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A growing number of technologies are being developed to promote vascularization and innervation in engineered tissues. Organ-on-a-chip, organoid and 3D printing technologies, as well as pre-vascularized and oriented scaffolds, have been employed for vascularization and innervation of engineered tissues both in vivo and in vitro. Both vascularization and innervation are critical for neural tissue engineering, as these complex tissues require provision of both blood and nerves. As such, this review will have particular focus on neural tissue engineering. We examine state-of-the-art approaches for tissue vascularization and innervation and identify promising methods for developing vascularized and innervated engineered neural constructs.

Whole genome sequencing is instrumental for the study of genome variation in natural populations, delivering important knowledge on genomic modifications and potential targets of natural selection at the population level. Large dormant eggbanks of aquatic invertebrates such as the keystone herbivore Daphnia, a microcrustacean widespread in freshwater ecosystems, provide detailed sedimentary archives to study genomic processes over centuries. To overcome the problem of limited DNA amounts in single Daphnia dormant eggs, we developed an optimized workflow for whole genome amplification (WGA), yielding sufficient amounts of DNA for downstream whole genome sequencing of individual historical eggs, including polyploid lineages. We compare two WGA kits, applied to recently produced Daphnia magna dormant eggs from laboratory cultures, and to historical dormant eggs of Daphnia pulicaria collected from Arctic lake sediment between 10 and 300 years old. Resulting genome coverage breadth in most samples was ~70%, including those from >100-year-old isolates. Sequence read distribution was highly correlated among samples amplified with the same kit, but less correlated between kits. Despite this, a high percentage of genomic positions with single nucleotide polymorphisms in one or more samples (maximum of 74% between kits, and 97% within kits) were recovered at a depth required for genotyping. As a by-product of sequencing we obtained 100% coverage of the mitochondrial genomes even from the oldest isolates (~300 years). The mitochondrial DNA provides an additional source for evolutionary studies of these populations. We provide an optimized workflow for WGA followed by whole genome sequencing including steps to minimize exogenous DNA.

Small ceramic vessels with spouts, from which liquid can be poured, became popular during the Late Bronze and Early Iron Ages in Central Europe (c. 1200–600 BC). Such feeding vessels represent a functional type and are highly variable in size, shape and decoration. Found both on settlements and within graves, their association with child burials suggest they might have been used to feed babies and small children. Combined lipid and isotope analysis was performed on 24 of these feeding vessels, with seven delivering interpretable results. Feeding vessels associated with child burials tend to deliver a ruminant milk signal, whereas other vessels were used to process ruminant and non-ruminant adipose fats. Here, we highlight the potential significance of feeding vessels as indicators of changing childcare practices during times of population increase, settlement nucleation and mobility, possibly involving out-sourcing the feeding of babies and small children to persons other than the mother.

An accurate estimate of one’s performance is an important prerequisite for success, and prevents people from taking excessive risks. Based on the selection-margins paradigm (Riediger et al., 2006), the current paper assessed maximum speed rope-skipping (study 1), soccer dribbling (study 2), and the fine motor task of tracing (study 3) in 5- to 37-year-olds. Participants predicted their performances for the upcoming trial. The better the predicted performance, the more points were gained in case of success. To discourage overestimations, participants received no points for unsuccessful trials. In rope skipping, older and more experienced athletes outperformed the beginners, and had fewer trials with 0 points. In soccer dribbling and tracing, older individuals again showed less overestimation, as reflected by a smaller deviation of predicted and actual performance (selection margins) and fewer 0 point trials. Athletes and coaches should be aware that younger and less-experienced athletes tend to overestimate their motor performances.

Multiple sclerosis (MS), which is a chronic inflammatory disease of the central nervous system, still represents one of the most common causes of persisting disability with an early disease onset. Growing evidence suggests B cells to play a crucial role in its pathogenesis and progression. Over the last decades, monoclonal antibodies (mabs) against the surface protein CD20 have been intensively studied as a B cell targeting therapy in relapsing MS (RMS) as well as primary progressive MS (PPMS). Pivotal studies on anti-CD20 therapy in RMS showed remarkable clinical and radiological effects, especially on acute inflammation and relapse biology. These results paved the way for further research on the implication of B cells in the pathogenesis of MS. Besides controlling relapse development in RMS, ocrelizumab (OCR) also showed clinical benefits in patients with PPMS and became the first approved drug for this disease course. In this review, we provide an overview of the current anti-CD20 mabs used or tested for the treatment of MS—namely rituximab (RTX), OCR, ofatumumab (OFA), and ublituximab (UB). Besides their effectiveness, we also discuss possible limitations and safety concerns especially in regard to long-term treatment, both for this class of drugs overall as well as for each anti-CD20 mab individually. Additionally, we elucidate to what extent anti-CD20 therapy may alter the function of other immune cells, both directly or indirectly. Finally, we cover the current knowledge on repopulation of CD20+ cells after cessation of anti-CD20 treatment and discuss future aspirations towards alternative, further developed B cell silencing therapies. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-021-01048-z.

Genome-wide association studies (GWAS) have identified polymorphism in the Apolipoprotein E gene (APOE) to be the most prominent risk factor for Alzheimer’s disease (AD). Compared to individuals homozygous for the APOE3 variant, individuals with the APOE4 variant have a significantly elevated risk of AD. On the other hand, longitudinal studies have shown that the presence of the APOE2 variant reduces the lifetime risk of developing AD by 40 percent. While there has been significant research that has identified the risk-inducing effects of APOE4, the underlying mechanisms by which APOE2 influences AD onset and progression have not been extensively explored. In this study, we utilize an isogenic human induced pluripotent stem cell (hiPSC)-based system to demonstrate that conversion of APOE3 to APOE2 greatly reduced the production of amyloid-beta (Aβ) peptides in hiPSC-derived neural cultures. Mechanistically, analysis of pure populations of neurons and astrocytes derived from these neural cultures revealed that mitigating effects of APOE2 are mediated by cell autonomous and non-autonomous effects. In particular, we demonstrated the reduction in Aβ is potentially driven by a mechanism related to non-amyloidogenic processing of amyloid precursor protein (APP), suggesting a gain of the protective function of the APOE2 variant. Together, this study provides insights into the risk-modifying effects associated with the APOE2 allele and establishes a platform to probe the mechanisms by which APOE2 enhances neuroprotection against AD.

Simulations highlight the potential of genomic selection to substantially increase genetic gain for complex traits in sugarcane. The success rate depends on the trait genetic architecture and the implementation strategy. Genomic selection (GS) has the potential to increase the rate of genetic gain in sugarcane beyond the levels achieved by conventional phenotypic selection (PS). To assess different implementation strategies, we simulated two different GS-based breeding strategies and compared genetic gain and genetic variance over five breeding cycles to standard PS. GS scheme 1 followed similar routines like conventional PS but included three rapid recurrent genomic selection (RRGS) steps. GS scheme 2 also included three RRGS steps but did not include a progeny assessment stage and therefore differed more fundamentally from PS. Under an additive trait model, both simulated GS schemes achieved annual genetic gains of 2.6-2.7% which were 1.9 times higher compared to standard phenotypic selection (1.4%). For a complex non-additive trait model, the expected annual rates of genetic gain were lower for all breeding schemes; however, the rates for the GS schemes (1.5-1.6%) were still greater than PS (1.1%). Investigating cost-benefit ratios with regard to numbers of genotyped clones showed that substantial benefits could be achieved when only 1500 clones were genotyped per 10-year breeding cycle for the additive genetic model. Our results show that under a complex non-additive genetic model, the success rate of GS depends on the implementation strategy, the number of genotyped clones and the stage of the breeding program, likely reflecting how changes in QTL allele frequencies change additive genetic variance and therefore the efficiency of selection. These results are encouraging and motivate further work to facilitate the adoption of GS in sugarcane breeding.

ObjectiveThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic challenges national health systems and the global economy. Monitoring of infection rates and seroprevalence can guide public health measures to combat the pandemic. This depends on reliable tests on active and former infections. Here, we set out to develop and validate a specific and sensitive enzyme linked immunosorbent assay (ELISA) for detection of anti-SARS-CoV-2 antibody levels.MethodsIn our ELISA, we used SARS-CoV-2 receptor-binding domain (RBD) and a stabilized version of the spike (S) ectodomain as antigens. We assessed sera from patients infected with seasonal coronaviruses, SARS-CoV-2 and controls. We determined and monitored IgM-, IgA- and IgG-antibody responses towards these antigens. In addition, for a panel of 22 sera, virus neutralization and ELISA parameters were measured and correlated.ResultsThe RBD-based ELISA detected SARS-CoV-2-directed antibodies, did not cross-react with seasonal coronavirus antibodies and correlated with virus neutralization (R2 = 0.89). Seroconversion started at 5 days after symptom onset and led to robust antibody levels at 10 days after symptom onset. We demonstrate high specificity (99.3%;N = 1000) and sensitivity (92% for IgA, 96% for IgG and 98% for IgM; > 10 days after PCR-proven infection;N = 53) in serum.ConclusionsWith the described RBD-based ELISA protocol, we provide a reliable test for seroepidemiological surveys. Due to high specificity and strong correlation with virus neutralization, the RBD ELISA holds great potential to become a preferred tool to assess thresholds of protective immunity after infection and vaccination.

ObjectiveA significant decrease in aneurysm related survival is observed at long term follow up after infrarenal endovascular aneurysm repair (EVAR) compared with open repair. Therefore, longer term results with new generation endografts are essential. The aim of this post-approval French multicentre prospective observational study (EPI-ANA-01) was to evaluate the technical success and five year mortality and secondary intervention rates of the third generation AnacondaTM endograft.MethodsFrom June 2012 to October 2013, 176 consecutive unruptured infrarenal abdominal aortic aneurysms were included (160 male patients, mean age 75.3 ± 8.4 years). Survival, freedom from type Ia endoleak, limb events, and re-interventions were estimated using the Kaplan–Meier method. Anatomical and clinical characteristics were compared according to the occurrence of migration, conversion, adverse limb events, endoleak, and sac enlargement.ResultsThe primary technical and clinical success rates were 98.3% and 94.9%, respectively. A hostile neck was identified in 33.9% of patients and 10.7% were treated outside instructions for use (IFU). An early post-operative (≤30 days) mortality rate of 1.7% was observed. At one and five years, respectively, the overall survival rate was 94.9% and 65.9% (aneurysm related in four patients [2.3%]) and the clinical success rate was 90.9% and 70.6%. Secondary interventions were performed in 35 of 176 patients (19.9%). The overall limb occlusion rate was 7.9% and the aneurysm sac diameter decreased significantly (pre-operative diameter 53.9 ± 8.6 mm vs. 42.3 ± 14.7 mm at five years; p < .001). Patients treated outside the instructions for use (IFU) had significantly higher rates of migration, surgical conversion, and aneurysm sac expansion (p = .03).ConclusionThe Anaconda endograft provides high technical success and satisfactory five year aneurysm exclusion and clinical success rates. However, implantation outside the IFU should be avoided, as it leads to significantly worse outcomes, and caution over the risk of limb occlusion and distal embolisation should be observed.

Since December 2019, the global pandemic caused by the highly infectious novel coronavirus 2019-nCoV (COVID-19) has been rapidly spreading. As of April 2020, the outbreak has spread to over 210 countries, with over 2,400,000 confirmed cases and over 170,000 deaths [1]. COVID-19 causes a severe pneumonia characterized by fever, cough, and shortness of breath. Similar coronavirus outbreaks have occurred in the past causing severe pneumonia like COVID-19, most recently, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). However, over time, SARS-CoV and MERS-CoV were shown to cause extra-pulmonary signs and symptoms including hepatitis, acute renal failure, encephalitis, myositis, and gastroenteritis. Similarly, sporadic reports of COVID-19 related extrapulmonary manifestations emerge. Unfortunately, there is no comprehensive summary of the multi-organ manifestations of COVID-19, making it difficult for clinicians to quickly educate themselves about this highly contagious and deadly pathogen. What's more, is that SARS-CoV and MERS-CoV are the closest humanity has come to combating something similar to COVID-19, however, there exists no comparison between the manifestations of any of these novel coronaviruses. In this review, we summarize the current knowledge of the manifestations of the novel coronaviruses SARS-CoV, MERS-CoV, and COVID-19, with a particular focus on the latter, and highlight their differences and similarities.

DNA can be preserved in marine and freshwater sediments both in bulk sediment and in intact, viable resting stages. Here, we assess the potential for combined use of ancient, environmental, DNA and timeseries of resurrected long-term dormant organisms, to reconstruct trophic interactions and evolutionary adaptation to changing environments. These new methods, coupled with independent evidence of biotic and abiotic forcing factors, can provide a holistic view of past ecosystems beyond that offered by standard palaeoecology, help us assess implications of ecological and molecular change for contemporary ecosystem functioning and services, and improve our ability to predict adaptation to environmental stress., Ellegaard et al. discuss the potential for using ancient environmental DNA (eDNA), combined with resurrection ecology, to analyse trophic interactions and evolutionary adaptation to changing environments. Their Review suggests that these techniques will improve our ability to predict genetic and phenotypic adaptation to environmental stress.

