Methods: Plasma samples were profiled for genomic alterations (GAs) in 70 genes and tumor tissue FFPE samples for GAs in 395 genes by Foundation Medicine, Inc., using next-generation sequencing (NGS) assays. Deleterious alterations included frameshift, nonsense, and deleterious missense mutations, protein-truncating rearrangements, and (for tissue samples) homozygous loss. Tissue samples included both archival and more recent specimens, whereas plasma samples were collected at the time of disease progression on prior therapy. Results: As of July 2, 2018, 359 plasma samples from patients with mCRPC were screened for deleterious GAs in a DDR gene. Of the plasma samples, 96% (343/359) were successfully sequenced for a comprehensive genomic profile. The most commonly altered genes were AR (49%) and TP53 (48%). Deleterious GAs were detected in BRCA1 (2%), BRCA2 (10%), ATM (15%), CDK12 (6%), or other DDR genes (6%). GAs in the MAPK pathway were observed in 5% of plasma samples. Additionally, 738 tissue samples from primary prostate cancer tumors (78%) or metastases (22%) were profiled. Only 66% of tissue samples (487/738) were sequenced successfully, highlighting the challenges associated with NGS of predominantly archival prostate tissues (median sample age, 2.5 years [range, 4 days to 21 years]). The most commonly altered genes were TP53 (38%), PTEN (33%), ERG-TEMPRSS2 fusions (28%), AR (15%), and MYC (9%). Deleterious GAs were observed in BRCA1(2%), BRCA2 (9%), ATM (7%), CDK12 (7%), or other DDR genes (5%), as well as in the PI3K/AKT (41%), Wnt (11%), MAPK (5%), and mismatch repair (3%) pathways. Further, GAs in the DDR, PI3K/AKT, and Wnt pathways were observed at a higher rate in metastatic (42%, 40%, and 15%, respectively) than in primary prostate tissues (32%, 34%, and 12%, respectively). Updated and expanded genomic analyses and plasma-tissue concordance analyses will be presented. Conclusions: Genomic NGS profiling of plasma and FFPE tumor tissue samples successfully identified patients with GAs in a DDR gene for the evaluation of rucaparib in mCRPC. The plasma assay is convenient for patients and has a low NGS failure rate, whereas the tumor tissue assay has a higher failure rate but can detect more alteration types. Taken together, these data highlight the strengths and limitations of tissue and plasma testing to identify GAs for targeted therapies in mCRPC. Citation Format: Foad Green, Jeremy D. Shapiro, Ray McDermott, Josep Maria Piulats, Alison Reid, Peter Ostler, Jingsong Zhang, David Campbell, Dominique Spaeth, Ivor Percent, Arif Hussain, Andrew D. Simmons, Tony Golsorkhi, Simon P. Watkins, Andrea Loehr, Simon Chowdhury, Wassim Abida. Comprehensive genomic profiling of >1000 plasma and tumor tissue samples from metastatic castration-resistant prostate cancer (mCRPC) patients gives insight into targeted treatment strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 727.
Published: 2019
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41. Identification of KIF11 As a Novel Target in Meningioma

