bluuebunny/crossref_metadata_2025_split huggingface dataset:
CRYPTOCHROMES confer robustness, not rhythmicity, to circadian timekeeping
Authors: Putker Marrit , Wong David , Seinkmane Estere , Rzechorzek Nina Marie , Zeng Aiwei , Hoyle Nathaniel P. , Chesham Johanna E. , Edwards Mathew D. , Feeney Kevin A. , Fischer Robin , Peschel Nicolai , Chen Ko-Fan , Selby Christopher P. , Sancar Aziz , O’Neill John S. 
Published: May 2020

AbstractSummaryCircadian (approximately daily) rhythms are a pervasive property of mammalian cells, tissues, and behaviour, ensuring physiological and metabolic adaptation to solar time. Models of daily cellular timekeeping revolve around transcriptional feedback repression, whereby CLOCK and BMAL1 activate the expression of ‘clock proteins’ PERIOD (PER) and CRYPTOCHROME (CRY), which in turn repress CLOCK/BMAL1 activity. CRY proteins are thus considered essential negative regulators of the oscillation; a function supported by behavioural arrhythmicity of CRY-deficient mice when kept under constant conditions. Challenging this interpretation, however, we find evidence for persistent circadian rhythms in mouse behaviour and cellular PER2 levels when CRY is absent. CRY-less oscillations are variable in their expression and have a shorter period than wild type controls. Importantly, we find classic circadian hallmarks such as temperature compensation and determination of period by casein kinase 1δ/ε activity to be maintained. In the absence of CRY-mediated transcriptional feedback repression and rhythmicPer2transcription, PER2 protein rhythms are sustained for several cycles, accompanied by circadian variation in protein stability. We suggest that, whereas circadian transcriptional feedback imparts robustness and functionality onto biological clocks, the core timekeeping mechanism is post-translational. Our findings suggest that PER proteins normally act as signalling hubs that transduce timing information to the nucleus, imparting daily rhythms upon the activity of transcriptional effectors.Highlights➢PER/CRY-mediated negative feedback is dispensable for mammalian circadian timekeeping➢Circadian variation in PER2 levels persists in the absence of rhythmicPer2transcription➢CK1 and GSK3 are plausible mechanistic components of a ‘cytoscillator’ mechanism➢CRY-mediated feedback repression imparts robustness to biological timekeepingIn briefCircadian turnover of mammalian clock protein PERIOD2 persists in the absence of canonical transcriptional feedback repression and rhythmic clock gene activity, demanding a re-evaluation of cellular clock function and evolution.
Adaptation, ancestral variation and gene flow in a ‘Sky Island’Drosophilaspecies
Authors: Hill Tom , Unckless Robert L. 
Published: May 2020

AbstractOver time, populations of species can expand, contract, fragment and become isolated, creating subpopulations that must adapt to local conditions. Understanding how species maintain variation after divergence as well as adapt to these changes in the face of gene flow, is of great interest, especially as the current climate crisis has caused range shifts and frequent migrations for many species. Here, we characterize how a mycophageous fly species,Drosophila innubila, came to inhabit and adapt to its current range which includes mountain forests in southwestern USA separated by large expanses of desert. Using population genomic data from more than 300 wild-caught individuals, we examine four populations to determine their population history in these mountain forests, looking for signatures of local adaptation. We findD. innubilaspread northwards during the previous glaciation period (30-100 KYA), and has recently expanded even further (0.2-2 KYA).D. innubilashows little evidence of population structure, consistent with a recent establishment and genetic variation maintained since before geographic stratification. We also find some signatures of recent selective sweeps in chorion proteins and population differentiation in antifungal immune genes suggesting differences in the environments to which flies are adapting. However, we find little support for long-term recurrent selection in these genes. In contrast, we find evidence of long-term recurrent positive selection in immune pathways such as the Toll-signaling system and the Toll-regulated antimicrobial peptides.
Transcriptional profiling reveals potential involvement of microvillous TRPM5-expressing cells in viral infection of the olfactory epithelium
Authors: Baxter B. Dnate’ , Larson Eric D. , Merle Laetitia , Feinstein Paul , Polese Arianna Gentile , Bubak Andrew N. , Niemeyer Christy S. , Hassell James , Shepherd Doug , Ramakrishnan Vijay R. , Nagel Maria A. , Restrepo Diego 
Published: May 2020

