bluuebunny/crossref_metadata_2025_split huggingface dataset:
Shining new light on sensory brain activation and physiological measurement in seals using wearable optical technology
Authors: McKnight J. Chris , Ruesch Alexander , Bennett Kimberley , Bronkhorst Mathijs , Balfour Steve , Moss Simon E. W. , Milne Ryan , Tyack Peter L. , Kainerstorfer Jana M. , Hastie Gordon D. 
Published: June 2021

Sensory ecology and physiology of free-ranging animals is challenging to study but underpins our understanding of decision-making in the wild. Existing non-invasive human biomedical technology offers tools that could be harnessed to address these challenges. Functional near-infrared spectroscopy (fNIRS), a wearable, non-invasive biomedical imaging technique measures oxy- and deoxyhaemoglobin concentration changes that can be used to detect localized neural activation in the brain. We tested the efficacy of fNIRS to detect cortical activation in grey seals (Halichoerus grypus) and identify regions of the cortex associated with different senses (vision, hearing and touch). The activation of specific cerebral areas in seals was detected by fNIRS in responses to light (vision), sound (hearing) and whisker stimulation (touch). Physiological parameters, including heart and breathing rate, were also extracted from the fNIRS signal, which allowed neural and physiological responses to be monitored simultaneously. This is, to our knowledge, the first time fNIRS has been used to detect cortical activation in a non-domesticated or laboratory animal. Because fNIRS is non-invasive and wearable, this study demonstrates its potential as a tool to quantitatively investigate sensory perception and brain function while simultaneously recording heart rate, tissue and arterial oxygen saturation of haemoglobin, perfusion changes and breathing rate in free-ranging animals.This article is part of the theme issue ‘Measuring physiology in free-living animals (Part I)’.
Deaths involving COVID-19 by disability status: a retrospective analysis of 29 million adults during the first two waves of the Coronavirus pandemic in England
Authors: Bosworth Matthew L. , Ayoubkhani Daniel , Nafilyan Vahé , Foubert Josephine , Glickman Myer , Davey Calum , Kuper Hannah 
Published: June 2021

AbstractObjectivesTo assess the association between self-reported disability and deaths involving COVID-19 among adults in England.DesignCohort study of >29 million adults using data from the Office for National Statistics Public Health Data Asset.SettingPeople living in private households or communal establishments (including care homes) in England.Participants29,293,845 adults (47% male) aged 30-100 years (mean age = 56) present at the 2011 Census who were alive on 24 January 2020. The main exposure was self-reported disability from the 2011 Census.Main outcome measuresDeath involving COVID-19, occurring between 24 January 2020 and 28 February 2021. We estimated the age-standardised mortality rate per 100,000 person-years at-risk, stratified by sex, disability status, and wave of the pandemic. We calculated hazard ratios (HRs) for disabled people compared with non-disabled people, adjusted for geographical factors, socio-demographic characteristics, and pre-pandemic health conditions.ResultsDisabled people made up 17% of the study population, including 7% who were ‘more-disabled’ and 10% ‘less-disabled’. From 24 January 2020 to 28 February 2021, 105,213 people died from causes involving COVID-19 in England, 58% of whom were disabled. Age-adjusted analyses showed that, compared to non-disabled people, mortality involving COVID-19 was higher among both more-disabled people (HR=3.05, 95% CI: 2.98 to 3.11 in males; 3.48, 3.41 to 3.56 in females) and less-disabled people (HR=1.88, 95% CI: 1.84 to 1.92 in males; 2.03, 1.98 to 2.08 in females). Among people aged 30-69, HRs reached 8.47 (8.01 to 8.95) among more-disabled females and 5.42 (5.18 to 5.68) for more-disabled males. Sequential adjustment for residence type, geography, socio-demographics, and health conditions partly explained the associations, indicating that a combination of these factors contributed towards the increased risk.ConclusionDisabled people in England had markedly increased risk of mortality involving COVID-19 compared to non-disabled people and should be prioritised within the pandemic response.
FiberSim: a flexible open-source model of myofilament-level contraction
Authors: Kosta S. , Colli D. , Ye Q. , Campbell K. S. 
Published: June 2021

