bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lung expression of genes encoding SARS-CoV-2 cell entry molecules and antiviral restriction factors: interindividual differences are associated with age and germline variants
Authors: Cotroneo Chiara E. , Mangano Nunzia , Dragani Tommaso A. , Colombo Francesca 
Published: June 2020

AbstractGermline variants in genes involved in SARS-CoV-2 cell entry (i.e.ACE2andTMPRSS2) may influence the susceptibility to infection, as may polymorphisms in genes involved in the innate host response to viruses (e.g. APOBEC3 family). We searched for polymorphisms acting, in lung tissue, as expression quantitative trait loci (eQTLs) for 15 candidate COVID-19 susceptibility genes, selected for their roles in virus cell entry and host antiviral responses. No significant eQTLs were identified forACE2andTMPRSS2genes, whose expression levels did not associate with either sex or age of the 408 patients whose non-diseased lung tissue was analyzed. Instead, we identified sevencis-eQTLs (FDR<0.05) forAPOBEC3DandAPOBEC3G(rs139296, rs9611092, rs139331, rs8177832, rs17537581, rs61362448, and rs738469). The genetic control of the expression of APOBEC3 genes, which encode enzymes that interfere with virus replication, may explain interindividual differences in risk or severity of viral infections. Future studies should investigate the role of host genetics in COVID-19 patients using a genome-wide approach, to identify other genes whose expression levels are associated with susceptibility to SARS-CoV-2 infection or COVID-19 severity.Author summaryIdentification of expression quantitative trait loci (eQTLs) has become commonplace in functional studies on the role of individual genetic variants in susceptibility to diseases. In COVID-19, it has been proposed that individual variants in SARS-CoV-2 cell entry and innate host response genes may influence the susceptibility to infection. We searched for polymorphisms acting, in non-diseased lung tissue of 408 patients, as eQTLs for 15 candidate COVID-19 susceptibility genes, selected for their roles in virus cell entry and host antiviral responses. Sevencis-eQTLs were detected forAPOBEC3DandAPOBEC3Ggenes, which encode enzymes that interfere with virus replication. No significant eQTLs were identified forACE2andTMPRSS2genes. Therefore, the identified eQTLs may represent candidate loci modulating interindividual differences in risk or severity of SARS-CoV-2 virus infection.
Defining the signalling determinants of a posterior ventral spinal cord identity in human neuromesodermal progenitor derivatives
Authors: Wind Matthew , Gogolou Antigoni , Manipur Ichcha , Granata Ilaria , Butler Larissa , Andrews Peter W. , Barbaric Ivana , Ning Ke , Guarracino Mario R. , Placzek Marysia , Tsakiridis Anestis 
Published: June 2020

AbstractThe anteroposterior axial identity of motor neurons (MNs) determines their functionality and vulnerability to neurodegeneration. Thus it is a critical parameter in the design of strategies aiming to produce MNs from human pluripotent stem cells (hPSCs) for regenerative medicine and disease modelling applications. However, thein vitrogeneration of posterior spinal cord MNs has been challenging. Although the induction of cells resembling neuromesodermal progenitors (NMPs), thebona fideprecursors of the mammalian spinal cord, offers a promising solution, the progressive specification of posterior MNs from these cells is not well-defined. Here we determine the signals guiding the transition of human NMP-like cells toward posterior ventral spinal cord neurectoderm. We show that combined WNT-FGF activities drive a posterior dorsal early neural state while suppression of TGFβ-BMP signalling pathways, combined with SHH stimulation, promotes a ventral identity. Based on these results, we define an optimised protocol for the generation of posterior MNs that can efficiently integrate within the neural tube of chick embryos. We expect that our findings will facilitate the functional comparison of hPSC-derived spinal cord cells of distinct axial identities.
Targeted over-expression of PPARγ in pig skeletal muscle improves oxidative fiber formation and intramuscular fat deposition
Authors: Gu Hao , Zhou Ying , Yang Jinzeng , Li Jianan , Peng Yaxin , Zhang Xia , Miao Yiliang , Jiang Wei , Bu Guowei , Hou Liming , Li Ting , Zhang Lin , Xia Xiaoliang , Ma Zhiyuan , Xiong Yuanzhu , Zuo Bo 
Published: June 2020

