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Made available in DSpace on 2022-04-28T19:52:06Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-03-18 Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale. Department of Biology University of Toronto Mississauga ON Centre for Urban Environments University of Toronto Mississauga ON Department of Biology University of North Carolina, Chapel Hill Department of Biology University of Louisiana LA Department of Biology Queen's University ON Department of Biology Concordia University QC Department of Biological Sciences DePaul University Department of Biology DePauw University IN Department of Urban Design and Planning, University of Washington, Seattle, WA, USA Colegio de Ciencias Biológicas y Ambientales Universidad San Francisco de Quito USFQ Department of Genetics University of Georgia Department of Ecology and Genetics Evolutionary Biology Centre Uppsala University Field Science Center for Northern Biosphere Hokkaido University Natural History Museum Zoology University of New England NSW Programa de Pós-Graduação em Geografia da UFMT campus de Rondonópolis Department of Botany and Biodiversity Research Centre University of British Columbia Graduate Program in Genome Sciences and Technology Genome Sciences Centre University of British Columbia Department of Microbiology and Immunology University of British Columbia Red de Biología Evolutiva Instituto de Ecología A. C. School of the Environment Yale University CT Departamento de Ciencias Ecológicas Universidad de Chile, Facultad de Ciencias Instituto de Ecología y Biodiversidad Universidad de Chile Department of Biology Mount Allison University Red de Ecoetología Instituto de Ecología A. C. Department of Biology University of Ottawa ON Department of Zoology University of Cambridge Department of Biology, Washington University in St. Louis, St. Louis, MO, USA Department of Biology University of Miami FL Centro de Investigación en Recursos Naturales y Sustentabilidad (CIRENYS) Universidad Bernardo O'Higgins Department of Biology, University of La Verne, La Verne, CA, USA Département des sciences du bois et de la forêt Université Laval QC Evolution & Ecology Research Centre School of Biological Earth and Environmental Sciences UNSW Sydney NSW Department of Biology Ghent University Department of Biology Monmouth University West Long Branch Centre for Ecology Evolution and Environmental Changes Faculdade de Ciências Universidade de Lisboa Lisboa Department of Biology KU Leuven School of Agriculture and Environment Wildlife and Ecology group Massey University, Palmerston North Department of Biological Sciences University of Cape Town Institute of Landscape Ecology University of Münster Gosnell School of Life Sciences, Rochester Institute of Technology, Rochester, NY, USA Department of Biological Sciences University of Alberta AB Louis Calder Center and Department of Biological Sciences, Fordham University, Armonk, NY, USA Departamento de Ecología Tropical, Universidad Autónoma de Yucatán, Mérida, Yucatán, México School of Life Sciences University of Sussex Department of Ecology Environment and Plant Sciences Stockholm University iBIOTROP Instituto de Biodiversidad Tropical Universidad San Francisco de Quito Department of Biology, San Francisco State University, San Francisco, CA, USA Unidad de Recursos Naturales, Centro de Investigación Científica de Yucatán AC, Mérida, Yucatán, México School of Ecological and Environmental Sciences East China Normal University Shanghai Engineering Research Center of Sustainable Plant Innovation Centre for Ecosystem Science School of Biological Earth and Environmental Sciences UNSW Sydney NSW Department of Ecology and Evolutionary Biology University of Michigan MI Department of Biosciences Rice University TX IFEVA Universidad de Buenos Aires Facultad de Agronomía, CONICET Biology Department Saint Mary's University NS Department of Biological Sciences, Universidad de los Andes Department of Biology and Biochemistry University of Houston TX Université de Rennes Department of Zoology and Biodiversity Research Centre University of British Columbia Department of Environmental Studies Dordt University Sioux Center IA Department of Biology Minneapolis Community and Technical College MN Department of Natural Sciences Ecology and Environment Research Centre Manchester Metropolitan University Instituto de Investigaciones en Ecosistemas y Sustentabilidad UNAM Department of Botany School of Biology Aristotle University of Thessaloniki Faculty of Biological and Environmental Science Organismal & Evolutionary Biology Research Programme University of Helsinki Institute of Biodiversity Animal Health and Comparative Medicine University of Glasgow Department of Biology Hendrix College Department of Ecological Science Vrije Universiteit Amsterdam Departamento de Ciencias Biológicas y Agropecuarias Universidad Técnica Particular de Loja Departamento de Biologia Universidade Federal de Santa Maria (UFSM) Department of Plant Sciences School of Biology College of Science University of Tehran NTNU University Museum Norwegian University of Science and Technology Red de Estudios Moleculares Avanzados Instituto de Ecología A. C. School of Biological Sciences, University of Reading, Whiteknights Park, Reading, Berkshire, UK Department of Biology Northern Arizona University AZ Department of Biological Sciences MacEwan University AB Max Planck Institute for Plant Breeding Research Departamento de Ecología Evolutiva Instituto de Ecología Universidad Nacional Autónoma de México Max Planck Institute of Molecular Plant Physiology Potsdam-Golm BIO5 Institute University of Arizona AZ Alaska Center for Conservation Science University of Alaska Anchorage Tropical Diversity, Royal Botanical Garden of Edinburgh Département de biologie Université de Moncton Department of Biological Sciences University of Manitoba MB Departments of Microbiology & Statistics University of Manitoba MB Department of Biology University of New Brunswick Department of Biology Kalamazoo College MI BioProtection Research Centre Lincoln University Departamento de Ciencias Facultad de Artes Liberales Universidad Adolfo Ibáñez Department of Ecology Evolution Behaviour University of Minnesota MN Department of Biological Sciences Brock University Department of Environmental Toxicology, University of California, Davis, CA, USA ICB - University of Talca School of Molecular and Life Science Curtin University College of Science Health Engineering and Education Murdoch University, Murdoch School of Life and Environmental Sciences University of Sydney NSW School of Biological Sciences, Monash University, Melbourne, VIC, Australia Department of Biological Sciences Wayne State University MI Department of Biology Western Oregon University, OR School of Natural Resources and the Environment University of Arizona AZ Departamento de Ecología Humana, Cinvestav Mérida Departamento de Ciencias Biológicas y Departamento de Ecología y Biodiversidad Facultad de Ciencias de la Vida, Universidad Andrés Bello Institute of Ecology and Biodiversity (IEB) Department of Biology Lund University Department of Biology Norwegian University of Science and Technology Escuela Superiro de Desarrollo Sustentable Universidad Autónoma de Guerrero -CONACYT Clarkson Secondary School Peel District School Board ON Homelands Sr. Public School Peel District School Board ON Department of Biological Sciences University of Illinois at Chicago Dufferin-Peel Catholic District School Board, St. James Catholic Global Learning Centre Department of Biosciences University of Calgary AB Ecological Processes Branch U.S. Army ERDC-CERL Department of Biology, Oberlin College, Oberlin, OH, USA Escuela Nacional de Estudios Superiores Unidad Morelia UNAM Institute of Evolution and Ecology University of Tübingen Tübingen Department of Evolutionary Biology and Environmental Studies University of Zurich, Winterthurerstrasse Urban Wildlife Institute Department of Conservation and Science, Lincoln Park Zoo Departamento de Ecología Universidad Católica de la Santísima Concepción Department of Biological Sciences University of Denver CO Department of Biological Sciences Mississippi State University MS Department of Biology Center for Computational & Integrative Biology Rutgers University-Camden Kunming Institute of Botany Chinese Academy of Sciences Department of Chemistry & Biochemistry Laurentian University ON Ministry of Education Key Laboratory for Biodiversity Science and Ecological Engineering College of Life Sciences Beijing Normal University School of BioSciences, University of Melbourne, Melbourne, VIC, Australia Posgrado en Ciencias Biológicas Universidad Nacional Autónoma de México Department of Biological Sciences, Auburn University, Auburn, AL, USA Department of Entomology and Nematology, University of California, Davis, CA, USA Department of Biology University of New Mexico NM Department of Biology University of Wisconsin - Eau Claire Agriculture Institute Iranian Research Organization for Science and Technology (IROST) Department of Biology Colby College ME Instituto de Biología Universidad de Antioquia Department of Biology University of Massachusetts Boston MA Agricultural Biology Colorado State University CO Departamento de Biología Vegetal y Ecología Facultad de Biología Universidad de Sevilla, Av. Reina Mercedes s/n Facultad de Estudios Interdisciplinarios Centro GEMA- Genómica Universidad Mayor Evolutionary Ecology Group Naturalis Biodiversity Center Department of Biology and Chemistry Nipissing University ON, North Bay Center for Ecological Research Kyoto University Bonanza Creek Long Term Ecological Research Program University of Alaska Fairbanks Department of Botany and Molecular Evolution Senckenberg Research Institute and Natural History Museum Frankfurt Departamento de Biodiversidade Instituto de Biociências Univ Estadual Paulista - UNESP Nelson Institute for Environmental Studies University of Wisconsin-Madison WI Department of Biology, California State University, Northridge, Los Angeles, CA, USA Department of Ecology Swedish University of Agricultural Sciences Facultad de Ciencias y Biotecnologia Universidad CES Department of Biology Hofstra University Faculty of Biosciences and Aquaculture Nord University, Bodø Division of Biological Sciences, University of California San Diego, San Diego, CA, USA Department of Biology University of Richmond VA Estación de Biodiversidad Tiputini Colegio de Ciencias Biológicas y Ambientales Universidad San Francisco de Quito USFQ Department of Biological Sciences Institute of Environment Florida International University FL Agronomy Department University of Almería Department of Biological Sciences and Center for Urban Ecology and Sustainability Butler University IN Department of Biological Sciences Louisiana State University LA Faculty of Biological Sciences, Goethe University Frankfurt Institute of Biology Leiden Leiden University Department of Biological and Environmental Science University of Jyväskylä Jyväskylä Department of Biology University of Louisville KY Organization for Programs on Environmental Science University of Tokyo CNRS AgroParisTech Ecologie Systématique et Evolution, Université Paris-Saclay Department of Biology, Providence College, Providence, RI, USA General Zoology Institute for Biology Martin Luther University Halle-Wittenberg International Arctic Research Center University of Alaska Fairbanks Science, Technology and Society Department, Rochester Institute of Technology, Rochester, NY, USA SLU Swedish Species Information Centre Swedish University of Agricultural Sciences Department of Biology Westfield State University MA Centre of New Technologies University of Warsaw Department of Biology, Stanford University, Stanford, CA, USA Plant Biology Department Michigan State University MI Biology Department Davidson College College of Horticulture and Forestry Sciences/ Hubei Engineering Technology Research Center for Forestry Information Huazhong Agricultural University School of Life Sciences Technical University of Munich School of Life Sciences Lanzhou University Institute of Ecology and Evolution University of Bern Department of Evolution Ecology and Behaviour University of Liverpool Departamento de Biodiversidade Instituto de Biociências Univ Estadual Paulista - UNESP

