bluuebunny/crossref_metadata_2025_split huggingface dataset:
The EEG multiverse of schizophrenia
Authors: Gordillo Dario , Ramos da Cruz Janir , Chkonia Eka , Lin Wei-Hsiang , Favrod Ophélie , Brand Andreas , Figueiredo Patrícia , Roinishvili Maya , Herzog Michael H. 
Published: December 2020

AbstractResearch on schizophrenia typically focuses on one paradigm, for which clear-cut differences between patients and controls are established. Great care is taken to understand the underlying genetical, neurophysiological, and cognitive mechanism, which eventually may explain the clinical outcome. One tacit assumption of these deep rooting approaches is that paradigms tap into common and representative aspects of the disorder. Here, we analyzed the resting-state electroencephalogram (EEG) of 121 schizophrenia patients and 75 controls. Using multiple signal processing methods, we extracted 194 EEG features. Sixty-nine out of the 194 EEG features showed a significant difference between patients and controls indicating that these features detect an important aspect of schizophrenia. Surprisingly, the correlations between these features were very low, suggesting that each feature picks up a different aspect of the disorder. We propose that complementing deep with shallow rooting approaches, where many roughly independent features are extracted from one paradigm (or several paradigms), will strongly improve diagnosis and potential treatment of schizophrenia.
SARS-CoV-2 testing of 11,884 healthcare workers at an acute NHS hospital trust in England: a retrospective analysis
Authors: Hanrath Aidan T. , Schim van der Loeff Ina , Lendrem Dennis W. , Baker Kenneth F. , Price David A. , McDowall Peter , McDowall Kiera , Cook Sue , Towns Peter , Schwab Ulrich , Evans Adam , Dixon Jill , Collins Jennifer , Burton-Fanning Shirelle , Saunders David , Harwood Jayne , Samuel Julie , Schmid Matthias L. , Pareja-Cebrian Lucia , Hunter Ewan , Murphy Elizabeth , Taha Yusri , Payne Brendan A. I. , Duncan Christopher J.A. 
Published: December 2020

ABSTRACTHealthcare workers (HCWs) are known to be at increased risk of infection with SARS-CoV-2, although whether these risks are equal across all roles is uncertain. Here we report a retrospective analysis of a large real-world dataset obtained from 10 March to 6 July 2020 in an NHS Foundation Trust in England with 17,126 employees. 3,338 HCWs underwent symptomatic PCR testing (14.4% positive, 2.8% of all staff) and 11,103 HCWs underwent serological testing for SARS-CoV-2 IgG (8.4% positive, 5.5% of all staff). Seropositivity was lower than other hospital settings in England but higher than community estimates. Increased test positivity rates were observed in HCWs from BAME backgrounds and residents in areas of higher social deprivation. A logistic regression model adjusting for these factors showed significant increases in the odds of testing positive in certain occupational groups, most notably domestic services staff, nurses and health-care assistants. PCR testing of symptomatic HCWs appeared to underestimate overall infection levels, probably due to asymptomatic seroconversion. Clinical outcomes were reassuring, with only a small minority of HCWs with COVID-19 requiring hospitalisation (2.3%) or ICU management (0.7%) and with no deaths. Despite a relatively low level of HCW infection compared to other UK cohorts, there were nevertheless important differences in test positivity rates between occupational groups, robust to adjustment for demographic factors such as ethnic background and social deprivation. Quantitative and qualitative studies are needed to better understand the factors contributing to this risk. Robust informatics solutions for HCW exposure data are essential to inform occupational monitoring.
When months matter; modelling the impact of the COVID-19 pandemic on the diagnostic pathway of Motor Neurone Disease (MND)
Authors: Burchill Ella , Rawji Vishal , Styles Katy , Rooney Siobhan , Stone Patrick , Astin Ronan , Sharma Nikhil 
Published: December 2020

