bluuebunny/crossref_metadata_2025_split huggingface dataset:
Probabilistic tensor decomposition extracts better latent embeddings from single-cell multiomic data
Authors: Wang Ruohan , Wang Jianping , Li Shuai Cheng 
Published: August 2022

ABSTRACTSingle-cell sequencing technology enables the simultaneous capture of multiomic data from multiple cells. The captured data can be represented by tensors, i.e., the higher-rank matrices. However, the proposed analysis tools often take the data as a collection of two-order matrices, renouncing the correspondences among the features. Consequently, we propose a probabilistic tensor decomposition framework, SCOIT, to extract embeddings from single-cell multiomic data. To deal with sparse, noisy, and heterogeneous single-cell data, we incorporate various distributions in SCOIT, including Gaussian, Poisson, and negative binomial distributions. Our framework can decompose a multiomic tensor into a cell embedding matrix, a gene embedding matrix, and an omic embedding matrix, allowing for various downstream analyses. We applied SCOIT to seven single-cell multiomic datasets from different sequencing protocols. With cell embeddings, SCOIT achieves superior performance for cell clustering compared to seven state-of-the-art tools under various metrics, demonstrating its ability to dissect cellular heterogeneity. With the gene embeddings, SCOIT enables cross-omics gene expression analysis and integrative gene regulatory network study. Furthermore, the embeddings allow cross-omics imputation simultaneously, outperforming conventional imputation methods with the Pearson correlation coefficient increased by 0.03-0.28.
Niacinamide enhances cathelicidin mediated SARS-CoV-2 membrane disruption
Authors: Bhatt Tanay , Khedkar Sneha Uday , Dam Binita , Lall Sahil , Pandey Subhashini , Kataria Sunny , Dias Paul M , Waskar Morris , Raut Janhavi , Sundaramurthy Varadharajan , Vemula Praveen Kumar , Ghatlia Naresh , Majumdar Amitabha , Jamora Colin 
Published: August 2022

AbstractThe continual emergence of new SARS-CoV-2 variants threatens the effectiveness of worldwide vaccination programs and highlights the need for complementary strategies for a sustainable containment plan. A promising approach is to mobilize the body⍰s own antimicrobial peptides (AMPs), to combat SARS-CoV-2 infection and propagation. We have found that human cathelicidin (LL37), an AMP found at epithelial barriers as well as in various bodily fluids, has the capacity to neutralise multiple strains of SARS-CoV-2. Biophysical and computational studies indicate that LL37⍰s mechanism of action is through the disruption of the viral membrane. This antiviral activity of LL37 is enhanced by the hydrotropic action of niacinamide, which may increase the bioavailability of the AMP. Interestingly, we observed inverse correlation between LL37 levels and disease severity of COVID-19 positive patients, suggesting enhancement of AMP response would be an effective therapeutic avenue to mitigate disease severity and overcome vaccine escape.
Activation of mTOR by release of extracellular cholesterol stores controls the transition from quiescence to growth in C. elegans
Authors: Schmeisser Kathrin , Kaptan Damla , Raghuraman Bharath Kumar , Shevchenko Andrej , Penkov Sider , Kurzchalia Teymuras V. 
Published: August 2022

AbstractRecovery from the quiescent developmental stage called dauer is an essential process in C. elegans and provides an excellent model to understand how metabolic transitions contribute to developmental plasticity. We here show that the depletion of sterol-binding proteins SCL-12 and SCL-13 is the key change in the C. elegans proteome in early dauer recovery. This process releases a cholesterol store that is sequestered in the gut lumen during the dauer state to facilitate the transition into reproductive development. First, the stored cholesterol undergoes endocytosis into the lysosomes of the intestinal cells, where it activates mTOR to promote protein synthesis and growth. Second, it is used for the production of dafachronic acids that switch metabolic programs at the transcriptional level. These processes are essential for population fitness and survival, as loss of SCL-12 and SCL-13, depletion of sterols, and loss of mTOR precludes quiescence exit, ultimately leading to the expiration of the entire population.
Circadian Gene Expression in Mouse Renal Proximal Tubule
Authors: Bingham Molly A. , Neijman Kim , Kikuchi Hiroaki , Jung Hyun Jun , Poll Brian G. , Raghuram Viswanathan , Park Euijung , Yang Chin-Rang , Chou Chung-Lin , Chen Lihe , Leipziger Jens , Knepper Mark A. , Dona Margo 
Published: August 2022

