bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct tumor-immune ecologies in NSCLC patients predict progression and define a clinical biomarker of therapy response
Authors: Prabhakaran Sandhya , Gatenbee Chandler , Robertson-Tessi Mark , Beg Amer A. , Gray Jhanelle , Antonia Scott , Gatenby Robert A. , Anderson Alexander R. A. 
Published: October 2022

1.AbstractLung cancer is the leading cause of cancer death worldwide with 1.76 million people die as a result of the disease yearly. Analyzing high-throughput multiplexed images of tissues has recently emerged as a routine clinical procedure for early detection, clinical cancer diagnosis, treatment planning and prognosis for many cancer types including non-small cell lung cancer (NSCLC). Multiplexed images enable the precise interpretation of spatial distribution of cells and cellular states and the characterization of tumor-immune interactions in situ and at the single-cell level. Through two cornerstone image processing techniques - cell segmentation and image tiling generating quadrats - we perform an in-depth analysis of multiplexed images based on the frequency, phenotype, and spatial distribution of immune and tumor cells within the immune landscape of NSCLC. Multiplexed images were obtained from nine patients with advanced/metastatic NSCLC with progression who were treated with an oral HDAC inhibitor (vorinostat) combined with a PD-1 inhibitor (pembrolizumab). Images were collected from all patients both pre- and on-treatment (days 15-21). We profile ∼100K cells and ∼10K quadrats from tumor and adjacent tissues to characterize cellular composition and spatial neighborhoods and elucidate that distinct spatial cellular ecologies exist across progressive disease (PD) and stable disease (SD) patients where tumors of PD patients are characterized by a highly suppressed immune environment prior to treatment enabling higher chances of disease progression during treatment. These fundamentally distinct architectures across PD and SD patients enable disease progression prediction and clinical biomarker identification. Our results also provide a potential companion biomarker for PD-L1 in NSCLC. Validating the biomarker and its feasibility will require further in-depth investigation.
Unsupervised Discovery of Ancestry Informative Markers and Genetic Admixture Proportions in Biobank-Scale Data Sets
Authors: Ko Seyoon , Chu Benjamin B. , Peterson Daniel , Okenwa Chidera , Papp Jeanette C. , Alexander David H. , Sobel Eric M. , Zhou Hua , Lange Kenneth L. 
Published: October 2022

AbstractAdmixture estimation plays a crucial role in ancestry inference and genomewide association studies (GWAS). Computer programs such as ADMIXTURE and STRUCTURE are commonly employed to estimate the admixture proportions of sample individuals. However, these programs can be overwhelmed by the computational burdens imposed by the 105to 106samples and millions of markers commonly found in modern biobanks. An attractive strategy is to run these programs on a set of ancestry informative SNP markers (AIMs) that exhibit substantially different frequencies across populations. Unfortunately, existing methods for identifying AIMs require knowing ancestry labels for a subset of the sample. This supervised learning approach creates a chicken and the egg scenario. In this paper, we present an unsupervised, scalable framework that seamlessly carries out AIM selection and likelihood-based estimation of admixture proportions. Our simulated and real data examples show that this approach is scalable to modern biobank data sets. Our implementation of the method is called OpenADMIXTURE.
Genomic Variation, Population Structure, and Gene Flow across Asian Pikas
Authors: Dahal Nishma , Romine Melia G , Khatiwada Sunita , Ramakrishnan Uma , Lamichhaney Sangeet 
Published: October 2022

AbstractAsian pikas have one of the most complex systematics and evolutionary history. The Himalayas is an important habitat for Asian pikas as it hosts 23 – 25% of pika’s global diversity and has provided the ancestral training ground for local adaptation to high altitudes. They are one of the most abundant species in the Himalayas and Qinghai Tibetan Plateau (QTP), however genetic studies to explore their population structure and evolution are limited. Here, we utilize a population genomics approach using ~28,000 genome-wide SNP markers obtained from restriction-site associated DNA sequencing in six species of Asian Pikas(Ochotonaspp.)that are distributed across the Himalayas and neighboring high-altitude mountains. We examined intra- and inter-species genetic diversity, population structure, phylogenetic history and explored processes that shaped the current genetic diversity of Pikas across the Himalayas. We identified low nucleotide diversity and high inbreeding coefficient across all species which possibly indicated decreasing population size in these species. We also identified extensive evidence of gene flow (both historic and contemporary) across these species. Our findings indicate that inter-species gene flow is a key evolutionary process that has been countering the negative effect of low genetic diversity among Asian pikas.
The conformational ensemble of an intrinsically disordered protein explains peak shapes under DNP conditions
Authors: Kragelj Jaka , Dumarieh Rania , Xiao Yiling , Frederick Kendra K. 
Published: October 2022

