bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Resolution analysis of Transmission Dynamics of Sars-Cov-2 in Two Major Hospital Outbreaks in South Africa Leveraging Intrahost Diversity
Authors: James San Emmanuel , Ngcapu Sinaye , Kanzi Aquillah M , Tegally Houriiyah , Fonseca Vagner , Giandhari Jennifer , Wilkinson Eduan , Chimukangara Benjamin , Pillay Sureshnee , Singh Lavanya , Fish Maryam , Gazy Inbal , Khanyile Khulekani , Lessells Richard , de Oliveira Tulio 
Published: November 2020

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes acute, highly transmissible respiratory infection in both humans and wide range of animal species. Its rapid spread globally and devasting effects have resulted into a major public health emergency prompting the need for methodological interventions to understand and control its spread. In particular, The ability to effectively retrace its transmission pathways in outbreaks remains a major challenge. This is further exacerbated by our limited understanding of its underlying evolutionary mechanism. Using NGS whole-genome data, we determined whether inter- and intra-host diversity coupled with bottleneck analysis can retrace the pathway of viral transmission in two epidemiologically well characterised nosocomial outbreaks in healthcare settings supported by phylogenetic analysis. Additionally, we assessed the mutational landscape, selection pressure and diversity of the identified variants. Our findings showed evidence of intrahost variant transmission and evolution of SARS-CoV-2 after infection These observations were consistent with the results from the bottleneck analysis suggesting that certain intrahost variants in this study could have been transmitted to recipients. In both outbreaks, we observed iSNVs and SNVs shared by putative source-recipients pairs. Majority of the observed iSNVs were positioned in the S and ORF1ab region. AG, CT and TC nucleotide changes were enriched across SARS-COV-2 genome. Moreover, SARS-COV-2 genome had limited diversity in some loci while being highly conserved in others. Overall, Our findings show that the synergistic effect of combining withinhost diversity and bottleneck estimations greatly enhances resolution of transmission events in Sars-Cov-2 outbreaks. They also provide insight into the genome diversity suggesting purifying selection may be involved in the transmission. Together these results will help in developing strategies to elucidate transmission events and curtail the spread of Sars-Cov-2
Breadth of humoral immune responses to the C-terminus of the circumsporozoite protein is associated with protective efficacy induced by the RTS,S malaria vaccine
Authors: Chaudhury Sidhartha , MacGill Randall S. , Early Angela M. , Bolton Jessica S. , King C. Richter , Locke Emily , Pierson Tony , Wirth Dyann F. , Neafsey Daniel E. , Bergmann-Leitner Elke S. 
Published: November 2020

AbstractThe circumsporozoite protein (CSP) is the main surface antigen of malaria sporozoites and a prime vaccine target. Responses induced by the CSP-based RTS,S vaccine towards the polymorphic C-terminal region of P.falciparum-CSP raise concerns that vaccines using single alleles may have lower efficacy against genotypic variants. We characterized the extent of C-terminal cross-reactivity of antibodies induced by RTS,S (based on the 3D7 allele) with variants representing seven circulating field isolates through a novel HTS-multiplex assay for screening closely related peptides. Reactivity to variants showed approximately 30-fold reduction in recognition relative to 3D7. The degree of reduced cross-reactivity,ranging from 21 to 69-fold, directly correlated with the number of polymorphisms between variants and 3D7. Surprisingly, protection assessed by challenge with 3D7 parasites was strongly associated with higher C-terminal antibody breadth suggesting that C-terminal specific avidity or fine-specificity may play a role in RTS,S/AS01B-mediated protection and that breadth of C-terminal CSP-specific antibody responses may be a marker of protection.
Identifying cell type specific driver genes in autism-associated copy number loci from cerebral organoids
Authors: Lim Elaine T. , Chan Yingleong , Burns Mannix J. , Guo Xiaoge , Erdin Serkan , Tai Derek J.C. , Reichert Julia M. , Chan Ying Kai , Chiang Jessica J. , Meyers Katharina , Zhang Xiaochang , Walsh Christopher A. , Yankner Bruce A. , Raychaudhuri Soumya , Hirschhorn Joel N. , Gusella James F. , Talkowski Michael E. , Church George M. 
Published: November 2020