ABSTRACTCircadian variability in kidney function has long been recognized but is often ignored as a potential confounding variable in in vivo physiological experiments. To provide a guide for physiological studies on the kidney proximal tubule, we have now created a data resource consisting of expression levels for all measurable mRNA transcripts in microdissected proximal tubule segments from mice as a function of the time of day. This approach employs small-sample RNA-sequencing (RNA-seq) applied to microdissected renal proximal tubules including both S1 proximal convoluted tubules (PCTs) and S2 proximal straight tubules (PSTs). The data were analyzed using JTK-Cycle to detect periodicity. The data are provided as a user-friendly web page at https://esbl.nhlbi.nih.gov/Databases/Circadian-Prox/. In PCTs, 234 transcripts were found to vary in a circadian manner (3.7 % of total quantified). In PSTs, 334 transcripts were found to vary in a circadian manner (5.3 % of total quantified). Transcripts previously known to be associated with corticosteroid action and transcripts associated with increased flow were found to be overrepresented among circadian transcripts peaking during the “dark” portion of the day (Zeitgeber 14-22), corresponding to the peak levels of corticosterone and glomerular filtration rate in mice.BlurbCircadian variation in gene expression can be an important determinant in the regulation of kidney function. The authors used RNA-seq in microdissected proximal S1 and S2 segments to identify transcripts that vary in a circadian manner. The data were used to construct a user-friendly web resource.
CNTNAP4 signaling regulates osteosarcoma disease progression
Authors: Qin Qizhi , Ramesh Sowmya , Gomez-Salazar Mario , Zhong Lingke , Cherief Masnsen , Pratapneni Aniket , Morris Carol D. , McCarthy Edward F. , Zhang Xinli , James Aaron W. 
Published: August 2022

AbstractImproved treatment strategies for sarcoma rely on clarification of the molecular mediators of disease progression. Recently, we reported that the secreted glycoprotein NELL-1 modulates osteosarcoma (OS) disease progression in part via altering the sarcomatous extracellular matrix (ECM) and cell-ECM interactions. Of known NELL-1 interactor proteins, Contactin-associated protein-like 4 (Cntnap4) encodes a member of the neurexin superfamily of transmembrane molecules best known for its presynaptic functions in the central nervous system. Here, CRISPR/Cas9 gene deletion ofCNTNAP4reduced OS tumor growth, sarcoma-associated angiogenesis, and pulmonary metastases.CNTNAP4knockout (KO) in OS tumor cells largely phenocopied the effects ofNELL-1KO, including reductions in sarcoma cell attachment, migration, and invasion. Further,CNTNAP4KO cells were found to be unresponsive to the effects of NELL-1 treatment. Transcriptomic analysis combined with protein phospho-array demonstrated notable reductions in the MAPK/ERK signaling cascade withCNTNAP4deletion, and the ERK1/2 agonist isoproterenol restored cell functions amongCNTNAP4KO tumor cells. Finally, human primary cells and tissues in combination with sequencing datasets confirmed the significance ofCNTNAP4signaling in human sarcomas. In summary, our findings demonstrate the biological importance of NELL-1/CNTNAP4 signaling axis in disease progression of human sarcomas and suggest that targeting the NELL-1/CNTNAP4 signaling pathway represents a strategy with potential therapeutic benefit in sarcoma patients.
Intestinal lamina propria supports acquired eTreg suppressor function
Authors: Gu Yisu , Bartolomé-Casado Raquel , Xu Chuan , Janney Alina , Heuberger Cornelia , Pearson Claire , Teichmann Sarah , Thornton Emily E , Powrie Fiona 
Published: August 2022

