bluuebunny/crossref_metadata_2025_split huggingface dataset:
MRSD: a novel quantitative approach for assessing suitability of RNA-seq in the clinical investigation of mis-splicing in Mendelian disease
Authors: Rowlands Charlie F. , Taylor Algy , Rice Gillian , Whiffin Nicola , Hall Hildegard Nikki , Newman William G. , Black Graeme C.M. ,   kConFab Investigators, O’Keefe Raymond T. , Hubbard Simon , Douglas Andrew G.L. , Baralle Diana , Briggs Tracy A. , Ellingford Jamie M. 
Published: March 2021

AbstractBackgroundRNA-sequencing of patient biosamples is a promising approach to delineate the impact of genomic variants on splicing, but variable gene expression between tissues complicates selection of appropriate tissues. Relative expression level is often used as a metric to predict RNA-sequencing utility. Here, we describe a gene- and tissue-specific metric to inform the feasibility of RNA-sequencing, overcoming some issues with using expression values alone.ResultsWe derive a novel metric, Minimum Required Sequencing Depth (MRSD), for all genes across three human biosamples (whole blood, lymphoblastoid cell lines (LCLs) and skeletal muscle). MRSD estimates the depth of sequencing required from RNA-sequencing to achieve user-specified sequencing coverage of a gene, transcript or group of genes of interest. MRSD predicts levels of splice junction coverage with high precision (90.1-98.2%) and overcomes transcript region-specific sequencing biases. Applying MRSD scoring to established disease gene panels shows that LCLs are the optimum source of RNA, of the three investigated biosamples, for 69.3% of gene panels. Our approach demonstrates that up to 59.4% of variants of uncertain significance in ClinVar predicted to impact splicing could be functionally assayed by RNA-sequencing in at least one of the investigated biosamples.ConclusionsWe demonstrate the power of MRSD as a metric to inform choice of appropriate biosamples for the functional assessment of splicing aberrations. We apply MRSD in the context of Mendelian genetic disorders and illustrate its benefits over expression-based approaches. We anticipate that the integration of MRSD into clinical pipelines will improve variant interpretation and, ultimately, diagnostic yield.
Agreement of parent- and child-reported wheeze: are they associated with FeNO and lung function?
Authors: Mozun Rebeca , Ardura-Garcia Cristina , Pedersen Eva S. L. , Goutaki Myrofora , Usemann Jakob , Singer Florian , Latzin Philipp , Moeller Alexander , Kuehni Claudia E. 
Published: March 2021

AbstractIn epidemiological studies, childhood asthma is usually assessed with questionnaires directed at parents or children, and these may give different answers. We studied how well parents and children agreed when asked to report symptoms of wheeze and investigated whose answers were closer to measurable traits of asthma.LuftiBus in the schoolis a cross-sectional survey of respiratory health among Swiss schoolchildren aged 6-17 years. We applied questionnaires to parents and children asking about wheeze and exertional wheeze in the past year. We assessed agreement between parent-child answers with Cohen’s kappa (k), and associations of answers from children and parents with physiological measurements (i.e. FeNO and FEV1/FVC), using quantile regression.We received questionnaires from 3079 children and their parents. Agreement was poor for reported wheeze (k=0.37) and exertional wheeze (k=0.36). Median FeNO varied when wheeze was reported by children (19 ppb, IQR: 9-44), parents (22 ppb, IQR: 12-46), both (31 ppb, IQR: 16-55) or neither (11 ppb, IQR: 7-19). Median absolute FEV1/FVC was the same when wheeze was reported by children (84%, IQR: 78-89) and by parents (84%, IQR: 78-89), lower when reported by both (82%, IQR: 78-87) and higher when reported by neither (87%, IQR: 82-91). For exertional wheeze findings were similar. Results did not differ by age or sex.Our findings suggest that surveying both parents and children and combining their responses can help us to better identify children with measurable asthma traits.Take home messageThere is poor agreement between schoolchildren and their parents when reporting current wheeze. However, wheeze correlates best with lung function and FeNO when reported by both children and parents.
Invariant representation of physical stability in the human brain
Authors: Pramod R.T. , Cohen M. , Tenenbaum J. , Kanwisher N. 
Published: March 2021