Author: Ralf Ketter, Rolf Warta, Almuth F. Keßler, Christine Jungk, Gerhard Jungwirth, Andreas Unterberg, Steffen Dettling, Katrin Lamszus, Christel Herold-Mende, Mario Loehr, Felix Sahm, Juergen Debus, Tao Yu, Matthias Simon, Andreas von Deimling, Carmen Rapp, Manfred Westphal, Mahmoud Moustafa, Amir Abdollahi, Christian Senft, and Klaus Zweckberger
Subjects: 0301 basic medicine, Cancer Research, Microarray, macromolecular substances, Biology, lcsh:RC254-282, meningioma, kinesin, Article, Meningioma, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, medicine, ddc:610, KIF, Gene knockdown, Intracellular vesicle, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, KIF11, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, Immunohistochemistry, KIF4A, KIFC1, NCH93
Abstract: Kinesins play an important role in many physiological functions including intracellular vesicle transport and mitosis. The emerging role of kinesins in different cancers led us to investigate the expression and functional role of kinesins in meningioma. Therefore, we re-analyzed our previous microarray dataset of benign, atypical, and anaplastic meningiomas (n = 62) and got evidence for differential expression of five kinesins (KIFC1, KIF4A, KIF11, KIF14 and KIF20A). Further validation in an extended study sample (n = 208) revealed a significant upregulation of these genes in WHO&deg, I to &deg, III meningiomas (WHO&deg, I n = 61, WHO&deg, II n = 88, and WHO&deg, III n = 59), which was most pronounced in clinically more aggressive tumors of the same WHO grade. Immunohistochemical staining confirmed a WHO grade-associated upregulated protein expression in meningioma tissues. Furthermore, high mRNA expression levels of KIFC1, KIF11, KIF14 and KIF20A were associated with shorter progression-free survival. On a functional level, knockdown of kinesins in Ben-Men-1 cells and in the newly established anaplastic meningioma cell line NCH93 resulted in a significantly inhibited tumor cell proliferation upon siRNA-mediated downregulation of KIF11 in both cell lines by up to 95% and 71%, respectively. Taken together, in this study we were able to identify the prognostic and functional role of several kinesin family members of which KIF11 exhibits the most promising properties as a novel prognostic marker and therapeutic target, which may offer new treatment options for aggressive meningiomas.
Published: 2019
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42. Ultrastructure of Eggshells from Wild and Captive Speckled Dwarf Tortoises, Chersobius signatus

Author: Carlos G.P. Voogdt, Declan Nolan, and Victor J. T. Loehr
Subjects: 0106 biological sciences, Reproductive success, 010607 zoology, Zoology, Interspecific competition, Biology, biology.organism_classification, 010603 evolutionary biology, 01 natural sciences, Ultrastructure, Animal Science and Zoology, Eggshell, Homopus, Incubation, Ecology, Evolution, Behavior and Systematics
Abstract: Ultrastructures of chelonian eggshells show wide interspecific variation, which might, in part, reflect requirements to protect embryos in various incubation environments. Relationships be...
Published: 2019
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43. APOM and high-density lipoprotein cholesterol are associated with lung function and per cent emphysema

Author: Demondes Haynes, Kristin M. Burkart, Michael Y. Tsai, Susan R. Heckbert, Charles A. Powell, Paul L. Enright, Elizabeth C. Oelsner, Jerome I. Rotter, María Soler Artigas, Martin D. Tobin, Marcy F. Petrini, Stephanie J. London, Tess D. Pottinger, Taylor Young, George T. O'Connor, Stephen S. Rich, Eric A. Hoffman, Ani Manichaikul, Jun Kurai, Joel D. Kaufman, Laura R. Loehr, Yang Meng, Lewis J. Smith, R. Graham Barr, Nadia N. Hansel, Gregory L. Burke, Firas S. Ahmed, Karol E. Watson, Susan Redline, Jemma B. Wilk, and Wendy B. White
Subjects: Pulmonary and Respiratory Medicine, Spirometry, medicine.medical_specialty, COPD, Pathology, Apolipoprotein B, biology, medicine.diagnostic_test, Cholesterol, business.industry, PCSK9, respiratory system, medicine.disease, Gastroenterology, respiratory tract diseases, FEV1/FVC ratio, chemistry.chemical_compound, APOM, High-density lipoprotein, chemistry, Internal medicine, biology.protein, medicine, business
Abstract: Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD. We assessed the association of lung function with 2,100 genes selected for cardiovascular diseases among 20,077 European-Americans and 6,900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with percent emphysema, and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with FEV1/FVC and percent emphysema. We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10−6) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10−7). Both SNPs flank the gene for apolipoprotein M (apoM), a component of HDL. Both replicated in an independent cohort. SNPs in a second gene related to apoM and HDL, PCSK9 , were associated with FEV1/FVC among African-Americans. rs707974 was associated with percent emphysema among European-Americans and African-Americans, and APOM expression was related to FEV1/FVC and percent emphysema. Higher HDL levels were associated with lower FEV1/FVC and greater percent emphysema. These findings suggest a novel role for the APOM/HDL pathway in the pathogenesis of COPD and emphysema.
Published: 2013
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44. Marker-free coselection for CRISPR-driven genome editing in human cells