Background Cystic fibrosis (CF) is a genetic condition that affects multiple organ systems. Allergic bronchopulmonary aspergillosis (ABPA) is a well‐recognised problem but other allergic conditions are less well documented in CF. Objective To characterise the allergic profile of a cohort of children with CF, with a focus on those with ABPA. Methods A cohort of children with CF were interviewed and retrospective data were collected regarding their allergic histories and other relevant clinical features. Results The cohort included 37 children with median age of 9 years (interquartile range: 6‐12). There was a history of ≥1 allergic condition(s) in 28/37 children (76%). The most common allergic condition was allergic rhinitis (AR) in 21/37 (57%) and 16 of these 21 children (76%) had another allergic condition. All children with ABPA (8) had another allergic condition. In some children ABPA exacerbations appeared to be seasonal, suggesting possible cross‐sensitisation between Aspergillus fumigatus and aeroallergens associated with seasonal AR. Allergic conditions were also common in children with Pseudomonas aeruginosa infection., “Example allergic timelines for children with CF”

Climate change projections indicate that precipitation events in the central United States are expected to become more intense, more frequent in the spring, and less frequent in the summer. Such a precipitation shift could adversely impact crop yields, especially in subfield areas known as farmed potholes, which are highly susceptible to flooding and ponding, and crop death is more likely to occur, particularly early in the growing season. This suggests that planting alternative crops, such as more flood tolerant perennials, in these areas may be a more profitable option. Using observations of crop growth and yield along with ponding depth of a specific field and farmed pothole in the central United States, we developed a spatially explicit version of the agroecosystem model Agro‐IBIS to estimate water depth and crop yield. After evaluating the model, we conducted a case study for a specific farmed pothole with a range of future precipitation scenarios with Agro‐IBIS to simulate the effects of contemporary (2002–2016) and future precipitation on a conventional corn/soybean (Zea mays L. and Glycine max Merr.) rotation and an alternative perennial miscanthus (Miscanthus × giganteus Greef et Deu.) cropping system. The depth and frequency of ponding increased under most future precipitation scenarios. The corn/soybean rotation had greater total loss (i.e., no yield) on average (>30%) for all scenarios in comparison to miscanthus (

Leishmaniasis, a disease caused by protozoa of the Leishmania species, afflicts roughly 12 million individuals worldwide. Most existing drugs for leishmaniasis are toxic, expensive, difficult to administer, and subject to drug resistance. We report a new class of antileishmanial leads, the 3-arylquinolines, that potently block proliferation of the intramacrophage amastigote form of Leishmania parasites with good selectivity relative to the host macrophages. Early lead 34 was rapidly acting and possessed good potency against L. mexicana (EC50 = 120 nM), 30-fold selectivity for the parasite relative to the macrophage (EC50 = 3.7 μM), and also blocked proliferation of Leishmania donovani parasites resistant to antimonial drugs. Finally, another early lead, 27, which exhibited reasonable in vivo tolerability, impaired disease progression during the dosing period in a murine model of cutaneous leishmaniasis. These results suggest that the arylquinolines provide a fruitful departure point for the development of new antileishmanial drugs.

Alterations in maternal physiological adaptation during pregnancy lead to complications, including abnormal birthweight and gestational diabetes. Maternal adaptations are driven by placental hormones, although the full identity of these is lacking. This study unbiasedly characterized the secretory output of mouse placental endocrine cells and examined whether these data could identify placental hormones important for determining pregnancy outcome in humans. Secretome and cell peptidome analyses were performed on cultured primary trophoblast and fluorescence-activated sorted endocrine trophoblasts from mice and a placental secretome map was generated. Proteins secreted from the placenta were detectable in the circulation of mice and showed a higher relative abundance in pregnancy. Bioinformatic analyses showed that placental secretome proteins are involved in metabolic, immune and growth modulation, are largely expressed by human placenta and several are dysregulated in pregnancy complications. Moreover, proof-of-concept studies found that secreted placental proteins (sFLT1/MIF and ANGPT2/MIF ratios) were increased in women prior to diagnosis of gestational diabetes. Thus, placental secretome analysis could lead to the identification of new placental biomarkers of pregnancy complications., This work was supported by a Royal Society Dorothy Hodgkin Research Fellowship, Academy of Medical of Sciences Springboard Grant, Isaac Newton Trust Grant and Lister Institute Research Prize grant to ANSP (grant numbers DH130036 / RG74249, SBF002/1028 / RG88501, RG97390 and RG93692, respectively). TN was supported by an EU Marie Skłodowska-Curie Fellowship (PlaEndo/703160) and an Early Career Grant from the Society for Endocrinology. CLM is supported by the Diabetes UK Harry Keen Intermediate Clinical Fellowship (DUK-HKF 17/0005712) and the EFSD-Novo Nordisk Foundation Future Leader’s Award (NNF19SA058974). Work in the FR/FMG laboratory was supported by the Wellcome Trust (106262/Z/14/Z,106263/Z/14/Z), the MRC (MRC_MC_UU_12012/3 and MRC -Enhancing UK clinical research grant MR/M009041/1) and the Cambridge Biomedical Research Centre (NIHR-BRC Gastrointestinal Diseases theme).