Introduction: Uveal melanoma (UM) is a rare and malignant intraocular tumour with a dismal prognosis. Despite a good control of the primary tumour by radiation or surgery, up to 50% of patients subsequently develop metastasis for which no efficient treatment is yet available.Methodology: To identify therapeutic opportunities, we performed an in vitro screen of 30 combinations of different inhibitors of pathways that are dysregulated in UM. Effects of drug combinations on viability, cell cycle and apoptosis were assessed in eight UM cell lines. The best synergistic combinations were further evaluated in six UM patient-derived xenografts (PDXs).Results: We demonstrated that the Bcl-2/X-L/W inhibitor (ABT263) sensitised the UM cell lines to other inhibitors, mainly to mammalian target of rapamycin (mTOR), mitogen-activated protein kinase kinase (MEK) and murine double minute 2 (MDM2) inhibitors. mTOR (RAD001) and MEK1/2 (trametinib) inhibitors were efficient as single agents, but their combinations with ABT263 displayed no synergism in UM PDXs. In contrast, the combination of ABT263 with MDM2 inhibitor (HDM201) showed a trend for a synergistic effect.Conclusion: We showed that inhibition of Bcl-2/X-L/W sensitised the UM cell lines to other treatments encouraging investigation of the underlying mechanisms. Furthermore, our findings highlighted Bcl-2/X-L/W and MDM2 co-inhibition as a promising strategy in UM. (C) 2019 The Author(s). Published by Elsevier Ltd.

Objective:To characterize nontuberculous mycobacteria (NTM) associated with case clusters at 3 medical facilities.Design:Retrospective cohort study using molecular typing of patient and water isolates.Setting:Veterans Affairs Medical Centers (VAMCs).Methods:Isolation and identification of NTM from clinical and water samples using culture, MALDI-TOF, and gene population sequencing to determine species and genetic relatedness. Clinical data were abstracted from electronic health records.Results:An identical strain of Mycobacterium conceptionense was isolated from 41 patients at VA Medical Centers (VAMCs A, B, and D), and from VAMC A’s ICU ice machine. Isolates were initially identified as other NTM species within the M. fortuitum clade. Sequencing analyses revealed that they were identical M. conceptionense strains. Overall, 7 patients (17%) met the criteria for pulmonary or nonpulmonary infection with NTM, and 13 of 41 (32%) were treated with effective antimicrobials regardless of infection or colonization status. Separately, a M. mucogenicum patient strain from VAMC A matched a strain isolated from a VAMC B ICU ice machine. VAMC C, in a different state, had a 4-patient cluster with Mycobacterium porcinum. Strains were identical to those isolated from sink-water samples at this facility.Conclusion:NTM from hospital water systems are found in hospitalized patients, often during workup for other infections, making attribution of NTM infection problematic. Variable NTM identification methods and changing taxonomy create challenges for epidemiologic investigation and linkage to environmental sources.

BackgroundWhile checkpoint blockade cancer immunotherapies reawaken dormant antitumor immunity, adoptive cell therapies (ACT) bolster an immune response through infusion of expanded tumor infiltrating lymphocytes (TIL), or healthy T cell redirected to tumors via chimeric antigen receptor (CAR), or T cell receptor (TCR) expression. However, the harsh, nutrient depleted tumor microenvironment (TME) creates metabolic barriers for T cell persistence and effector function. We and others have shown that glucose availability is key for T cell effector functions through multiple non-redundant mechanisms. We thus asked whether therapeutic T cells harbor increased sensitivity for glucose and whether this could be mitigated to increase efficacy.MethodsB16 and Pten deficient, Braf mutant melanomas were used as models in C57BL/6 mice. Tumor cell glucose uptake was inhibited using stable expression of shRNA to Slc2a1, encoding Glut1. Glut1 was retrovirally overexpressed in therapeutic, Pmel-1 (gp100-specific) T cells, and phosphomimetic mutations were engineered (S226D) into Glut1, stabilizing cell surface trafficking. Glucose uptake and glycolysis were measured using fluorescent glucose tracers and Seahorse analysis, respectively.ResultsHere we sought to equip glucose sensitive therapeutic T cells with heightened ability to compete for glucose within the TME. Murine therapeutic T cells, expanded in hyperglycemic conditions in vitro, that infiltrate solid tumors compete poorly for glucose tracers compared to endogenous T cells. Knockdown or deletion of Glut1 in tumor cells sensitizes tumors to T cell therapies, but not checkpoint blockade, highlighting a role for glucose competition specifically in ACT. Overexpression of WT Glut1 in therapeutic T cells yields only modest increased glucose competition due to various modes of Glut1 regulation. We thus engineered a cell surface stabilized Glut1 construct. This construct’s competitive advantage manifests robust increases in glucose uptake and glycolytic capacity, leading to superior effector functions even in extremely hypoglycemic conditions. This enhanced effector function manifests in therapeutic efficacy in highly glycolytic melanomas and with heightened competition for glucose tracers, tumor infiltration, and effector function in vivo.ConclusionsOur study suggests that, due to the hyperglycemic conditions of their ex vivo expansion, therapeutic T cells display a distinct metabolic disadvantage when they enter the nutrient poor TME in comparison to their endogenous counterparts. Overexpression of our surface engineered Glut1 in these therapeutic T cells rescues their ability to compete with highly glycolytic tumor cells for glucose, resulting in robust glycolytic metabolism and curative response to immunotherapy for cancer.

Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN. Publisher’s Note A first version of this text was prepared by the first eight authors and the last one, given here. The other listed co-authors in the article PDF support the content, and their actual contributions varied from only support to additions that substantially improved the content. The full details of all co-authors, with their affiliations, are included in Supplementary Table 1 after p.175 of the article for reasons of clarity and space. Slavomír Adamčík Institute of Botany, Plant Science and Biodiversity Centre, Slovak Academy of Sciences, Dúbravská cesta 9, 845 23 Bratislava, Slovakia Teuvo Ahti Finnish Museum of Natural History, P.O. Box 7, 00014 University of Helsinki, Finland M. Catherine Aime Purdue University, 915 W. State St., West Lafayette, Indiana 47907, U.S.A. A. Martyn Ainsworth Royal Botanic Gardens, Kew, Richmond, Surrey, TW9 3AB, United Kingdom László Albert Hungarian Mycological Society, 1087 Könyves Kálmán krt. 40, Budapest, Hungary Edgardo Albertó Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús, Universidad Nacional de San Martin-Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina Alberto Altés García Facultad de Biología, Ciencias Ambientales y Química, Universidad de Alcalá, 28805 Alcalá de Henares, Madrid, Spain Dmitry Ageev SIGNATEC Ltd., 630090, Novosibirsk, Akademgorodok (Novosibirsk Scientific Center), Inzhenernaya str., 22, Russia Reinhard Agerer Ludwig-Maximilians-Universität München, Menzinger Str. 67, 80638 München, Germany Begona Aguirre-Hudson Royal Botanic Gardens, Kew, Richmond, Surrey, TW9 3AB, United Kingdom Joe Ammirati University of Washington, Seattle, Washington 98195-1800, U.S.A. Harry Andersson Eichhahnweg 29a, 38108 Braunschweig, Germany Claudio Angelini Jardín Botánico Nacional Dr. Rafael Ma. Moscoso, Apartado 21-9, Santo Domingo, Dominican Republic Vladimír Antonín Moravian Museum, Zeny trh 6, 659 37 Brno, Czech Republic Takayuki Aoki Genetic Resources Center, National Agriculture and Food Research Organization, 2-1-2 Kannondai, Tsukuba, Ibaraki 305-8602, Japan André Aptroot ABL Herbarium, G.v.d.Veenstraat 107, 3762 XK Soest, The Netherlands Didier Argaud 40 rue du Justemont, 57290 Fameck, France Blanca Imelda Arguello Sosa Instituto Tecnológico de Ciudad Victoria, Tecnológico Nacional de México, Ciudad Victoria, Tamaulipas, Mexico Arne Aronsen Torødveien 54, 3135 Torød, Norway Ulf Arup Biological Museum, Lund University, Box 117, 221 00 Lund, Sweden Bita Asgari Iranian Research Institute of Plant Protection, Agricultural Research, Education and Extension Organization, Tehran, Iran Boris Assyov Institute of Biodiversity and Ecosystem Research, Bulgarian Academy of Sciences, 2 Gagarin Str., 1113 Sofia, Bulgaria Violeta Atienza Facultad de Ciencias Biológicas, Universitat de València, C/Dr Moliner 50, 46100, Burjasot, Valencia, Spain Ditte Bandini Panoramastr 47, 69257 Wiesenbach, Germany João Luís Baptista-Ferreira Instituto de Biossistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, 1749-016 Lisboa, Portugal Hans-Otto Baral Blaihofstr. 42, 72074 Tübingen, Germany Tim Baroni The State University of New York, 340 Bowers Hall, P.O. Box 2000, Cortland, New York 13045, U.S.A. Robert Weingart Barreto Universidade Federal de Viçosa, 36570-000, Viçosa, Minas Gerais, Brazil Henry Beker (1) Royal Holloway, University of London, United Kingdom; (2) Botanic Garden Meise, Nieuwelaan 38, 1860 Meise, Belgium Ann Bell 45 Gurney Road, Lower Hutt, New Zealand Jean-Michel Bellanger CEFE UMR5175, CNRS, Université de Montpellier, Université Paul-Valéry Montpellier, EPHE, INSERM, 1919 Route de Mende, 34293 Montpellier Cédex 5, France Francesco Bellù Naturmusem of Bolzano, CP 104, 39100, Bolzano, Italy Martin Bemmann Kleingemünderstraße 111, 69118 Heidelberg, Germany Mika Bendiksby NTNU, University Museum, Norwegian University of Science and Technology, 7491 Trondheim, Norway Egil Bendiksen Norwegian Institute for Nature Research, Gaustadalleen 21, 0349 Oslo, Norway Katriina Bendiksen Natural History Museum, University of Oslo, P.O. Box 1172 Blindern, 0318 Oslo, Norway Lajos Benedek Szent Istvan University, Hungary Anna Bérešová-Guttová Institute of Botany, Plant Science and Biodiversity Centre, Slovak Academy of Sciences, Dúbravská cesta 9, 845 23 Bratislava, Slovakia Franz Berger University of Salzburg, Salzburg, Austria Reinhard Berndt Herbaria Z+ZT, ETH Zürich, CHN D37, Universitätstr. 16, 8092 Zürich, Switzerland Annarosa Bernicchia Via A. Guidotti 39, 40134 Bologna, Italy Alona Yu. Biketova Institute of Biochemistry, BRC-HAS, 6726 Szeged, Temesvari krt. 62, 6726 Szeged, Hungary Enrico Bizio Società Veneziana di Micologia, Società Veneziana di Scienze Naturali, Fontego dei Turchi, Santa Croce 1730, 30135 Venice, Italy Curtis Bjork UBC Herbarium, Beaty Biodiversity Museum, University of British Columbia, Canada Teun Boekhout (1) Westerdijk Fungal Biodiversity Institute, P.O. Box 85167, 3508 AD, Utrecht, The Netherlands; (2) Institute for Biodiversity and Ecosystem Dynamics, University of Amsterdam, Amsterdam, The Netherlands David Boertmann Aarhus University, Frederiksborgvej 399, 4000 Roskilde, Denmark Tanja Böhning AG Geobotanik Schleswig-Holstein & Hamburg, c/o University of Kiel, Olshausenstraße 75, 24098 Kiel, Germany Florent Boittin Ascomycete.org, 36 rue de la Garde, 69005 Lyon, France Carlos G. Boluda Conservatoire et Jardin botaniques de la Ville de Genève, 1292 Genève, Switzerland Menno W. Boomsluiter T.v.Lohuizenstraat 34, 8172xl, Vaassen, The Netherlands Jan Borovička Institute of Geology, Czech Academy of Sciences, Rozvojova 269, 165 00 Prague 6, Czech Republic Tor Erik Brandrud Norwegian Institute for Nature Research, Gaustadalleen 21, 0349 Oslo, Norway Uwe Braun Martin-Luther-Universität, Institut für Biologie, Bereich Geobotanik, und Botanischer Garten, Herbarium, Neuwerk 21, 06099 Halle, Germany Irwin Brodo Canadian Museum of Nature, 240 McLeod Street, Ottawa, Ontario, Canada Tatiana Bulyonkova A.P. Ershov Institute of Informatics Systems, Russian Academy of Sciences, Siberian Branch, 6 Acad. Lavrentjev pr., Novosibirsk 630090, Russia Harold H. Burdsall Jr. Fungal & Decay Diagnostics, LLC, 9350 Union Valley Road, Black Earth, Wisconsin 53515, U.S.A. Bart Buyck Muséum National d’Histoire Naturelle, CP 39, ISYEB, UMR 7205 CNRS MNHN UPMC EPHE, 12 rue Buffon, 75005 Paris, France Ana Rosa Burgaz Facultad de Ciencias Biológicas, Universidad Complutense de Madrid, 28040 Madrid, Spain Vicent Calatayud Fundación CEAM, c/ Charles R. Darwin, 14, Parque Tecnológico, 46980 Paterna, Valencia, Spain Philippe Callac INRA, MycSA, CS 20032, 33882 Villenave d’Ornon, France Emanuele Campo Associazione Micologica Bresadola, Via Alessandro Volta 46, 38123 Trento, Italy Massimo Candusso Via Ottone Primo 90, 17021, Alassio, Savona, Italy Brigitte Capoen Queffioec, rue de Saint Gonval, 22710 Penvenan, France Joaquim Carbó Roser, 60, 17257 Torroella de Montgrí, Girona, Spain Matteo Carbone Via Don Luigi Sturzo 173 16148 Genova, Italy Rafael F. Castañeda-Ruiz Instituto de Investigaciones Fundamentales en Agricultura, Tropical ‘Alejandro de Humboldt’, OSDE, Grupo Agrícola, Calle 1 Esq. 2, Santiago de Las Vegas, C. Habana 17200, Cuba Michael A. Castellano USDA, Forest Service, Northern Research Station, Corvallis, Oregon 97330, U.S.A. Jie Chen Mae Fah Luang University, Chang Wat Chiang Rai 57100, Thailand Philippe Clerc Conservatoire et Jardin botaniques de la Ville de Genève, 1292 Genève, Switzerland Giovanni Consiglio Via C. Ronzani 61, 40033 Casalecchio Bologna, Italy Gilles Corriol National Botanical Conservatory for Pyrenees and Midi-Pyrénées Region of France and BBF Herbarium, Vallon de Salut. B.P. 315. 65203 Bagnères-de-Bigorre, France Régis Courtecuisse Université Lille, Fac. Pharma. Lille, EA4483 IMPECS, 59000 Lille, France Ana Crespo Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain Cathy Cripps Plant Sciences & Plant Pathology, 119 Plant Biosciences Building, Montana State University, Bozeman, Montana 59717, U.S.A. Pedro W. Crous Westerdijk Fungal Biodiversity Institute, P.O. Box 85167, 3508 AD, Utrecht, The Netherlands Gladstone Alves da Silva Universidade Federal de Pernambuco, Centro de Biociências, Avenida da Engenharia, S/N, Cidade Universitária, Recife, Pernambuco, Brazil Meiriele da Silva Universidade Federal de Viçosa, 36570-000, Viçosa, Minas Gerais, Brazil Marjo Dam Hooischelf 13, 6581 SL Malden, The Netherlands Nico Dam Hooischelf 13, 6581 SL Malden, The Netherlands Frank Dämmrich The Bavarian Natural History Collections (SNSB Munich), Menzinger Strasse 71, 80638, München, Germany Kanad Das Botanical Survey of India, Cryptogamic Unit, P.O. Botanic Garden, Howrah 711103, W.B., India Linda Davies Centre for Environmental Policy, Imperial College London, SW7 2AZ, United Kingdom Eske De Crop Ghent University K.L. Ledeganckstraat 35, 9000 Ghent, Belgium Andre De Kesel Botanic Garden Meise, Nieuwelaan 38, 1860 Meise, Belgium Ruben De Lange Ghent University, K.L. Ledeganckstraat 35, 9000 Gent, Belgium Bárbara De Madrignac Bonzi Instituto de Botánica del Nordeste, Universidad Nacional de Nordeste-Consejo Nacional de Investigaciones Científicas y Técnicas, Sargento Cabral 2131, CC 209, Corrientes Capital, Argentina Thomas Edison E. dela Cruz University of Santo Tomas, Espana 1008 Manila, Philippines Lynn Delgat Ghent University, K.L. Ledeganckstraat 35, 9000 Gent, Belgium Vincent Demoulin Institut de Botanique, B.22, Université de Liège, 4000 Liège I, Belgium Dennis E. Desjardin HD Thiers Herbarium (SFSU), San Francisco State University, 1600 Holloway Ave, San Francisco, California 94132, U.S.A. Paul Diederich Musée national d’histoire naturelle, 25 rue Münster, 2160 Luxembourg, Luxembourg Bálint Dima (1) Institute of Biology, Eötvös Loránd University, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary; (2) Viikki Plant Science Centre, University of Helsinki, P.O. Box 65, 00014 Helsinki, Finland Maria Martha Dios Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Catamarca, Av Belgrano 300, 4700 San Fernando del Valle de Catamarca, Argentina Pradeep Kumar Divakar Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain Clovis Douanla-Meli Julius Kühn-Institut, Federal Research Centre for Cultivated Plants, Institute for National and International Plant Health, Messeweg 11-12, 38104 Braunschweig, Germany Brian Douglas Royal Botanic Gardens, Kew, Richmond, Surrey, TW9 3AB, United Kingdom Elisandro Ricardo Drechsler-Santos Universidade Federal de Santa Catarina, Campus Universitário Reitor João David Ferreira Lima, Trindade, Florianópolis, Santa Catarina CEP 88040-900, Brazil Paul S. Dyer School of Life Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom Ursula Eberhardt Abt. Botanik, Staatliches Museum für Naturkunde Stuttgart, Rosenstein 1, 70191 Stuttgart, Germany Damien Ertz Botanic Garden Meise, Nieuwelaan 38, 1860 Meise, Belgium Fernando Esteve-Raventós Facultad de Biología, Ciencias Ambientales y Química, Universidad de Alcalá, 28805 Alcalá de Henares, Madrid, Spain Javier Angel Etayo Salazar Navarro Villoslada 16, 3º dcha., 31003 Pamplona, Navarra, Spain Vera Evenson Sam Mitchel Herbarium of Fungi, Denver Botanic Gardens, 1007 York Street, Denver, Colorado 80206, U.S.A. Guillaume Eyssartier Muséum national d’histoire naturelle, Jardin des plantes, 57 rue Cuvier, 75005 Paris, France Edit Farkas Institute of Ecology and Botany, MTA Centre for Ecological Research, 2163 Vácrátót, Hungary Alain Favre Fédération Mycologique et Botanique Dauphiné Savoie, Le Prieuré, 144 Place de l’Eglise, 74320 Sevrier, France Anna G. Fedosova Komarov Botanical Institute of the Russian Academy of Sciences, 2 Prof. Popov Street, St. Petersburg, 197376, Russia Mario Filippa Regione Monsarinero 36, 14041 Agliano Terme, Italy Péter Finy 8000 Székesfehérvár, Zsombolyai u. 56, Hungary Adam Flakus W. Szafer Institute of Botany, Polish Academy of Sciences, Lubicz 46, 31-512 Krakow, Poland Simón Fos Facultad de Ciencias Biológicas, Universitat de València, C/Dr Moliner 50, 46100, Burjasot, Valencia, Spain Jacques Fournier Las Muros, F. 09420 Rimont, France André Fraiture Botanic Garden Meise, Nieuwelaan 38, 1860 Meise, Belgium Paolo Franchi Associazione Micologica Bresadola, Via Alessandro Volta 46, 38123 Trento, Italy Ana Esperanza Franco Molano Escuela de Microbiología, Universidad de Antioquia, AA1226, Fundación Biodiversa Colombia, Medellín, Colombia Gernot Friebes Centre of Natural History, Botany & Mycology, Universalmuseum Joanneum, Weinzöttlstraße 16, 8045 Graz, Austria Andreas Frisch NTNU, University Museum, Norwegian University of Science and Technology, 7491 Trondheim, Norway Alan Fryday Michigan State University, East Lansing, Michigan 48824, U.S.A. Giuliana Furci The Fungi Foundation, Paseo Bulnes 79 of. 112A, Santiago, Chile Ricardo Galán Márquez Facultad de Biología, Ciencias Ambientales y Química, Universidad de Alcalá, 28805 Alcalá de Henares, Madrid, Spain Matteo Garbelotto University of California, 130 Mulford Hall #3114 Berkeley, California 94720, U.S.A. Joaquina Maria Garcia-Martin Real Jardín Botánico-CSIC, Plaza de Murillo 2, 28014, Madrid, Spain Mónica A. García Otálora Herbaria Z+ZT, ETH Zürich, CHN D37, Universitätstr. 16, 8092 Zürich, Switzerland Dania García Sánchez Universitat Rovira i Virgili, C/ Sant Llorenç 21, 43201 Reus, Tarragona, Spain Alain Gardiennet 14 rue Roulette, 21260 Véronnes, France Sigisfredo Garnica Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Isla Teja Campus, Casilla 567, Valdivia, Chile Isaac Garrido Benavent Real Jardín Botánico-CSIC, Plaza de Murillo 2, 28014, Madrid, Spain Genevieve Gates Tasmanian Institute of Agriculture, Private Bag 54, Hobart, Tasmania 7001, Australia Alice da Cruz Lima Gerlach Conservatoire et Jardin Botaniques de la ville de Genève, Genève, Switzerland Masoomeh Ghobad-Nejhad Iranian Research Organization for Science and Technology, P.O. Box 15815-3538, Tehran 15819, Iran Tatiana B. Gibertoni Universidade Federal de Pernambuco, Centro de Biociências, Avenida da Engenharia, S/N, Cidade Universitária, Recife, Pernambuco, Brazil Tine Grebenc Slovenian Forestry Institute, Vecna pot 2, 100 Ljubljana, Slovenia Irmgard Greilhuber University of Vienna, Rennweg 14, 1030 Vienna, Austria Bella Grishkan Institute of Evolution, University of Haifa, Aba Khoushi Ave. 199, Mt. Carmel, Haifa 3498838, Israel Johannes Z. Groenewald Westerdijk Fungal Biodiversity Institute, P.O. Box 85167, 3508 AD, Utrecht, The Netherlands Martin Grube Institute of Biology, University of Graz, Holteiasse 6, 8010 Graz, Austria Gérald Gruhn Office National des Forêts, 2 Avenue de Saint-Mandé, 75570 Paris Cedex 12, France Cécile Gueidan CSIRO — Australian National Herbarium, Clunies Ross Street, Canberra ACT 2601, Australia Gro Gulden Natural History Museum, University of Oslo, P.O. Box 1172 Blindern, 0318 Oslo, Norway Luis FP Gusmão Universidade Estadual de Feira de Santana, Av. Transnordestina, s/n, Bairro Novo Horizonte, CEP:44036-900, Feira de Santana, Bahia, Brazil Josef Hafellner Institute of Biology, University of Graz, Holteiasse 6, 8010 Graz, Austria Michel Hairaud 2 Impasse des Marronniers, 79360 Poivendre de Marigny, France Marek Halama Museum of Natural History, Wrocław University, ul. H. Sienkiewicza 5, 50-335 Wrocław, Poland Nils Hallenberg University of Gothenburg, Box 461, 40530 Göteborg, Sweden Roy E. Halling Institute of Systematic Botany, New York Botanical Garden, 2900 Southern Blvd, Bronx, New York 10458-5126, U.S.A. Karen Hansen Swedish Museum of Natural History, P.O. Box 50007, 104 05 Stockholm, Sweden Christoffer Bugge Harder Texas Tech University, Box 42122, Lubbock, Texas 79409, U.S.A. Jacob Heilmann-Clausen Natural History Museum of Denmark, Universitetsparken 15, 2100 København, Denmark Stip Helleman Sweelinck 78, 5831KT Boxmeer, The Netherlands Alain Henriot Mycological Society of France, 20 rue Rottembourg, 12th arrondissement, Paris, France Margarita Hernandez-Restrepo Westerdijk Fungal Biodiversity Institute, P.O. Box 85167, 3508 AD, Utrecht, The Netherlands Raphaël Herve 24 rue des Fougères, 86550 Mignaloux-Beauvoir, France Caroline Hobart 84 Stafford Road, Sheffield, South Yorkshire S2 2SF, United Kingdom Mascha Hoffmeister Julius Kühn-Institut, Institute for Epidemiology and Pathogen Diagnostics, Braunschweig, Germany Klaus Høiland University of Oslo, P.O.Box 1066, Blindern, 0316 Oslo, Norway Jan Holec National Museum, Herbarium PRM, Cirkusová 1740, 193 00 Praha 9, Czech Republic Håkon Holien Faculty of Bioscience and Aquaculture, NORD University, P.O. Box 2501, 7729 Steinkjer, Norway Karen Hughes University of Tennessee, Knoxville, Tennessee 37996, U.S.A. Vit Hubka Faculty of Science, Charles University, Benátská 2, 128 01 Praha 2, Czech Republic Seppo Huhtinen Herbarium TUR, Biodiversity Unit, University of Turku, 20014 Turku, Finland Boris Ivančević Natural History Museum, Njegoševa 51, P.O. Box 401, 11000 Belgrade, Serbia Marian Jagers Reelaan 13, 7522 LR Enschede, The Netherlands Walter Jaklitsch Institute of Forest Entomology, Forest Pathology and Forest Protection, University of Natural Resources and Life Sciences Vienna, Vienna, Austria AnnaElise Jansen Stationsstraat 10, 6701 AM Wageningen, the Netherlands Ruvishika S. Jayawardena Mae Fah Luang University, Chang Wat Chiang Rai 57100, Thailand Thomas Stjernegaard Jeppesen Global Biodiversity Information Facility, Universitetsparken 15, 2100 København Ø, Denmark Mikael Jeppson Lilla Håjumsgatan 4, 46135 Trollhättan, Sweden Peter Johnston Manaaki Whenua Landcare Research, Private Bag 92170, Auckland 1072, New Zealand Per Magnus Jørgensen University of Bergen, Allégaten 41, P.O. Box 7800, 5020 Bergen, Norway Ingvar Kärnefelt Biological Museum, Lund University, Box 117, 221 00 Lund, Sweden Liudmila B. Kalinina Komarov Botanical Institute of the Russian Academy of Sciences, 2 Prof. Popov Street, St. Petersburg, 197376, Russia Gintaras Kantvilas Tasmanian Herbarium (HO), Tasmanian Museum and Art Gallery, P.O. Box 5058, UTAS LP.O., Sandy Bay, Tasmania 7005, Australia Mitko Karadelev Institute of Biology, Faculty of Natural Science and Mathematics, Ss. Cyril and Methodius University, Arhimedova 5, 1000 Skopje, Republic of Macedonia Taiga Kasuya Faculty of Risk and Crisis Management, Chiba Institute of Science, 3 Shiomi-cho, Choshi, Chiba 288-0025, Japan Ivona Kautmanová Natural History Museum, Slovak National Museum, Bratislava, Slovakia Richard W. Kerrigan RWK Research, Kittanning, Pennsylvania 16201, U.S.A. Martin Kirchmair Institut für Mikrobiologie, Universität Innsbruck, Technikerstraße 25, 6020 Innsbruck, Austria Anna Kiyashko Komarov Botanical Institute of the Russian Academy of Sciences, 2 Prof. Popov Street, St. Petersburg, 197376, Russia Dániel G. Knapp Institute of Biology, Eötvös Loránd University, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary Henning Knudsen Natural History Museum of Denmark, Universitetsparken 15, 2100 København, Denmark Kerry Knudsen Faculty of Environmental Sciences, University of Life Sciences at Prague, Prague, Czech Republic Tommy Knutsson Nedra Västerstad 111, 380 62 Mörbylånga, Sweden Miroslav Kolařík Institute of Microbiology ASCR, Videnska 1083, 142 20 Prague 4, Czech Republic Urmas Kõljalg Institute of Ecology and Earth Sciences, 40 Lai Street, Tartu 51005, Estonia Alica Košuthová Swedish Museum of Natural History, P.O. Box 50007, 104 05 Stockholm, Sweden Attila Koszka Faculty of Agricultural and Environmental Sciences, Kaposvar University, 7400 Kaposvar, Hungary Heikki Kotiranta Finnish Environment Institute, P.O. Box 140, 00251 Helsinki, Finland Vera Kotkova Komarov Botanical Institute of the Russian Academy of Sciences, 2 Prof. Popov Street, St. Petersburg, 197376, Russia Ondřej Koukol Faculty of Science, Charles University, Benátská 2, 128 01 Praha 2, Czech Republic Jiří Kout University of West Bohemia, Faculty of Education, Klatovska 51, 306 19 Pilsen, Czech Republic Gábor M. Kovács Institute of Biology, Eötvös Loránd University, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary Martin Kříž Faculty of Science, Charles University, Benátská 2, 128 01 Praha 2, Czech Republic Åsa Kruys Museum of Evolution, Uppsala University, Norbyvägen 16, 75236 Uppsala, Sweden Viktor Kučera Institute of Botany, Plant Science and Biodiversity Centre, Slovak Academy of Sciences, Dúbravská cesta 9, 845 23 Bratislava, Slovakia Linas Kudzma 37 Maple Ave. Annandale, New Jersey 08801, U.S.A. Francisco Kuhar Instituto Multidisciplinario de Biología Vegetal, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de Córdoba, Casilla de Correo 495, 5000 Córdoba, Argentina Martin Kukwa Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland T. K. Arun Kumar The Zamorin’s Guruvayurappan College, Kozhikode, Kerala 673014, India Vladimír Kunca Technical University in Zvolen, Ul. T. G. Masaryka 24, 960 53 Zvolen,Slovakia Ivana Kušan Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia Thomas W. Kuyper Wageningen University & Research, Droevendaalsesteeg 4, 6708 PB Wageningen, The Netherlands Carlos Lado Real Jardín Botánico-CSIC, Plaza de Murillo 2, 28014, Madrid, Spain Thomas Læssøe Natural History Museum of Denmark, Universitetsparken 15, 2100 København, Denmark Patrice Lainé 123 rue Saint Antoine, 75004, Paris, France Ewald Langer University of