AbstractBackgroundA diagnosis of MND takes an average 10-16 months from symptom onset. Early diagnosis is important to access supportive measures to maximise quality of life. The COVID-19 pandemic has caused significant delays in NHS pathways; the majority of GP appointments now occur online with subsequent delays in secondary care assessment. Given the rapid progression of MND, patients may be disproportionately affected resulting in late stage new presentations. We used Monte Carlo simulation to model the pre-COVID-19 diagnostic pathway and then introduced plausible COVID-19 delays.MethodsThe diagnostic pathway was modelled using gamma distributions of time taken: 1) from symptom onset to GP presentation, 2) for specialist referral, and 3) for diagnosis reached after neurology appointment. We incorporated branches to simulate delays: when patients did not attend their GP and when the GP consultation did not result in referral. An emergency presentation was triggered when diagnostic pathway time was within 30 days of projected median survival. Total time-to-diagnosis was calculated over 100,000 iterations. The pre-COVID-19 model was estimated using published data and the Improving MND Care Survey 2019. We estimated COVID-19 delays using published statistics.ResultsThe pre-COVID model reproduced known features of the MND diagnostic pathway, with a median time to diagnosis of 399 days and predicting 5.2% of MND patients present as undiagnosed emergencies. COVID-19 resulted in diagnostic delays from 558 days when only primary care was 25% delayed, to 915 days when both primary and secondary care were 75%. The model predicted an increase in emergency presentations ranging from 15.4%-44.5%.InterpretationsThe model suggests the COVID-19 pandemic will result in later-stage diagnoses and more emergency presentations of undiagnosed MND. Late-stage presentations may require rapid escalation to multidisciplinary care. Proactive recognition of acute and late-stage disease with altered service provision will optimise care for people with MND.FundingThis research was supported and funded by a grant from the Reta Lila Weston Trust. NS was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.
Wnt signaling recruits KIF2A to the spindle to ensure chromosome congression and alignment during mitosis
Authors: Bufe Anja , del Arco Ana García , Hennecke Magdalena-Isabell , Ostermaier Matthias , de Jaime-Soguero Anchel , Lin Yu-Chih , Ciprianidis Anja , Engel Ulrike , Beli Petra , Bastians Holger , Acebrón Sergio P. 
Published: December 2020

AbstractCanonical Wnt signaling plays critical roles in development and tissue renewal by regulating β-catenin target genes. Recent evidence showed that β-catenin-independent Wnt signaling is also required for faithful execution of mitosis. This mitotic Wnt signaling functions through Wnt-dependent stabilization of proteins (Wnt/STOP), as well as through components of the LRP6 signalosome. However, the targets and specific functions of mitotic Wnt signaling still remain uncharacterized. Using phosphoproteomics, we identified that Wnt signaling regulates the microtubule depolymerase KIF2A during mitosis. We found that Dishevelled recruits KIF2A via its N-terminal and motor domains, which is further promoted upon LRP6 signalosome formation during mitosis. We show that Wnt signaling modulates KIF2A interaction with PLK1, which is critical for KIF2A localization at the spindle. Accordingly, Wnt signaling promotes chromosome congression and alignment by monitoring KIF2A protein levels at the spindle poles both in somatic cells and in pluripotent stem cells. Our findings highlight a novel function of Wnt signaling during cell division, which could have important implications for genome maintenance, notably in stem cells.SIGNIFICANCEWnt signaling plays essential roles in embryonic patterning, stem cell renewal, and cell cycle progression from G1 to S phase via the regulation ofβ-catenin target genes. Here, we show that Wnt signaling also promotes faithful execution of mitosis by ensuring chromosome congression and alignment before cell division, including in pluripotent stem cells. We demonstrate that the Wnt signaling transducer Dishevelled recruits the mitotic kinesin KIF2A, and mediates its binding to the spindle. KIF2A is a microtubule depolymerase that controls chromosome alignment and congression during mitosis. Consequently, we found that inhibition of Wnt signaling leads to KIF2A-dependent chromosome congression and alignment defects.
Evolutionary tracking of SARS-CoV-2 genetic variants highlights an intricate balance of stabilizing and destabilizing mutations
Authors: Jacob Jobin John , Vasudevan Karthick , Pragasam Agila Kumari , Gunasekaran Karthik , Veeraraghavan Balaji , Mutreja Ankur 
Published: December 2020