Author: Caroline C. Huard, Daniel Agudelo, Yannick Doyon, Josee Laganiere, Mathieu Drouin, Jeremy Loehr, Graham Dellaire, Lusine Bozoyan, Sophie Carter, Jayme Salsman, Dafni Synodinou, and Alexis Duringer
Subjects: 0301 basic medicine, Genetic Markers, DNA Repair, DNA repair, Computational biology, Biology, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Genome editing, CRISPR, Humans, Progenitor cell, Molecular Biology, Cells, Cultured, Genetics, Gene Editing, Gene targeting, Cell Biology, Non-homologous end joining, Haematopoiesis, 030104 developmental biology, Genetic marker, Mutagenesis, Site-Directed, CRISPR-Cas Systems, 030217 neurology & neurosurgery, Biotechnology
Abstract: Targeted genome editing enables the creation of bona fide cellular models for biological research and may be applied to human cell-based therapies. Therefore, broadly applicable and versatile methods for increasing its efficacy in cell populations are highly desirable. We designed a simple and robust coselection strategy for enrichment of cells with either nuclease-driven nonhomologous end joining (NHEJ) or homology-directed repair (HDR) events by harnessing the multiplexing capabilities of CRISPR-Cas9 and Cpf1 systems. Selection for dominant alleles of the ubiquitous sodium/potassium pump (Na+/K+ ATPase) that rendered cells resistant to ouabain was used to enrich for custom genetic modifications at another unlinked locus of interest, thereby effectively increasing the recovery of engineered cells. The process is readily adaptable to transformed and primary cells, including hematopoietic stem and progenitor cells. The use of universal CRISPR reagents and a commercially available small-molecule inhibitor streamlines the incorporation of marker-free genetic changes in human cells.
Published: 2016

45. The Effect of Serum 25-Hydroxyvitamin D Concentrations on Elevated Serum C-Reactive Protein Concentrations in Normal Weight, Overweight and Obese Participants of a Preventive Health Program

Author: John Paul Ekwaru, Marco Fabio Mastroeni, Silmara Salete de Barros Silva Mastroeni, Lalani L. Munasinghe, Truong-Minh Pham, Paul J. Veugelers, and Sarah Loehr
Subjects: Adult, Male, medicine.medical_specialty, obesity, 030209 endocrinology & metabolism, Inflammation, vitamin D, lcsh:TX341-641, Disease, Health Promotion, 030204 cardiovascular system & hematology, Overweight, Article, C-reactive protein, 03 medical and health sciences, 0302 clinical medicine, cardiovascular disease, Internal medicine, Preventive Health Services, medicine, Vitamin D and neurology, Humans, Life Style, Aged, Nutrition and Dietetics, biology, business.industry, Body Weight, Middle Aged, medicine.disease, Obesity, Confidence interval, 3. Good health, Endocrinology, Normal weight, serum 25-hydroxyvitamin D, Cardiovascular Diseases, inflammation, Dietary Supplements, biology.protein, Female, medicine.symptom, business, lcsh:Nutrition. Foods and food supply, Food Science
Abstract: The hypothesized effect of vitamin D on C-reactive protein (CRP) has received substantial attention as a potential means to alleviate the risk for cardiovascular disease. However, observational studies have been inconsistent in their reporting of associations between serum 25-hydroxyvitamin D (25(OH)D) and CRP concentrations, and trials and meta analyses have been inconsistent in their conclusions regarding the effect of vitamin D supplementation on CRP concentrations. These supplementation trials were mostly conducted among patients with more or less inflammatory complications and did not consider potential distinctive effects by weight status. To further our understanding of the potential influences of vitamin D on CRP, we analyzed longitudinal observations of 6755 participants of a preventative health program. On average, serum 25(OH)D concentrations increased from 88.3 to 121.0 nmol/L and those of CRP decreased from 1.7 to 1.6 mg/L between baseline and follow up. Relative to obese participants without temporal increases in 25(OH)D, those who showed improvements of
Published: 2016