AbstractSuccessful engagement with the world requires the ability to predict what will happen next. Here we investigate how the brain makes the most basic prediction about the physical world: whether the situation in front of us is stable, and hence likely to stay the same, or unstable, and hence likely to change in the immediate future. Specifically, we ask if judgements of stability can be supported by the kinds of representations that have proven to be highly effective at visual object recognition in both machines and brains, or instead if the ability to determine the physical stability of natural scenes may require generative algorithms that simulate the physics of the world. To find out, we measured responses in both convolutional neural networks (CNNs) and the brain (using fMRI) to natural images of physically stable versus unstable scenarios. We find no evidence for generalizable representations of physical stability in either standard CNNs trained on visual object and scene classification (ImageNet), or in the human ventral visual pathway, which has long been implicated in the same process. However, in fronto-parietal regions previously implicated in intuitive physical reasoning we find both scenario-invariant representations of physical stability, and higher univariate responses to unstable than stable scenes. These results demonstrate abstract representations of physical stability in the dorsal but not ventral pathway, consistent with the hypothesis that the computations underlying stability entail not just pattern classification but forward physical simulation.
The inhibitory effects of toothpaste and mouthwash ingredients on the interaction between the SARS-CoV-2 spike protein and ACE2, and the protease activity of TMPRSS2,in vitro
Authors: Tateyama-Makino Riho , Abe-Yutori Mari , Iwamoto Taku , Tsutsumi Kota , Tsuji Motonori , Morishita Satoru , Kurita Kei , Yamamoto Yukio , Nishinaga Eiji , Tsukinoki Keiichi 
Published: March 2021

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells when the viral spike protein is cleaved by transmembrane protease serine 2 (TMPRSS2) after binding to the host angiotensin-converting enzyme 2 (ACE2). Since ACE2 and TMPRSS2 are expressed in the mucosa of the tongue and gingiva, the oral cavity seems like it is an entry point for SARS-CoV-2. Daily oral care using mouthwash seems to play an important role in preventing SARS-CoV-2 infection. However, the relationship between daily oral care and the mechanisms of virus entry into host cells is unclear. In this study, we evaluated the inhibitory effects of ingredients that are generally contained in toothpaste and mouthwash on the interaction between the spike protein and ACE2 and on the serine protease activity of TMPRSS2 using an enzyme-linked immunosorbent assay andin vitroenzyme assay, respectively. Both assays detected inhibitory effects of sodium tetradecene sulfonate, sodium N-lauroyl-N-methyltaurate, sodium N-lauroylsarcosinate, sodium dodecyl sulfate, and copper gluconate. Molecular docking simulations suggested that these ingredients could bind to the inhibitor-binding site of ACE2. In addition, tranexamic acid and 6-aminohexanoic acid, which act as serine protease inhibitors, exerted inhibitory effects on TMPRSS2 protease activity. Further experimental and clinical studies are needed to further elucidate these mechanisms. Our findings support the possibility that toothpaste and mouthwash contain ingredients that inhibit SARS-CoV-2 infection.
Multiomics Interrogation into HBV (Hepatitis B Virus)-Host Interaction Reveals Novel Coding potential in Human Genome, and Identifies Canonical and Non-canonical Proteins as Host Restriction Factors against HBV
Authors: Yuan Shilin , Liao Guanghong , Zhang Menghuan , Zhu Yuanfei , Xiao Weidi , Wang Kun , Jia Caiwei , Deng Qiang , Zhang Jian , Xu Ping , Hu Ronggui 
Published: March 2021

AbstractHepatitis B Virus constitutes a major threat to global public health. Current understanding of HBV-host interaction is yet limited. Here, ribosome profiling, quantitative mass spectrometry and RNA-sequencing are conducted on a recently established HBV replication system. We have identified multiomic DEGs (differentially expressed genes) that HBV orchestrated to remodel host proteostasis networks. Our multiomics interrogation revealed that HBV induced significant changes in both transcription and translation of 35 canonical genes including PPP1R15A, PGAM5 and SIRT6, as well as the expression of at least 15 non-canonical ORFs including ncPON2 and ncGRWD1, thus revealing an extra coding potential of human genome. Overexpression of these five genes but not the enzymatically deficient SIRT6 mutants suppressed HBV replication while knockdown SIRT6 had opposite effect. Furthermore, the expression ofSIRT6was down-regulated in patients, cells or animal models of HBV infection. Mechanistic study further indicated that SIRT6 directly binds to mini-chromosome and deacetylates histone H3 lysine 9 (H3K9ac) and histone H3 lysine 56 (H3K56ac), and chemical activation of endogenous SIRT6 with MDL800 suppressed HBV infectionin vitroandin vivo. By generating the first multiomics landscape of host-HBV interaction, our work is thus opening a new avenue to facilitate therapeutic development against HBV infection.
Two-pore channel 2 is a key regulator of adipocyte differentiation via the cAMP signaling pathway with calpain as downstream effector
Authors: Zhang Yuxuan , Chan Lai-Hing , Tunn Ruth , Ruas Margarida , Gay David , Todorcevic Marijana , Christodoulides Costas , Parrington John 
Published: March 2021