AbstractPPARγ is a master regulator of adipogenesis and lipogenesis. To understand its roles in fat deposition and fiber formation in skeletal muscle, we successfully generated muscle-specific overexpression of PPARγ by pig cloning procedures. The content of intramuscular fat was significantly increased in PPARγ transgenic pigs while the muscle mass as lean percentage of body weight was not changed. The proteomics analysis demonstrated oxidative metabolism of fatty acids and respiratory chain were increased in PPARγ pigs. Furthermore, expressions of oxidative muscle fiber-related genes such as MyHC1 and TNNT1 were enhanced. CAMK2, MEF2 and PGC1α were also significantly increased in skeletal muscle of PPARγ pigs, indicating that Ca2+-sensitive phosphatases and kinases may play an important role in the switch of muscle fiber types when PPARγ activity is elevated in skeletal muscle. The results support skeletal muscle-specific overexpression of PPARγ can promote oxidative fiber formation and intramuscular fat deposition in pigs.
Identification of the critical replication targets of CDK reveals direct regulation of replication initiation factors by the embryo polarity machinery inC. elegans
Authors: Gaggioli Vincent , Kieninger Manuela R. , Klucnika Anna , Butler Richard , Zegerman Philip 
Published: June 2020

AbstractDuring metazoan development, the cell cycle is remodelled to coordinate proliferation with differentiation. Developmental cues cause dramatic changes in the number and timing of replication initiation events, but the mechanisms and physiological importance of such changes are poorly understood. Cyclin-dependent kinase (CDK) is important for regulating S-phase length in many metazoa, and here we show in the nematodeCaenorhabditis elegansthat an essential function of CDK during early embryogenesis is to regulate the interactions between three replication initiation factors SLD-3, SLD-2 and MUS-101 (Dpb11/TopBP1). Mutations that bypass the requirement for CDK to generate interactions between these factors is sufficient for viability in the absence of CyclinE/Cdk2, demonstrating that this is a critical embryonic function of this cyclin/CDK complex. Both SLD-2 and SLD-3 are asymmetrically localised in the early embryo and the levels of these proteins inversely correlate with S-phase length. We also show that SLD-2 asymmetry is determined by direct interaction with the polarity protein PKC-3. This study explains the essential function of CDK for replication initiation in a metazoan and provides the first direct molecular mechanism through which polarization of the embryo is coordinated with DNA replication initiation.Author SummaryHow and when a cell divides changes as the cell assumes different fates. How these changes in cell division are brought about are poorly understood, but are critical to ensure that cells do not over-proliferate leading to cancer. The nematodeC. elegansis an excellent system to study the role of cell cycle changes during animal development. Here we show that two factors SLD-2 and SLD-3 are critical to control the decision to begin genome duplication. We show that these factors are differently distributed to different cell lineages in the early embryo, which may be a key event in determining the cell cycle rate in these cells. For the first time we show that, PKC-3, a key component of the machinery that determines the front (anterior) from the back (posterior) of the embryo directly controls SLD-2 distribution, which might explain how the polarisation of the embryo causes changes in the proliferation of different cell lineages. As PKC-3 is frequently mutated in human cancers, how this factor controls cell proliferation may be important to understand tumour progression.
AN ADMIXTURE SIGNAL IN ARMENIANS AROUND THE END OF THE BRONZE AGE REVEALS WIDESPREAD POPULATION MOVEMENT ACROSS THE MIDDLE EAST
Authors: Hovhannisyan Anahit , Jones Eppie , Delser Pierpaolo Maisano , Schraiber Joshua , Hakobyan Anna , Margaryan Ashot , Hrechdakian Peter , Sahakyan Hovhannes , Saag Lehti , Khachatryan Zaruhi , Yepiskoposyan Levon , Manica Andrea 
Published: June 2020