46. Structural and functional analysis of a novel interaction motif within UFM1-activating enzyme 5 (UBA5) required for binding to ubiquitin-like proteins and ufmylation

Author: Jessica Huber, Masato Akutsu, Masaaki Komatsu, Sabrina Habisov, Volker Doetsch, Terje Johansen, Vladimir Kirkin, David G. McEwan, Vladimir V. Rogov, Yoshinobu Ichimura, Ivan Dikic, Frank Loehr, and Natalia Yu. Rogova
Subjects: 0301 basic medicine, GABARAP, Amino Acid Motifs, Ubiquitin-Activating Enzymes, Biochemistry, Protein Structure, Secondary, 03 medical and health sciences, Structure-Activity Relationship, 0302 clinical medicine, Ubiquitin, Transcription (biology), Humans, Structural motif, Molecular Biology, Adaptor Proteins, Signal Transducing, chemistry.chemical_classification, biology, C-terminus, Proteins, Cell Biology, In vitro, Cell biology, 030104 developmental biology, Enzyme, HEK293 Cells, chemistry, Ubiquitin-Conjugating Enzymes, biology.protein, Signal transduction, Apoptosis Regulatory Proteins, Microtubule-Associated Proteins, Protein Processing, Post-Translational, 030217 neurology & neurosurgery, Signal Transduction
Abstract: The covalent conjugation of ubiquitin-fold modifier 1 (UFM1) to proteins generates a signal that regulates transcription, response to cell stress, and differentiation. Ufmylation is initiated by ubiquitin-like modifier activating enzyme 5 (UBA5), which activates and transfers UFM1 to ubiquitin-fold modifier-conjugating enzyme 1 (UFC1). The details of the interaction between UFM1 and UBA5 required for UFM1 activation and its downstream transfer are however unclear. In this study, we described and characterized a combined linear LC3-interacting region/UFM1-interacting motif (LIR/UFIM) within the C terminus of UBA5. This single motif ensures that UBA5 binds both UFM1 and light chain 3/γ-aminobutyric acid receptor-associated proteins (LC3/GABARAP), two ubiquitin (Ub)-like proteins. We demonstrated that LIR/UFIM is required for the full biological activity of UBA5 and for the effective transfer of UFM1 onto UFC1 and a downstream protein substrate both in vitro and in cells. Taken together, our study provides important structural and functional insights into the interaction between UBA5 and Ub-like modifiers, improving the understanding of the biology of the ufmylation pathway.
Published: 2016

47. Asymmetry in threespine stickleback lateral plates

Author: Juha Merilä, S. Van Dongen, Gábor Herczeg, Abigél Gonda, John Loehr, and Tuomas Leinonen
Subjects: 0106 biological sciences, media_common.quotation_subject, Population, Zoology, Gasterosteus, 010603 evolutionary biology, 01 natural sciences, Environmental stress, Asymmetry, Fluctuating asymmetry, 03 medical and health sciences, education, Biology, Gasterosteus aculeatus, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, media_common, 0303 health sciences, education.field_of_study, biology, Ecology, Stickleback, biology.organism_classification, Directional bias, Habitat, Animal Science and Zoology
Abstract: The study of asymmetry can provide insights into genetic and environmental influences on organismal development. Directional asymmetry (DA) can be either adaptive or non-adaptive, whereas fluctuating asymmetry (FA) – defined as small non-directional departures from symmetry in bilateral traits – is thought to be an indicator of genetic or environmental stress experienced during development. Using data from 28 European populations, we assessed the degree of DA and FA in the lateral plates of threespine sticklebacks Gasterosteus aculeatus and surveyed the direction of DA and differences in levels of DA and FA in different habitat types (viz. marine, lake and river populations). DA differed between habitats, with right-biased DA found in the marine populations and no directional bias found in lake and river populations. Differences in DA among habitats may be a by-product of habitat-specific developmental instability resulting in asymmetry, or it may indicate habitat-specific differences in selection against/for symmetry, as has been proposed in previous research of sticklebacks. Also, the presence of FA varied depending upon habitat type, but it also depended on plate morph – a variable confounded with the habitat effect. While we cannot rule out factors such as stress as a cause of population differences in FA, it may also simply be a by-product of other evolutionary processes (e.g. lateral plate number reduction) without functional basis.
Published: 2012
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48. Road Mortality in the Greater Padloper,Homopus femoralis(Testudinidae)