Kassel, Heinrich-Plett-Strasse 40, 34132 Kassel, Germany Ellen Larsson University of Gothenburg, Box 461, 40530 Göteborg, Sweden Karl-Henrik Larsson Natural History Museum, University of Oslo, P.O. Box 1172 Blindern, 0318 Oslo, Norway Gary Laursen Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, Alaska 99775-7000, U.S.A. Christian Lechat Ascofrance, 64 route de Chizé, 79360 Villiers en Bois, France Serena Lee Herbarium Singapore Botanic Gardens, National Parks Board, Singapore James C. Lendemer (1) Institute of Systematic Botany, New York Botanical Garden, 2900 Southern Blvd, Bronx, New York 10458-5126, U.S.A.; (2) Graduate Center, City University of New York, 365 5th Ave, New York, New York 10016, U.S.A. Laura Levin University of Buenos Aires, Junin 956, 1113, Buenos Aires, Argentina Uwe Lindemann Landesmuseum für Naturkunde, Münster, Germany Håkan Lindström Östansjö 150, 840 64 Kälarne, Sweden Xingzhong Liu Institute of Microbiology, Chinese Academy of Sciences, No 3 Park 1, Beichen West Road, Chaoyang District, Beijing 100101, China Regulo Carlos Llarena Hernandez Facultad de Ciencias Biológicas y Agropecuarias, Peñuela, Universidad Veracruzana, Amatlán de los Reyes, Ver., Mexico Esteve Llop Facultat de Biologia, Universitat de Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain Csaba Locsmándi Hungarian Natural History Museum, 1087 Budapest, Hungary Deborah Jean Lodge USDA Forest Service, NRS, P.O. Box 1377, Luquillo, Puerto Rico 00773-1377, U.S.A. Michael Loizides P.O. Box 58499, 3734 Limassol, Cyprus László Lőkös Hungarian Natural History Museum, 1087 Budapest, Hungary Jennifer Luangsa-ard National Center for Genetic Engineering and Biotechnology (BIOTEC), NSTDA, 113 Thailand Science Park, Phaholyothin Rd., Klong Nueng, Klong Luang, Pathum Thani 12120, Thailand Matthias Lüderitz AG Geobotanik Schleswig-Holstein & Hamburg, c/o University of Kiel, Olshausenstraße 75, 24098 Kiel, Germany Thorsten Lumbsch Field Museum, 1400 S. Lake Shore Dr., Chicago, Illinois 60605, U.S.A. Matthias Lutz Institute of Evolution and Ecology, University of Tübingen, Auf der Morgenstelle 5, 72076 Tübingen, Germany Dan Mahoney Callaghan Innovation, 69 Gracefield Road, Lower Hutt 5010, New Zealand Ekaterina Malysheva Komarov Botanical Institute of the Russian Academy of Sciences, 2 Prof. Popov Street, St. Petersburg, 197376, Russia Vera Malysheva Komarov Botanical Institute of the Russian Academy of Sciences, 2 Prof. Popov Street, St. Petersburg, 197376, Russia Patinjareveettil Manimohan University of Calicut, Kerala, 673 635, India Yasmina Marin-Felix Westerdijk Fungal Biodiversity Institute, P.O. Box 85167, 3508 AD, Utrecht, The Netherlands Guilhermina Marques Centre for the Research and Technology of Agro-Environmental and Biological Sciences, University of Tras-os-Montes and Alto Douro, Laboratory of Mycology and Soil Microbiology, 5000-801 Vila Real, Portugal Rubén Martínez-Gil Ascomycete.org, 36 rue de la Garde, 69005 Lyon, France Guy Marson Musée national d’histoire naturelle, 25 rue Münster, 2160 Luxembourg, Luxembourg Gerardo Mata Instituto de Ecología, A.C., Carretera antigua a Coatepec 351, El Haya, Xalapa 91070, Veracruz, Mexico P. Brandon Matheny University of Tennessee, Knoxville, Tennessee 37996, U.S.A. Geir Harald Mathiassen Tromsø University Museum, University of Tromsø — The Arctic University of Norway, 9037 Tromsø, Norway Neven Matočec Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia Helmut Mayrhofer Institute of Biology, University of Graz, Holteiasse 6, 8010 Graz, Austria Mehdi Mehrabi Iranian Research Institute of Plant Protection, Agricultural Research, Education and Extension Organization, Tehran, Iran Ireneia Melo Botanical Garden, National Museum of Natural History and Science, University of Lisbon, Portugal Armin Mešić Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia Andrew S. Methven Savannah State University, Savannah, Georgia 31404, U.S.A Otto Miettinen Finnish Museum of Natural History, P.O. Box 7, 00014 University of Helsinki, Finland Ana M. Millanes Romero Universidad Rey Juan Carlos, 28933 Móstoles, Madrid, Spain Andrew N. Miller Illinois Natural History Survey, University of Illinois Urbana-Champaign, 1816 South Oak Street, Champaign, Illinois 61820-6970, U.S.A. James K. Mitchell Harvard University, 22 Divinity Avenue, Cambridge, Massachusetts 02138, U.S.A. Roland Moberg Museum of Evolution, Uppsala University, Norbyvägen 16, 75236 Uppsala, Sweden Pierre-Arthur Moreau Université Lille, Fac. Pharma. Lille, EA4483 IMPECS, 59000 Lille, France Gabriel Moreno Facultad de Biología, Ciencias Ambientales y Química, Universidad de Alcalá, 28805 Alcalá de Henares, Madrid, Spain Olga Morozova Komarov Botanical Institute of the Russian Academy of Sciences, 2 Prof. Popov Street, St. Petersburg, 197376, Russia Asunción Morte Facultad de Biología, Universidad de Murcia, Campus de Espinardo, 30100 Murcia, Spain Lucia Muggia University of Trieste, via L. Giorgieri 10, 34127 Trieste, Italy Guillermo Muñoz González Avda Valvanera N.32, 5D, 26500 Calahorra, La Rioja, Spain Leena Myllys Finnish Museum of Natural History, P.O. Box 7, 00014 University of Helsinki, Finland István Nagy Institute of Biology, Eötvös Loránd University, Pázmány Péter sétány 1/c, 1117 Budapest, Hungary László G. Nagy Institute of Biochemistry, BRC-HAS, 6726 Szeged, Temesvari krt. 62, 6726 Szeged, Hungary Maria Alice Neves Universidade Federal de Santa Catarina, Campus Universitário Reitor João David Ferreira Lima, Trindade, Florianópolis, Santa Catarina CEP 88040-900, Brazil Tuomo Niemelä Finnish Museum of Natural History, P.O. Box 7, 00014 University of Helsinki, Finland Pier Luigi Nimis University of Trieste, via L. Giorgieri 10, 34127 Trieste, Italy Nicolas Niveiro Instituto de Botánica del Nordeste, Universidad Nacional de Nordeste-Consejo Nacional de Investigaciones Científicas y Técnicas, Sargento Cabral 2131, CC 209, Corrientes Capital, Argentina Machiel E. Noordeloos Naturalis Biodiversity Center, P.O. Box 9517, 2300 RA, Leiden, The Netherlands Anders Nordin Museum of Evolution, Uppsala University, Norbyvägen 16, 75236 Uppsala, Sweden Sara Raouia Noumeur Faculty of Natural and Life Sciences, University of Batna 2, 05000 Batna, Algeria Yuri Novozhilov Komarov Botanical Institute of the Russian Academy of Sciences, 2 Prof. Popov Street, St. Petersburg, 197376, Russia Jorinde Nuytinck Naturalis Biodiversity Center, P.O. Box 9517, 2300 RA Leiden, The Netherlands Esteri Ohenoja Botanical Museum, University of Oulu, Finland Patricia Oliveira Fiuza Universidade Estadual de Feira de Santana, Av. Transnordestina, s/n, Bairro Novo Horizonte, CEP:44036-900, Feira de Santana, Bahia, Brazil Alan Orange National Museum of Wales, Cardiff CF10 3NP, United Kingdom Alexander Ordynets University of Kassel, Heinrich-Plett-Strasse 40, 34132 Kassel, Germany Beatriz Ortiz-Santana USDA Forest Service, Northern Research Station, One Gifford Pinchot Dr, Madison, Wisconsin 53726, U.S.A. Leticia Pacheco Universidad Autónoma Metropolitana-Iztapalapa, Av. San Rafael Atlixco 186, Col. Vicentina, 09340 México, D. F., Mexico Ferenc Pál-Fám Faculty of Agricultural and Environmental Sciences, Kaposvar University, 7400 Kaposvar, Hungary Melissa Palacio Universidade Federal do Rio Grande do Sul, Brazil Zdeněk Palice Faculty of Science, Charles University, Benátská 2, 128 01 Praha 2, Czech Republic Viktor Papp Szent Istvan University, 1118 Budapest, Menesi st. 44, Hungary Kadri Pärtelv Institute of Ecology and Earth Sciences, 40 Lai Street, Tartu 51005, Estonia Julia Pawlowska Faculty of Biology, Biological and Chemical Research Centre, University of Warsaw, Żwirki i Wigury 101, 02-089 Warsaw, Poland Aurelia Paz Urb. La Llosa, 219, 39509 Villanueva de la Peña, Mazcuerras, Cantabria, Spain Ursula Peintner Institut für Mikrobiologie, Universität Innsbruck, Technikerstraße 25, 6020 Innsbruck, Austria Shaun Pennycook Manaaki Whenua Landcare Research, Private Bag 92170, Auckland 1072, New Zealand Olinto Liparini Pereira Universidade Federal de Viçosa, 36570-000, Viçosa, Minas Gerais, Brazil Pablo Pérez Daniëls University of Córdoba, 14071, Córdoba, Spain Miquel À. Pérez-De-Gregorio Capella C/ Pau Casals, 6, 1º, 1ª, 17001, Girona, Spain Carlos Manuel Pérez del Amo C/ Luis de Ulloa, 1, 7º I, 26004 Logroño, Navarra, Spain Sergio Pérez Gorjón Universidad de Salamanca, Avda. Licenciado Mendez Nieto s/n, 37007 Salamanca, Spain Sergio Pérez-Ortega Real Jardín Botánico-CSIC, Plaza de Murillo 2, 28014, Madrid, Spain Israel Pérez-Vargas Facultad de Farmacia, Universidad de La Laguna, c/ Astrofísico Sánchez s/n 38071 La Laguna, Tenerife, Canary Islands, Spain Brian A. Perry California State University East Bay, Hayward, California 94542, U.S.A. Jens H. Petersen Nøruplundvej 2, 8400 Ebeltoft, Denmark Ronald H. Petersen University of Tennessee, Knoxville, Tennessee 37996, U.S.A. Donald H. Pfister Harvard University, 22 Divinity Avenue, Cambridge MA 02138, U.S.A. Chayanard Phukhamsakda Mae Fah Luang University, Chang Wat Chiang Rai 57100, Thailand Marcin Piątek W. Szafer Institute of Botany, Polish Academy of Sciences, Lubicz 46, 31-512 Krakow, Poland Meike Piepenbring Faculty of Biosciences, Goethe University Frankfurt am Main, Germany Raquel Pino-Bodas Real Jardín Botánico-CSIC, Plaza de Murillo 2, 28014, Madrid, Spain Juan Pablo Pinzón Esquivel Universidad Autónoma de Yucatán, Carretera Mérida-Xmatkuil Km. 15.5, Apdo. Postal: 4-116 Itzimná,C.P: 97100, Merida, Yucatan, Mexico Paul Pirot Rue des Peupliers 10, 6840 Neufchâteau, Belgium Eugene S. Popov Komarov Botanical Institute of the Russian Academy of Sciences, 2 Prof. Popov Street, St. Petersburg, 197376, Russia Orlando Popoff Instituto de Botánica del Nordeste, Universidad Nacional de Nordeste-Consejo Nacional de Investigaciones Científicas y Técnicas, Sargento Cabral 2131, CC 209, Corrientes Capital, Argentina María Prieto Álvaro Universidad Rey Juan Carlos, 28933 Móstoles, Madrid, Spain Christian Printzen Senckenberg Forschungsinstitut und Naturmuseum Frankfurt, Abteilung Botanik und Molekulare Evolutionsforschung, Herbarium Senckenbergianum (FR), Senckenberganlage 25, 60325 Frankfurt am Main, Germany Nadezhda Psurtseva Komarov Botanical Institute of the Russian Academy of Sciences, 2 Prof. Popov Street, St. Petersburg, 197376, Russia Witoon Purahong Helmholtz Centre for Environmental Research GmbH — UFZ, Theodor-Lieser-Straße 4, 06120 Halle, Germany Luis Quijada Harvard University, 22 Divinity Avenue, Cambridge, Massachusetts 02138, U.S.A. Gerhard Rambold University of Bayreuth, Universitätsstrasse 30, 95447 Bayreuth, Germany Natalia A. Ramírez Instituto de Botánica del Nordeste, Universidad Nacional de Nordeste-Consejo Nacional de Investigaciones Científicas y Técnicas, Sargento Cabral 2131, CC 209, Corrientes Capital, Argentina Huzefa Raja University of North Carolina at Greensboro, 435 Sullivan Science Building, PO Box 26170, Greensboro North Carolina 27402-6170, U.S.A. Olivier Raspé Botanic Garden Meise, Nieuwelaan 38, 1860 Meise, Belgium Tania Raymundo Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala s/n, Miguel Hidalgo, Santo Tomás, 11340 Ciudad de México, Mexico Martina Réblová Institute of Botany, Czech Academy of Sciences, Pruhonice, Czech Republic Yury A. Rebriev Southern Scientific Center, Russian Academy of Sciences, 41 Chehova str., Rostov-on-Don, 344006, Russia Juan de Dios Reyes García Paseo Virgen de Linarejos 6 2 D, Linares, Jaen, Spain Miguel Ángel Ribes Ripoll Avda. Pablo Neruda 120 F, 2°D, 28018 Madrid, Spain Franck Richard CEFE UMR5175, CNRS, Université de Montpellier, Université Paul-Valéry Montpellier, EPHE, INSERM, 1919 Route de Mende, 34293 Montpellier Cédex 5, France Mike J. Richardson Royal Botanic Garden Edinburgh, 20A Inverleith Row, Edinburgh, EH3 5LR, United Kingdom Víctor J. Rico Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain Gerardo Lucio Robledo Instituto Multidisciplinario de Biología Vegetal, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de Córdoba, Casilla de Correo 495, 5000 Córdoba, Argentina Flavia Rodrigues Barbosa Universidade Federal de Mato Grosso, Av. Alexandre Ferronato, 1200, Setor Industrial, Sinop, Mato Grosso, Brazil Cristina Rodriguez-Caycedo UT Southwestern Medical Center, Dallas, Texas 75390, U.S.A. Pamela Rodriguez-Flakus W. Szafer Institute of Botany, Polish Academy of Sciences, Lubicz 46, 31-512 Krakow, Poland Anna Ronikier W. Szafer Institute of Botany, Polish Academy of Sciences, Lubicz 46, 31-512 Krakow, Poland Luis Rubio Casas Ul. Andrieja Sacharowa 1/1, 30-806 Kraków, Poland Katerina Rusevska Institute of Biology, Faculty of Natural Science and Mathematics, Ss. Cyril and Methodius University, Arhimedova 5, 1000 Skopje, Republic of Macedonia Günter Saar Dammenmühle 7, 77933 Lahr-Sulz, Germany Irja Saar Institute of Ecology and Earth Sciences, 40 Lai Street, Tartu 51005, Estonia Isabel Salcedo University of the Basque Country (UPV/EHU), Apdo 644, 48080 Bilbao, Spain Sergio M. Salcedo Martínez Facultad de Ciencias Biológicas, UANL. Ave. Pedro de Alba s/n esq. Manuel Barragán Cd. Universitaria, San Nicolás de los Garza Nuevo León, CP. 66451, Mexico Carlos A. Salvador Montoya Instituto de Botánica del Nordeste, Universidad Nacional de Nordeste-Consejo Nacional de Investigaciones Científicas y Técnicas, Sargento Cabral 2131, CC 209, Corrientes Capital, Argentina Santiago Sánchez-Ramírez University of Toronto, 100 Queen’s Park, Toronto, Ontario M5S 2C6, Canada J. Vladimir Sandoval-Sierra Health Science Centre, University of Tennessee, U.S.A. Sergi Santamaria Facultat de Biociències, Edifici C, Despatx C1/331, Campus de la UAB, 08193 Bellaterra, (Cerdanyola del Vallès), Barcelona, Spain Josiane Santana Monteiro Botany Coordination, Museu Paraense Emílio Goeldi, 66077-830, Belém, Pará, Brazil Hans Josef Schroers Agricultural Institute of Slovenia, Hacquetova ulica 17, 1000 Ljubljana, Slovenia Barbara Schulz Institute of Microbiology, Technische Universität Braunschweig, Germany Geert Schmidt-Stohn Burgstr. 25, 29553 Bienenbüttel, Germany Trond Schumacher University of Oslo, P.O.Box 1066, Blindern, 0316 Oslo, Norway Beatrice Senn-Irlet RU Biodiversity and Conservation Biology, Swiss Federal Institute for Forest, Snow and Landscape Research WSL, Zürcherstr. 111, 8903 Birmensdorf, Switzerland Hana Ševčíková Moravian Museum, Zeny trh 6, 659 37 Brno, Czech Republic Oleg Shchepin Komarov Botanical Institute of the Russian Academy of Sciences, 2 Prof. Popov Street, St. Petersburg, 197376, Russia Takashi Shirouzu Graduate School of Bioresources, Mie University, 1577 Kurima-machiya, Tsu, Mie 514-8507, Japan Anton Shiryaev Institute of Plant & Animal Ecology Ural Branch of the Russian Academy of Sciences, 620144 Ekaterinburg, 8 March str., 202/3, Russia Klaus Siepe Geeste 133, 46342 Velen, Germany Esteban B. Sir Fundación Miguel Lillo, Consejo Nacional de Investigaciones Científicas y Técnicas, Miguel Lillo 251, San Miguel de Tucumán 4000, Tucumán, Argentina Mohammad Sohrabi Iranian Research Organization for Science and Technology, P.O. Box 33535111, Tehran, Iran Karl Soop Swedish Museum of Natural History, P.O. Box 50007, 104 05 Stockholm, Sweden Viacheslav Spirin Finnish Museum of Natural History, P.O. Box 7, 00014 University of Helsinki, Finland Toby Spribille University of Alberta, Edmonton, Alberta T6G 2R3, Canada Marc Stadler Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany Joost Stalpers Torenlaan 43, 3742CR Baarn, The Netherlands Soili Stenroos Finnish Museum of Natural History, P.O. Box 7, 00014 University of Helsinki, Finland Ave Suija Institute of Ecology and Earth Sciences, 40 Lai Street, Tartu 51005, Estonia Stellan Sunhede Hökaskog Sandbacken 1, 533 92 Lundsbrunn, Sweden Sten Svantesson University of Gothenburg, Box 461, 40530 Göteborg, Sweden Sigvard Svensson Biological Museum, Lund University, Box 117, 221 00 Lund, Sweden Tatyana Yu. Svetasheva (1) Komarov Botanical Institute of the Russian Academy of Sciences, 2 Prof. Popov Street, St. Petersburg, 197376, Russia; (2) Department of Technologies of Living Systems, Tula State Lev Tolstoy Pedagogical University, Lenin ave. 125, Tula, 300026, Russia Krzysztof Świerkosz Museum of Natural History, Wrocław University, ul. H. Sienkiewicza 5, 50-335 Wrocław, Poland Heidi Tamm Institute of Ecology and Earth Sciences, 40 Lai Street, Tartu 51005, Estonia Hatira Taskin Faculty of Agriculture, University of Çukurova, 01330 Adana, Turkey Adrien Taudière CEFE UMR5175, CNRS, Université de Montpellier, Université Paul-Valéry Montpellier, EPHE, INSERM, 1919 Route de Mende, 34293 Montpellier Cédex 5, France Jan-Olof Tedebrand Sundsvall Mycological Society, Medelpad, Sweden Raúl Tena Lahoz C/Arreñales del Portillo B 21 1°D, 44003 Teruel, Spain Marina Temina Institute of Evolution, University of Haifa, Aba Khoushi Ave. 199, Mt. Carmel, Haifa 3498838, Israel Arne Thell Biological Museum, Lund University, Box 117, 221 00 Lund, Sweden Marco Thines Faculty of Biosciences, Goethe University Frankfurt am Main, Germany Göran Thor Swedish University of Agricultural Sciences, P. O. Box 7044, 750 07 Uppsala, Sweden Holger Thüs State Museum of Natural History Stuttgart, Rosenstein 1, 70191 Stuttgart, Germany Leif Tibell Evolutionary Biology Centre, Norbyvägen 18D, 75236 Uppsala, Sweden Sanja Tibell Evolutionary Biology Centre, Norbyvägen 18D, 75236 Uppsala, Sweden Einar Timdal Natural History Museum, University of Oslo, P.O. Box 1172 Blindern, 0318 Oslo, Norway Zdenko Tkalčec Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia Tor Tønsberg University of Bergen, Allégaten 41, P.O. Box 7800, 5020 Bergen, Norway Gérard Trichies 5, impasse des Écoles S7700 Neufchef, France Dagmar Triebel Botanische Staatssammlung München, Menzinger Straße 67, 80638 München, Germany Andrei Tsurykau (1) F. Skorina Gomel State University, Sovetskaja Str. 104, 246019 Gomel, Belarus; (2) Institute of Natural Sciences, Samara National Research University, Moskovskoye shosse 34, 443086 Samara, Russia Rodham E. Tulloss Herbarium Amanitarum Rooseveltensis, P. O. Box 57, Roosevelt, New Jersey 08555-0057, U.S.A. Veera Tuovinen University of Alberta, Edmonton, Alberta T6G 2R3, Canada Miguel Ulloa Sosa Universidad Nacional Autónoma de México, Tercer Circuito/Sin Número, Ciudad Universitaria, Ciudad de México, C. P. 04510, Mexico Carlos Urcelay Instituto Multidisciplinario de Biología Vegetal, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de Córdoba, Casilla de Correo 495, 5000 Córdoba, Argentina François Valade 11 rue haras, le boqueteau, 91240 Saint-Michel-sur-Orge, France Ricardo Valenzuela Garza Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala s/n, Miguel Hidalgo, Santo Tomás, 11340 Ciudad de México, Mexico Pieter van den Boom Arafura 16, 5691 JA Son, The Netherlands Nicolas Van Vooren Ascomycete.org, 36 rue de la Garde, 69005 Lyon, France Aida M. Vasco-Palacios Escuela de Microbiología, Universidad de Antioquia, AA1226, Fundación Biodiversa Colombia, Medellín, Colombia Jukka Vauras Herbarium TUR, Biodiversity Unit, University of Turku, 20014 Turku, Finland Juan Manuel Velasco Santos 3 C/Pontevedra, 18, 1º C, 37003 Salamanca, Spain Else Vellinga 861 Keeler Avenue, Berkeley, California 94708, U.S.A. Annemieke Verbeken Ghent University, K.L. Ledeganckstraat 35, 9000 Gent, Belgium Per Vetlesen Norges Sopp- og Nyttevekstforbund, Schweigaards gate 34F, 0191 Oslo, Norway Alfredo Vizzini University of Torino, Viale P.A. Mattioli 25, 10125, Torino, Italy Hermann Voglmayr University of Vienna, Rennweg 14, 1030 Vienna, Austria Sergey Volobuev Komarov Botanical Institute of the Russian Academy of Sciences, 2 Prof. Popov Street, St. Petersburg, 197376, Russia Wolfgang von Brackel Kirchenweg 2, 91341 Röttenbach, Germany Elena Voronina Lomonosov Moscow State University, Biology Faculty, Moscow, Russia Grit Walther Arvid-Harnack-Str. 4, 07743 Jena, Germany Roy Watling Royal Botanic Garden Edinburgh, 20A Inverleith Row, Edinburgh, EH3 5LR, United Kingdom Evi Weber Blaihofstr. 42, 72074 Tübingen, Germany Mats Wedin Swedish Museum of Natural History, P.O. Box 50007, 104 05 Stockholm, Sweden Øyvind Weholt Nord University, Nesna, 8700 Nesna, Norway Martin Westberg Museum of Evolution, Uppsala University, Norbyvägen 16, 75236 Uppsala, Sweden Eugene Yurchenko Polessky State University, Dnyaprouskai flatylii str. 23, 225710, Pinsk, Belarus Petr Zehnálek Faculty of Science, Charles University, Benátská 2, 128 01 Praha 2, Czech Republic Huang Zhang Kunming University of Science & Technology, Kunming, China Mikhail P. Zhurbenko Komarov Botanical Institute of the Russian Academy of Sciences, 2 Prof. Popov Street, St. Petersburg, 197376, Russia The following institutions are also supporting the present text (institutional support means that committees from the mentioned) Asociación Micológica Carlos Spegazzini (Argentina) Austrian Mycological Society (Austria) Croatian Mycological Society (Croatia) Committee of the Czech Scientific Society for Mycology (Czech Republic) The Netherlands Mycological Society (The Netherlands) Sociedad Española de Liquenología (Portugal/Spain) Iberian Mycological Society (which is under constitution, Portugal/Spain) Federación de Asociaciones Micológicas Andaluzas (FAMA) (Spain) Asociación Botánica y Micológica de Jaén (Spain) Asociación Micológica Hispalense Muscaria (Spain) Societat Micològica Valenciana (Spain)