ABSTRACTNeuropsychiatric and neurodevelopmental disorders have been particularly challenging to study using animal models, and recently, human-derived cerebral organoids demonstrate great promise for discovering molecular processes that are important in these disorders. However, several challenges remain in achieving robust phenotyping to discover cell type specific genes. We perform RNA sequencing on 71 samples comprising of 1,420 cerebral organoids from 25 donors, and describe a framework (Orgo-Seq) to identify cell type specific driver genes, for 16p11.2 deletions and 15q11-13 duplications. We identify neuroepithelial cells as critical cell types for 16p11.2 deletions, and discover novel and previously reported cell type specific driver genes. Finally, we validated our results that mutations inKCTD13in the 16p11.2 locus lead to imbalances in the proportion of neuroepithelial cells, using CRISPR/Cas9-edited mosaic organoids. Our work presents a quantitative discovery and validation framework for identifying cell type specific driver genes associated with complex diseases using cerebral organoids.
Comprehensive mapping of tissue cell architecture via integrated single cell and spatial transcriptomics
Authors: Kleshchevnikov Vitalii , Shmatko Artem , Dann Emma , Aivazidis Alexander , King Hamish W , Li Tong , Lomakin Artem , Kedlian Veronika , Jain Mika Sarkin , Park Jun Sung , Ramona Lauma , Tuck Elizabeth , Arutyunyan Anna , Vento-Tormo Roser , Gerstung Moritz , James Louisa , Stegle Oliver , Bayraktar Omer Ali 
Published: November 2020

AbstractThe spatial organization of cell types in tissues fundamentally shapes cellular interactions and function, but the high-throughput spatial mapping of complex tissues remains a challenge. We present сell2location, a principled and versatile Bayesian model that integrates single-cell and spatial transcriptomics to map cell typesin situin a comprehensive manner. We show that сell2location outperforms existing tools in accuracy and comprehensiveness and we demonstrate its utility by mapping two complex tissues. In the mouse brain, we use a new paired single nucleus and spatial RNA-sequencing dataset to map dozens of cell types and identify tissue regions in an automated manner. We discover novel regional astrocyte subtypes including fine subpopulations in the thalamus and hypothalamus. In the human lymph node, we resolve spatially interlaced immune cell states and identify co-located groups of cells underlying tissue organisation. We spatially map a rare pre-germinal centre B-cell population and predict putative cellular interactions relevant to the interferon response. Collectively our results demonstrate how сell2location can serve as a versatile first-line analysis tool to map tissue architectures in a high-throughput manner.
Evolution of two-component quorum sensing systems
Authors: Giannakara Marina , Koumandou Vassiliki Lila 
Published: November 2020

AbstractQuorum sensing (QS) is a cell-to-cell communication system that enables bacteria to coordinate their gene expression depending on their population density, via the detection of small molecules called autoinducers. In this way bacteria can act collectively to initiate processes like bioluminescence, virulence and biofilm formation. Autoinducers are detected by receptors, some of which are part of Two Component Signal Transduction Systems (TCS), which comprise of a (usually membrane-bound) sensor histidine kinase (HK) and a cognate response regulator (RR). Different QS systems are used by different bacterial taxa, and their relative evolutionary relationships have not been extensively studied. To address this, we used the KEGG database to identify all the QS HKs and RRs that are part of TCS and examined their conservation across microbial taxa. We compared the combinations of the highly conserved domains in the different families of receptors and response regulators using the SMART and KEGG databases, and we also carried out phylogenetic analyses for each family, and all families together. The distribution of the different QS systems across taxa, indicates flexibility in HK/RR pairing, and highlights the need for further study of the most abundant systems. For both the QS receptors and the response regulators, our analysis indicates close evolutionary relationships between certain families, highlighting a common evolutionary history which can inform future applications, such as the design of novel inhibitors for pathogenic QS systems.
Trimeric SARS-CoV-2 Spike proteins produced from CHO-cells in bioreactors are high quality antigens
Authors: Pino Paco , Kint Joeri , Kiseljak Divor , Agnolon Valentina , Corradin Giampietro , Kajava Andrey V. , Rovero Paolo , Dijkman Ronald , den Hartog Gerco , McLellan Jason S. , Byrne Patrick O. , Wurm Maria J , Wurm Florian M 
Published: November 2020