In celebration of the 20th anniversary of Nature Reviews Genetics, we asked 12 leading researchers to reflect on the key challenges and opportunities faced by the field of genetics and genomics. Keeping their particular research area in mind, they take stock of the current state of play and emphasize the work that remains to be done over the next few years so that, ultimately, the benefits of genetic and genomic research can be felt by everyone., To celebrate the first 20 years of Nature Reviews Genetics, we asked 12 leading scientists to reflect on the key challenges and opportunities faced by the field of genetics and genomics., The contributors Amy L. McGuire is the Leon Jaworski Professor of Biomedical Ethics and Director of the Center for Medical Ethics and Health Policy at Baylor College of Medicine. She has received numerous teaching awards at Baylor College of Medicine, was recognized by the Texas Executive Women as a Woman on the Move in 2016 and was invited to give a TedMed talk titled “There is No Genome for the Human Spirit” in 2014. In 2020, she was elected as a Hastings Center Fellow. Her research focuses on ethical and policy issues related to emerging technologies, with a particular focus on genomic research, personalized medicine and the clinical integration of novel neurotechnologies. Stacey Gabriel is the Senior Director of the Genomics Platform at the Broad Institute since 2012 and has led platform development, execution and operation since its founding. She is Chair of Institute Scientists and serves on the institute’s executive leadership team. She is widely recognized as a leader in genomic technology and project execution. She has led the Broad’s contributions to numerous flagship projects in human genetics, including the International HapMap Project, the 1000 Genomes Project, The Cancer Genome Atlas, the National Heart, Lung, and Blood Institute’s Exome Sequencing Project and the TOPMed programme. She is Principal Investigator of the Broad’s All of Us (AoU) Genomics Center and serves on the AoU Program Steering Committee. Sarah A. Tishkoff is the David and Lyn Silfen University Associate Professor in Genetics and Biology at the University of Pennsylvania, Philadelphia, USA, and holds appointments in the School of Medicine and the School of Arts and Sciences. She is a member of the US National Academy of Sciences and a recipient of an NIH Pioneer Award, a David and Lucile Packard Career Award, a Burroughs/Wellcome Fund Career Award and an American Society of Human Genetics Curt Stern Award. Her work focuses on genomic variation in Africa, human evolutionary history, the genetic basis of adaptation and phenotypic variation in Africa, and the genetic basis of susceptibility to infectious disease in Africa. Ambroise Wonkam is Professor of Medical Genetics, Director of GeneMAP (Genetic Medicine of African Populations Research Centre) and Deputy Dean Research in the Faculty of Health Sciences, University of Cape Town, South Africa. He has successfully led numerous NIH- and Wellcome Trust-funded projects over the past decade to investigate clinical variability in sickle cell disease, hearing impairment genetics and the return of individual findings in genetic research in Africa. He won the competitive Clinical Genetics Society International Award for 2014 from the British Society of Genetic Medicine. He is president of the African Society of Human Genetics. Aravinda Chakravarti is Director of the Center for Human Genetics and Genomics, the Muriel G. and George W. Singer Professor of Neuroscience and Physiology, and Professor of Medicine at New York University School of Medicine. He is an elected member of the US National Academy of Sciences, the US National Academy of Medicine and the Indian National Science Academy. He has been a key participant in the Human Genome Project, the International HapMap Project and the 1000 Genomes Project. His research attempts to understand the molecular basis of multifactorial disease. He was awarded the 2013 William Allan Award by the American Society of Human Genetics and the 2018 Chen Award by the Human Genome Organization. Eileen E. M. Furlong is Head of the Genome Biology Department at the European Molecular Biology Laboratory (EMBL) and a member of the EMBL Directorate. She is an elected member of the European Molecular Biology Organization (EMBO) and the Academia Europaea, and a European Research Council (ERC) advanced investigator. Her group dissects fundamental principles of how the genome is regulated and how it drives cell fate decisions during embryonic development, including how developmental enhancers are organized and function within the 3D nucleus. Her work combines genetics, (single-cell) genomics, imaging and computational approaches to understand these processes. Her research has advanced the development of genomic methods for use in complex multicellular organisms. Barbara Treutlein is Associate Professor of Quantitative Developmental Biology in the Department of Biosystems Science and Engineering of ETH Zurich in Basel, Switzerland. Her group uses and develops single-cell genomics approaches in combination with stem cell-based 2D and 3D culture systems to study how human organs develop and regenerate and how cell fate is regulated. For her work, Barbara has received multiple awards, including the Friedmund Neumann Prize of the Schering Foundation, the Dr. Susan Lim Award for Outstanding Young Investigator of the International Society of Stem Cell Research and the EMBO Young Investigator Award. Alexander Meissner is a scientific member of the Max Planck Society and currently Managing Director of the Max Planck Institute (MPI) for Molecular Genetics in Berlin, Germany. He heads the Department of Genome Regulation and is a visiting scientist in the Department of Stem Cell and Regenerative Biology at Harvard University. Before his move to the MPI, he was a tenured professor at Harvard University and a senior associate member of the Broad Institute, where he co-directed the epigenomics programme. In 2018, he was elected as an EMBO member. His laboratory uses genomic tools to study developmental and disease biology with a particular focus on epigenetic regulation. Howard Y. Chang is the Virginia and D. K. Ludwig Professor of Cancer Genomics at Stanford University and an investigator at the Howard Hughes Medical Institute. He is a physician–scientist who has focused on deciphering the hidden information in the non-coding genome. His laboratory is best known for studies of long non-coding RNAs in gene regulation and development of new epigenomic technologies. He is an elected member of the US National Academy of Sciences, the US National Academy of Medicine, and the American Academy of Arts and Sciences. Núria López-Bigas is ICREA research Professor at the Institute for Research in Biomedicine and Associate Professor at the University Pompeu Fabra. She obtained an ERC Consolidator Grant in 2015 and was elected as an EMBO member in 2016. Her work has been recognized with the prestigious Banc de Sabadell Award for Research in Biomedicine, the Catalan National Award for Young Research Talent and the Career Development Award from the Human Frontier Science Program. Her research focuses on the identification of cancer driver mutations, genes and pathways across tumour types and in understanding the mutational processes that lead to the accumulation of mutations in cancer cells. Eran Segal is Professor in the Department of Computer Science and Applied Mathematics at the Weizmann Institute of Science, heading a multidisciplinary laboratory with extensive experience in machine learning, computational biology and analysis of heterogeneous high-throughput genomic data. His research focuses on the microbiome, nutrition and genetics, and their effect on health and disease and aims to develop personalized medicine based on big data from human cohorts. He has published more than 150 publications and received several awards and honours for his work, including the Overton and the Michael Bruno awards. He was recently elected as an EMBO member and as a member of the Israel Young Academy. Jin-Soo Kim is Director of the Center for Genome Engineering in the Institute for Basic Science in Daejon, South Korea. He has received numerous awards, including the 2017 Asan Award in Medicine, the 2017 Yumin Award in Science and the 2019 Research Excellence Award (Federation of Asian and Oceanian Biochemists and Molecular Biologists). He was featured as one of ten Science Stars of East Asia in Nature (558, 502–510 (2018)) and has been recognized as a highly cited researcher by Clarivate Analytics since 2018. His work focuses on developing tools for genome editing in biomedical research.