Immunotherapy has changed cancer treatment with major clinical successes, but response rates remain low due in part to elevated prevalence of dysfunctional, terminally exhausted T cells. However, the mechanisms promoting progression to terminal exhaustion remain undefined. We profiled the histone modification landscape of tumor-infiltrating CD8 T cells throughout differentiation, finding terminally exhausted T cells possessed chromatin features limiting their transcriptional potential. Active enhancers enriched for bZIP/AP-1 transcription factor motifs lacked correlated gene expression, which were restored by immunotherapeutic costimulatory signaling. Epigenetic repression was also driven by an increase in histone bivalency, which we linked directly to hypoxia exposure. Our study is the first to profile the precise epigenetic changes during intratumoral differentiation to exhaustion, highlighting their altered function is driven by both improper costimulatory signals and environmental factors. These data suggest even terminally exhausted T cells remain poised for transcription in settings of increased costimulatory signaling and reduced hypoxia.

The biodiversity of northern South American and Central American Liogenys Guérin-Méneville, 1831 (Coleoptera: Scarabaeidae: Melolonthinae: Diplotaxini) is reviewed. Four new species are described: L. clipeosetosa Cherman, new species; L. genieri Smith & Cherman, new species; L. granadina Cherman, new species; and L. schneiderae Cherman, new species. The male of L. quadridens (Fabricius, 1798) and the female of L. quadridentata Blanchard, 1851 are described for the first time. Liogenys gebieni Moser, 1921 is a new junior subjective synonym of L. macropelma Bates, 1887. The northernmost record of Liogenys is emended to Trinidad and Tobago for L. granadina Cherman, new species and L. schneiderae new species. Diplotaxis puberea cuprascens (Bates, 1887) new combination, Diplotaxis puberea puberea (Bates, 1887) new combination, and Diplotaxis pubisternis (Bates, 1887) new combination are all transferred from Liogenys to Diplotaxis Kirby, 1837. Lectotypes are designated for Liogenys gebieni Moser, 1921; Melolontha quadridens Fabricius, 1798; and Liogenys quadridentatus Blanchard, 1851. An identification key to northern South American Liogenys is presented.