AbstractWe investigated whether the endolysosomal two-pore channel TPC2 is a mediator of adipocyte differentiation. We show thatTpcn2mRNA is expressed transiently during induction of C3H10T1/2 mesenchymal stem cells to differentiate into adipocytes, and that this expression is triggered by cAMP. This is the first demonstration of a cell signaling pathway that can regulate TPC gene expression. We also identified an important functional role for TPC2 in adipocyte differentiation. First, ectopic TPC2 expression in C3H10T1/2 cells partially rescued the block to adipocyte differentiation caused by cAMP absence. Second, inhibition of endogenous TPC2 expression in primary preadipocytes substantially reduced their ability to differentiate into adipocytes. Finally, genetic variation at theTpcn2locus is associated with increased upper-body fat distribution in women concomitant with reducedTpcn2expression in abdominal adipose tissue. Our findings implicate TPC2 as an important mediator of adipogenesis and may aid identification of new drug targets for treatment of obesity.
Unbiased transcriptomic analysis of chondrocyte differentiation in a high-density cell culture model
Authors: Kruger Claudia , Limpach Aimee , Kappen Claudia 
Published: March 2021

ABSTRACTIn the developing vertebrate skeleton, cartilage is an important precursor to the formation of bones. Cartilage is produced by chondrocytes, which derive from embryonic mesoderm and undergo a stereotypical program of differentiation and maturation. Here we modeled this processin vitro, using primary fetal mouse rib chondrocytes in a high-density cell culture model of cartilage differentiation, and performed genome-wide gene expression profiling over the course of culture. The overarching goal of this study was to characterize the molecular pathways involved in cartilage differentiation and maturation. Our results also enable a comprehensive appraisal of distinctions between commonin vitromodels for cartilage differentiation, and of differences in their molecular resemblance to cartilage formationin vivo.
The lifetime cost of reproductive potential – who spends the most?
Authors: Fuchs Shai , Goldenfeld Miki , Dviri Michal , Librach Clifford , Baum Micha 
Published: March 2021

AbstractObjectivesTo determine who spends more energy over a lifetime on maintaining their reproductive potential: men or women?DesignAs a model and energetic equivalent, we set the mass of gametes supported over time from birth until exhaustion of fertility. We calculated gender-specific dynamics of gamete pool mass over time. To this purpose we collated data from existing literature, accounting for gamete volume over stages of development, time in each stage, mass density, and count. Our model generates the integral, or area under the curve (AUC) of the gamete pool mass over a lifetime as a proxy to energetic requirements.Main outcome measuresThe area under gamete mass curve over a lifetime in men and women.ResultsThe number of gametes over a lifetime is 600,000 in women and close to 1 trillion in men. Accounting for mass and time, women invest approximately 100 gram*days in maintaining the female oocyte pool. Women reach 50% of lifetime AUC by age 10, and 90% by age 25. Men invest approximately 30 Kg*days over a lifetime (300-fold more), reaching 50% of lifetime AUC at age 37 and 90% at age 62 years old.ConclusionsThe study quantifies for the first time the area under gamete mass in men and women through a nuanced calculation accounting for all components of post-natal gamete dynamics. We found a 300-fold excess is supported male gamete mass over a lifetime (100g*days vs. 30 Kg*days in females vs. males, respectively). Our methodology offers a framework for assessing other components of the reproductive system in a similar quantitative manner.
Heightened virulence ofYersiniais associated with decreased function of the YopJ protein
Authors: Mares Chris A. , Lugo Fernando P. , Albataineh Mohammad , Goins Beth A. , Newton Irene G. , Isberg Ralph R. , Bergman Molly A. 
Published: March 2021