ABSTRACTThe Spike protein of SARS-CoV-2 is essential for virus entry into human cells. In fact, most neutralizing antibodies against SARS-CoV-2 are directed against the Spike, making it the antigen of choice for use in vaccines and diagnostic tests. In the current pandemic context, global demand for Spike proteins has rapidly increased and could exceed hundreds of grams to kilograms annually. Coronavirus Spikes are large, heavily glycosylated, homotrimeric complexes, with inherent instability. Their poor manufacturability now threatens availability of these proteins for vaccines and diagnostic tests. Here, we outline a scalable, GMP-compliant, chemically defined process for production of a cell secreted, stabilized form of the trimeric Spike protein. The process is chemically defined and based on clonal, suspension-CHO cell populations and on protein purification via a two-step, scalable downstream process. The trimeric conformation was confirmed using electron microscopy and HPLC analysis. Binding to susceptible cells was shown using a virus-inhibition assay. The diagnostic sensitivity and specificity for detection of serum SARS-CoV-2 specific IgG1 was investigated and found to exceed that of Spike fragments (S1 and RBD). The process described here will enable production of sufficient high-quality trimeric Spike protein to meet the global demand for SARS-CoV-2 vaccines and diagnostic tests.
lra: the Long Read Aligner for Sequences and Contigs
Authors: Ren Jingwen , Chaisson Mark JP 
Published: November 2020

AbstractMotivationIt is computationally challenging to detect variation by aligning long reads from single-molecule sequencing (SMS) instruments, or megabase-scale contigs from SMS assemblies. One approach to efficiently align long sequences is sparse dynamic programming (SDP), where exact matches are found between the sequence and the genome, and optimal chains of matches are found representing a rough alignment. Sequence variation is more accurately modeled when alignments are scored with a gap penalty that is a convex function of the gap length. Because previous implementations of SDP used a linear-cost gap function that does not accurately model variation, and implementations of alignment that have a convex gap penalty are either inefficient or use heuristics, we developed a method, lra, that uses SDP with a convex-cost gap penalty. We use lra to align long-read sequences from PacBio and Oxford Nanopore (ONT) instruments as well asde novoassembly contigs.ResultsAcross all data types, the runtime of lra is between 52-168% of the state of the art aligner minimap2 when generating SAM alignment, and 9-15% of an alternative method, ngmlr. This alignment approach may be used to provide additional evidence of SV calls in PacBio datasets, and an increase in sensitivity and specificity on ONT data with current SV detection algorithms. The number of calls discovered using pbsv with lra alignments are within 98.3-98.6% of calls made from minimap2 alignments on the same data, and give a nominal 0.2-0.4% increase in F1 score by Truvari analysis. On ONT data with SV called using Sniffles, the number of calls made from lra alignments is 3% greater than minimap2-based calls, and 30% greater than ngmlr based calls, with a 4.6-5.5% increase in Truvari F1 score. When applied to calling variation from de novo assembly contigs, there is a 5.8% increase in SV calls compared to minimap2+paftools, with a 4.3% increase in Truvari F1 score.Availability and implementationAvailable in bioconda:https://anaconda.org/bioconda/lraand github:https://github.com/ChaissonLab/LRAContactmchaisso@usc.edu,jingwenr@usc.edu
Chondrocytes in the resting zone of the growth plate are maintained in a Wnt-inhibitory environment
Authors: Hallett Shawn A. , Ono Wanida , Matsushita Yuki , Sakagami Naoko , Mizuhashi Koji , Tokavanich Nicha , Nagata Mizuki , Zhou Annabelle , Hirai Takao , Kronenberg Henry M. , Ono Noriaki 
Published: November 2020