Many anemone and anemonefish populations have been depleted by environmental disturbance and over-fishing. However, little is known about recovery potential of these populations, limiting the ability of resource managers to optimise recovery strategies. Depleted populations of multiple anemone and anemonefish species were monitored for ten years after commencement of a species-specific fishing moratorium at the Keppel Islands (Australia), which have recently been impacted by several environmental disturbances including flooding, mass bleaching and a cyclone. Although the moratorium was found to have positive effects on populations of Entacmaea quadricolor (anemone) and Amphiprion melanopus (anemonefish), rates of recovery were very slow, potentially due to Allee effects (depensation), reduced habitat quality, and (or) demographic constraints associated with obligate mutualism. Contemporary densities of E. quadricolor and A. melanopus appeared to be much lower than historical densities, suggesting that ten years without fishing was insufficient to facilitate population recovery in an era punctuated by environmental disturbances. Anemone and anemonefish species that were excluded from the moratorium either declined slightly in density (Amphiprion akindynos) or became so rare that they were not seen again during later surveys (Heteractis crispa and Amphiprion clarkii). We conclude that anemone and anemonefish populations can only support relatively light fishing pressure and likely require extended timeframes to recover from over-exploitation and disturbance. Strong precautionary management, including harvest limits with broad safety margins as insurance against future environmental disturbances, is therefore warranted.

Banderas Bay, located in the Mexican Pacific, is a breeding/calving ground for the North Pacific stock of humpback whales (Megaptera novaeangliae) during the winter. While sporadic registers of humpback whales feeding on their mating grounds exist, this is the first occasion where feeding activity was observed intensively and extensively on a breeding ground. Between 19 December 2011 and 6 March 2012, 26 such occurrences were registered in Banderas Bay, along the mainland pacific coast. On five occasions, groups of 20 or more individuals were recorded feeding. They were feeding over and under the surface using lunging and gulping techniques. On several occasions humpbacks were observed feeding alongside Bryde´s whales (Balaenoptera edeni), Pantropical spotted dolphins (Stenella attenuata) and Bottlenose dolphins (Tursiops truncatus). Two different samples of fish at two different feeding sites were taken and the fish identifications showed these were Pacific anchovies (Cetengraulis mysticetus). Among the 26 sightings, nine different species of birds were registered feeding in the same area as the humpback whales. The number of whales feeding over an extended period of time in their breeding ground could be an indicator that there was not enough food in their feeding grounds, but the possibility that they might just be taking advantage of good food availability is also possible.

Opegrapha multipunctaandSchismatomma quercicolaare two sterile European lichens reproducing only vegetatively by means of soredia. RAxML and Bayesian analyses of newly generated sequence data from the mitochondrial ribosomal RNA small subunit provide clear evidence that these two species do not belong to the Arthoniomycetes, but to the Lecanoromycetes. In our phylogenetic analyses,O. multipunctais nested in the genusPorina(Porinaceae) as sister toP. austroatlantica, whileS. quercicolais nested in the genusSchizotrema(Graphidaceae) as sister toS. zebrinum. The following new combinations are introduced:Porina multipuncta(Coppins & P. James) Ertz, Coppins & Frisch andSchizotrema quercicola(Coppins & P. James) Ertz, Frisch & Sanderson.Schizotrema quercicolarepresents the first record of the genusSchizotremafor Europe and the first sorediate member in this genus. The species is newly recorded from Norway. The lichenicolous habit ofArthonia invadensis confirmed.

The world cropping area for wheat exceeds that of any other crop, and high grain yields in intensive wheat cropping systems are essential for global food security. Breeding has raised yields dramatically in high-input production systems; however, selection under optimal growth conditions is widely believed to diminish the adaptive capacity of cultivars to less optimal cropping environments. Here, we demonstrate, in a large-scale study spanning five decades of wheat breeding progress in western Europe, where grain yields are among the highest worldwide, that breeding for high performance in fact enhances cultivar performance not only under optimal production conditions but also in production systems with reduced agrochemical inputs. New cultivars incrementally accumulated genetic variants conferring favourable effects on key yield parameters, disease resistance, nutrient use efficiency, photosynthetic efficiency and grain quality. Combining beneficial, genome-wide haplotypes could help breeders to more efficiently exploit available genetic variation, optimizing future yield potential in more sustainable production systems.

The heterogeneity of multiple sclerosis is reflected by dynamic changes of different lesion types in the brain white matter (WM). To identify potential drivers of this process, we RNA-sequenced 73 WM areas from patients with progressive MS (PMS) and 25 control WM. Lesion endophenotypes were described by a computational systems medicine analysis combined with RNAscope, immunohistochemistry, and immunofluorescence. The signature of the normal-appearing WM (NAWM) was more similar to control WM than to lesions: one of the six upregulated genes in NAWM was CD26/DPP4 expressed by microglia. Chronic active lesions that become prominent in PMS had a signature that were different from all other lesion types, and were differentiated from them by two clusters of 62 differentially expressed genes (DEGs). An upcoming MS biomarker, CHI3L1 was among the top ten upregulated genes in chronic active lesions expressed by astrocytes in the rim. TGFβ-R2 was the central hub in a remyelination-related protein interaction network, and was expressed there by astrocytes. We used de novo networks enriched by unique DEGs to determine lesion-specific pathway regulation, i.e. cellular trafficking and activation in active lesions; healing and immune responses in remyelinating lesions characterized by the most heterogeneous immunoglobulin gene expression; coagulation and ion balance in inactive lesions; and metabolic changes in chronic active lesions. Because we found inverse differential regulation of particular genes among different lesion types, our data emphasize that omics related to MS lesions should be interpreted in the context of lesion pathology. Our data indicate that the impact of molecular pathways is substantially changing as different lesions develop. This was also reflected by the high number of unique DEGs that were more common than shared signatures. A special microglia subset characterized by CD26 may play a role in early lesion development, while astrocyte-derived TGFβ-R2 and TGFβ pathways may be drivers of repair in contrast to chronic tissue damage. The highly specific mechanistic signature of chronic active lesions indicates that as these lesions develop in PMS, the molecular changes are substantially skewed: the unique mitochondrial/metabolic changes and specific downregulation of molecules involved in tissue repair may reflect a stage of exhaustion.

Enhanced nitrogen uptake and number of seeds per plant are associated with breeding-driven improvement of nitrogen use efficiency. Direct or indirect selection decisions led to a negative correlation between seed weight and oil content., Oilseed rape is one of the most important dicotyledonous field crops in the world, where it plays a key role in productive cereal crop rotations. However, its production requires high nitrogen fertilization and its nitrogen footprint exceeds that of most other globally important crops. Hence, increased nitrogen use efficiency (NUE) in this crop is of high priority for sustainable agriculture. We report a comprehensive study of macrophysiological characteristics associated with breeding progress, conducted under contrasting nitrogen fertilization levels in a large panel of elite oilseed rape varieties representing breeding progress over the past 20 years. The results indicate that increased plant biomass at flowering, along with increases in primary yield components, have increased NUE in modern varieties. Nitrogen uptake efficiency has improved through breeding, particularly at high nitrogen. Despite low heritability, the number of seeds per silique is associated positively with increased yield in modern varieties. Seed weight remains unaffected by breeding progress; however, recent selection for high seed oil content and for high seed yields appears to have promoted a negative correlation (r= –0.39 at high and r= –0.49 at low nitrogen) between seed weight and seed oil concentration. Overall, our results reveal valuable breeding targets to improve NUE in oilseed rape.

Hematopoietic stem cells (HSCs) require a supportive microenvironment to regulate their function and produce sufficient hematopoietic cells over the lifetime of an individual. With the exception of fish, all vertebrates, including mammals, maintain HSCs in a complex niche within the bone marrow. Several bone specific cellular populations have been implicated as components of the HSC niche and are part of a complex network that regulates HSC functions. However, the full extent of interactions within the HSC niche, and the role of individual cell populations remain to be fully elucidated. Further, it is not clear why fish are the exception, and what advantage is gained by housing HSCs in the bone marrow. To gain a better understanding of hematopoiesis and the mechanisms that drive hematopoietic disease processes a clearer picture of the complex HSC regulatory interactions in the bone marrow microenvironment is required.