Breast cancer is the most common tumor among women with inherited variants in the TP53 tumor suppressor, but onset varies widely suggesting interactions with genetic or environmental factors. Rodent models haploinsufficent for Trp53 also develop a wide variety of malignancies associated with Li-Fraumeni Syndrome, but BALB/c mice are uniquely susceptible to mammary tumors and is genetically linked to the Suprmam1 locus on chromosome 7. To define mechanisms that interact with deficiencies in p53 to alter susceptibility to mammary tumors, we fine-mapped the Suprmam1 locus in females from an N2 backcross of BALB/cMed and C57BL/6J mice. A major modifier was localized within a 10 cM interval on chromosome 7. The effect of the locus on DNA damage responses was examined in the parental strains and mice that are congenic for C57BL/6J alleles on the BALB/cMed background (SM1-Trp53+/−). The mammary epithelium of C57BL/6J-Trp53+/− females exhibited little radiation-induced apoptosis compared to BALB/cMed-Trp53+/− and SM1-Trp53+/− females indicating that the Suprmam1B6/B6 alleles could not rescue repair of radiation-induced DNA double-strand breaks mostly relying on non-homologous end joining. In contrast, the Suprmam1B6/B6 alleles in SM1-Trp53+/− mice were sufficient to confer the C57BL/6J-Trp53+/− phenotypes in homology-directed repair and replication fork progression. The Suprmam1B6/B6 alleles in SM1-Trp53+/− mice appear to act in trans to regulate a panel of DNA repair and replication genes which lie outside the locus. Significance: Genetic variation in replication-associated DNA repair can modify consequences of heterozygous mutations in Trp53 and contribute to susceptibility to mammary tumors in mouse models of Li-Fraumeni syndrome.

Climate change is increasing drought intensity, threatening biodiversity. Rapid evolution of drought adaptations might be required for population persistence, particularly in rear-edge populations that may already be closer to physiological limits. Resurrection studies are a useful tool to assess adaptation to climate change, yet these studies rarely encompass the geographic range of a species. Here, we sampled 11 populations of scarlet monkeyflower (Mimulus cardinalis), collecting seeds across the plants’ northern, central, and southern range to track trait evolution from the lowest to the greatest moisture anomaly over a 7-year period. We grew families generated from these populations across well-watered and terminal drought treatments in a greenhouse and quantified five traits associated with dehydration escape and avoidance. When considering pre-drought to peak-drought phenotypes, we find that later date of flowering evolved across the range of M. cardinalis, suggesting a shift away from dehydration escape. Instead, traits consistent with dehydration avoidance evolved, with smaller and/or thicker leaves evolving in central and southern regions. The southern region also saw a loss of plasticity in these leaf traits by the peak of the drought, whereas flowering time remained plastic across all regions. This observed shift in traits from escape to avoidance occurred only in certain regions, revealing the importance of geographic context when examining adaptations to climate change.

Because of their relatively short lifespan (

Although cells of mushroom-producing fungi typically contain paired haploid nuclei (n + n), most Armillaria gallica vegetative cells are uninucleate. As vegetative nuclei are produced by fusions of paired haploid nuclei, they are thought to be diploid (2n). Here we report finding haploid vegetative nuclei in A. gallica at multiple sites in southeastern Massachusetts, USA. Sequencing multiple clones of a single-copy gene isolated from single hyphal filaments revealed nuclear heterogeneity both among and within hyphae. Cytoplasmic bridges connected hyphae in field-collected and cultured samples, and we propose nuclear migration through bridges maintains this nuclear heterogeneity. Growth studies demonstrate among- and within-hypha phenotypic variation for growth in response to gallic acid, a plant-produced antifungal compound. The existence of both genetic and phenotypic variation within vegetative hyphae suggests that fungal individuals have the potential to evolve within a single generation in response to environmental variation over time and space.

We aerosolized severe acute respiratory syndrome coronavirus 2 and determined that its dynamic aerosol efficiency surpassed those of severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome. Although we performed experiment only once across several laboratories, our findings suggest retained infectivity and virion integrity for up to 16 hours in respirable-sized aerosols.

Background Resistance to front-line antimalarials (artemisinin combination therapies) is spreading, and development of new drug treatment strategies to rapidly kill Plasmodium spp. malaria parasites is urgently needed. Azithromycin is a clinically used macrolide antibiotic proposed as a partner drug for combination therapy in malaria, which has also been tested as monotherapy. However, its slow-killing ‘delayed-death’ activity against the parasite’s apicoplast organelle and suboptimal activity as monotherapy limit its application as a potential malaria treatment. Here, we explore a panel of azithromycin analogues and demonstrate that chemical modifications can be used to greatly improve the speed and potency of antimalarial action. Results Investigation of 84 azithromycin analogues revealed nanomolar quick-killing potency directed against the very earliest stage of parasite development within red blood cells. Indeed, the best analogue exhibited 1600-fold higher potency than azithromycin with less than 48 hrs treatment in vitro. Analogues were effective against zoonotic Plasmodium knowlesi malaria parasites and against both multi-drug and artemisinin-resistant Plasmodium falciparum lines. Metabolomic profiles of azithromycin analogue-treated parasites suggested activity in the parasite food vacuole and mitochondria were disrupted. Moreover, unlike the food vacuole-targeting drug chloroquine, azithromycin and analogues were active across blood-stage development, including merozoite invasion, suggesting that these macrolides have a multi-factorial mechanism of quick-killing activity. The positioning of functional groups added to azithromycin and its quick-killing analogues altered their activity against bacterial-like ribosomes but had minimal change on ‘quick-killing’ activity. Apicoplast minus parasites remained susceptible to both azithromycin and its analogues, further demonstrating that quick-killing is independent of apicoplast-targeting, delayed-death activity. Conclusion We show that azithromycin and analogues can rapidly kill malaria parasite asexual blood stages via a fast action mechanism. Development of azithromycin and analogues as antimalarials offers the possibility of targeting parasites through both a quick-killing and delayed-death mechanism of action in a single, multifactorial chemotype.

The disassembly of apoptotic cells into small membrane-bound vesicles termed apoptotic bodies (ApoBDs) is a hallmark of apoptosis; however, the functional significance of this process is not well defined. We recently discovered a new membrane protrusion (termed beaded apoptopodia) generated by apoptotic monocytes which fragments to release an abundance of ApoBDs. To investigate the function of apoptotic monocyte disassembly, we used influenza A virus (IAV) infection as a proof-of-concept model, as IAV commonly infects monocytes in physiological settings. We show that ApoBDs generated from IAV-infected monocytes contained IAV mRNA, protein and virions and consequently, could facilitate viral propagation in vitro and in vivo, and induce a robust antiviral immune response. We also identified an antipsychotic, Haloperidol, as an unexpected inhibitor of monocyte cell disassembly which could impair ApoBD-mediated viral propagation under in vitro conditions. Together, this study reveals a previously unrecognised function of apoptotic monocyte disassembly in the pathogenesis of IAV infections., Atkin-Smith et al. study apoptotic bodies formed when Influenza A (IAV)-infected monocytes undergo apoptosis. They find that apoptotic bodies contain components of IAV and can contribute to IAV propagation in vitro and in mice, and stimulate an innate and adaptive immune response. This study suggests that apoptotic bodies may take part in virus propagation and/or clearance.

Native pollinators are important for providing vital services in agroecosystems; however, their numbers are declining globally. Bees are the most efficient and diverse members of the pollinator community; therefore, it is imperative that management strategies be implemented that positively affect bee community composition and health. Here, we test responses of the bee and flowering plant communities to land management treatments in the context of grasslands in the upper Midwestern United States, a critical area with respect to bee declines. Twelve sites were selected to examine floral resources and wild bee communities based on three different types of grasslands: tallgrass prairie remnants, ungrazed restorations, and grazed restorations. Total bee abundance was significantly higher in ungrazed restorations than remnants, but there were no significant differences among grasslands in community composition or Shannon diversity. Across the three grassland types we also examined mass and lipid stores as nutritional health indicators in three sweat bees (Halictidae), Augochlora pura, Agapostemon virescens, and Halictus ligatus. Although there were no differences in lipid content, total average bee mass was significantly higher in Ag. virescens collected from ungrazed restorations as compared to remnants. Floral abundance of native and non-native species combined was significantly higher in grazed restorations compared to remnants and ungrazed restorations. However, ungrazed restorations had higher abundance and richness of native flowering ramets. These data suggest that bee abundance and nutrition are driven by high abundance of native flowering plant species, rather than total flowering plants.

