bluuebunny/crossref_metadata_2025_split huggingface dataset:
The breast pre-cancer atlas illustrates the molecular and micro-environmental diversity of ductal carcinoma in situ
Authors: Nachmanson Daniela , Officer Adam , Mori Hidetoshi , Gordon Jonathan , Evans Mark F. , Steward Joseph , Yao Huazhen , O’Keefe Thomas , Hasteh Farnaz , Stein Gary S. , Jepsen Kristen , Weaver Donald L. , Hirst Gillian L. , Sprague Brian L. , Esserman Laura J. , Borowsky Alexander D. , Stein Janet L. , Harismendy Olivier 
Published: May 2021

AbstractMicro-environmental and molecular factors mediating the progression of Breast Ductal Carcinoma In Situ (DCIS) are not well understood, impeding the development of prevention strategies and the safe testing of treatment de-escalation. We addressed methodological barriers and characterized the mutational, transcriptional, histological and microenvironmental landscape across 85 multiple micro-dissected regions from 39 cases. Most somatic alterations, including whole genome duplications, were clonal, but genetic divergence increased with physical distance. Phenotypic and subtype heterogeneity frequently associated with underlying genetic heterogeneity and regions with low-risk features preceded those with high-risk features according to the inferred phylogeny. B- and T-lymphocytes spatial analysis identified 3 immune states, including an epithelial excluded state located preferentially at DCIS regions, and characterized by histological and molecular features of immune escape, independently from molecular subtypes. Such breast pre-cancer atlas with uniquely integrated observations will help scope future expansion studies and build finer models of outcomes and progression risk.
Incorporating topological and age uncertainty into event-based biogeography supports paleo-islands in Galapagos and ancient connections among Neotropical dry forests
Authors: Magalhaes Ivan L. F. , Santos Adalberto J. , Ramírez Martín J. 
Published: May 2021

AbstractEvent-based biogeographic methods, such as dispersal-extinction-cladogenesis, have become increasingly popular for attempting to reconstruct the biogeographic history of organisms. Such methods employ distributional data of sampled species and a dated phylogenetic tree to estimate ancestral distribution ranges. Because the input tree is often a single consensus tree, uncertainty in topology and age estimates are seldom taken into account, even when they may affect the outcome of biogeographic estimates. Even when such uncertainties are taken into account for estimates of ancestral ranges, they are usually ignored when researchers compare competing biogeographic hypotheses. We explore the effect of incorporating this uncertainty in a biogeographic analysis of the 21 species of sand spiders (Sicariidae: Sicarius) from Neotropical xeric biomes, based on a total-evidence phylogeny including a complete sampling of the genus. By using a custom R script made available here, we account for uncertainty in ages and topology by estimating ancestral ranges over a sample of trees from the posterior distribution of a Bayesian analysis, and for uncertainty in biogeographic estimates by using stochastic maps. This approach allows for counting biogeographic events such as dispersal among areas, counting lineages through time per area, and testing biogeographic hypotheses, while not overestimating the confidence in a single topology. Including uncertainty in ages indicates that Sicarius dispersed to the Galapagos Islands when the archipelago was formed by paleo-islands that are now drowned; model comparison strongly favors a scenario where dispersal took place before the current islands emerged. We also investigated past connections among currently disjunct Neotropical dry forests; failing to account for topological uncertainty underestimates possible connections among the Caatinga and Andean dry forests in favor of connections among Caatinga and Caribbean+Mesoamerican dry forests. Additionally, we find that biogeographic models including a founder-event speciation parameter (“+J”) are more prone to suffer from the overconfidence effects of estimating ancestral ranges using a single topology. This effect is alleviated by incorporating topological and age uncertainty while estimating stochastic maps, increasing the similarity in the inference of biogeographic events between models with or without a founder-event speciation parameter. We argue that incorporating phylogenetic uncertainty in biogeographic hypothesis-testing is valuable and should be a commonplace approach in the presence of rogue taxa or wide confidence intervals in age estimates, and especially when using models including founder-event speciation.
A clusterability measure for single-cell transcriptomics reveals phenotypic subpopulations
Authors: Mircea Maria , Hochane Mazène , Fan Xueying , de Sousa Lopes Susana M. Chuva , Garlaschelli Diego , Semrau Stefan 
Published: May 2021