AbstractBackgroundUnderstanding viral infection of the olfactory epithelium is essential because the olfactory nerve is an important route of entry for viruses to the central nervous system. Specialized chemosensory epithelial cells that express the transient receptor potential cation channel subfamily M member 5 (TRPM5) are found throughout the airways and intestinal epithelium and are involved in responses to viral infection.ResultsHerein we performed deep transcriptional profiling of olfactory epithelial cells sorted by flow cytometry based on the expression of mCherry as a marker for olfactory sensory neurons and for eGFP in OMP-H2B::mCherry/TRPM5-eGFP transgenic mice (Mus musculus). We find profuse expression of transcripts involved in inflammation, immunity and viral infection in TRPM5-expressing microvillous cells.ConclusionOur study provides new insights into a potential role for TRPM5-expressing microvillous cells in viral infection of the olfactory epithelium. We find that, as found for solitary chemosensory cells (SCCs) and brush cells in the airway epithelium, and for tuft cells in the intestine, the transcriptome of TRPM5-expressing microvillous cells indicates that they are likely involved in the inflammatory response elicited by viral infection of the olfactory epithelium.
Impaired spatial learning and suppression of sharp wave ripples by cholinergic activation at the goal location
Authors: Jarzebowski Przemyslaw , Tang Clara S. , Paulsen Ole , Hay Y. Audrey 
Published: May 2020

AbstractThe hippocampus plays a central role in long-term memory formation, and different hippocampal network states are thought to have different functions in this process. These network states are controlled by neuromodulatory inputs, including the cholinergic input from the medial septum. Here, we used optogenetic stimulation of septal cholinergic neurons to understand how cholinergic activity affects different stages of spatial memory formation in a reward-based navigation task in mice. We found that optogenetic stimulation of septal cholinergic neurons (1) impaired memory formation when activated at goal location but not during navigation; (2) reduced sharp wave-ripple (SWR) incidence at goal location; and (3) reduced SWR incidence and enhanced the-ta-gamma oscillations during sleep. These results underscore the importance of appropriate timing of cholinergic input in long-term memory formation, which might help explain the limited success of cholinesterase inhibitor drugs in treating memory impairment in Alzheimer’s disease.
Soil microbial diversity and litter decomposition increase along a forest recovery gradient in tropical montane forests of Malaysian Borneo
Authors: Sniegocki Renee , Moon Jessica B. , Rutrough Abigail L. , Gireneus Jude , Seelan Jaya Seelan S. , Weindorf David C. , Farmer Michael C. , Naithani Kusum 
Published: May 2020

AbstractLogging and forest conversion are occurring at alarming rates in the tropical forests. These disturbances alter soil chemistry and microbial diversity, and disrupt carbon cycling through shifts in litter decomposition. Direct links between microbial diversity and soil properties such as pH are well established; however, the indirect impacts of logging and forest conversion on microbial diversity and litter decomposition are poorly understood. We investigated how soil properties and soil functions change across a forest recovery gradient in the tropical montane forests of Malaysian Borneo. We used surface (top 5 cm) soil to assess soil physicochemical properties, next-generation DNA sequencing to assess soil microbial diversity, and standardized litterbags to assess litter decomposition and stabilization. Our results show that soils of the older forests harbored significantly greater microbial diversity, decomposed litter faster, and stabilized greater amounts of litter than soils of the younger forests and converted sites. These results suggest that logging and forest conversion significantly affect soil microbial diversity and can have lasting effects on carbon cycling in tropical montane forests.
Neuronal and glial 3D chromatin architecture illustrates cellular etiology of brain disorders
Authors: Hu Benxia , Won Hyejung , Mah Won , Park Royce , Kassim Bibi , Spiess Keeley , Kozlenkov Alexey , Crowley Cheynna A , Pochareddy Sirisha ,   PsychENCODE consortium, Li Yun , Dracheva Stella , Sestan Nenad , Akbarian Schahram , Geschwind Daniel H. 
Published: May 2020