AbstractChondrocytes in the resting zone of the postnatal growth plate are characterized by slow cell cycle progression, and encompass a population of parathyroid hormone-related protein (PTHrP)-expressing skeletal stem cells that contribute to the formation of columnar chondrocytes. However, how these chondrocytes are maintained in the resting zone remains undefined. We undertook a genetic pulse-chase approach to isolate slow cycling, label-retaining chondrocytes (LRCs) from the growth plate using a chondrocyte-specific doxycycline-controllable Tet-Off system regulating expression of histone 2B-linked GFP. Comparative RNA-seq analysis identified significant enrichment of inhibitors and activators for Wnt/β-catenin signaling in LRCs and non-LRCs, respectively. Activation of Wnt/β-catenin signaling in PTHrP+resting chondrocytes usingPthrp-creERandApc-floxed allele impaired their ability to form columnar chondrocytes. Therefore, slow-cycling chondrocytes are maintained in a canonical Wnt-inhibitory environment within the resting zone, unraveling a novel mechanism regulating maintenance and differentiation of PTHrP+skeletal stem cells of the postnatal growth plate.
Design and implementation of an intelligent framework for supporting evidence-based treatment recommendations in precision oncology
Authors: Lin Frank P.Y. 
Published: November 2020

AbstractBACKGROUNDThe advances in genome sequencing technologies have provided new opportunities for delivering targeted therapy to patients with advanced cancer. However, these high-throughput assays have also created a multitude of challenges for oncologists in treatment selection, demanding a new approach to support decision-making in clinics.METHODSTo address this unmet need, this paper describes the design of a symbolic reasoning framework using the method of hierarchical task analysis. Based on this framework, an evidence-based treatment recommendation system was implemented for supporting decision-making based on a patient’s clinicopathologic and biomarker profiles.RESULTSThis intelligent framework captures a six-step sequential decision process: (1) concept expansion by ontology matching, (2) evidence matching, (3) evidence grading and value-based prioritisation, (4) clinical hypothesis generation, (5) recommendation ranking, and (6) recommendation filtering. The importance of balancing evidence-based and hypothesis-driven treatment recommendations is also highlighted. Of note, tracking history of inference has emerged to be a critical step to allow rational prioritisation of recommendations. The concept of inference tracking also enables the derivation of a novel measure — level of matching — that helps to convey whether a treatment recommendation is drawn from incomplete knowledge during the reasoning process.CONCLUSIONSThis framework systematically encapsulates oncologist’s treatment decisionmaking process. Further evaluations in prospective clinical studies are warranted to demonstrate how this computational pipeline can be integrated into oncology practice to improve outcomes.
Epigenetic Instability May Alter Cell State Transitions and Anticancer Drug Resistance
Authors: Saini Anshul , Gallo James M. 
Published: November 2020

AbstractDrug resistance is a significant obstacle to successful and durable anti-cancer therapy. Targeted therapy is often effective during early phases of treatment; however, eventually cancer cells adapt and transition to drug-resistant cells states rendering the treatment ineffective. It is proposed that cell state can be a determinant of drug efficacy and manipulated to affect the development of anticancer drug resistance. In this work, we developed two stochastic cell state models – referenced to brain tumors - that included transcriptionally-permissive and -restrictive states based on the underlying hypothesis that epigenetic instability mitigates lock-in of drug-resistant states. One model used single-step state transitions, whereas the other considered a multi-step process to lock-in drug resistance. The latter model showed that with moderate epigenetic instability the drug-resistant cell populations were reduced, on average, by 60%, whereas a high level of epigenetic disruption reduced them by about 90%. Generation of epigenetic instability via epigenetic modifier therapy could be a viable strategy to mitigate anticancer drug resistance.
Reduced alpha amplitudes predict perceptual suppression
Authors: Poland Eva , Bhonsle Aishwarya , Steinmann Iris , Wilke Melanie 
Published: November 2020

ABSTRACTThe amplitude of prestimulus alpha oscillations over parieto-occipital cortex has been shown to predict visual detection of masked and threshold-level stimuli. Whether alpha activity similarly predicts target visibility in perceptual suppression paradigms, another type of illusion commonly used to investigate visual awareness, is presently unclear. Here, we examined prestimulus alpha activity in the electroencephalogram (EEG) of healthy participants in the context of a generalized flash suppression (GFS) task during which salient target stimuli are rendered subjectively invisible in a subset of trials following the onset of a full-field motion stimulus. Unlike for masking or threshold paradigms, alpha (8-12 Hz) amplitude prior to motion onset was significantly higher when targets remained subjectively visible compared to trials during which the targets became perceptually suppressed. Furthermore, individual prestimulus alpha amplitudes strongly correlated with the individual trial-to-trial variability quenching following motion stimulus onset, indicating that variability quenching in visual cortex is closely linked to prestimulus alpha activity. We conclude that predictive correlates of conscious perception derived from perceptual suppression paradigms differ substantially from those of obtained with “near threshold paradigms”, possibly reflecting the effectiveness of the suppressor stimulus.
Genomic and anatomical comparisons of skin support independent adaptation to life in water by cetaceans and hippos
Authors: Springer Mark S. , Guerrero-Juarez Christian F. , Huelsmann Matthias , Collin Matthew A. , Danil Kerri , McGowen Michael R. , Oh Ji Won , Ramos Raul , Hiller Michael , Plikus Maksim V. , Gatesy John 
Published: November 2020