AbstractThe ability to discover new cell populations by unsupervised clustering of single-cell transcriptomics data has revolutionized biology. Currently, there is no principled way to decide, whether a cluster of cells contains meaningful subpopulations that should be further resolved. Here we present SIGMA, a clusterability measure derived from random matrix theory, that can be used to identify cell clusters with non-random sub-structure, testably leading to the discovery of previously overlooked phenotypes.
Climate risks to carbon sequestration in US forests
Authors: Anderegg William R.L. , Chegwidden Oriana S. , Badgley Grayson , Trugman Anna T. , Cullenward Danny , Abatzoglou John T. , Hicke Jeffrey A. , Freeman Jeremy , Hamman Joseph J. 
Published: May 2021

AbstractForests are currently a substantial carbon sink globally. Many climate change mitigation strategies rely on forest preservation and expansion, but the effectiveness of these approaches hinges on forests sequestering carbon for centuries despite anthropogenic climate change. Yet climate-driven disturbances pose critical risks to the long-term stability of forest carbon. We quantify the key climate drivers that fuel wildfire, drought, and insects, for the United States over 1984-2018 and project future disturbance risks over the 21st century. We find that current risks are widespread and projected to increase across different emission scenarios by a factor of 4-14 for fire and 1.3-1.8 for drought and insects. Our results provide insights for carbon cycle modeling, conservation, and climate policy, underscoring the escalating climate risks facing forests and the need for emissions reductions to mitigate climate change.
Modeling SARS-CoV-2 and Influenza Infections and Antiviral Treatments in Human Lung Epithelial Tissue Equivalents
Authors: Zarkoob Hoda , Allué-Guardia Anna , Chen Yu-Chi , Jung Olive , Garcia-Vilanova Andreu , Song Min Jae , Park Jun-Gyu , Oladunni Fatai , Miller Jesse , Tung Yen-Ting , Kosik Ivan , Schultz David , Yewdell Jonathan , Torrelles Jordi B. , Martinez-Sobrido Luis , Cherry Sara , Ferrer Marc , Lee Emily M. 
Published: May 2021

AbstractSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the third coronavirus in less than 20 years to spillover from an animal reservoir and cause severe disease in humans. High impact respiratory viruses such as pathogenic beta-coronaviruses and influenza viruses, as well as other emerging respiratory viruses, pose an ongoing global health threat to humans. There is a critical need for physiologically relevant, robust and ready to use, in vitro cellular assay platforms to rapidly model the infectivity of emerging respiratory viruses and discover and develop new antiviral treatments. Here, we validate in vitro human alveolar and tracheobronchial tissue equivalents and assess their usefulness as in vitro assay platforms in the context of live SARS-CoV-2 and influenza A virus infections. We establish the cellular complexity of two distinct tracheobronchial and alveolar epithelial air liquid interface (ALI) tissue models, describe SARS-CoV-2 and influenza virus infectivity rates and patterns in these ALI tissues, the viral-induced cytokine production as it relates to tissue-specific disease, and demonstrate the pharmacologically validity of these lung epithelium models as antiviral drug screening assay platforms.
Energy Landscape of the SARS-CoV-2 Reveals Extensive Conformational Heterogeneity
Authors: Mashayekhi Ghoncheh , Vant John , Singharoy Abhishek , Ourmazd Abbas 
Published: May 2021