AbstractDespite the maintenance of YopP/J alleles throughout the human-pathogenicYersinialineage, the benefit of YopP/J-induced phagocyte death forYersiniapathogenesis in animals is not obvious. To determine how sequence divergence of YopP/J has impactedYersiniavirulence, we examined protein polymorphisms in this Type III secreted effector protein across 17Yersiniaspecies, and tested the consequences of polymorphism in a murine model of sub-acute systemic yersiniosis. Our evolutionary analysis revealed that codon 177 has been subjected to positive selection - theY. enterocoliticaresidue had been altered from a leucine to a phenylalanine in nearly allY. pseudotuberculosisandY. pestisstrains examined. Despite being a minor change, as both leucine and phenylalanine have hydrophobic side chains, reversion of YopJF177to the ancestral YopJL177variant yielded aY. pseudotuberculosisstrain with enhanced cytotoxicity towards macrophages, consistent with previous findings. Surprisingly, expression of YopJF177Lin the mildly attenuatedksgA-background rendered the strain completely avirulent in mice. Consistent with this hypothesis that YopJ activity indirectly relates toYersiniapathogenesisin vivo,ksgA-strains lacking functional YopJ failed to kill macrophages but actually regained virulence in animals. Also, treatment with the anti-apoptosis drug suramin prevented YopJ-mediated macrophage cytotoxicity and enhancedY. pseudotuberculosisvirulencein vivo. Our results demonstrate thatYersinia-induced cell death is detrimental for bacterial pathogenesis in this animal model of illness, and indicate that positive selection has driven YopJ/P andYersiniaevolution towards diminished cytotoxicity and increased virulence, respectively.
Label-free screening of brain tissue myelin content using phase imaging with computational specificity (PICS)
Authors: Fanous Michael , Shi Chuqiao , Caputo Megan P. , Rund Laurie A. , Johnson Rodney W. , Das Tapas , Kuchan Matthew J. , Sobh Nahil , Popescu Gabriel 
Published: March 2021

ABSTRACTInadequate myelination in the central nervous system is associated with neurodevelopmental complications. Thus, quantitative, high spatial resolution measurements of myelin levels are highly desirable. We used spatial light interference microcopy (SLIM), a highly sensitive quantitative phase imaging (QPI) technique, to correlate the dry mass content of myelin in piglet brain tissue with dietary changes and gestational size. We combined SLIM micrographs with an AI classifying model that allows us to discern subtle disparities in myelin distributions with high accuracy. This concept of combining QPI label-free data with AI for the purpose of extracting molecular specificity has recently been introduced by our laboratory as phase imaging with computational specificity (PICS). Training on nine thousand SLIM images of piglet brain tissue with the 71-layer transfer learning model Xception, we created a two-parameter classification to differentiate gestational size and diet type with an accuracy of 82% and 80%, respectively. To our knowledge, this type of evaluation is impossible to perform by an expert pathologist or other techniques.
Targeting tau mitigates mitochondrial fragmentation and oxidative stress in amyotrophic lateral sclerosis
Authors: Petrozziello Tiziana , Bordt Evan A. , Mills Alexandra N. , Kim Spencer E. , Sapp Ellen , Devlin Benjamin A. , Obeng-Marnu Abigail A. , Farhan Sali M.K. , Amaral Ana C. , Dujardin Simon , Dooley Patrick M. , Henstridge Christopher , Oakley Derek H. , Neueder Andreas , Hyman Bradley T. , Spires-Jones Tara L. , Bilbo Staci D. , Vakili Khashayar , Cudkowicz Merit E. , Berry James D. , DiFiglia Marian , Silva M. Catarina , Haggarty Stephen J. , Sadri-Vakili Ghazaleh 
Published: March 2021