Most H1 influenza A viruses (IAVs) of swine are derived from past human viruses. As human population immunity against these IAVs gradually decreases, the risk of reintroduction to humans increases. We examined 549 serum samples from persons 0-97 years of age collected in Belgium during 2017-2018 for hemagglutination inhibiting and virus neutralizing antibodies against 7 major H1 swine IAV (swIAV) clades and 3 human progenitor IAVs. Seroprevalence (titers >= 40) rates were >= 50% for classical swine and European human-like swIAVs, >= 24% for North American human-like delta 1a and Asian avian-like swIAVs, and

The plasma levels of tissue-specific microRNAs can be used as diagnostic, disease severity and prognostic biomarkers for chronic and acute diseases and drug-induced injury. Thereby, the combination of diverse microRNAs into biomarker signatures using multivariate statistics seems especially powerful from the perspective of tissue and condition specific microRNA shedding into the plasma. Although next-generation sequencing (NGS) technology enables one to analyse circulating microRNAs on a genome-scale level, it suffers from potential biases (e.g., adapter ligation bias) and lacks absolute transcript quantitation as well as tailor-made quality controls. In order to develop a robust NGS discovery assay for genome-scale quantitation of circulating microRNAs, we first evaluated the sensitivity, repeatability and ligation bias of four commercially available small RNA library preparation protocols. The protocol from RealSeq Biosciences was selected based on its performance and usability and coupled with a novel panel of exogenous small RNA spike-in controls to enable quality control and absolute quantitation, thus ensuring comparability of data across independent NGS experiments. The established microRNA Next-Generation-Sequencing Discovery Assay (miND) was validated for its relative accuracy, precision, analytical measurement range and sequencing bias and was considered fit-for-purpose for microRNA biomarker discovery. Summarized, all these criteria were met, and thus, our analytical platform is considered fit-for-purpose for microRNA biomarker discovery from biofluids in the setting of any diagnostic, prognostic or patient stratification need. The established miND assay was tested on serum, cerebrospinal fluid (CSF), synovial fluid (SF) and extracellular vesicles (EV) extracted from cell culture medium of primary cells and proved its potential to be used across different sample types.

We report on manufacturing outcomes for 41 autologous polyclonal regulatory T cell (PolyTreg) products for 7 different Phase 1 clinical trials over a 10-year period (2011-2020). Data on patient characteristics, manufacturing parameters, and manufacturing outcomes were collected from manufacturing batch records and entered into a secure database. Overall, 88% (36/41) of PolyTreg products met release criteria and 83% (34/41) of products were successfully infused into patients. Of the 7 not infused, 5 failed release criteria, and 2 were not infused because the patient became ineligible due to a change in clinical status. The median fold expansion over the 14-day manufacturing process was 434.8 -fold (range 29.8-2,232), resulting in a median post-expansion cell count of 1,841 x 106 (range 56.9-16,179 x 106). The main correlate of post-expansion cell number was starting cell number, which positively correlates with absolute circulating Treg cell count. Other parameters, including date of PolyTreg production, patient sex, and patient age did not significantly correlate with fold expansion of Treg during product manufacturing. In conclusion, PolyTreg manufacturing outcomes are consistent across trials and dates of production.

Valentina Saccomanno was an exchange MSc student in the University of St Andrews with a scholarship by the Erasmus+ Programme for Traineeship and the University of Trieste. This project was partly supported by a BBSRC grant (BB/T003146). Xenopus laevis has a lateral line mechanosensory system throughout its full life cycle, and a previous study on prefeeding stage tadpoles revealed that it may play a role in motor responses to both water suction and water jets. Here, we investigated the physiology of the anterior lateral line system in newly hatched tadpoles and the motor outputs induced by its activation in response to brief suction stimuli. High-speed videoing showed tadpoles tended to turn and swim away when strong suction was applied close to the head. The lateral line neuromasts were revealed by using DASPEI staining, and their inactivation with neomycin eliminated tadpole motor responses to suction. In immobilized preparations, suction or electrically stimulating the anterior lateral line nerve reliably initiated swimming but the motor nerve discharges implicating turning was observed only occasionally. The same stimulation applied during ongoing fictive swimming produced a halting response. The anterior lateral line nerve showed spontaneous afferent discharges at rest and increased activity during stimulation. Efferent activities were only recorded during tadpole fictive swimming and were largely synchronous with the ipsilateral motor nerve discharges. Finally, calcium imaging identified neurons with fluorescence increase time-locked with suction stimulation in the hindbrain and midbrain. A cluster of neurons at the entry point of the anterior lateral line nerve in the dorsolateral hindbrain had the shortest latency in their responses, supporting their potential sensory interneuron identity. Future studies need to reveal how the lateral line sensory information is processed by the central circuit to determine tadpole motor behavior. Publisher PDF

Background: Upregulation of Heath Shock Protein 70 (HSP70) chaperones supports cancer cell survival. Their high homology causes a challenge to differentiate them in experimental or prevention and treatment strategies. The objective of this investigation was to determine similarities and differences of Hsp70, hsc70, Grp78 and Mortalin members of the HSP70 family encoded by HSPA1, HSPA8, HSPA5 and HSPA9 genes, respectively. Methods: Literature reviews were conducted using HSPA1, HSPA5, HSPA8 and HSPA9 gene or protein names or synonyms combined with biological or cancer-relevant terms. Ingenuity Pathway Analysis was used to identify and compare profiles of proteins that directly bind individual chaperones and their associated pathways. TCGA data was probed to identify associations of hsc70 with cancer patient survival. ClinicalTrials.gov was used to identify HSP70 family studies. Results: The chaperones have similar protein folding functions. Their different cellular effects are determined by co-chaperones and client proteins combined with their intra- and extra-cellular localizations. Their upregulation is associated with worse patient prognosis in multiple cancers and can stimulate tumor immune responses or drug resistance. Their inhibition selectively kills cancer over healthy cells. Conclusions: Differences in Hsp70, hsc70, Grp78 and mortalin provide opportunities to calibrate HSP70 inhibitors for individual cancers and combination therapies.

The changing epidemiologic role of wildlife as reservoirs of antimicrobial-resistant bacteria (ARB) is poorly understood. In this study, we characterize the phenotypic resistance of commensal Escherichia coli from fecal samples of 879 individual white-tailed (Odocoileus virginianus; WTD) over a ten-year period and analyze resistance patterns. Our results show commensal E. coli from WTD had significant linear increases in reduced susceptibility to 5 of 12 antimicrobials, including broad-spectrum cephalosporins and fluoroquinolones, from 2006 to 2016. In addition, the relative frequency distribution of minimal inhibitory concentrations of two additional antimicrobials shifted towards higher values from across the study period. The prevalence of multidrug-resistant commensal E. coli increased over the study period with a prevalence of 0%, 2.2%, and 3.7% in 2006, 2012, and 2016, respectively. WTD may be persistently and increasingly exposed to antibiotics or their residues, ARB, and/or antimicrobial resistance genes via contaminated environments like surface water receiving treated wastewater effluent. El papel epidemiológico cambiante de la fauna silvestre como reservorio de bacterias resistentes a los antimicrobianos (ARB) es se conoce poco. En este estudio, caracterizamos la resistencia fenotípica de Escherichia coli comensal de fecales de 879 ejemplares de cola blanca (Odocoileus virginianus; WTD) durante un periodo de diez años y analizamos patrones de resistencia. Nuestros resultados muestran que la E. coli comensal de WTD tuvo aumentos lineales significativos en la reducción de la susceptibilidad a 5 de 12 antimicrobianos, incluyendo cefalosporinas de amplio espectro y fluoroquinolonas, desde 2006 a 2016. Además, la distribución de la frecuencia relativa de las concentraciones inhibitorias mínimas de dos antimicrobianos adicionales se desplazó hacia valores más altos a lo largo del periodo de estudio. La prevalencia de E. coli comensal multirresistente aumentó a lo largo del periodo de estudio con una prevalencia del 0%, 2,2% y 3,7% en 2006, 2012 y 2016, respectivamente. Los WTD pueden estar expuestos de forma persistente y creciente a los antibióticos o a sus residuos, ARB, y/o genes de resistencia antimicrobiana a través de entornos contaminados como las aguas superficiales que reciben efluentes de aguas residuales tratadas. Escuela de Medicina Veterinaria