AbstractCellular heterogeneity in the human brain obscures the identification of robust cellular regulatory networks. Here we integrated genome-wide chromosome conformation in purified neurons and glia with transcriptomic and enhancer profiles to build the gene regulatory landscape of two major cell classes in the human brain. Within glutamatergic and GABAergic neurons, we were able to link enhancers to their cognate genes via neuronal chromatin interaction profiles. These cell-type-specific regulatory landscapes were then leveraged to gain insight into the cellular etiology of several brain disorders. We found that Alzheimer’s disease (AD)-associated epigenetic dysregulation was linked to neurons and oligodendrocytes, whereas genetic risk factors for AD highlighted microglia as a central cell type, suggesting that different cell types may confer risk to the disease via different genetic mechanisms. Moreover, neuronal subtype-specific annotation of genetic risk factors for schizophrenia and bipolar disorder identified shared (parvalbumin-expressing interneurons) and distinct cellular etiology (upper layer neurons for bipolar and deeper layer projection neurons for schizophrenia) between these two closely related psychiatric illnesses. Collectively, these findings shed new light on cell-type-specific gene regulatory networks in brain disorders.
How are adversities during COVID-19 affecting mental health? Differential associations for worries and experiences and implications for policy
Authors: Wright Liam , Steptoe Andrew , Fancourt Daisy 
Published: May 2020

AbstractImportanceMultiple data sources suggest that COVID-19 is having adverse effects on mental health. But it is vital to understand what is causing this: worries over potential adversities due to the pandemic, or the toll of experiencing adverse events.ObjectiveTo explore the time-varying longitudinal relationship between (i) worries about adversity, and (ii) experience of adversity, and both anxiety and depression and test the moderating role of socio-economic position.DesignLongitudinal cohort studySettingCommunity studyParticipantsA well-stratified sample of UK adults recruited into the UCL COVID -19 Social Study (a panel study collecting data weekly during the Covid-19 pandemic) via a combination of convenience and targeted recruitment. The sample was weighted to population proportions of gender, age, ethnicity, education and geographical location.ExposuresWorries or experiences of adversities during the COVID-19 pandemicOutcomesAnxiety (GAD-7) and depression (PHQ-9)ResultsData were analysed from 41,909 UK adults (weighted data: 51% female, aged 18-99) followed up across 6 weeks (178,430 observations). Using fixed effects regression was used to explore within-person variation over time, cumulative number of worries and experience of adversities were both related to higher levels of anxiety and depression. Number of worries were associated more with anxiety than depression, but number of experiences were equally related to anxiety and depression. Individuals of lower socio-economic position were more negatively affected psychologically by adverse experiences.Conclusions & relevanceMeasures over the first few weeks of lockdown in the UK appear to have been insufficient at reassuring people given we are still seeing clear associations with poor mental health both for cumulative worries and also for a range of specific worries relating to finance, access to essentials, personal safety and COVID-19. Interventions are required that both seek to prevent adverse events (e.g. redundancies) and that reassure individuals and support adaptive coping strategies.Key pointsQuestionHow do worries over potential adversities due to the COVID-19 pandemic, or the toll of experiencing adverse events affect mental health?FindingsCumulative number of worries and experience of adversities were both related to higher levels of anxiety and depression during COVID-19, especially amongst individuals of lower socio-economic position.MeaningDuring a pandemic, interventions are required that both seek to prevent adverse events (e.g. redundancies) and that reassure individuals and support adaptive coping strategies.
Semantic and geographical analysis of Covid-19 trials reveals a fragmented clinical research landscape likely to impair informativeness
Authors: Tini Giulia , Duso Bruno Achutti , Bellerba Federica , Corso Federica , Gandini Sara , Minucci Saverio , Pelicci Piergiuseppe , Mazzarella Luca 
Published: May 2020