Natural Killer (NK) cells suppress tumor initiation and metastasis. Most carcinomas are heterogeneous mixtures of epithelial, mesenchymal and hybrid tumor cells, but the relationships of these phenotypes to NK susceptibility are understood incompletely. Grainyhead-like-2 (GRHL2) is a master programmer of the epithelial phenotype, that is obligatorily down-regulated during experimentally induced Epithelial-Mesenchymal Transition (EMT). Here, we utilize GRHL2 re-expression to discover unifying molecular mechanisms that link the epithelial phenotype with NK-sensitivity. GRHL2 enhanced the expression of ICAM-1, augmenting NK-target cell synaptogenesis and NK killing of target cells. The expression of multiple interferon response genes, including ICAM1, anti-correlated with EMT. We identified two novel GRHL2-interacting proteins, the histone methyltransferases KMT2C and KMT2D. Mesenchymal-epithelial transition, NK-sensitization and ICAM-1 expression were promoted by GRHL2-KMT2C/D interactions and by GRHL2 inhibition of p300, revealing novel and potentially targetable epigenetic mechanisms connecting the epithelial phenotype with target cell susceptibility to NK killing.

Whole genome sequencing is instrumental for the study of genome variation in natural populations, delivering important knowledge on genomic modifications and potential targets of natural selection at the population level. Large dormant eggbanks of aquatic invertebrates such as the keystone herbivore Daphnia, a microcrustacean widespread in freshwater ecosystems, provide detailed sedimentary archives to study genomic processes over centuries. To overcome the problem of limited DNA amounts in single Daphnia dormant eggs, we developed an optimised workflow for whole genome amplification (WGA), yielding sufficient amounts of DNA for downstream whole genome sequencing of individual historical eggs, including polyploid lineages. We compare two WGA kits, applied to recently produced Daphnia magna dormant eggs from laboratory cultures, and to historical dormant eggs of Daphnia pulicaria collected from Arctic lake sediment between 10y and 300y old. Resulting genome coverage breadth in most samples was ~70%, including those from >100y old isolates. Sequence read distribution was highly correlated among samples amplified with the same kit, but less correlated between kits. Despite this, a high percentage of genomic positions with SNPs in one or more samples (maximum of 74% between kits, and 97% within kits) were recovered at a depth required for genotyping. As a by-product of sequencing we obtained 100% coverage of the mitochondrial genomes even from the oldest isolates (~300y). The mtDNA provides an additional source for evolutionary studies of these populations. We provide an optimised workflow for WGA followed by whole genome sequencing including steps to minimise exogenous DNA.

Ornithine decarboxylase 1 (ODC1 gene) has been linked through gain-of-function variants to a rare disease featuring developmental delay, alopecia, macrocephaly, and structural brain anomalies. ODC1 has been linked to additional diseases like cancer, with growing evidence for neurological contributions to schizophrenia, mood disorders, anxiety, epilepsy, learning, and suicidal behavior. The evidence of ODC1 connection to neural disorders highlights the need for a systematic analysis of ODC1 genotype-to-phenotype associations. An analysis of variants from ClinVar, Geno2MP, TOPMed, gnomAD, and COSMIC revealed an intellectual disability and seizure connected loss-of-function variant, ODC G84R (rs138359527, NC_000002.12:g.10444500C &gt, T). The missense variant is found in ~1% of South Asian individuals and results in 2.5-fold decrease in enzyme function. Expression quantitative trait loci (eQTLs) reveal multiple functionally annotated, non-coding variants regulating ODC1 that associate with psychiatric/neurological phenotypes. Further dissection of RNA-Seq during fetal brain development and within cerebral organoids showed an association of ODC1 expression with cell proliferation of neural progenitor cells, suggesting gain-of-function variants with neural over-proliferation and loss-of-function variants with neural depletion. The linkage from the expression data of ODC1 in early neural progenitor proliferation to phenotypes of neurodevelopmental delay and to the connection of polyamine metabolites in brain function establish ODC1 as a bona fide neurodevelopmental disorder gene.

A taxonomic revision of the Liogenys Guérin-Méneville, 1831 (Coleoptera: Scarabaeidae: Melolonthinae: Diplotaxini) from the Chacoan Biogeographical Province is presented. Liogenys now includes 92 species, including four new species described here: L. neoforcipata Cherman, new species; L. foveata Cherman, new species; L. isotarsis Cherman, new species; and L. truncata Cherman, new species; and the female of L. tarsalis Moser is described for the first time. Six new synonymies are proposed: L. denticulata Moser, 1918 is a new synonym of L. denticeps Blanchard, 1851; L. ophtalmica Frey, 1973 is a new synonym of L. bidenticeps Moser, 1919; L. mendozana incisa Frey, 1969 is a new synonym of L. mendozana Moser, 1918; L. flavicollis Blanchard, 1851 and L. fulvescens Blanchard, 1851 are new synonyms of L. pallens Blanchard, 1851; and L. densicollis Moser, 1921 is a new synonym of L. opacicollis Fairmaire, 1892. Liogenys cribricollis Moser, 1921 species status is revalidated from its synonymy with L. densicollis. A neotype is designated for Liogenys mendozana incisa Frey, 1969, as well as lectotypes for: L. bruchi Moser, 1924; L. cribricollis, L. denticulata, L. denticeps, L. fulvescens, L. latitarsis Moser, 1918; L. mendozana Moser, 1918; L. obscura Blanchard, 1851; L. opacicollis; and L. pallens. Redescriptions and/or diagnoses and updated geographical distributions are provided for 16 species. Six species previously known only from Argentina have their distribution expanded to Bolivia (L. mendozana; L. opacicollis; L. rectangula Frey, 1969), Paraguay (L. nigrofusca Moser, 1918; L. pallens), or to both of these countries (L. latitarsis).

Osteosarcoma is an often‐fatal mesenchyme‐derived malignancy in children and young adults. Overexpression of EMT‐transcription factors (EMT‐TFs) has been associated with poor clinical outcome. Here, we demonstrated that the EMT‐TF ZEB1 is able to block osteoblastic differentiation in normal bone development as well as in osteosarcoma cells. Consequently, overexpression of ZEB1 in osteosarcoma characterizes poorly differentiated, highly metastatic subgroups and its depletion induces differentiation of osteosarcoma cells. Overexpression of ZEB1 in osteosarcoma is frequently associated with silencing of the imprinted DLK‐DIO3 locus, which encodes for microRNAs targeting ZEB1. Epigenetic reactivation of this locus in osteosarcoma cells reduces ZEB1 expression, induces differentiation, and sensitizes to standard treatment, thus indicating therapeutic options for ZEB1‐driven osteosarcomas. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Background: Human endogenous retrovirus (HERV) expression in multiple sclerosis (MS) brain lesions may contribute to chronic inflammation, but expression of genome-wide HERVs in different MS lesions is unknown. Objective: We examined the HERV expression landscape in different MS lesions compared to control brains. Methods: Transcripts from 71 MS brain samples and 25 control WM were obtained by next-generation RNA sequencing and mapped against HERV transcripts across the human genome. Differential expression of mapped HERV-W and HERV-H reads between MS lesion types and controls was analysed. Results: Out of 6.38 billion high-quality paired end reads, 174 million reads (2.73%) mapped to HERV transcripts. There was no difference in HERVs expression level between MS and control brains, but HERV-W transcripts were significantly reduced in chronic active lesions. Of the four HERV-W transcripts exclusively present in MS, ERV3633503 located on chromosome 7q21.13 close to the MS genetic risk locus had the highest number of reads. In the HERV-H family, 75% of transcripts located to nearby 7q21-22 were overrepresented in MS, and ERV3643914 was expressed more than 16 times in MS compared to control brains. Conclusion: Novel HERV-W and HERV-H transcripts located at chromosome 7 regions were uniquely expressed in MS lesions, indicating their potential role in brain lesion evolution.

Leukemias are challenging diseases to treat due, in part, to interactions between leukemia cells and the bone marrow microenvironment (BMME) that contribute significantly to disease progression. Studies have shown that leukemic cells secrete C-chemokine (C-C motif) ligand 3 (CCL3), to disrupt the BMME resulting in loss of hematopoiesis and support of leukemic cell survival and proliferation. In this study, a murine model of blast crisis chronic myelogenous leukemia (bcCML) that expresses the translocation products BCR/ABL and Nup98/HoxA9 was used to determine the role of CCL3 in BMME regulation. Leukemic cells derived from CCL3(−/−) mice were shown to minimally engraft in a normal BMME, thereby demonstrating that CCL3 signaling was necessary to recapitulate bcCML disease. Further analysis showed disruption in hematopoiesis within the BMME in the bcCML model. To rescue the altered BMME, therapeutic inhibition of CCL3 signaling was investigated using bone-targeted nanoparticles (NP) to deliver Maraviroc, an inhibitor of C-C chemokine receptor type 5 (CCR5), a CCL3 receptor. NP-mediated Maraviroc delivery partially restored the BMME, significantly reduced leukemic burden, and improved survival. Overall, our results demonstrate that inhibiting CCL3 via CCR5 antagonism is a potential therapeutic approach to restore normal hematopoiesis as well as reduce leukemic burden within the BMME.

Severe intra-abdominal infection commonly requires intensive care. Mortality is high and is mainly determined by disease-specific characteristics, i.e. setting of infection onset, anatomical barrier disruption, and severity of disease expression. Recent observations revealed that antimicrobial resistance appears equally common in community-acquired and late-onset hospital-acquired infection. This challenges basic principles in anti-infective therapy guidelines, including the paradigm that pathogens involved in community-acquired infection are covered by standard empiric antimicrobial regimens, and second, the concept of nosocomial acquisition as the main driver for resistance involvement. In this study, we report on resistance profiles of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecalis and Enterococcus faecium in distinct European geographic regions based on an observational cohort study on intra-abdominal infections in intensive care unit (ICU) patients. Resistance against aminopenicillins, fluoroquinolones, and third-generation cephalosporins in E. coli, K. pneumoniae and P. aeruginosa is problematic, as is carbapenem-resistance in the latter pathogen. For E. coli and K. pneumoniae, resistance is mainly an issue in Central Europe, Eastern and South-East Europe, and Southern Europe, while resistance in P. aeruginosa is additionally problematic in Western Europe. Vancomycin-resistance in E. faecalis is of lesser concern but requires vigilance in E. faecium in Central and Eastern and South-East Europe. In the subcohort of patients with secondary peritonitis presenting with either sepsis or septic shock, the appropriateness of empiric antimicrobial therapy was not associated with mortality. In contrast, failure of source control was strongly associated with mortality. The relevance of these new insights for future recommendations regarding empiric antimicrobial therapy in intra-abdominal infections is discussed.

LGBTQ neighborhoods face change. Planning for these neighborhoods requires data about LGBTQ residential concentration. Some analysts have used US Census same-sex partner data to make judgments about LGBTQ neighborhoods. Two agency actions make this reliance problematic. The US Census was required to enforce the Defense of Marriage Act and reassigned some LGBTQ responses in a heteronormal way. The Census also assigned sex based upon patterns of names. These US Census actions of gay removal and sex assignment to datasets raise questions about the usefulness of the partner dataset. A queer reading of the census may give a better representation of neighborhood development and decline. Data are developed for four queer neighborhoods: the West Village in New York City, Center City Philadelphia, Midtown Atlanta, and Midtown Kansas City. The results show that queer attributes of these areas grew to about 1990. Some queer attributes may have declined some from their peak. The results raise questions about social surveys, the closet, and the direction of LBGTQ neighborhoods in the twenty-first century. LGBTQ displacement has occurred.

Sensitive and reproducible pharmacokinetic (PK) assays and immunogenicity assessment are required as part of the complex and lengthy development process for biotherapeutic proteins. Ligand binding assays (LBAs) are included in a range of approaches applied to understand the nature and properties of the drug as well as the induction of anti-drug antibodies (ADA) against the therapeutic, which can cause adverse events and loss of efficacy. Currently, most biotherapeutics are monoclonal human or humanized antibodies. Anti-idiotypic antibodies, targeting the idiotopic determinants of individual antibody drugs are recognized as perfect reagents for such LBAs. Here we describe the typical setups for these assays and how different types of anti-biotherapeutic antibodies can be used to establish selective and sensitive assays.