XRN1 is a highly conserved exoribonuclease which degrades uncapped RNAs in a 5′–3′ direction. Degradation of RNAs by XRN1 is important in many cellular and developmental processes and is relevant to human disease. Studies in D. melanogaster demonstrate that XRN1 can target specific RNAs, which have important consequences for developmental pathways. Osteosarcoma is a malignancy of the bone and accounts for 2% of all pediatric cancers worldwide. Five-year survival of patients has remained static since the 1970s and therefore furthering our molecular understanding of this disease is crucial. Previous work has shown a down-regulation of XRN1 in osteosarcoma cells; however, the transcripts regulated by XRN1 which might promote osteosarcoma remain elusive. Here, we confirm reduced levels of XRN1 in osteosarcoma cell lines and patient samples and identify XRN1-sensitive transcripts in human osteosarcoma cells. Using RNA-seq in XRN1-knockdown SAOS-2 cells, we show that 1178 genes are differentially regulated. Using a novel bioinformatic approach, we demonstrate that 134 transcripts show characteristics of direct post-transcriptional regulation by XRN1. Long noncoding RNAs (lncRNAs) are enriched in this group, suggesting that XRN1 normally plays an important role in controlling lncRNA expression in these cells. Among potential lncRNAs targeted by XRN1 is HOTAIR, which is known to be up-regulated in osteosarcoma and contributes to disease progression. We have also identified G-rich and GU motifs in post-transcriptionally regulated transcripts which appear to sensitize them to XRN1 degradation. Our results therefore provide significant insights into the specificity of XRN1 in human cells which are relevant to disease.

The extracellular matrix protein fibronectin (FN) is alternatively spliced in a variety of inflammatory conditions, resulting in increased inclusion of alternative exons EIIIA and EIIIB. Inclusion of these exons affects fibril formation, fibrosis, and inflammation. To define upstream regulators of alternative splicing in FN, we have developed an in vitro flow-cytometry based assay, using RNA-binding probes to determine alternative exon inclusion level in aortic endothelial cells. This approach allows us to detect exon inclusion in the primary transcripts themselves, rather than in surrogate splicing reporters. We validated this assay in cells with and without FN-EIIIA and –EIIIB expression. In a small-scale CRISPR KO screen of candidate regulatory splice factors, we successfully detected known regulators of EIIIA and EIIIB splicing, and detected several novel regulators. Finally, we show the potential in this approach to broadly interrogate upstream signaling pathways in aortic endothelial cells with a genome-wide CRISPR-KO screen, implicating the TNFalpha and RIG-I-like signaling pathways and genes involved in the regulation of fibrotic responses. Thus, we provide a novel means to screen the regulation of splicing of endogenous transcripts, and predict novel pathways in the regulation of FN-EIIIA inclusion.

Rift Valley Fever Virus (RVFV) is a zoonotic pathogen with pandemic potential. RVFV entry is mediated by the viral glycoprotein (Gn), but host entry factors remain poorly defined. Our genome-wide CRISPR screen identified low-density lipoprotein receptor-related protein 1 (mouse Lrp1/human LRP1), heat shock protein (Grp94), and receptor associated protein (RAP) as critical host factors for RVFV infection. RVFV Gn directly binds to specific clusters Lrp1 and is glycosylation independent. Exogenous addition of murine RAP domain 3 (mRAP(D3)) and anti-Lrp1 antibodies neutralize RVFV infection in taxonomically diverse cell lines. Mice treated with mRAP(D3) and infected with pathogenic RVFV are protected from disease and death. A mutant mRAPD3 that binds Lrp1 weakly failed to protect from RVFV infection. Altogether, these data support Lrp1 as a host entry factor for RVFV infection and defines a new target to limit RVFV infections.

Circoviridae is a family of circular single-stranded DNA viruses whose members infect a wide variety of hosts. While well characterized in avian and mammalian hosts, little is known about circoviruses associated with Antarctic animals. From 48 Weddell seal (Leptonychotes weddellii) fecal samples collected on the sea ice in McMurdo between Nov 2014 and Dec 2014, we identified and determined the genomes of novel viruses that fall within two genera of the family Circoviridae, i.e. Circovirus (n = 7) and Cyclovirus (n = 45). We named these viruses as werosea circovirus (WerCV) and werosea cyclovirus (WerCyV). The genomes of WerCV and WerCyV share ~63–64% genome-wide pairwise identity with classified circoviruses and cycloviruses, respectively. Based on the species demarcation threshold of 80% for members of the Circoviridae, the genomes of WerCV and WerCyV represent new species in their respective genera. Evidence indicated recombination in five of the 45 WerCyV genomes identified in this study. These are the first circoviruses found associated with Antarctic pinnipeds, adding to those recently identified associated with Adelie (Pygoscelis adeliae) and chinstrap penguins (P. antarcticus).

Diabetes mellitus (DM) is characterized by hyperglycemia caused by a lack of insulin, insulin resistance, or both. It is associated with the development of secondary complications resulting in several comorbidities. Recent studies have revealed an increased risk of developing cognitive dysfunction or dementia in diabetes patients. Diabetes mellitus is considered a risk factor for many neurodegenerative diseases, including Alzheimer's disease (AD). There is increasing evidence to support a link between DM and AD. Studies have shown the dysfunction of insulin signaling in the brain, resulting in increased tau protein phosphorylation (hyperphosphorylation), a hallmark and biomarker of AD pathology, leading to accumulation of neurofibrillary tangles. In DM, the insulin dysfunction in the brain is reported to alter the glycogen synthase kinase-3β (GSK-3β) activity showing to enhance tau phosphorylation. In DM and AD, GSK-3β signaling has been involved in the physiological and pathological processes, respectively. This potentially explains why DM patients have an increased risk of developing AD with disease progression and aging. Interestingly, several in vivo studies with oral antidiabetic drugs and insulin treatment in DM have improved cognitive function and decreased tau hyperphosphorylation. This article will review the relationship between DM and AD as it relates to tau pathology. More understanding of the link between DM and AD could change the approach researchers and clinicians take toward both diseases, potentially leading to new treatments and preventative strategies in the future.

African painted dogs (Lycaon pictus, APD) are highly endangered, with fewer than 7000 remaining in nature. Captive breeding programs can preserve a genetically diverse population and provide a source of individuals for reintroductions. However, most programs are initiated from few founders and suffer from low genetic diversity and inbreeding. The aims of this study were to use molecular markers to assess genetic variation, inbreeding, and relatedness among APDs in the North American captive population, to use these data to realign studbook records, and to compare these data to wild populations and to the European captive population to facilitate the development of a global management plan. We sequenced mitochondrial and major histocompatibility (MHC) class II loci and genotyped 14 microsatellite loci from 109 APDs from 34 institutions in North America. We identified three likely studbook errors and resolved ten cases of uncertain paternity. Overall, microsatellite heterozygosity was higher than reported in Europe, but effective population size estimates were lower. Mitochondrial sequence variation was extremely limited, and there were fewer MHC haplotypes than in Europe or the wild. Although the population did not show evidence of significant inbreeding overall, several individuals shared high relatedness values, which should be incorporated into future breeding programs.