AbstractThe intestinal immune system must maintain tolerance to commensal microbiota and self antigens whilst defending against invading pathogens. Recognising how homeostasis is established and maintained in a complex immune environment such as the gut is critical to understanding how to re-establish tolerance once broken in inflammatory disorders. Peripherally induced regulatory T cells (Tregs) play a key role in homeostasis. In intestinal tissue, Tregs work in concert with a diverse network of cells but which cellular interactions occur to instruct Treg adaptation and acquisition of distinct Treg suppressor function is not clear. We used two-photonin vivolive imaging and NICHE-seq [1] to deep phenotypeHelicobacter hepaticus(Hh)-specific Tregs with shared specificity but distinct spatially compartmentalised functions in the tissue. We show transcriptionally distinct central Treg (cTreg) and effector Treg (eTreg) populations in lymphoid versus gut tissue. The lamina propria (LP), and not embedded lymphoid aggregates (LA), is the key location of acquired immune suppressor eTreg function. Tregs recruited to the LP compartment are the dominant interacting cell type and acquired a more effector Treg profile with upregulation ofAreg, Gzmb, Icos, Tigit, Tnfrsf4(OX40), andTnfrsf18(GITR). We identify IL-1β+macrophages, CD206+ macrophages, and ILC2 in the LP niche as the key players governing Treg survival and function. In contrast, LA, dominated by interactions with ILC3s and populations of IL-6+DCs, are equipped to tip the balance towards a pro-inflammatory response. By functionally isolating the gut tissue from secondary lymphoid organs, we show that eTregs maintain their phenotype in the context of inflammatory insult. Blocking their key effector molecule, IL-10, results in locally differentiated Th17 cell proliferation without overt inflammation due to local IL-10 independent mechanisms that constrain inflammation. Our results reveal a previously unrecognised spatial mechanism of tolerance, and demonstrate how knowledge of local interactions can guide cell function and potentially be manipulated for the next generation of tolerance-inducing therapies.
The differential effect of age on upper limb sensory processing, proprioception and motor function
Authors: Saenen Leen , Verheyden Geert , Orban de Xivry Jean-Jacques 
Published: August 2022

AbstractSensory processing consists in the integration and interpretation of somatosensory information. It builds upon proprioception but is a distinct function requiring complex processing by the brain over time. Currently little is known about the effect of aging on sensory processing ability, nor the influence of other covariates such as motor function, proprioception, or cognition. In this study, we measured upper limb passive and active sensory processing, motor function, proprioception, and cognition in 40 healthy younger adults and 54 older adults. We analyzed age differences across all measures and evaluated the influence of covariates on sensory processing through regression. Our results showed larger effect sizes for age differences in sensory processing (r=0.38) compared to motor function (r=0.18-0.22) and proprioception (r=0.10-0.27), but smaller than for cognition (r=0.56-0.63). Aside from age, we found no evidence that sensory processing performance was related to motor function or proprioception, but active sensory processing was related to cognition (β=0.30-0.42). In conclusion, sensory processing showed an age-related decline, while some proprioceptive and motor abilities were preserved across age.
Probabilistic axon targeting dynamics lead to individualized brain wiring
Authors: Andriatsilavo Maheva , Dumoulin Alexandre , Dutta Suchetana Bias , Stoeckli Esther T. , Hiesinger P. Robin , Hassan Bassem A. 
Published: August 2022

SummaryDevelopmental variation in brain-wiring contributes to behavioural individuality1,2. However, how and when individualized wiring diagrams emerge and become stable during development remains largely unknown. Here, we explored axon targeting dynamics in individual brains using live-imaging of a developing Drosophila visual circuit and discovered that targeting choice is an algorithmic multi-step growth process with variable outcomes. Using optogenetics, we found that temporally restricted Notch lateral-inhibition defines a subset of neurons with a probabilistic potential to innervate distal targets. Next, axons from NotchOFF neurons amplify into long actin-rich multi-fibre structures necessary for distal growth. A subset of these NotchOFF neurons create distal targeting axons by stabilizing microtubule growth in one of their actin fibres. Amplified axons without tubulin-stabilized fibres retract, resulting in the stochastic selection of a different number of distal targeting axons in each brain. Pharmacological microtubule destabilization suffices to inhibit this targeting. We observed a similar axonal amplification-stabilization process in the developing chick spinal cord, suggesting a conserved mechanism. Finally, early microtubule patterns predict the adult brain-wiring of an individual in a target-independent manner prior to synapse formation3,4. Thus, we show that a temporal succession of genetically encoded stochastic processes explains the emergence of individual wiring variation.One-Sentence SummaryThe temporal succession of stochastic developmental processes explains the emergence of individual wiring variation.
Relating enhancer genetic variation across mammals to complex phenotypes using machine learning
Authors: Kaplow Irene M. , Lawler Alyssa J. , Schäffer Daniel E. , Srinivasan Chaitanya , Wirthlin Morgan E. , Phan BaDoi N. , Zhang Xiaomeng , Foley Kathleen , Prasad Kavya , Brown Ashley R. ,   Zoonomia Consortium, Meyer Wynn K. , Pfenning Andreas R. 
Published: August 2022