SUMMARYThe macroevolutionary transition from terra firma to obligatory inhabitance of the marine hydrosphere has occurred twice in the history of Mammalia: Cetacea and Sirenia. In the case of Cetacea (whales, dolphins, porpoises), molecular phylogenies provide unambiguous evidence that fully aquatic cetaceans and semiaquatic hippopotamids (hippos) are each other’s closest living relatives. Ancestral reconstructions further suggest that some adaptations to the aquatic realm evolved in the common ancestor of Cetancodonta (Cetacea+Hippopotamidae). An alternative hypothesis is that these adaptations evolved independently in cetaceans and hippos. Here, we focus on the integumentary system and evaluate these hypotheses by integrating new histological data for cetaceans and hippos, the first genome-scale data for pygmy hippopotamus, and comprehensive genomic screens and molecular evolutionary analyses for protein-coding genes that have been inactivated in hippos and cetaceans. We identified ten skin-related genes that are inactivated in both cetaceans and hippos, including genes that are related to sebaceous glands, hair follicles, and epidermal differentiation. However, none of these genes exhibit inactivating mutations that are shared by cetaceans and hippos. Mean dates for the inactivation of skin genes in these two clades serve as proxies for phenotypic changes and suggest that hair reduction/loss, the loss of sebaceous glands, and changes to the keratinization program occurred ~16 million years earlier in cetaceans (~46.5 Ma) than in hippos (~30.5 Ma). These results, together with histological differences in the integument and prior analyses of oxygen isotopes from stem hippopotamids (“anthracotheres”), support the hypothesis that aquatic adaptations evolved independently in hippos and cetaceans.
Multiscale PHATE Exploration of SARS-CoV-2 Data Reveals Multimodal Signatures of Disease
Authors: Kuchroo Manik , Huang Jessie , Wong Patrick , Grenier Jean-Christophe , Shung Dennis , Tong Alexander , Lucas Carolina , Klein Jon , Burkhardt Daniel , Gigante Scott , Godavarthi Abhinav , Israelow Benjamin , Mao Tianyang , Oh Ji Eun , Silva Julio , Takahashi Takehiro , Odio Camila D. , Casanovas-Massana Arnau , Fournier John ,   Yale IMPACT Team, Farhadian Shelli , Dela Cruz Charles S. , Ko Albert I. , Wilson F. Perry , Hussin Julie , Wolf Guy , Iwasaki Akiko , Krishnaswamy Smita 
Published: November 2020

1SummaryThe biomedical community is producing increasingly high dimensional datasets, integrated from hundreds of patient samples, which current computational techniques struggle to explore. To uncover biological meaning from these complex datasets, we present an approach called Multiscale PHATE, which learns abstracted biological features from data that can be directly predictive of disease. Built on a continuous coarse graining process called diffusion condensation, Multiscale PHATE creates a tree of data granularities that can be cut at coarse levels for high level summarizations of data, as well as at fine levels for detailed representations on subsets. We apply Multiscale PHATE to study the immune response to COVID-19 in 54 million cells from 168 hospitalized patients. Through our analysis of patient samples, we identify CD16hiCD66bloneutrophil and IFNγ+GranzymeB+Th17 cell responses enriched in patients who die. Further, we show that population groupings Multiscale PHATE discovers can be directly fed into a classifier to predict disease outcome. We also use Multiscale PHATE-derived features to construct two different manifolds of patients, one from abstracted flow cytometry features and another directly on patient clinical features, both associating immune subsets and clinical markers with outcome.