Background Leader cells are a subset of cancer cells that coordinate the complex cell-cell and cell-matrix interactions required for ovarian cancer migration, invasion, tumour deposition and are negatively associated with progression-free survival and response to therapy. Emerging evidence suggests leader cells may be enriched in response to chemotherapy, underlying disease recurrence following treatment. Methods CRISPR was used to insert a bicistronic T2A-GFP cassette under the native KRT14 (leader cell) promoter. 2D and 3D drug screens were completed in the presence of chemotherapies used in ovarian cancer management. Leader cell; proliferative (Ki67); and apoptotic status (Cleaved Caspase 3) were defined by live cell imaging and flow cytometry. Quantitative real-time PCR defined “stemness” profiles. Proliferation was assessed on the xCELLigence real time cell analyser. Statistical Analysis was performed using unpaired non-parametric t-tests or one-way ANOVA and Tukey’s multiple comparison post hoc. Results Leader cells represent a transcriptionally plastic subpopulation of ovarian cancer cells that arise independently of cell division or DNA replication, and exhibit a “stemness” profile that does not correlate with epithelial-to-mesenchymal transition. Chemotherapeutics increased apoptosis-resistant leader cells in vitro, who retained motility and expressed known chemo-resistance markers including ALDH1, Twist and CD44v6. Functional impairment of leader cells restored chemosensitivity, with leader cell-deficient lines failing to recover following chemotherapeutic intervention. Conclusions Our data demonstrate that ovarian cancer leader cells are resistant to a diverse array of chemotherapeutic agents, and are likely to play a critical role in the recurrence of chemo-resistant disease as drivers of poor treatment outcomes.

The central floral development gene LEAFY (LFY), whose mutation leads to striking changes in flowering and often sterility, is commonly expressed in non-floral structures, however, its role in vegetative development is poorly understood. Sterility associated with suppression of LFY expression is an attractive means for mitigating gene flow by both seeds and pollen in vegetatively propagated forest trees, but the consequences of its suppression for tree form and wood production are unclear. To study the vegetative effects of RNAi suppression of LFY, we created a randomized, multiple-year field study with 30–40 trees (ramets) in each of two sterile gene insertion events, three transgenic control events, and a wild-type control population. We found that floral knock-down phenotypes were stable across years and propagation cycles, but that several leaf morphology and productivity traits were statistically and often substantially different in sterile vs. normal flowering RNAi-LFY trees. Though trees with suppressed LEAFY expression looked visibly normal, they appear to have reduced growth and altered leaf traits. LFY appears to have a significant role in vegetative meristem development, and evaluation of vegetative impacts from LFY suppression would be prudent prior to large-scale use for genetic containment.

The consequences of early-life experiences are far reaching. In particular, the social and nutritional environments that developing animals experience can shape their adult phenotypes. In honeybees, larval nutrition determines the eventual social roles of adults as reproductive queens or sterile workers. However, little is known about the effects of developmental nutrition on important adult worker phenotypes such as disease resilience. In this study, we manipulated worker developmental nutrition in two distinct ways under semi-natural field conditions. In the first experiment, we restricted access to nutrition via social isolation by temporarily preventing alloparental care. In the second experiment, we altered the diet quality experienced by the entire colony, leading to adult bees that had developed entirely in a nutritionally restricted environment. When bees from these two experiments reached the adult stage, we challenged them with a common bee virus, Israeli acute paralysis virus (IAPV) and compared mortality, body condition, and the expression of immune genes across diet and viral inoculation treatments. Our findings show that both forms of early life nutritional stress, whether induced by lack of alloparental care or diet quality restriction, significantly reduced bees’ resilience to virus infection and affected the expression of several key genes related to immune function. These results extend our understanding of how early life nutritional environment can affect phenotypes relevant to health and highlight the importance of considering how nutritional stress can be profound even when filtered through a social group. These results also provide important insights into how nutritional stress can affect honeybee health on a longer time scale and its potential to interact with other forms of stress (i.e. disease).

Many bacteria communicate with kin and coordinate group behaviors through a form of cell-cell signaling called acyl-homoserine lactone (AHL) quorum sensing (QS). In these systems, a signal synthase produces an AHL to which its paired receptor selectively responds. Selectivity is fundamental to cell signaling. Despite its importance, it has been challenging to determine how this selectivity is achieved and how AHL QS systems evolve and diversify. We hypothesized that we could use covariation within the protein sequences of AHL synthases and receptors to identify selectivity residues. We began by identifying about 6000 unique synthase-receptor pairs. We then used the protein sequences of these pairs to identify covariation patterns and mapped the patterns onto the LasI/R system from Pseudomonas aeruginosa PAO1. The covarying residues in both proteins cluster around the ligand-binding sites. We demonstrate that these residues are involved in system selectivity toward the cognate signal and go on to engineer the Las system to both produce and respond to an alternate AHL signal. We have thus demonstrated that covariation methods provide a powerful approach for investigating selectivity in protein-small molecule interactions and have deepened our understanding of how communication systems evolve and diversify., eLife digest Communication is vital in any community and it is no different for bacteria. Some of the microbes living in bacterial communities are closely related to one another and can help each other survive and grow. They do this by releasing chemical signals that coordinate their behaviors, including those that are damaging to the infected host. A key aspect of this coordination is knowing how many related bacteria are present in a given environment. In a process known as quorum sensing, the bacteria release a chemical signal which neighboring sibling bacteria detect and respond to. The larger the population of bacteria, the more the signal accumulates. At a certain threshold, the signal activates the genes needed to trigger a coordinated action, such as producing toxins or antibiotics. Many bacteria communicate using acylhomoserine lactone signaling systems, which involve different signals depending on the species of bacteria. But it is unclear how this diversity evolved, and how bacteria can distinguish between signals from related and unrelated bacterial cells. To understand this, Wellington Miranda et al. used computational techniques to analyze how the proteins responsible for acylhomoserine lactone signaling coevolved. The analysis identified specific parts of these proteins that determine which signal will be produced and which will trigger a bacterium into action. Wellington Miranda et al. then used these insights to engineer the bacteria Pseudomonas aeruginosa to produce and respond to a signal that is naturally made by another bacterial species. These computational methods could be used to analyze other proteins that have coevolved but do not physically interact. Within the area of quorum sensing, this approach will help to better understand the costs and benefits of signal selectivity. This may help to predict bacterial interactions and therefore behaviors during infections.

Vast repertoires of unique antigen receptors are created in developing B and T lymphocytes. The antigen receptor loci contain many variable (V), diversity (D) and joining (J) gene segments that are arrayed across very large genomic expanses and are joined to form variable-region exons of expressed immunoglobulins and T cell receptors. This process creates the potential for an organism to respond to large numbers of different pathogens. Here, we consider the possibility that genetic polymorphisms with alterations in a vast array of regulatory elements in the immunoglobulin heavy chain (IgH) locus lead to changes in locus topology and impact immune-repertoire formation.

Simple Summary Many different human leukocyte antigen (HLA)-types exist across the population that each binds a specific motif of amino acids. HLA-peptide complexes are the driving force behind recognition of cancers and infected cells by cytotoxic T cells. HLA-immunopeptidomics aims to identify peptides derived from (cancer) antigens in the HLA-binding cleft with mass spectrometry (MS). Peptides eluted from HLA are analyzed by MS and translated to a protein derived amino acid sequence by specialized software. These software packages use statistical thresholds to limit false discoveries and return only the most confidently identified peptides. However, we believe, as do others, that many useful peptides can still be found in the excluded pool of peptides. This idea drove the development of specialized algorithms that utilize HLA specific motifs to retrieve additional relevant peptides. It is unknown, however, how many peptides could potentially be found in this pool. By adjusting the statistical threshold, we empirically demonstrate the vastness of valuable data beyond the traditional thresholds that await to be discovered. Abstract Immunopeptidomics is used to identify novel epitopes for (therapeutic) vaccination strategies in cancer and infectious disease. Various false discovery rates (FDRs) are applied in the field when converting liquid chromatography-tandem mass spectrometry (LC-MS/MS) spectra to peptides. Subsequently, large efforts have recently been made to rescue peptides of lower confidence. However, it remains unclear what the overall relation is between the FDR threshold and the percentage of obtained HLA-binders. We here directly evaluated the effect of varying FDR thresholds on the resulting immunopeptidomes of HLA-eluates from human cancer cell lines and primary hepatocyte isolates using HLA-binding algorithms. Additional peptides obtained using less stringent FDR-thresholds, although generally derived from poorer spectra, still contained a high amount of HLA-binders and confirmed recently developed tools that tap into this pool of otherwise ignored peptides. Most of these peptides were identified with improved confidence when cell input was increased, supporting the validity and potential of these identifications. Altogether, our data suggest that increasing the FDR threshold for peptide identification in conjunction with data filtering by HLA-binding prediction, is a valid and highly potent method to more efficient exhaustion of immunopeptidome datasets for epitope discovery and reveals the extent of peptides to be rescued by recently developed algorithms.