ABSTRACTElucidating the conformational preferences of regions of intrinsic disorder in biologically relevant contexts represents a frontier of structural biology. The sensitivity enhancements conferred by DNP enable structural studies of proteins in native contexts by MAS NMR. However, DNP requires low temperatures which results in broad peaks, particularly for for regions of intrinsic disorder. We describe an approach to predict and interpret peak shapes for frozen regions of intrinsic disorder in terms of dihedral angle populations. We demonstrate the method using the protein a-synuclein. This approach can be used to obtain experimental structural restraints for regions of intrinsic disorder in both simplified and biological settings, providing information that eludes characterization by diffraction-based methods as well as solution-state NMR spectroscopy and molecular dynamics due to molecular size limitations.
Transcription-replication interactions reveal principles of bacterial genome regulation
Authors: Pountain Andrew W. , Jiang Peien , Yao Tianyou , Homaee Ehsan , Guan Yichao , Podkowik Magdalena , Shopsin Bo , Torres Victor J. , Golding Ido , Yanai Itai 
Published: October 2022

AbstractOrganisms determine the transcription rates of thousands of genes through a few modes of regulation that recur across the genome. These modes interact with a changing cellular environment to yield highly dynamic expression patterns. In bacteria, the relationship between a gene’s regulatory architecture and its expression is well understood for individual model gene circuits. However, a broader perspective of these dynamics at the genome-scale is lacking, in part because bacterial transcriptomics have hitherto captured only a static snapshot of expression averaged across millions of cells. As a result, the full diversity of gene expression dynamics and their relation to regulatory architecture remains unknown. Here we present a novel genome-wide classification of regulatory modes based on each gene’s transcriptional response to its own replication, which we term the Transcription-Replication Interaction Profile (TRIP). We found that the response to the universal perturbation of chromosomal replication integrates biological regulatory factors with biophysical molecular events on the chromosome to reveal a gene’s local regulatory context. While the TRIPs of many genes conform to a gene dosage-dependent pattern, others diverge in distinct ways, including altered timing or amplitude of expression, and this is shaped by factors such as intra-operon position, repression state, or presence on mobile genetic elements. Our transcriptome analysis also simultaneously captures global properties, such as the rates of replication and transcription, as well as the nestedness of replication patterns. This work challenges previous notions of the drivers of expression heterogeneity within a population of cells, and unearths a previously unseen world of gene transcription dynamics.
Forest bird decline and community change over 19 years in long-isolated South Asian tropical rainforest fragments
Authors: Surendra Akshay , Raman T. R. Shankar 
Published: October 2022

AbstractRecent evidence of forest bird declines worldwide is attributed to climate change and its interactive effects with recent land-use changes such as forest loss and fragmentation, and avian life-history traits. In Asian tropical forests, such effects are poorly understood as long-term data are lacking from fragments that are long-isolated rather than recently fragmented. Here, we use data from ~2000 point-counts from bird surveys carried out between 2000 – 2005 and 2019 in 19 long-isolated (~80 y) South Asian tropical rainforest fragments to examine changes in bird species richness, density, and composition in relation to fragment area (0.7 – 4310 ha), habitat structure, and time. Over the 19 y timespan, despite stable fragment areas, we uncovered a 29% decline in rainforest bird density and 7% decline in individual-rarefied species richness of rainforest birds, while density and richness of open-country birds remained stable. With increasing fragment area, rainforest bird species richness (jackknife estimate) increased, while open country bird richness (individual-rarefied) and density decreased. Larger fragments housed more compositionally stable bird communities, while poorer habitat was associated with lower diversity of rainforest birds but higher diversity, density, and compositional variation of open-country birds. Threshold analysis however indicated relatively small area thresholds (~20 ha) for rainforest bird species abundance. Besides identifying alarming declines in rainforest birds, the study confirms some but not all predictions for bird diversity in long-isolated forest fragments with stable forest-matrix boundaries, indicating that small fragments and habitat quality also matter.
Methods for Evaluating Effects of Transgenes for Quantitative Traits
Authors: Linares Julien F. , Coles Nathan D. , Mo Hua , Habben Jeffrey E. , Humbert Sabrina , Messina Carlos , Tang Tom , Cooper Mark , Gho Carla , Carrasco Ricardo , Carter Javier , Wicher Flounders Jillian , Brummer E. Charles 
Published: October 2022