ABSTRACTThe currently ongoing COVID-19 pandemic caused by SARS-CoV-2 has accounted for millions of infections and deaths across the globe. Genome sequences of SARS-CoV-2 are being published daily in public databases and the availability of this genome datasets has allowed unprecedented access into the mutational patterns of SARS-CoV-2 evolution. We made use of the same genomic information for conducting phylogenetic analysis and identifying lineage-specific mutations. The catalogued lineage defining mutations were analysed for their stabilizing or destabilizing impact on viral proteins. We recorded persistence of D614G, S477N, A222V V1176F variants and a global expansion of the PANGOLIN variant B.1. In addition, a retention of Q57H (B.1.X), R203K/G204R (B.1.1.X), T85I (B.1.2-B.1.3), G15S+T428I (C.X) and I120F (D.X) variations was observed. Overall, we recorded a striking balance between stabilizing and destabilizing mutations, therefore well-maintained protein structures. With selection pressures in the form of newly developed vaccines and therapeutics to mount soon in coming months, the task of mapping of viral mutations and recording of their impact on key viral proteins would be crucial to pre-emptively catch any escape mechanism that SARS-CoV-2 may evolve for.STUDY IMPORTANCEAs large numbers of the SARS CoV-2 genome sequences are shared in publicly accessible repositories, it enables scientists a detailed evolutionary analysis since its initial isolation in Wuhan, China. We investigated the evolutionarily associated mutational diversity overlaid on the major phylogenetic lineages circulating globally, using 513 representative genomes. We detailed phylogenetic persistence of key variants facilitating global expansion of the PANGOLIN variant B.1, including the recent, fast expanding, B.1.1.7 lineage. The stabilizing or destabilizing impact of the catalogued lineage defining mutations on viral proteins indicates their possible involvement in balancing the protein function and structure. A clear understanding of this mutational profile is of high clinical significance to catch any vaccine escape mechanism, as the same proteins make crucial components of vaccines recently approved and in development. In this direction, our study provides an imperative framework and baseline data upon which further analysis could be built as newer variants of SARS-CoV-2 continue to appear.
Computational prediction of CRISPR-impaired non-coding regulatory regions
Authors: Baumgarten Nina , Schmidt Florian , Wegner Martin , Hebel Marie , Kaulich Manuel , Schulz Marcel H. 
Published: December 2020

AbstractGenome-wide CRISPR screens are becoming more widespread and allow the simultaneous interrogation of thousands of genomic regions. Although recent progress has been made in the analysis of CRISPR screens, it is still an open problem how to interpret CRISPR mutations in non-coding regions of the genome. Most of the tools concentrate on the interpretation of mutations introduced in gene coding regions. We introduce a computational pipeline that uses epigenomic information about regulatory elements for the interpretation of CRISPR mutations in non-coding regions. We illustrate our approach on the analysis of a genome-wide CRISPR screen in hTERT-RPE-1 cells and reveal novel regulatory elements that mediate chemoresistance against doxorubicin in these cells. We infer links to established and to novel chemoresistance genes. Our approach is general and can be applied on any cell type and with different CRISPR enzymes.
Hidden dynamics of ubiquitin-mediated autoregulation of human 26S proteasome during substrate degradation
Authors: Wu Zhaolong , Chen Enbo , Zou Shitao , Hou Yanzhen , Zhang Shuwen , Wang Wei Li , Dong Yuanchen , Mao Youdong 
Published: December 2020

SummaryThe 26S proteasome regulates proteostasis and myriad cellular processes. Here we reconstitute the hidden dynamics of human 26S proteasome during protein degradation using cryo-EM data-driven deep learning, which identified 64 proteasomal conformers. These conformers revealed substrate-dependent conformational entanglement of two 19S regulatory particles in the doubly capped holocomplexes. The rate-limiting step in single-nucleotide exchange dynamics of the AAA-ATPase motor is ATPase re-engagement with the substrate, while the rate-limiting step in proteasomal degradation is the initiation of substrate unfolding by the AAA-ATPase motor following deubiquitylation. Nine rare conformers delineated novel ubiquitin-binding sites on the RPN2 and α5 subunits, along with a ubiquitylation site on RPN10, which were verified using site-directed mutagenesis and liquid chromatography-tandem mass spectrometry. Opening of the 20S core particle gate was found to upregulate proteolytic activity by allosterically promoting nucleophilic attack on the scissile peptide bond. Our systematic analyses illuminate a grand hierarchical allostery underlying ubiquitin-mediated proteasome autoregulation.
Estradiol enhances ethanol stimulation of ventral tegmental area dopamine neuron firing without limiting ethanol inhibition onto those neurons
Authors: Lambeth Philip S. , Lasek Amy W. , Mangieri Regina A. 
Published: December 2020