AbstractThe Armenians, a population inhabiting the region in West Asia known as the Armenian Highland, has been argued to show a remarkable degree of population continuity since the Early Neolithic. Here we test the degree of continuity of this population as well as its plausible origin, by collating modern and ancient genomic data, and adding a number of novel contemporary genomes. We show that Armenians have indeed remained unadmixed through the Neolithic and at least until the first part of the Bronze Age, and fail to find any support for historical suggestions by Herodotus of an input from the Balkans. However, we do detect a genetic input of Sardinian-like ancestry during or just after the Middle-Late Bronze Age. A similar input at approximately the same time was detected in East Africa, suggesting large-scale movement both North and South of the Middle East. Whether such large-scale population movement was a result of climatic or cultural changes is unclear, as well as the true source of gene flow remains an open question that needs to be addressed in future ancient DNA studies.
Virus-derived peptide inhibitors of the herpes simplex virus type 1 nuclear egress complex
Authors: Draganova Elizabeth B. , Heldwein Ekaterina E. 
Published: June 2020

AbstractHerpesviruses infect a majority of the human population, establishing lifelong latent infections for which there is no cure. Periodic viral reactivation spreads infection to new hosts while causing various disease states particularly detrimental in the immunocompromised. Efficient viral replication, and ultimately the spread of infection, is dependent on the nuclear egress complex (NEC), a conserved viral heterodimer that helps translocate mature viral capsids from the nucleus to the cytoplasm where they mature into infectious virions. Here, we have identified peptides capable of inhibiting the membrane-budding activity of the NECin vitro. Biophysical characterization of these peptides using circular dichroism suggests that secondary structure, rather than amino acid sequence, influences the extent of inhibition. Current therapeutics that target viral DNA replication machinery are rendered ineffective by drug resistance due to viral mutations. Our results establish a basis for the development of an alternative class of inhibitors against nuclear egress, an essential step in herpesvirus replication, potentially expanding the current repertoire of available therapeutics.
Central oxytocin signaling inhibits food reward-motivated behaviors and VTA dopamine responses to food-predictive cues in male rats
Authors: Liu Clarissa M. , Hsu Ted M. , Suarez Andrea N. , Subramanian Keshav S. , Fatemi Ryan A. , Cortella Alyssa M. , Noble Emily E. , Roitman Mitchell F. , Kanoski Scott E. 
Published: June 2020

ABSTRACTOxytocin potently reduces food intake and is a potential target system for obesity treatment. A better understanding of the behavioral and neurobiological mechanisms mediating oxytocin’s anorexigenic effects may guide more effective obesity pharmacotherapy development. The present study examined the effects of central (lateral intracerebroventricular [ICV]) administration of oxytocin in rats on motivated responding for palatable food. Various conditioning procedures were employed to measure distinct appetitive behavioral domains, including food seeking in the absence of consumption (conditioned place preference expression), impulsive responding for food (differential reinforcement of low rates of responding), effort-based appetitive decision making (high-effort palatable vs. low-effort bland food), and postingestive reward value encoding (incentive learning). Results reveal that ICV oxytocin potently reduces food-seeking behavior, impulsivity, and effort-based palatable food choice, yet does not influence encoding of postingestive reward value in the incentive learning task. To investigate a potential neurobiological mechanism mediating these behavioral outcomes, we utilized in vivo fiber photometry in ventral tegmental area (VTA) dopamine neurons to examine oxytocin’s effect on phasic dopamine neuron responses to sucrose-predictive Pavlovian cues. Results reveal that ICV oxytocin significantly reduced food cue-evoked dopamine neuron activity. Collectively, these data reveal that central oxytocin signaling inhibits various obesity-relevant conditioned appetitive behaviors, potentially via reductions in food cue-driven phasic dopamine neural responses in the VTA.HighlightsCentral oxytocin inhibits motivated responding for palatable food reinforcementCentral oxytocin does not play a role in encoding postingestive reward valueCentral oxytocin blunts VTA dopamine neuron activity in response to food cues
Thermodynamic analysis of point mutations inhibiting high-temperature reversible oligomer of PDZ3
Authors: Saotome T. , Mezaki T. , Subbaian B. , Unzai S. , Martinez J. C. , Kidokoro S-i. , Kuroda Y. 
Published: June 2020