ABSTRACTTransgenes that improve quantitative traits have traditionally been evaluated in one or a few genetic backgrounds across multiple environments. However, testing across multiple genetic backgrounds can be equally important to accurately quantify the value of a transgene for breeding objectives. Creating near-isogenic lines across a wide germplasm space is costly and time consuming, which renders it impractical during early stages of testing. In this experiment, we evaluate three approaches to sample the genetic space while concurrently testing across environments. We created both transgenic and non-transgenic doubled haploid lines, F2:3lines, and bulk F3families to determine if all methods resulted in similar estimation of transgene value and to identify the number of yield trial plots from each method necessary to obtain a stable estimate of the transgene value. With one exception, the three methods consistently estimated a similar effect of the transgene. We suggest that bulked F3lines topcrossed to a tester inbred is the most effective method to estimate the value of a transgene across both genetic space and environments.
Genomic epidemiology ofCorynebacterium diphtheriaein New Caledonia
Authors: Tessier Eve , Hennart Melanie , Badell Edgar , Passet Virginie , Toubiana Julie , Biron Antoine , Gourinat Ann-Claire , Merlet Audrey , Colot Julien , Brisse Sylvain 
Published: October 2022

AbstractObjectivesAn increasing number of isolations ofCorynebacterium diphtheriaehas been observed in recent years in the archipelago of New Caledonia. We aimed to analyze the clinical and microbiological features of samples withC. diphtheriae.MethodsAllC. diphtheriaeisolates identified in New Caledonia from May 2015 to May 2019 were included. For each case, a retrospective consultation of the patient files was conducted. Antimicrobial susceptibility phenotypes,toxgene and diphtheria toxin expression, biovar and the genomic sequence were determined. Core genome multilocus sequence typing (cgMLST), 7-gene MLST and search of genes of interest were performed from genomic assemblies.Results58 isolates were included, with a median age of patients of 28 years (range: 9 days to 78 years). Cutaneous origin accounted for 51 of 58 (87.9%) isolates, andC. diphtheriaewas associated withStaphylococcus aureusand/orStreptococcus pyogenesin three quarters of cases. Half of cases came either from the main city Noumea (24%, 14/58) or from the sparsely populated island of Lifou (26%, 15/58). Six tox-positive isolates were identified, associated with recent travel to Vanuatu; 5 of these cases were linked and cgMLST confirmed recent transmission. Two cases of endocarditis in young female patients with a history of rheumatic fever involved tox-negative isolates. The 58 isolates were mostly susceptible to commonly used antibiotics. In particular, no isolate was resistant to the first-line molecules amoxicillin or erythromycin. Resistance to tetracycline was found in a genomic cluster of 17 (29%) isolates, 16 of which carried thetetOgene. There were 13 cgMLST sublineages, most of which were also observed in the neighboring country Australia.ConclusionsCutaneous infections may harbor non-toxigenicC. diphtheriaeisolates, which circulate largely silently in non-specific wounds. The possible introduction of tox-positive strains from a neighboring island illustrates that diphtheria surveillance should be maintained in New Caledonia, and that immunization in neighboring islands must be improved. Genomic sequencing uncovers how genotypes circulate locally and across neighboring countries.
Eusocial evolution without a nest: kin structure of social aphids forming open colonies on bamboo
Authors: Uematsu Keigo , Yang Man-Miao , Amos William , Foster William A. 
Published: October 2022