AbstractFemales can progress to alcohol and other substance use disorders more quickly than males. The ovarian hormone 17β-estradiol (E2) contributes to sex differences observed in drug use and abuse and may be a principal driver of these differences. However, it is not entirely clear how E2 acts to affect processing of ethanol reward, and several brain regions and mechanisms are implicated. We sought to clarify the role of E2 in modulating the response of ventral tegmental area dopamine neurons to ethanol. To this end, we recorded spontaneous action potentials and inhibitory post synaptic currents from dopaminergic neurons in acute horizontal brain slices from ovariectomized (OVX) dopamine neuron reporter mice (Pitx3-eGFP) treated with either vehicle (VEH) or E2. On the basis of prior work, we hypothesized that E2 administration would cause dopamine cells from OVX+E2 animals to show a more substantial ethanol-induced increase in firing rate compared to control animals. Our data confirmed that ethanol stimulation of the firing rate of dopamine neurons from OVX+E2 mice was greater than that of OVX+VEH animals. Further, we hypothesized that the firing rate increase would be accompanied by a concomitant decrease in ethanol stimulated inhibition onto those same neurons. We found that although ethanol caused the expected increase in GABAAreceptor-mediated synaptic inhibition in both groups, there was no difference in this response between OVX+E2 and OVX+VEH animals. Our findings lend additional support for the ability of E2 to enhance ventral tegmental area dopamine neuron responses to ethanol and suggest that this effect is not mediated by an E2-elicited suppression of synaptic inhibition.
No support for white matter microstructural properties and connectivity differences in the combined and inattentive adhd presentations
Authors: Saad Jacqueline F. , Griffiths Kristi R. , Kohn Michael R. , Braund Taylor A , Clarke Simon , Williams Leanne M. , Korgaonkar Mayuresh S. 
Published: December 2020

AbstractEvidence from functional neuroimaging studies support neural differences between the Attention Deficit Hyperactivity Disorder (ADHD) presentation types. It remains unclear if these neural deficits also manifest at the structural level. We have previously shown that the ADHD combined, and ADHD inattentive types demonstrate differences in graph properties of structural covariance suggesting an underlying difference in neuroanatomical organization. The goal of this study was to examine and validate white matter brain organization between the two subtypes using both scalar and connectivity measures of brain white matter. We used both tract-based spatial statistical (TBSS) and tractography analyses with network-based Statistics (NBS) and graph-theoretical analyses in a cohort of 35 ADHD participants (aged 8-17 years) defined using DSM-IV criteria as combined (ADHD-C) type (n=19) or as predominantly inattentive (ADHD-I) type (n=16), and 28 matched neurotypical controls. We performed TBSS analyses on scalar measures of fractional anisotropy (FA), mean (MD), radial (RD), and axial (AD) diffusivity to assess differences in WM between ADHD types and controls. NBS and graph theoretical analysis of whole brain inter-regional tractography examined connectomic differences and brain network organization, respectively. None of the scalar measures significantly differed between ADHD types or relative to controls. Similarly, there were no tractography connectivity differences between the two subtypes and relative to controls using NBS. Global and regional graph measures were also similar between the groups. A single significant finding was observed for nodal degree between the ADHD-C and controls, in the right insula (corrected p=.029). Our result of no white matter differences between the subtypes is consistent with most previous findings. These findings together might suggest that the white matter structural architecture is largely similar between the DSM-based ADHD presentations.
Experimental warming influences species abundances in aDrosophilahost community through direct effects on species performance rather than altered competition and parasitism
Authors: Thierry Mélanie , Pardikes Nicholas A. , Lue Chia-Hua , Lewis Owen T. , Hrček Jan 
Published: December 2020