AbstractBackgroundThe unprecedented impact of the Covid-19 pandemics on modern society has ignited a “gold rush” for effective treatment and diagnostic strategies, with a significant diversion of economical, scientific and human resources towards dedicated clinical research. We aimed to describe trends in this rapidly changing landscape to inform adequate resource allocation.MethodsWe developed informatic tools (Covid Trial Monitor) to analyze in real time growth rate, geographical distribution and characteristics of Covid-19 related trials. We defined structured semantic ontologies with controlled vocabularies to categorize trial interventions, study endpoints and study designs. Data and analyses are publicly available at https://bioinfo.ieo.it/shiny/app/CovidCTResultsWe observe a clear prevalence of monocentric trials with highly heterogeneous endpoints and a significant disconnect between geographic distribution and disease prevalence, implying that most countries would need to recruit unrealistic percentages of their total prevalent cases to fulfill enrolment.ConclusionsThis geographically and methodologically incoherent growth sheds doubts on the actual feasibility of locally reaching target sample sizes and the probability of most of these trials providing reliable and transferable result. We call for the harmonization of clinical trial design criteria for Covid19 and the increased use of larger master protocols incorporating elements of adaptive designs. Covid Trial Monitor identifies critical issues in current Covid19-related clinical research and represents a useful resource for researchers and policymakers to improve the quality and efficiency of related trials
Testing, tracing and isolation in compartmental models
Authors: Sturniolo Simone , Waites William , Colbourn Tim , Manheim David , Panovska-Griffiths Jasmina 
Published: May 2020

AbstractExisting compartmental mathematical modelling methods for epidemics, such as SEIR models, cannot accurately represent effects of contact tracing. This makes them inappropriate for evaluating testing and contact tracing strategies to contain an outbreak. An alternative used in practice is the application of agent- or individual-based models (ABM). However ABMs are complex, less well-understood and much more computationally expensive. This paper presents a new method for accurately including the effects of Testing, contact-Tracing and Isolation (TTI) strategies in standard compartmental models. We derive our method using a careful probabilistic argument to show how contact tracing at the individual level is reflected in aggregate on the population level. We show that the resultant SEIR-TTI model accurately approximates the behaviour of a mechanistic agent-based model at far less computational cost. The computational efficiency is such that it can be easily and cheaply used for exploratory modelling to quantify the required levels of testing and tracing, alone and with other interventions, to assist adaptive planning for managing disease outbreaks.Author SummaryThe importance of modeling to inform and support decision making is widely acknowledged. Understanding how to enhance contact tracing as part of the Testing-Tracing-Isolation (TTI) strategy for mitigation of COVID is a key public policy questions. Our work develops the SEIR-TTI model as an extension of the classic Susceptible, Exposed, Infected and Recovered (SEIR) model to include tracing of contacts of people exposed to and infectious with COVID-19. We use probabilistic argument to derive contact tracing rates within a compartmental model as aggregates of contact tracing at an individual level. Our adaptation is applicable across compartmental models for infectious diseases spread. We show that our novel SEIR-TTI model can accurately approximate the behaviour of mechanistic agent-based models at far less computational cost. The SEIR-TTI model represents an important addition to the theoretical methodology of modelling infectious disease spread and we anticipate that it will be immediately applicable to the management of the COVID-19 pandemic.
Changing travel patterns in China during the early stages of the COVID-19 pandemic
Authors: Gibbs Hamish , Liu Yang , Pearson Carl AB , Jarvis Christopher I , Grundy Chris , Quilty Billy J , Diamond Charlie ,   LSHTM CMMID COVID-19 working group, Eggo Rosalind M 
Published: May 2020

AbstractUnderstanding changes in human mobility in the early stages of the COVID-19 pandemic is crucial for assessing the impacts of travel restrictions designed to reduce disease spread. Here, relying on data from mainland China, we investigated the spatio-temporal characteristics of human mobility between 1st January and 1st March 2020 and discussed their public health implications. An outbound travel surge from Wuhan before travel restrictions were implemented was also observed across China due to the Lunar New Year, indicating that holiday travel may have played a larger role in mobility changes compared to impending travel restrictions. Holiday travel also shifted healthcare pressure related to COVID-19 towards locations with lower access to care. Network analyses showed no sign of major changes in the transportation network after Lunar New Year. Changes observed were temporary and have not yet led to structural reorganisation of the transportation network at the time of this study.One sentence summary:Understanding travel before, during, and after the introduction of travel restrictions in China in response to the COVID-19 Pandemic.
Viral manipulation of mechanoresponsive signaling disassembles processing bodies
Authors: Castle Elizabeth L. , Robinson Carolyn-Ann , Douglas Pauline , Rinker Kristina D. , Corcoran Jennifer A. 
Published: May 2020