ABSTRACTCryo-electron microscopy (cryo-EM) has produced a number of structural models of the SARS-CoV-2 spike, already prompting biomedical outcomes. However, these reported models and their associated electrostatic potential maps represent an unknown admixture of conformations stemming from the underlying energy landscape of the spike protein. As for any protein, some of the spike’s conformational motions are expected to be biophysically relevant, but cannot be interpreted only by static models. Using experimental cryo-EM images, we present the energy landscape of the spike protein conformations, and identify molecular rearrangements along the most-likely conformational path in the vicinity of the open (so called 1RBD-up) state. The resulting global and local atomic refinements reveal larger movements than those expected by comparing the reported 1RBD-up and 1RBD-down cryo-EM models. Here we report greater degrees of “openness” in global conformations of the 1RBD-up state, not revealed in the single-model interpretations of the density maps, together with conformations that overlap with the reported models. We discover how the glycan shield contributes to the stability of these conformations along the minimum free-energy pathway. A local analysis of seven key binding pockets reveals that six out them, including those for engaging ACE2, therapeutic mini-proteins, linoleic acid, two different kinds of antibodies, and protein-glycan interaction sites, switch conformations between their known apo- and holo-conformations, even when the global spike conformation is 1RBD-up. This is reminiscent of a conformational pre-equilibrium. We found only one binding pocket, namely antibody AB-C135 to remain closed along the entire minimum free energy path, suggesting an induced fit mechanism for this enzyme.
RTK-dependent inducible degradation of mutant PI3Kα drives GDC-0077 (Inavolisib) efficacy
Authors: Song Kyung W. , Edgar Kyle A. , Hanan Emily J. , Hafner Marc , Oeh Jason , Merchant Mark , Sampath Deepak , Nannini Michelle A. , Hong Rebecca , Phu Lilian , Forrest William F. , Stawiski Eric , Schmidt Stephen , Endres Nicholas , Guan Jane , Wallin Jeffrey J. , Cheong Jonathan , Plise Emile , Philips Gail , Salphati Laurent , Heffron Timothy P. , Olivero Alan , Malek Shiva , Staben Steven T. , Kirkpatrick Donald S. , Dey Anwesha , Friedman Lori S. 
Published: May 2021

AbstractPIK3CA is one of the most frequently mutated oncogenes; the p110α protein it encodes plays a central role in tumor cell proliferation and survival. Small molecule inhibitors targeting the PI3K p110α catalytic subunit have entered clinical trials, with early-phase GDC-0077 (Inavolisib) studies showing anti-tumor activity and a manageable safety profile in patients with PIK3CA-mutant, hormone receptor-positive breast cancer as a single agent or in combination therapy. Despite this, preclinical studies have shown that PI3K pathway inhibition releases negative feedback and activates receptor tyrosine kinase signaling, reengaging the pathway and attenuating drug activity. Here we discover that GDC-0077 and taselisib more potently inhibit mutant PI3K pathway signaling and cell viability through unique HER2-dependent degradation. Both are more effective than other PI3K inhibitors at maintaining prolonged pathway suppression, resulting in enhanced apoptosis and greater efficacy. This unique mechanism against mutant p110α reveals a new strategy for creating inhibitors that specifically target mutant tumors with selective degradation of the mutant oncoprotein and also provide a strong rationale for pursuing PI3Kα degraders in patients with HER2-positive breast cancer.
Remote spatially variant debiased profiling of cell and tissue mechanical properties
Authors: Mason Jonathan H , Luo Lu , Reinwald Yvonne , Taffetani Matteo , Hallas-Potts Amelia , Herrington C Simon , Srsen Vlastimil , Lin Chih-Jen , Barroso Inês A , Zhang Zhihua , Zhang Zhibing , Ghag Anita K. , Yang Ying , Waters Sarah , Haj Alicia El , Bagnaninchi Pierre O 
Published: May 2021