The American brine shrimp Artemia franciscana is important in aquaculture and has become invasive in other continents, aided by dispersal via waterbirds. However, little is known about processes underlying its genetic diversity and population structure in its natural habitat in North America. These processes, including dispersal and local adaptation, are pivotal drivers of species distribution and community structure, and therefore central to aquatic biodiversity. We studied 15 populations in natural saline lakes of Saskatchewan, Canada to determine the influence of variation in geological history, water chemistry, lake size, and location. We aimed to determine the relative importance of isolation by distance and isolation by environment using the cytochrome c oxidase subunit 1 gene (CO1) as a mitochondrial marker and five nuclear microsatellite markers. Geographic patterns for CO1 and microsatellites differed, with lakes clustering in different groups based on genetic distances according to the marker used. CO1 better indicated historical colonisation processes, suggesting potential routes of initial colonisation when lakes were formed after deglaciation 11,000–15,000 years ago. Differentiation between lakes based on nuclear markers was strongly related to variation in hydrochemistry, suggested by distance-based redundancy analysis, but there was no indication of isolation by distance. The ratio between alkalinity and the sum of Ca and Mg concentrations was particularly important, although a lake with a high Cl concentration caused by potash mining also had a unique Artemia population. Geochemistry is important in the adaptive radiation of anostracan crustaceans. Our study suggests that it also underlies intraspecific genetic variation between populations, promoting isolation by environment, and making dispersal ineffective when cysts are moved by birds between lakes with different hydrochemistry

The biodiversity of Liogenys Guérin-Méneville, 1831 (Coleoptera: Scarabaeidae: Melolonthinae: Diplotaxini) from the southern South American Transition Zone and boundaries is presented. Four new species are described: L. brachyclypeata Cherman, new species; L. lucialmeidae Cherman, new species; L. martinezi Cherman, new species; and L. maxillaricuspis Cherman, new species. The synonymy of L. flaveola Moser, 1924 (= L. kadleci Frey, 1970) is proposed. Lectotypes are designated for L. flavida Moser, 1918; L. pallidicornis Blanchard, 1851 (currently L. xanthocera Harold, 1869); and L. rufoflava Moser, 1918. Redescriptions are provided for all the species mentioned above plus L. calcarata Frey, 1970 and L. kunzteni Moser, 1921, as well as an identification key and updated geographical distributions to all species in the region. All species are present in the Monte province, except of L. kuntzeni (Andean provinces of Chile). Liogenys flavida and L. rufoflava have the broadest distribution, the latter here expanded to Paraguay and Chile.

BACKGROUND Rapid reperfusion reduces infarct size and mortality for acute coronary syndrome (ACS), but efficacy is time dependent. The aim of this study was to determine if transportation factors and clinical presentation predicted prehospital delay for suspected ACS, stratified by final diagnosis (ACS vs. no ACS). METHODS A heterogeneous sample of emergency department (ED) patients with symptoms suggestive of ACS was enrolled at 5 US sites. Accelerated failure time models were used to specify a direct relationship between delay time and variables to predict prehospital delay by final diagnosis. RESULTS Enrolled were 609 (62.5%) men and 366 (37.5%) women, predominantly white (69.1%), with a mean age of 60.32 (±14.07) years. Median delay time was 6.68 (confidence interval 1.91, 24.94) hours; only 26.2% had a prehospital delay of 2 hours or less. Patients presenting with unusual fatigue [time ratio (TR) = 1.71, P = 0.002; TR = 1.54, P = 0.003, respectively) or self-transporting to the ED experienced significantly longer prehospital delay (TR = 1.93, P < 0.001; TR = 1.71, P < 0.001, respectively). Predictors of shorter delay in patients with ACS were shoulder pain and lightheadedness (TR = 0.65, P = 0.013 and TR = 0.67, P = 0.022, respectively). Predictors of shorter delay for patients ruled out for ACS were chest pain and sweating (TR = 0.071, P = 0.025 and TR = 0.073, P = 0.032, respectively). CONCLUSION Patients self-transporting to the ED had prolonged prehospital delays. Encouraging the use of EMS is important for patients with possible ACS symptoms. Calling 911 can be positively framed to at-risk patients and the community as having advanced care come to them because EMS capabilities include 12-lead ECG acquisition and possibly high-sensitivity troponin assays.

Background Tumor-infiltrating CD8+ T cells have been characterized by their exhausted phenotype with decreased cytokine expression and increased expression of co-inhibitory receptors, such as PD-1 and Tim-3. These receptors mark the progression towards exhaustion from a progenitor stage (PD-1Low) to a terminally exhausted stage (PD-1+Tim-3+). While the epigenetics of tumor-infiltrating T cells are unique compared to naive, effector, and memory populations, how the chromatin landscape changes during this progression has not been described. Methods Using a low-input ChIP-based assay called Cleavage Under Targets and Release Using Nuclease (CUT&RUN), we profiled the histone modifications at the chromatin of tumor-infiltrating CD8+ T cell subsets to better understand the relationship between the epigenome and the transcriptome as TIL progress towards terminal exhaustion. Results We have identified two epigenetic characteristics unique to terminally exhausted cells. First, we found a substantial increase in the number of genes that exhibit bivalent chromatin marks, defined by the presence of both activating (H3K4me3) and repressive (H3K27me3) epigenetic modifications that inhibit gene expression. In contrast to stem cells which exhibit bivalency, bivalent genes in terminally exhausted T cells are not associated with plasticity and represent aberrant hypermethylation in response to tumor hypoxia. Secondly, we have also identified a unique set of enhancers, characterized by H3K27ac that do not drive gene expression. These enhancers are enriched for AP-1 transcription factors, whereas enhancers that correlate with gene transcription are enriched for nuclear receptor (NR) transcription factors. Intriguingly, while most AP-1 and NR transcription factors are not expressed in terminally exhausted cells, we found that Batf, an inhibitory AP-1 family member, and Nr4a2, a NR known to promote both exhaustion and modify chromatin were specifically expressed in terminally exhausted cells. These data suggest the balance of Batf and Nr4a2 may modulate the enhancer landscape to promote terminal exhaustion, while hypoxia simultaneously promotes hypermethylation and gene repression. Conclusions Our study defines for the first time the features of epigenetic dysfunction in tumor-mediated T cell exhaustion and deepens our understanding of the epigenetic regulation of gene expression. These observations are the bases for future work that will elucidate that factors that drive progression towards terminal T cell exhaustion at the epigenetic level and identify novel therapeutic targets to restore effector function of tumor T cells and mediate tumor clearance.

This review article addresses the largely unanticipated convergence of two landmark discoveries. The first is the discovery of interferons, critical signaling molecules for all aspects of both innate and adaptive immunity, discovered originally by Isaacs and Lindenmann at the National Institute for Medical Research, London, in 1957 (Proceedings of the Royal Society of London. Series B: Biological Sciences, 1957, 147, 258). The second, formerly unrelated discovery, by Leonard Hayflick and Paul Moorhead (Wistar Institute, Philadelphia) is that cultured cells undergo an irreversible but viable growth arrest, termed senescence, after a finite and predictable number of cell divisions (Experimental Cell Research, 1961, 25, 585). This phenomenon was suspected to relate to organismal aging, which was confirmed subsequently (Nature, 2011, 479, 232). Cell senescence has broad‐ranging implications for normal homeostasis, including immunity, and for diverse disease states, including cancer progression and response to therapy (Nature Medicine, 2015, 21, 1424; Cell, 2019, 179, 813; Cell, 2017, 169, 1000; Trends in Cell Biology, 2018, 28, 436; Journal of Cell Biology, 2018, 217, 65). Here, we critically address the bidirectional interplay between interferons (focusing on type I) and cell senescence, with important implications for health and healthspan., Interferon I (IFN‐I) expression is important not only for amplifying immune responses but also for enforcing cell senescence. Pattern recognition receptor activation, DNA damage signaling, and retrotransposition can trigger senescence through IFN‐I, and, reciprocally, IFN‐I can stimulate DNA damage signaling. Mechanisms are discussed in this review.

Introduction HEART score is widely used to stratify patients with chest pain in the emergency department but has never been validated for cocaine-associated chest pain (CACP). We sought to evaluate the performance of HEART score in risk stratifying patients with CACP compared to an age- and sex-matched cohort with non-CACP. Methods The parent study was an observational cohort study that enrolled consecutive patients with chest pain. We identified patients with CACP and age/sex matched them to patients with non-CACP in 1:2 fashion. HEART score was calculated retrospectively from charts. The primary outcome was major adverse cardiac events (MACE) within 30 days of indexed encounter. Results We included 156 patients with CACP and 312 age-and sex-matched patients with non-CACP (n = 468, mean age 51 ± 9, 22% females). There was no difference in rate of MACE between the groups (17.9% vs. 15.7%, p = 0.54). Compared to the non-CACP group, the HEART score had lower classification performance in those with CACP (AUC = 0.68 [0.56–0.80] vs. 0.84 [0.78–0.90], p = 0.022). In CACP group, Troponin score had the highest discriminatory value (AUC = 0.72 [0.60–0.85]) and Risk factors score had the lowest (AUC = 0.47 [0.34–0.59]). In patients deemed low-risk by the HEART score, those with CACP were more likely to experience MACE (14% vs. 4%, OR = 3.7 [1.3–10.7], p = 0.016). Conclusion In patients with CACP, HEART score performs poorly in stratifying risk and is not recommended as a rule out tool to identify those at low risk of MACE.

Penicillium expansum is the main cause of Blue Mold Decay, which is the economically most significant postharvest disease on fruits. It occurs especially on pomaceous fruits such as apples and pears but also on a wide range of other fruits such as grapes or strawberries. Besides its negative economic effects on the industry, the fungus is also of health concern as it produces patulin, a mycotoxin known to provoke harmful effects in humans. A specific and rapid detection of this fungus therefore is required. In the current study, a loop-mediated isothermal amplification (LAMP) assay was developed and optimized for the species-specific detection of P. expansum. The assay showed high specificity during tests with genomic DNA of 187 fungal strains. The detection limit of the developed assay was 25 pg genomic DNA of P. expansum per reaction. The assay was successfully applied for the detection of the fungus on artificially contaminated apples, grapes, apple juice, apple puree, and grape juice. The developed assay is a promising tool for rapid, sensitive, specific, and cost-efficient detection of P. expansum in quality control applications in the food and beverage industry.

Stimulation of brown adipose tissue (BAT) thermogenesis in humans has emerged as an attractive target to improve metabolic health. Pharmacological stimulations targeting the beta(3)-adrenergic receptor (beta(3)-AR), the adrenergic receptor believed to mediate BAT thermogenesis, have historically performed poorly in human clinical trials. Here we report that, in contrast to rodents, human BAT thermogenesis is not mediated by the stimulation of beta(3)-AR. Oral administration of the beta(3)-AR agonist mirabegron only elicited increases in BAT thermogenesis when ingested at the maximal allowable dose. This led to off-target binding to beta(1)-AR and beta(2)-AR, thereby increasing cardiovascular responses and white adipose tissue lipolysis, respectively. ADRB2 was co-expressed with UCP1 in human brown adipocytes. Pharmacological stimulation and inhibition of the beta(2)-AR as well as knockdown of ADRB1, ADRB2, or ADRB3 in human brown adipocytes all confirmed that BAT lipolysis and thermogenesis occur through beta(2)-AR signaling in humans (ClinicalTrials.gov NCT02811289).

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has challenged the speed at which laboratories can discover the viral composition and study health outcomes. The small ∼30-kb ssRNA genome of coronaviruses makes them adept at cross-species spread while enabling a robust understanding of all of the proteins the viral genome encodes. We have employed protein modeling, molecular dynamics simulations, evolutionary mapping, and 3D printing to gain a full proteome- and dynamicome-level understanding of SARS-CoV-2. We established the Viral Integrated Structural Evolution Dynamic Database (VIStEDD at RRID:SCR_018793) to facilitate future discoveries and educational use. Here, we highlight the use of VIStEDD for nsp6, nucleocapsid (N), and spike (S) surface glycoprotein. For both nsp6 and N, we found highly conserved surface amino acids that likely drive protein-protein interactions. In characterizing viral S protein, we developed a quantitative dynamics cross-correlation matrix to gain insights into its interactions with the angiotensin I-converting enzyme 2 (ACE2)-solute carrier family 6 member 19 (SLC6A19) dimer. Using this quantitative matrix, we elucidated 47 potential functional missense variants from genomic databases within ACE2/SLC6A19/transmembrane serine protease 2 (TMPRSS2), warranting genomic enrichment analyses in SARS-CoV-2 patients. These variants had ultralow frequency but existed in males hemizygous for ACE2. Two ACE2 noncoding variants (rs4646118 and rs143185769) present in ∼9% of individuals of African descent may regulate ACE2 expression and may be associated with increased susceptibility of African Americans to SARS-CoV-2. We propose that this SARS-CoV-2 database may aid research into the ongoing pandemic.

Invasion, metastasis and therapy resistance are the major cause of cancer‐associated deaths, and the EMT‐inducing transcription factor ZEB1 is a crucial stimulator of these processes. While work on ZEB1 has mainly focused on its role as a transcriptional repressor, it can also act as a transcriptional activator. To further understand these two modes of action, we performed a genome‐wide ZEB1 binding study in triple‐negative breast cancer cells. We identified ZEB1 as a novel interactor of the AP‐1 factors FOSL1 and JUN and show that, together with the Hippo pathway effector YAP, they form a transactivation complex, predominantly activating tumour‐promoting genes, thereby synergising with its function as a repressor of epithelial genes. High expression of ZEB1, YAP, FOSL1 and JUN marks the aggressive claudin‐low subtype of breast cancer, indicating the translational relevance of our findings. Thus, our results link critical tumour‐promoting transcription factors: ZEB1, AP‐1 and Hippo pathway factors. Disturbing their molecular interaction may provide a promising treatment option for aggressive cancer types., Aggressive cellular states in human breast cancer are defined by context‐dependent interplay between transcriptional regulators ZEB1, AP‐1 and YAP.