AbstractProtein-coding differences between mammals often fail to explain phenotypic diversity, suggesting involvement of enhancers, often rapidly evolving regions that regulate gene expression. Identifying associations between enhancers and phenotypes is challenging because enhancer activity is context-dependent and may be conserved without much sequence conservation. We developed TACIT (Tissue-Aware Conservation Inference Toolkit) to associate open chromatin regions (OCRs) with phenotypes using predictions in hundreds of mammalian genomes from machine learning models trained to learn tissue-specific regulatory codes. Applying TACIT for motor cortex and parvalbumin-positive interneurons to neurological phenotypes revealed dozens of new OCR-phenotype associations. Many associated OCRs were near relevant genes, including brain size-associated OCRs near genes mutated in microcephaly or macrocephaly. Our work creates a forward genomics foundation for identifying candidate enhancers associated with phenotype evolution.One Sentence SummaryA new machine learning-based approach associates enhancers with the evolution of brain size and behavior across mammals.
Challenges in Improving Genomic Literacy: Results from National and Regional Surveys of Genomic Knowledge, Attitudes, Concerns, and Behaviors
Authors: Jaeger Joseph , Hellwig Amanda , Schiavoni Elizabeth , Brace-MacDonald Bridget , Lamb Natalie A. , Tumiel-Berhalter Laurene , Halfon Marc S. , Vishwanath Arun , Surtees Jennifer A. 
Published: August 2022

AbstractPurposeInformation about genomics is increasingly available to mainstream society, with more and more emphasis on using genomic information to make health care decisions. To determine how prepared people are to use this knowledge to make critical health-related decisions, we assessed the public’s level of genomic literacy and whether this knowledge affects their engagement in behaviors related to genomics, such as getting genetic testing.MethodsA survey assessing perceived and actual knowledge, attitudes, concerns, sources of information, and behaviors related to genomics was administered to national and regional samples of participants. A hierarchical linear regression tested whether knowledge and attitudes predicted engagement in behaviors related to genomics.ResultsParticipants had good basic knowledge of genetics, though they were less familiar with the term “the human genome.” They also displayed positive attitudes towards genomic research, despite expressing many concerns. Both greater knowledge and more positive attitudes significantly and independently predicted greater engagement in genetic testing and other related proactive health behaviors.ConclusionKnowledge and concerns about genomics impact the public’s ability and willingness to obtain genetic testing and engage in other proactive health behaviors. The public’s genomic literacy could be enhanced by integrating their knowledge (e.g of DNA) with broader concepts (e.g. the human genome and genomics) and how they relate to health. Future research is needed on interventions that do this, to improve the public’s genomic literacy through relationships that build trust
DEEP LEARNING ENABLED MULTI-ORGAN SEGMENTATION OF MOUSE EMBRYOS
Authors: Rolfe S.M. , Maga A. M. 
Published: August 2022