AbstractUnderstanding the mechanisms underlying amyotrophic lateral sclerosis (ALS) is crucial for the development of new therapies. Recent evidence suggest that tau may be involved in ALS pathogenesis. Here, we demonstrated that hyperphosphorylated tau (pTau-S396) is mis-localized to synapses in human post-mortem motor cortex (mCTX) across ALS subtypes. Treatment with ALS synaptoneurosomes (SNs) derived from post-mortem mCTX, enriched in pTau-S396, increased oxidative stress, induced mitochondrial fragmentation, and altered mitochondrial connectivityin vitro. Furthermore, our findings revealed that pTau-S396 interacts with the pro-fission dynamin-related protein (DRP1), and similar to pTau-S396, DRP1 accumulated in ALS SNs across ALS subtypes. Lastly, reducing tau with a specific bifunctional degrader, QC-01-175, prevented ALS SNs-induced mitochondrial fragmentation and oxidative stressin vitro. Collectively, our findings suggest that increases in pTau-S396 may lead to mitochondrial fragmentation and oxidative stress in ALS and decreasing tau may provide a novel strategy to mitigate mitochondrial dysfunction in ALS.Graphical abstractpTau-S396 mis-localizes to synapses in ALS.ALS synaptoneurosomes (SNs), enriched in pTau-S396, increase oxidative stress and induce mitochondrial fragmentationin vitro.pTau-S396 interacts with the pro-fission GTPase DRP1 in ALS.Reducing tau with a specific degrader, QC-01-175, mitigates ALS SNs-induced mitochondrial fragmentation and increases in oxidative stressin vitro.
Microbiome Maps: Hilbert Curve Visualizations of Metagenomic Profiles
Authors: Valdes Camilo , Stebliankin Vitalii , Ruiz-Perez Daniel , Park Ji In , Lee Hajeong , Narasimhan Giri 
Published: March 2021

AbstractMotivationAbundance profiles from metagenomic sequencing data synthesize information from billions of sequenced reads coming from thousands of microbial genomes. Analyzing and understanding these profiles can be a challenge since the data they represent are complex. Particularly challenging is their visualization, as existing techniques are inadequate when the taxa number is in the thousands. We present a technique, and accompanying software, for the visualization of metagenomic abundance profiles using a space-filling curve that transforms a profile into an interactive 2D image.ResultsWe created Jasper, an easy to use tool for the visualization and exploration of metagenomic profiles from DNA sequencing data. It orders taxa using a space-filling Hilbert curve, and creates a “Microbiome Map”, where each position in the image represents the abundance of a single taxon from a reference collection. Jaspercan order taxa in multiple ways, and the resultingmicrobiome mapscan highlight “hot spots” of microbes that are dominant in taxonomic clades or biological conditions.We use Jasperto visualize samples from a variety of microbiome studies, and discuss ways in whichmicrobiome mapscan be an invaluable tool to visualize spatial, temporal, disease, and differential profiles. Our approach can create detailedmicrobiome mapsinvolving hundreds of thousands of microbial reference genomes with the potential to unravel latent relationships (taxonomic, spatio-temporal, functional, and other) that could remain hidden using traditional visualization techniques. The maps can also be converted into animated movies that bring to life the dynamicity of microbiomes.AvailabilityJasperis freely available atmicrobiomemaps.organd viabiorg.cs.fiu.edu/jasperContactcvaldes2@unl.edu;giri@fiu.eduSupplementary informationSupplementary materials are available atmicrobiomemaps.org
Brain kernel: a new spatial covariance function for fMRI data
Authors: Wu Anqi , Nastase Samuel A. , Baldassano Christopher A. , Turk-Browne Nicholas B. , Norman Kenneth A. , Engelhardt Barbara E. , Pillow Jonathan W. 
Published: March 2021

AbstractA key problem in functional magnetic resonance imaging (fMRI) is to estimate spatial activity patterns from noisy high-dimensional signals. Spatial smoothing provides one approach to regularizing such estimates. However, standard smoothing methods ignore the fact that correlations in neural activity may fall off at different rates in different brain areas, or exhibit discontinuities across anatomical or functional boundaries. Moreover, such methods do not exploit the fact that widely separated brain regions may exhibit strong correlations due to bilateral symmetry or the network organization of brain regions. To capture this non-stationary spatial correlation structure, we introduce thebrain kernel, a continuous covariance function for whole-brain activity patterns. We define the brain kernel in terms of a continuous nonlinear mapping from 3D brain coordinates to a latent embedding space, parametrized with a Gaussian process (GP). The brain kernel specifies the prior covariance between voxels as a function of the distance between their locations in embedding space. The GP mapping warps the brain nonlinearly so that highly correlated voxels are close together in latent space, and uncorrelated voxels are far apart. We estimate the brain kernel using resting-state fMRI data, and we develop an exact, scalable inference method based on block coordinate descent to overcome the challenges of high dimensionality (10-100K voxels). Finally, we illustrate the brain kernel’s usefulness with applications to brain decoding and factor analysis with multiple task-based fMRI datasets.