AbstractDifferential scanning calorimetry (DSC) indicated that PDZ3 undergoes a peculiar thermal denaturation exhibiting two endothermic peaks due to the formation of reversible oligomers at high temperature (N↔I6↔D). This contrasts sharply with the standard 2-state denaturation model observed for small, globular proteins. We performed an alanine scanning analysis by individually mutating three hydrophobic residues at the crystallographic oligomeric interface (Phe340, Leu342, Ile389) and one away from the interface (Leu349, as a control). DSC analysis indicated that PDZ3-F340A and PDZ3-L342A exhibited a single endothermic peak. Furthermore, PDZ3-L342A underwent a perfect 2-state denaturation, as evidenced by the single endothermic peak, and confirmed by detailed DSC analysis, including global fitting of data measured at different protein concentrations. Reversible oligomerization (RO) at high temperatures by small globular proteins is a rare event. While we designed the mutations based on our previous study showing that a point mutation Val380 to a nonhydrophobic amino acid inhibited RO in DEN4 ED3, the results are nevertheless surprising since high-temperature RO involves proteins in a denatured state, as assessed by circular dichroism. Future studies will determine how and why mutations designed using crystal structures determined at ambient temperatures influence the formation of RO at high temperatures, and whether high-temperature ROs are related to the propensity of proteins to aggregate or precipitate at lower temperatures, which would provide a novel and unique way of controlling protein solubility and aggregation.SignificanceDespite being a small globular protein, which normaly undergo a two-state unfolding, the thermal denaturation of PSD95-PDZ3, monitored by DSC, exhibited two endothermic peaks. The second peak resulted from a reversible oligomerization (RO) at high temperatures, which is, on its own, a rare phenomenon. In this study, we show that the substitution of a single hydrophobic residue to an alanine at the interface of the crystallographic tetramers inhibited high-temperature RO, resulting in a single endothermic peak. Future studies are required to determine why mutations designed using crystal structures determined at ambient temperatures can inhibit high-temperature RO, and whether the ROs are precursor of irreversible aggregation, If so, the present observations will provide an entirely new basis for creating aggregation-resistant proteins.
Striatal dopamine supports reward reactivity and learning: A simultaneous PET/fMRI study
Authors: Calabro Finnegan J , Montez David , Larsen Bart , Laymon Charles , Foran William , Hallquist Michael , Price Julie , Luna Beatriz 
Published: June 2020

AbstractConverging evidence from both human neuroimaging and animal studies has supported a model of mesolimbic processing in computing prediction errors, which form the basis of reward learning behaviors. However, direct evidence demonstrating how human dopamine signaling in the basal ganglia contributes to learning has been hampered by limitations of individual imaging modalities. Here, we present data from a large (N=81, 18-30 year olds), multi-modal neuroimaging study using simultaneously acquired task fMRI, affording temporal resolution of reward system function, and PET imaging with [11C]Raclopride (RAC) assessing striatal D2/3 receptor binding. Results indicated that task-related dopamine release in the ventral striatum, measured as a change in RAC binding, was greater among those who demonstrated successful reward learning on a probabilistic map learning task. This learning response was specific to the ventral striatum and was not present in fMRI BOLD reward response activation. This provides support for considering task-related DA release in ventral striatum as a key signal for translating reward outcomes into a learning signal, rather the representing the reward outcome in isolation. These data provide novel, humanin vivoevidence that dopaminergic function may support reward reactivity as well as reward learning as distinct processes.
Recording of DNA binding events during gut commensalism reveals the action of a repurposedCandida albicansregulatory network
Authors: Witchley Jessica N. , Brimacombe Cedric A. , Abon Nina V. , Noble Suzanne M. 
Published: June 2020

ABSTRACTCandida albicansis a central fungal component of the human gut microbiota and an opportunistic pathogen. TwoC. albicanstranscription factors, Wor1 and Efg1, control its ability to colonize the mammalian gut. They are also master regulators of an epigenetic switch required for mating. Here, we show that six additional mating regulators influence gut commensalism. Using an adapted Calling Card-Seq protocol to recordCandidatranscription factor DNA binding events in the host, we validated these relationships during murine gut colonization. Finally, by comparing the in-host transcriptomes of regulatory mutants with enhanced vs. diminished commensal fitness, we identified a set of candidate commensalism effectors. These include Cht2, a GPI-linked chitinase whose gene is bound by Wor1, Czf1, and Efg1in vivoand that we show to promote commensalism. We conclude that the network required for aC. albicanssexual switch is biochemically active in the host digestive tract, where it is repurposed to direct commensalism.
How Many Lives Has Lockdown Saved in the UK?
Authors: Nyman Rickard , Ormerod Paul 
Published: June 2020