AbstractProcessing bodies (PBs) are ribonucleoprotein granules that suppress cytokine mRNA translation that are targeted for disassembly by many viruses. Kaposi’s sarcoma-associated herpesvirus is the etiological agent of the inflammatory endothelial cancer, Kaposi’s sarcoma, and a PB-regulating virus. The virus encodes Kaposin B (KapB), which induces actin stress fibres (SFs) and cell spindling as well as PB disassembly. We now show that KapB-mediated PB disassembly requires actin rearrangements, RhoA effectors and the mechanoresponsive transcription activator, YAP. Moreover, ectopic expression of active YAP or exposure of ECs to mechanical forces caused PB disassembly in the absence of KapB and mechanoresponsive PB disassembly also required YAP. Using the viral protein KapB, we identified a new consequence of the exposure of cells to mechanical forces that alter actin dynamics and activate YAP, namely the disassembly of PBs.ImportanceFor the first time, we demonstrate that processing bodies (PBs), cytoplasmic sites of RNA decay, are regulated by mechanical signaling events that alter actin dynamics and that this requires the mechanoresponsive transcription factor, YAP. Using the overexpression of a viral protein called KapB, known previously to mediate PB disassembly, we show that actin stress fibers (SFs) and the mechanoresponsive transcription factor, YAP, are required for PB loss. We also show that other established mechanical signals (shear stress or stiff extracellular matrix) that lead to the formation of SFs and activate YAP also cause PB disassembly. This is important because it means that KapB activates, from the inside out, a pathway that links cell shape to post-transcriptional gene regulation via cytoplasmic PBs.
Characterisation of ovine bone marrow-derived stromal cells (oBMSC) and evaluation of chondrogenically inducedmicro-pellets for cartilage tissue repairin vivo
Authors: Futrega K. , Music E. , Robey P.G. , Gronthos S. , Crawford R.W. , Saifzadeh S. , Klein T.J. , Doran M.R. 
Published: May 2020

AbstractBackgroundBone marrow stromal cells (BMSC) show promise in cartilage repair, and sheep are the most common large animal pre-clinical model. The objective of this study was to characterize ovine BMSC (oBMSC)in vitro, and to evaluate the capacity of chondrogenicmicro-pellets manufactured from oBMSC or ovine articular chondrocytes (oACh) to repair osteochondral defects in sheep.MethodsoBMSC were characterised for surface marker expression using flow cytometry and evaluated for tri-lineage differentiation. oBMSCmicro-pellets were manufactured in a microwell platform, and chondrogenesis was compared at 2%, 5%, and 20% O2. The capacity of cartilagemicro-pellets manufactured from oBMSC or oACh to repair osteochondral defects in adult sheep was evaluated in an 8-week pilot study. Expanded oBMSC were positive for CD44 and CD146 and negative for CD45.ResultsThe common adipogenic induction medium ingredient, 3-Isobutyl-1-methylxanthine (IBMX) was toxic to oBMSC, but adipogenesis could be restored by excluding IBMX from the medium. BMSC chondrogenesis was optimal in a 2% O2atmosphere.Micro-pellets formed from oBMSC or oACh appeared morphologically similar, but hypertrophic genes were elevated in oBMSCmicro-pellets. While oAChmicro-pellets formed cartilage-like repair tissue in sheep, oBMSCmicro-pellets did not.ConclusionThe sensitivity of oBMSC to IBMX highlights species-species differences between oBMSC and hBMSC.Micro-pellets manufactured from oBMSC were not effective in repairing osteochondral defects, while oAChmicro-pellets enabled modest repair. While oBMSC can be driven to form cartilage-like tissue in vitro, their effective use in cartilage repair will require mitigation of hypertrophy.