ABSTRACTThe International Mouse Phenotyping Consortium (IMPC) has generated a large repository of 3D imaging data from mouse embryos, providing a rich resource for investigating phenotype/genotype interactions. While the data is freely available, the computing resources and human effort required to segment these images for analysis of individual structures can create a significant hurdle for research. In this paper, we present an open source, deep learning-enabled tool, Mouse Embryo Multi-Organ Segmentation (MEMOS), that estimates a segmentation of 50 anatomical structures with a support for manually reviewing, editing, and analyzing the estimated segmentation in a single application. MEMOS is implemented as an extension on the 3D Slicer platform and is designed to be accessible to researchers without coding experience. We validate the performance of MEMOS-generated segmentations through comparison to state-of-the-art atlas-based segmentation and quantification of previously reported anatomical abnormalities in a CBX4 knockout strain.SUMMARY STATEMENTWe present a new open source, deep learning-enabled tool, Mouse Embryo Multi-Organ Segmentation (MEMOS), to estimate the segmentation of 50 anatomical structures from microCT scans of embryonic mice.
Characterization of SARS-CoV-2 Omicron BA.2.75 clinical isolates
Authors: Uraki Ryuta , Iida Shun , Halfmann Peter J. , Yamayoshi Seiya , Hirata Yuichiro , Iwatsuki-Horimoto Kiyoko , Kiso Maki , Ito Mutsumi , Furusawa Yuri , Ueki Hiroshi , Sakai-Tagawa Yuko , Kuroda Makoto , Maemura Tadashi , Kim Taksoo , Mine Sohtaro , Iwamoto Noriko , Li Rong , Liu Yanan , Larson Deanna , Fukushi Shuetsu , Watanabe Shinji , Maeda Ken , Wang Zhongde , Ohmagari Norio , Theiler James , Fischer Will , Korber Bette , Imai Masaki , Suzuki Tadaki , Kawaoka Yoshihiro 
Published: August 2022

AbstractThe prevalence of the Omicron subvariant BA.2.75 is rapidly increasing in India and Nepal. In addition, BA.2.75 has been detected in at least 34 other countries and is spreading globally. However, the virological features of BA.2.75 are largely unknown. Here, we evaluated the replicative ability and pathogenicity of BA.2.75 clinical isolates in Syrian hamsters. Although we found no substantial differences in weight change among hamsters infected with BA.2, BA.5, or BA.2.75, the replicative ability of BA.2.75 in the lungs was higher than that of BA.2 and BA.5. Of note, BA.2.75 caused focal viral pneumonia in hamsters, characterized by patchy inflammation interspersed in alveolar regions, which was not observed in BA.5-infected hamsters. Moreover, in competition assays, BA.2.75 replicated better than BA.5 in the lungs of hamsters. These results suggest that BA.2.75 can cause more severe respiratory disease than BA.5 and BA.2 and should be closely monitored.
A polarized nuclear position is required for correct division plane specification during maize stomatal development
Authors: Ashraf M. Arif , Liu Le , Facette Michelle R. 
Published: August 2022

AbstractAsymmetric cell division generates new cell types and is a feature of development in multicellular organisms. Prior to asymmetric cell division, cell polarity is established.Zea maysstomatal development serves as an excellent plant model system for asymmetric cell division, especially the asymmetric division of the subsidiary mother cell (SMC). In SMCs, the nucleus migrates to a polar location after the accumulation of polarly localized proteins, but before the appearance of the preprophase band. We examined a mutant of the outer nuclear membrane protein, which is part of the LINC (linker of nucleoskeleton and cytoskeleton) complex that localizes to the nuclear envelope in interphase cells. Previously,mlks2(maize linc kash sine-like2) was observed to have abnormal stomata. We confirmed and identified the precise defects that lead to abnormal asymmetric divisions. Proteins that are polarly localized in SMCs prior to division polarize normally inmlks2. However, polar localization of the nucleus is sometimes impaired, even in cells that have otherwise normal polarity. This leads to a misplaced preprophase band and atypical division planes. MLKS2 is localized to mitotic structures, however the structure of the preprophase band, spindle and phragmoplast appeared normal inmlks2. Timelapse imaging revealed thatmlks2has defects in pre-mitotic nuclear migration towards the polarized site, and unstable position at the division site after formation of the preprophase band. We show that nuclear envelope proteins promote pre-mitotic nuclear migration and stable nuclear position, and that the position of the nucleus influences division plane establishment in asymmetrically dividing cells.One-sentence summaryNuclear movement and positioning prior to asymmetric cell division is required for deciding the future division site.