Neurons release specific signaling and pathological cargoes in membrane-bound extracellular vesicles. Walsh et al. show that cargo sorting into extracellular vesicles at presynaptic nerve terminals depends on a balance between the Alzheimer’s disease–implicated endosomal retromer complex and Rab11-mediated recycling., Neuronal extracellular vesicles (EVs) play important roles in intercellular communication and pathogenic protein propagation in neurological disease. However, it remains unclear how cargoes are selectively packaged into neuronal EVs. Here, we show that loss of the endosomal retromer complex leads to accumulation of EV cargoes including amyloid precursor protein (APP), synaptotagmin-4 (Syt4), and neuroglian (Nrg) at Drosophila motor neuron presynaptic terminals, resulting in increased release of these cargoes in EVs. By systematically exploring known retromer-dependent trafficking mechanisms, we show that EV regulation is separable from several previously identified roles of neuronal retromer. Conversely, mutations in rab11 and rab4, regulators of endosome-plasma membrane recycling, cause reduced EV cargo levels, and rab11 suppresses cargo accumulation in retromer mutants. Thus, EV traffic reflects a balance between Rab4/Rab11 recycling and retromer-dependent removal from EV precursor compartments. Our data shed light on previous studies implicating Rab11 and retromer in competing pathways in Alzheimer’s disease, and suggest that misregulated EV traffic may be an underlying defect.

Impaired mitochondrial function and aberrant neuronal network activity are believed to be early events in the pathogenesis of Alzheimer's disease (AD), but how mitochondrial alterations contribute to aberrant activity in neuronal circuits is unknown. In this study, we examined the function of mitochondrial protein deacetylase sirtuin 3 (SIRT3) in the pathogenesis of AD. Compared with AppPs1 mice, Sirt3-haploinsufficient AppPs1 mice (Sirt3(+/−)AppPs1) exhibit early epileptiform EEG activity and seizure. Both male and female Sirt3(+/−)AppPs1 mice were observed to die prematurely before 5 months of age. When comparing male mice among different genotypes, Sirt3 haploinsufficiency renders GABAergic interneurons in the cerebral cortex vulnerable to degeneration and associated neuronal network hyperexcitability. Feeding Sirt3(+/−)AppPs1 AD mice with a ketone ester-rich diet increases SIRT3 expression and prevents seizure-related death and the degeneration of GABAergic neurons, indicating that the aggravated GABAergic neuron loss and neuronal network hyperexcitability in Sirt3(+/−)AppPs1 mice are caused by SIRT3 reduction and can be rescued by increase of SIRT3 expression. Consistent with a protective role in AD, SIRT3 levels are reduced in association with cerebral cortical Aβ pathology in AD patients. In summary, SIRT3 preserves GABAergic interneurons and protects cerebral circuits against hyperexcitability, and this neuroprotective mechanism can be bolstered by dietary ketone esters. SIGNIFICANCE STATEMENT GABAergic neurons provide the main inhibitory control of neuronal activity in the brain. By preserving mitochondrial function, SIRT3 protects parvalbumin and calretinin interneurons against Aβ-associated dysfunction and degeneration in AppPs1 Alzheimer's disease mice, thus restraining neuronal network hyperactivity. The neuronal network dysfunction that occurs in Alzheimer's disease can be partially reversed by physiological, dietary, and pharmacological interventions to increase SIRT3 expression and enhance the functionality of GABAergic interneurons.

Woodpeckers can be difficult to detect, as they are often cryptic, secretive, occurring in low densities, and wary of humans. Several methods exist to detect woodpeckers (e.g., playback surveys, passive point counts), yet no research has established which technique best detects these elusive picids. Thus, we designed an experiment to determine which of three methods best results in a detection of Magellanic Woodpeckers (Campephilus magellanicus), and if weather variables influence detection probability.Mostly during austral summers 2015–2017, we (a) used a drumming device to simulate a double‐knock (i.e., territorial acoustical signal), (b) broadcasted a territorial call, and (c) passively listened (control) for Magellanic Woodpeckers. We conducted our experiment on Navarino Island, Chile, where the Magellanic Woodpecker is the sole picid.The drumming device most effectively influenced the likelihood of a woodpecker detection. The odds of a woodpecker responding to a double‐knock were 2.14 times more likely than responding to either a call or control. Moreover, the odds of a woodpecker detection decreased by 42% as wind increased by one category and decreased by 40% for every additional month (i.e., October–March), which was expected because woodpeckers become less territorial as the breeding season progresses.As Campephilus woodpeckers communicate via drums or double‐knocks, using a drumming device likely will be an effective technique to detect not only Magellanic Woodpeckers, but other woodpeckers within the Campephilus genus in Central and South America., We designed an experiment to determine which of three methods best results in a detection of Magellanic Woodpeckers (Campephilus magellanicus). The drumming device most effectively influenced the likelihood of a woodpecker detection. Using a drumming device likely will be an effective technique to detect not only Magellanic Woodpeckers, but other woodpeckers within the Campephilus genus in Central and South America.

TRAF3 is a versatile intracellular adapter protein with multiple context-specific roles. Uniquely in B cells, TRAF3 deficiency enhances survival and increases the risk of transformation, as loss of TRAF3 is observed in several types of B cell cancers. Here, we report a new mechanism for TRAF3 in the restraint of B cell survival. We found that TRAF3 deficiency was associated with induction of the pro-survival kinase Pim2 in mouse primary B cells and human malignant B cell lines. The increase in Pim2 was independent of NF-κB2 activation but was ameliorated with inhibition of STAT3 expression or function. TRAF3 deficiency also led to a Pim2-dependent increase in c-Myc protein levels and was associated with reduced c-Myc ubiquitination. TRAF3-deficient primary B cells were less sensitive to cell death induced by the Pim inhibitors SGI-1776 and TP-3654. Interestingly, human malignant B cell lines with low expression of TRAF3 were more sensitive to Pim inhibition-induced cell death. Combination treatment of TRAF3-deficient B cells and B cell tumor lines with c-Myc inhibitors enhanced their sensitivity to Pim inhibition, suggesting a possible therapeutic strategy. TRAF3 thus suppresses a Pim2-mediated B cell survival axis, which can be a potential target for treatment of B cell malignancies.

Evolutionary biologists tend to approach the study of the natural world within a framework of adaptation, inspired perhaps by the power of natural selection to produce fitness advantages that drive population persistence and biological diversity. In contrast, evolution has rarely been studied through the lens of adaptation's complement, maladaptation. This contrast is surprising because maladaptation is a prevalent feature of evolution: population trait values are rarely distributed optimally; local populations often have lower fitness than imported ones; populations decline; and local and global extinctions are common. Yet we lack a general framework for understanding maladaptation; for instance in terms of distribution, severity, and dynamics. Similar uncertainties apply to the causes of maladaptation. We suggest that incorporating maladaptation‐based perspectives into evolutionary biology would facilitate better understanding of the natural world. Approaches within a maladaptation framework might be especially profitable in applied evolution contexts – where reductions in fitness are common. Toward advancing a more balanced study of evolution, here we present a conceptual framework describing causes of maladaptation. As the introductory article for a Special Feature on maladaptation, we also summarize the studies in this Issue, highlighting the causes of maladaptation in each study. We hope that our framework and the papers in this Special Issue will help catalyze the study of maladaptation in applied evolution, supporting greater understanding of evolutionary dynamics in our rapidly changing world.