SummaryWe compare the trajectory of deaths (both in hospitals and care homes) on a daily basis in Sweden and England and Wales (which constitute 90 per cent of the UK population) from 11 March to 7 August 2020, the latest date at which the relevant data is available for England and Wales.Deaths in both Sweden and England and Wales peaked on 8 April. The build up to the peak was very similar in both. Given the time lag between infection and death, the lockdown would have had little effect on the peak number of deaths.By the first week of August, the deaths are very similar in both. However, from early May the decline in England and Wales has been much sharper.We estimate that to 7 August, lockdown saved 17,700 lives in England and Wales, or just under 20,000 extrapolating to a UK level.
Circulating CD34+ Progenitor Cells are Predictive of All-Cause and Cardiovascular Mortality and are Influenced by Physical Activity.
Authors: Muggeridge David , Dodd Jennifer , Ross Mark D. 
Published: June 2020

AbstractBackgroundCirculating progenitor cells (CPCs) play an important role in vascular repair and may influence cardiovascular (CV) health and longevity. Exercise is known to modulate these cells via mobilization from the bone marrow. The primary aims of this study were to evaluate the association of CPCs with mortality and explore the association between physical activity (PA) and CPCs.DesignWe studied 1,751 individuals from the Framingham Offspring cohort (66 ± 9 years [40-92 years], 54% female). CPCs (CD34+, CD34+CD133+, CD34+CD133+KDR+) were measured in participants using flow cytometry. Multivariable cox regression analyses were performed to investigate relationship of CPCs with future CV event, CV mortality and all-cause mortality. Multivariate regression analyses were performed to determine the relationship between self-reported PA and CPC counts.ResultsFollowing adjustment for standard risk factors, there was an inverse association between CD34+ CPCs and all-cause mortality (hazard ratio (HR) per unit increase in CD34+, 0.79; 95% CI 0.64 – 0.98, P=0.036). CD34+CD133+ CPCs were inversely associated with CV mortality (HR 0.63, 95% CI 0.44 – 0.91, P=0.013). Associations of CD34+ and CD34+CD133+ with mortality were strongest in participants with pre-existing CVD. PA was associated with CD34+ CPCs only in CVD participants. This relationship was maintained after adjustment for confounding variables.ConclusionsHigher number of CD34+ and CD34+ CD133+ CPCs were inversely associated with all-cause and CV mortality. These associations were strongest in participants already diagnosed with CVD. PA is independently associated with CD34+ CPCs in individuals with CVD only, suggestive of greater benefit for this population group.
How sequence populations persist inside a genome
Authors: Park Hye Jin , Gokhale Chaitanya S. , Bertels Frederic 
Published: June 2020

AbstractCompared to their eukaryotic counterparts, bacterial genomes are small and contain extremely tightly packed genes. Therefore, discovering a large number of short repetitive sequences in the genomes of Pseudomonads and Enterobacteria is unexpected. These sequences can independently replicate in the host genome and form populations that persist for millions of years. Here we model the interactions of intragenomic sequence populations with the bacterial host. In a simple model, sequence populations either expand until they drive the host to extinction or the sequence population gets purged from the genome. Including horizontal gene transfer does not change the qualitative outcome of the model and leads to the extinction of the sequence population. However, a sequence population can be stably maintained, if each sequence provides a benefit that decreases with increasing sequence population size. But concurrently, the replication of the sequence population needs to be costly to the host. Surprisingly, in regimes where horizontal gene transfer plays a role, the benefit conferred by the sequence population does not have to exceed the damage it causes. Together, our analyses provide a plausible scenario for the persistence of sequence populations in bacterial genomes. More importantly, we hypothesize a limited biologically relevant parameter range, which can be tested in future experiments.