AbstractThe role of the mechanical environment in defining tissue function, development and growth has been shown to be fundamental. Assessment of the changes in stiffness of tissue matrices at multiple scales has relied mostly on invasive and often specialist equipment such as AFM or mechanical testing devices poorly suited to the cell culture workflow.In this paper, we have developed a novel unbiased passive optical coherence elastography method, exploiting ambient vibrations in the sample that enables real-time noninvasive quantitative profiling of cells and tissues. We demonstrate a robust method that decouples optical scattering and mechanical properties by actively compensating for scattering associated noise bias and reducing variance. The efficiency for the method to retrieve ground truth is validated in silico and in vitro, and exemplified for key applications such as time course mechanical profiling of bone and cartilage spheroids, tissue engineering cancer models, tissue repair models and single cell. Our method is readily implementable with any commercial optical coherence tomography system without any hardware modifications, and thus offers a breakthrough in tissue mechanical assessment for novel on line assessment of spatial mechanical properties for organoids, soft tissues and tissue engineering.
Interferon-armed RBD dimer enhances the immunogenicity of RBD for sterilizing immunity against SARS-CoV-2
Authors: Sun Shiyu , Cai Yueqi , Song Tian-Zhang , Pu Yang , Cheng Lin , Xu Hairong , Meng Chaoyang , Lin Yifan , Sun Jing , Zhang Silin , Gao Yu , Han Jian-Bao , Feng Xiao-Li , Yu Dan-Dan , Zhu Yalan , Gao Pu , Tang Haidong , Zhao Jincun , Zhang Zheng , Yang Jiaming , Hu Zenxiang , Fu Yang-Xin , Zheng Yong-Tang , Peng Hua 
Published: May 2021

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global crisis, urgently necessitating the development of safe, efficacious, convenient-to-store, and low-cost vaccine options. A major challenge is that the receptor-binding domain (RBD)-only vaccine fails to trigger long-lasting protective immunity if used solely for vaccination. To enhance antigen processing and cross-presentation in draining lymph nodes (DLNs), we developed an interferon (IFN)-armed RBD dimerized by immunoglobulin fragment (I-R-F). I-R-F efficiently directs immunity against RBD to DLN. A low dose of I-R-F induces not only high titer long-lasting neutralizing antibodies but also comprehensive T cell responses than RBD, and even provides comprehensive protection in one dose without adjuvant. This study shows that the I-R-F vaccine provides rapid and complete protection throughout upper and lower respiratory tracts against high dose SARS-CoV-2 challenge in rhesus macaques. Due to its potency and safety, this engineered vaccine may become one of the next-generation vaccine candidates in the global race to defeat COVID-19.
First description of two immune escape indian B.1.1.420 and B.1.617.1 SARS-CoV2 variants in France
Authors: Garcia Vincent , Vig Véronique , Peillard Laurent , Ramdani Alaa , Mohamed Sofiane , Halfon Philippe 
Published: May 2021

AbstractFollowing the outbreak of the SARS-CoV2 virus worldwide in 2019, the rapid widespread overtime of variants suggests today an undergoing positive selection of variants which could potentially provide advantageous genetic property of the virus. Numerous variants have already been described across different countries including N501Y, E484K or L452R mutations on gene coding to spike protein. Most recently, 2 new Indian variants with N440K and E484Q and L452R mutations associated with impaired antibody response and immune reactions were identified in India. The potential consequences of emerging variants are increased transmissibility, increased pathogenicity and the ability to escape natural or vaccine-induced immunity.We described for the first time in France both variants: the N440K immune escape variant within a new strain detected in France in a couple of patients who did not have any history of travel abroad and the new E484Q and L452R Indian variant from a patient travelling from Indian to Marseille to embark on a ship as a crew member.Such study of the circulating viral strains and their variants within the increasing number of infected people worldwide will provide further insights into the viral dissemination. Hence, real time close monitoring variant could help the scientific community to prevent fast-spreading and raise alarms towards potentially harmful variants.
OVarFlow: a resource optimized GATK 4 based Open source Variant calling workFlow
Authors: Bathke Jochen , Lühken Gesine 
Published: May 2021