AbstractCurrent global warming trends are expected to have direct effects on species through their sensitivity to temperature, as well as on their biotic interactions, with cascading indirect effects on species, communities, and entire ecosystems. To predict the community-level consequences of global change we need to understand the relative roles of both the direct and indirect effects of warming. We used a laboratory experiment to investigate how warming affects a tropical community of three species ofDrosophilahosts interacting with two species of parasitoids over a single generation. Our experimental design allowed us to distinguish between the direct effects of temperature on host species performance, and indirect effects through altered biotic interactions (competition among hosts and parasitism by parasitoid wasps). Although experimental warming significantly decreased parasitism for all host-parasitoid pairs, the effects of parasitism and competition on host communities did not vary across temperatures. Instead, effects on host relative abundances were species-specific, with one host species dominating the community at warmer temperatures, independently of parasitism and competition treatments. Our results show that temperature shaped aDrosophilahost community directly through differences in species’ thermal performance, and not via its influences on biotic interactions.
Dissecting human skeletal stem cell ontogeny by single-cell transcriptomic and functional analyses
Authors: He Jian , Yan Jing , Wang Jianfang , Zhao Liangyu , Xin Qian , Zeng Yang , Sun Yuxi , Zhang Han , Bai Zhijie , Li Zongcheng , Ni Yanli , Gong Yandong , Li Yunqiao , He Han , Bian Zhilei , Lan Yu , Ma Chunyu , Bian Lihong , Zhu Heng , Liu Bing , Yue Rui 
Published: December 2020

AbstractHuman skeletal stem cells (SSCs) have been discovered in fetal and adult bones. However, the spatiotemporal ontogeny of human SSCs during embryogenesis has been elusive. Here we map the transcriptional landscape of human embryonic skeletogenesis at single-cell resolution to address this fundamental question. We found remarkable heterogeneity within human limb bud mesenchyme and epithelium, as well as the earliest osteo-chondrogenic progenitors. Importantly, embryonic SSCs (eSSCs) were found in the perichondrium of human long bones, which self-renew and generate osteochondral lineage cells, but not adipocytes or hematopoietic stroma. eSSCs are marked by the adhesion molecule CADM1 and highly enrich FOXP1/2 transcriptional network. Interestingly, neural crest-derived cells with similar phenotypic markers and transcriptional network were also found in the sagittal suture of human embryonic calvaria. Taken together, this study revealed the cellular heterogeneity and lineage hierarchy during human embryonic skeletogenesis, and identified distinct skeletal stem/progenitor cells that orchestrate endochondral and intramembranous ossification.
A WDR35-dependent coatomer transports ciliary membrane proteins from the Golgi to the cilia
Authors: Quidwai Tooba , Hall Emma A. , Keighren Margaret A. , Leng Weihua , Kiesel Petra , Wells Jonathan N. , Murphy Laura C. , Marsh Joseph A. , Pigino Gaia , Mill Pleasantine 
Published: December 2020

AbstractIntraflagellar transport (IFT) is a highly conserved mechanism for motor-driven transport of cargo within cilia, but how this cargo is selectively transported to cilia and across the diffusion barrier is unclear. WDR35/IFT121 is a component of the IFT-A complex best known for its role in ciliary retrograde transport. In the absence of WDR35, small mutant cilia form but fail to enrich in diverse classes of ciliary membrane proteins. InWdr35mouse mutants, the IFT-A peripheral components are degraded and core components accumulate at the transition zone. We reveal deep sequence homology and structural similarity of WDR35 and other IFT-As to the coatomer COPI proteinsaandβ′, and demonstrate an accumulation of ‘coat-less’ vesicles which fail to fuse withWdr35mutant cilia. Our data provides the firstin situevidence of a novel coatomer function for WDR35 likely with other IFT-A proteins in delivering ciliary membrane cargo from the Golgi necessary for cilia elongation.
CRISPR-based functional genomics in human dendritic cells
Authors: Jost Marco , Jacobson Amy N. , Hussmann Jeffrey A. , Cirolia Giana , Fischbach Michael A. , Weissman Jonathan S. 
Published: December 2020

AbstractDendritic cells (DCs) regulate processes ranging from antitumor and antiviral immunity to host-microbe communication at mucosal surfaces. It remains difficult, however, to genetically manipulate human DCs, limiting our ability to probe how DCs elicit specific immune responses. Here, we develop a CRISPR/Cas9 genome editing method for human monocyte-derived DCs (moDCs) that mediates knockouts with a median efficiency of >93% across >300 genes. Using this method, we perform genetic screens in moDCs, identifying mechanisms by which DCs tune responses to lipopolysaccharides from the human microbiome. In addition, we reveal donor-specific responses to lipopolysaccharides, underscoring the importance of assessing immune phenotypes in donor-derived cells, and identify genes that control this specificity, highlighting the potential of our method to pinpoint determinants of inter-individual variation in immune responses. Our work sets the stage for a systematic dissection of the immune signaling at the host-microbiome interface and for targeted engineering of DCs for neoantigen vaccination.