AbstractLiving in nests is an almost universal feature of eusocial animals. In some aphids, however, sterile soldier castes have evolved in open colonies without a nest. To clarify the factors promoting the evolution of eusociality in these colonies, we used newly developed microsatellite markers to compare the kin structure of the open colonies of two aphid species on bamboo: the non-eusocial colonies ofAstegopteryx bambucifoliaeand the eusocial colonies ofPseudoregma alexanderionDendrocalamus latiflorus.Our samples, from over 1,000 hectares, contained 99 clones ofA. bambucifoliaeand 19 ofP. alexanderi. Clonal mixing occurred in both species: average pairwise relatedness within a colony was 0.54 inA. bambucifoliaeand 0.71 inP. alexanderi. Each clone ofA. bambucifoliaeoccurred in a unique location, whereas those ofP. alexanderi occurred in multiple locations and more than 90% of individuals came from just four clones. There was significant genetic variation among different colonies in the same clump (stem-cluster) inA. bambucifoliaebut not inP. alexanderi, indicating thatP. alexandericolonies in a single clump are genetically homogenized, functioning as a large colony. InP. alexanderi, the proportion of sterile soldiers to normal first-instar nymphs was significantly different across the four clones.Our results indicate that the lack of input of migrants from the primary host and feeding on a large, stable host plant are important ecological factors that might favour the evolution of eusociality, enabling the production of genetically homogenised, large, and long-lived colonies. After eusociality evolves on the secondary host, the optimal strategy of soldier production might vary between different clones.Significance StatementNest-living has often been considered to be a necessary condition for the evolution of eusociality. In a small number of aphid species, however, sterile soldier castes have evolved in open colonies without a nest. To understand why these aphids are unique, we examined the kin structure and genetic relatedness of individuals within eusocial and non-eusocial open colonies of two aphid species on bamboo. We found that clonal mixing occurred in both species, but the eusocial colonies are more genetically homogenized, functioning as a large colony. Our results suggest that ecological conditions that promote genetically homogenized, large and long-lived colonies are important for the evolution of eusociality in these aphids. We propose that the open colonies of social aphids provide an ideal model system in which to study the evolution of altruism.
Microsecond pulse electrical stimulation modulates cell migration
Authors: Xiang Xiao-Wei , Liu Hao-Tian , Liu Wei , Yan Ze-Yao , Zeng Yu-Lian , Wang Ya-Jun , Liu Jing , Chen Yu-Chen , Yu Sai-Xi , Zhu Cai-Hui , Tao Xiao-Nan , Wang Chen , Wu Jin-Tao , Du Yang , Xu Xin-Xin , Gao Hai , Jiu Yaming , Ma Jiong , Qiu Jian , Chang Lingqian , Jing Guangyin , Liu Ke-Fu , Liu Yan-Jun 
Published: October 2022

AbstractWound healing is a complicated process for maintaining skin integrity after injury, for which electrical stimulations (ES) are ascribed to promote wound healing by facilitating cell migration. Time-shortening of the stimulation treatment from current hours to minutes for efficient wound healing but free of cell damage in return, is however rather a challenge. Here, a novel mechanism of ultrashort pulse electric field (PEF), microsecond PEF at higher voltage, is proposed and realized to promote wound healing under a much short time (seconds) for the total treatment. We revealed that microsecond PEF regulated actin cytoskeleton reorganization and focal adhesion turnover, promoting fibroblasts migration in 2D cell cultures under the pulse stimulation. This accelerated fibroblast migration was accompanied by the mutual promotion with extracellular matrix (ECM) alignment in 3D microenvironments, which cooperatively benefit the eventual wound healing, and these findings were further confirmed by the enhanced skin wound healing in a classic mouse model. Additionally, we coined an actin- and collagen-dependent mechanism of microsecond PEF-mediated wound healing. The quantitative mechanism proposed here for our novel microsecond pulse electric filed (μsPEF) methodology orients the new practical electric treatment in a wide range of biomedical applications, such as wound healing, regenerative medicine, and tissue engineering.
Astrocytic Sleep Homeostasis Model
Authors: Singh Ghanendra 
Published: October 2022