AbstractBackgroundNext generation sequencing technologies are opening new doors to researchers. One application is the direct discovery of sequence variants that are causative for a phenotypic trait or a disease. The detection of an organisms alterations from a reference genome is know as variant calling, a computational task involving a complex chain of software applications. One key player in the field is the Genome Analysis Toolkit (GATK). The GATK Best Practices are commonly referred recipe for variant calling on human sequencing data. Still the fact the Best Practices are highly specialized on human sequencing data and are permanently evolving is often ignored. Reproducibility is thereby aggravated, leading to continuous reinvention of pretended GATK Best Practice workflows.ResultsHere we present an automatized variant calling workflow, for the detection of SNPs and indels, that is broadly applicable for model as well as non-model diploid organisms. It is derived from the GATK Best Practice workflow for “Germline short variant discovery”, without being focused on human sequencing data. The workflow has been highly optimized to achieve parallelized data evaluation and also maximize performance of individual applications to shorten overall analysis time. Optimized Java garbage collection and heap size settings for the GATK applications SortSam, MarkDuplicates, HaplotypeCaller and GatherVcfs were determined by thorough benchmarking. In doing so, runtimes of an example data evaluation could be reduced from 67 h to less than 35 h.ConclusionsThe demand for standardized variant calling workflows is proportionally growing with the dropping costs of next generation sequencing methods. Our workflow perfectly fits into this niche, offering automatization, reproducibility and documentation of the variant calling process. Moreover resource usage is lowered to a minimum. Thereby variant calling projects should become more standardized, reducing the barrier further for smaller institutions or groups.
Responsive robotic prey reveal how predators adapt to predictability in escape tactics
Authors: Szopa-Comley Andrew W. , Ioannou Christos C. 
Published: May 2021

AbstractTo increase their chances of survival, prey often respond to predators by being unpredictable when escaping, but the response of predators to such tactics is unknown. We programmed interactive robot-controlled prey to flee from an approaching blue acara predator (Andinoacara pulcher), allowing us to manipulate the predictability of the prey’s initial escape direction. When repeatedly exposed to predictable prey, the predators adjusted their behaviour before the prey even began to escape: prey programmed to escape directly away were approached more rapidly than prey escaping at an acute angle. These faster approach speeds compensated for a longer time needed to capture such prey during the subsequent pursuit phase, and predators showed greater acceleration when pursuing unpredictable prey. Collectively, these behaviours resulted in the prey’s predictability having no net effect on the time to capture prey. Rather than minimising capture times, predators adjust their behaviour to maintain an adequate level of performance.
Comparative Transcriptome Profiling of High and Low oil yielding Santalum album L.
Authors: Fatima Tanzeem , Krishnan Rangachari , Srivastava Ashutosh , Hanur Vageeshbabu S. , Rao M. Srinivasa 
Published: May 2021

AbstractEast Indian Sandalwood (Santalum album L.) is highly valued for its heartwood and its oil. There have been no efforts to comparative study of high and low oil yielding genetically identical sandalwood trees grown in similar climatic condition. Thus we intend to study a genome wide transcriptome analysis to identify the corresponding genes involved in high oil biosynthesis in S. album. In this study, 15 years old S. album (SaSHc and SaSLc) genotypes were targeted for analysis to understand the contribution of genetic background on high oil biosynthesis in S. album. A total of 28,959187 and 25,598869 raw PE reads were generated by the Illumina sequencing. 2.12 million and 1.811 million coding sequences were obtained in respective accessions. Based on the GO terms, functional classification of the CDS 21262, & 18113 were assigned into 26 functional groups of three GO categories; (4,168; 3,641) for biological process (5,758;4,971) cellular component and (5,108;4,441) for molecular functions. Total 41,900 and 36,571 genes were functionally annotated and KEGG pathways of the DEGs resulted 213 metabolic pathways. In this, 14 pathways were involved in secondary metabolites biosynthesis pathway in S. album. Among 237 cytochrome families, nine groups of cytochromes were participated in high oil biosynthesis. 16,665 differentially expressed genes were commonly detected in both the accessions (SaHc and SaSLc). The results showed that 784 genes were upregulated and 339 genes were downregulated in SaHc whilst 635 upregulated 299 downregulated in SaSLc S. album. RNA-Seq results were further validated by quantitative RT-PCR. Maximum Blast hits were found to be against Vitis vinifera. From this study we have identified additional number of cytochrome family in SaHc. The accessibility of a RNA-Seq for high oil yielding sandalwood accessions will have broader associations for the conservation and selection of superior elite samples/populations for further genetic improvement program.