Author: Victor J. T. Loehr
Subjects: Fishery, Traffic volume, Ecology, Homopus femoralis, Tar, Animal Science and Zoology, Biology, biology.organism_classification, Ecology, Evolution, Behavior and Systematics
Abstract: Road mortality of South African tortoises has not been evaluated. I recorded the number and distribution of remains of Homopus femoralis directly along 8.4 km of tar road with low traffic volume in the Karoo, South Africa. I identified 48 carcasses, with a relatively high number found along 1.5 km of road. Multiple dry culverts already present under this stretch of road provide an opportunity to reduce mortality by adding structures to guide tortoises to the underpasses.
Published: 2012
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49. Serine phosphorylation and proline isomerization in RNAP II CTD control recruitment of Nrd1

Author: Hana Cerna, Josef Pasulka, Richard Štefl, Ctirad Hofr, Karel Kubíček, Frank Loehr, Stepanka Vanacova, Dominika Hrossova, and Peter Holub
Subjects: Models, Molecular, RNA, Untranslated, Saccharomyces cerevisiae Proteins, Proline, Cell Survival, viruses, genetic processes, RNA polymerase II, Saccharomyces cerevisiae, environment and public health, Serine, Research Communication, Transcription (biology), Genetics, Phosphorylation, biology, RNA-Binding Proteins, Protein Structure, Tertiary, enzymes and coenzymes (carbohydrates), Biochemistry, Covalent bond, health occupations, Biophysics, biology.protein, RNA Polymerase II, CTD, Isomerization, Protein Binding, Developmental Biology
Abstract: Recruitment of appropriate RNA processing factors to the site of transcription is controlled by post-translational modifications of the C-terminal domain (CTD) of RNA polymerase II (RNAP II). Here, we report the solution structure of the Ser5 phosphorylated (pSer5) CTD bound to Nrd1. The structure reveals a direct recognition of pSer5 by Nrd1 that requires the cis conformation of the upstream pSer5–Pro6 peptidyl-prolyl bond of the CTD. Mutations at the complex interface diminish binding affinity and impair processing or degradation of noncoding RNAs. These findings underpin the interplay between covalent and noncovalent changes in the CTD structure that constitute the CTD code.
Published: 2012
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50. High body temperatures in an arid, winter-rainfall environment: Thermal biology of the smallest tortoise

Author: Victor J. T. Loehr
Subjects: geography, Herbivore, geography.geographical_feature_category, Ecology, biology, Tortoise, Forage, Thermoregulation, biology.organism_classification, Arid, Homopus signatus, Ectotherm, Spring (hydrology), Ecology, Evolution, Behavior and Systematics, Earth-Surface Processes
Abstract: Herbivorous tortoises in arid, winter-rainfall regions need to forage in seasons that provide relatively little heat for their ectothermic metabolism. To help understand how tortoises exploit resources in winter-rainfall areas, I recorded ambient, soil, and body temperatures for Homopus signatus in four spring seasons, and in one summer, autumn, and winter. The spring thermal environment enabled H. signatus to maintain body temperatures that were high compared to other small tortoise species. Mature females had higher spring body temperatures than males and immature individuals, probably because mature females were developing eggs. In summer, autumn, and winter, body temperatures differed between males and females, relating to sexually different activities and retreat uses. The relatively high body temperatures of H. signatus in winter and spring, along with a non-isometric relationship between body temperature and soil temperature, suggest that tortoises thermoregulated and may need considerable time to gain heat. Additional studies should compare body temperatures of H. signatus to operative temperatures, and determine the vulnerability of the taxon to human interferences that affect behavioural time budgets and body temperatures.
Published: 2012
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