AbstractSleep awake cycle is critical for cognitive and functional abilities. Conventional sleep homeostasis mechanisms are neuronal in nature and recent views indicate glial regulation of the sleep-wake process. Mechanisms of homeostatic regulation of sleep remain to be understood. A simplified astrocytic sleep-awake homeostasis mathematical model with sleep pressure and synaptic strength dynamics is proposed using feedback control loops. The model provides insights into the emergence of two discrete states through sleep and awake promoting neuronal populations giving rise to a homeostatic process S and oscillatory process C is regulated by astrocytic sleep pressure. It also explains the variations seen in synaptic strength dynamics during sleep and awake states.
Defining amino acid pairs as structural units suggests mutation sensitivity to adjacent residues
Authors: Rosenberg Aviv A. , Yehishalom Nitsan , Marx Ailie , Bronstein Alex 
Published: October 2022

AbstractProteins fold from chains of amino acids, forming secondary structures, α-helices and β-strands, that, at least for globular proteins, subsequently fold into a three-dimensional structure. A large-scale analysis of high-resolution protein structures suggests that amino acid pairs constitute another layer of ordered structure, more local than these conventionally defined secondary structures. We develop a cross-peptide-bond Ramachandran plot that captures the conformational preferences of the amino acid pairs and show that the effect of a particular mutation on the stability of a protein depends in a predictable manner on the adjacent amino acid context.One-Sentence SummaryLarge-scale protein backbone analysis reveals amino acid pair conformational preferences and predicts how sequence context affects mutant stability.
OPS-γδ: allogeneic opsonin-secreting γδT cell immunotherapy for solid tumours mediates direct and bystander immunity
Authors: Fowler D , Barisa M , Southern A , Nattress C , Hawkins E , Vassalou E , Kanouta A , Counsell J , Rota E , Vlckova P , Draper B , Tape C , Chester K , Anderson J , Fisher J 
Published: October 2022

AbstractT cell-based cancer immunotherapy has typically relied on membrane-bound cytotoxicity enhancers such as chimeric antigen receptors expressed in autologous αβT cells. These approaches are limited by tonic signalling of synthetic constructs and costs associated with manufacture of bespoke patient products. γδT cells are an emerging alternative chassis for cellular therapy, possessing innate anti-tumour activity, potent antibody-dependent cytotoxicity (ADCC) and minimal alloreactivity. We present an immunotherapeutic platform technology built around the Vγ9Vδ2 γδT cell chassis, harnessing specific characteristics of this cell type and offering an allo-compatible means of delivering cellular therapy that recruits bystander immunity. We engineered γδT cells to secrete synthetic opsonins and stabilized IL15 (stIL15). Using GD2 as a model antigen we show how opsonin-secreting Vγ9Vδ2 (OPS-γδ) have enhanced cytotoxicity and also confer this benefit on lymphoid and myeloid bystander cells. Reflecting the secreted nature of the engineered efficacy modules, the entire product rather than just the gene-modified fraction exhibited enhanced activation and cytotoxic profiles, superior persistence and proliferative capacity even upon repeated tumour challenge. Secretion of stIL15 abrogated the need for exogenous cytokine supplementation during expansion and further mediated functional licensing of bystander NK cells. Compared to unmodified γδT cells, stIL15-OPS-γδ cells exhibited superiorin-vivocontrol of subcutaneous tumour and persistence in the blood. stIL15-OPS-γδ cells were further efficacious in 3D patient-derived osteosarcoma models, where efficacy could be boosted with the addition of immunomodulatory aminobisphosphonate drug, zoledronic acid. Together the data identify stIL15-OPS-γδ cells as a novel allogeneic platform combining direct cytolysis with bystander activation to effect solid tumour control.One Sentence SummaryArmoured, opsonin-secreting OPS-γδ cell immunotherapy is built on the innate strengths of the Vγ9Vδ2 cell chassis for allogeneic solid tumour targeting.