AbstractFiberSim is a flexible open-source model of myofilament-level contraction. The code uses a spatially explicit technique, meaning that it tracks the position and status of each contractile molecule within the lattice framework. This allows the model to simulate some of the mechanical effects modulated by myosin binding protein-C, as well as dose-dependence of myotropes and the effects of varying isoform expression levels. This paper provides a short introduction to FiberSim and presents simulations of tension-pCa curves with and without regulation of thick filament transitions by myosin-binding protein C. The software was designed to be flexible (the user can define their own model and/or protocol) and computationally efficient (simulations can be performed on a regular laptop). We hope that other investigators will use FiberSim to explore myofilament level mechanisms and to accelerate research focusing on the contractile properties of sarcomeres.Statement of significanceMyotropes, such as omecamtiv mecarbil and mavacamten, are new therapeutics that bind directly to sarcomeric proteins. Their clinical development has reenergized interest in mechanistic understanding of sarcomere level function. FiberSim is an open-source spatially-explicit computer model that simulates myofilament level mechanics and can predict how modulating the function of a sarcomeric protein will impact contractility. The software was specifically designed to be flexible and user-friendly and may help to further accelerate myofilament-research.
Anti-SARS-CoV-2 potential of Cissampelos pareira L. identified by Connectivity map-based analysis and in vitro studies
Authors: Haider Madiha , Anand Vivek , Dholakia Dhwani , Enayathullah M. Ghalib , Parekh Yash , Ram Sushma , Kumari Surekha , Anmol  , Bokara Kiran Kumar , Sharma Upendra , Prasher Bhavana , Mukerji Mitali 
Published: June 2021

AbstractBackgroundViral infections have a history of abrupt and severe eruptions through the years in the form of pandemics. And yet, definitive therapies or preventive measures are not present.PurposeHerbal medicines have been a source of various antiviral compounds. An accelerated repurposing potential of antiviral herbs can provide usable drugs and identify druggable targets. In this study, we dissect the anti-coronavirus activity of Cissampelos pareira L (Cipa). using an integrative approach.MethodsWe analysed the signature similarities between predicted antiviral agents and Cipa using the connectivity map (https://clue.io/). Next, we tested the anti-SARS-COV-2 activity of Cipa in vitro. A three-way comparative analysis of Cipa transcriptome, COVID-19 BALF transcriptome and CMAP signatures of small compounds was also performed.ResultsSeveral predicted antivirals showed a high positive connectivity score with Cipa such as apcidin, emetine, homoharringtonine etc. We also observed 98% inhibition of SARS-COV-2 replication in infected Vero cell cultures with the whole extract. Some of its prominent pure constituents e.g pareirarine, cissamine, magnoflorine exhibited 40-80% inhibition. Comparison of genes between BALF and Cipa showed an enrichment of biological processes like transcription regulation and response to lipids, to be downregulated in Cipa while being upregulated in COVID-19. CMAP also showed that Triciribine, torin-1 and VU-0365114-2 had positive connectivity with BALF 1 and 2, and negative connectivity with Cipa.
Plant biomechanics and resilience to environmental changes are controlled by specific lignin chemistries in each vascular cell type and morphotype
Authors: Ménard Delphine , Blaschek Leonard , Kriechbaum Konstantin , Lee Cheng Choo , Serk Henrik , Zhu Chuantao , Lyubartsev Alexander , Nuoendagula  , Bacsik Zoltán , Bergström Lennart , Mathew Aji , Kajita Shinya , Pesquet Edouard 
Published: June 2021

AbstractThe biopolymer lignin, deposited in the cell walls of vascular cells, is essential for long-distance water conduction and structural support of plants. Independently of the species, each different vascular cell type contains a conserved lignin chemistry with specific aromatic and aliphatic substitutions. Yet, the biological role of this conserved and specific lignin chemistry for each cell type remained unclear. Herein, we investigate the role of specific lignin chemistries for cellular function by producing single cell analyses on vascular cell morphotypes, all enabling sap conduction but differing in morphology. We found that specific lignin chemistries accumulate in each morphotype. Moreover, lignin accumulates dynamically, increasing in quantity and changing composition, to alter the cell wall biomechanics of each morphotype during their maturation. For similar aromatic substitution, residues with alcohol aliphatic functions increased stiffness whereas aldehydes increased flexibility. Modifying this specific lignin chemistry impairs the cell wall biomechanics of each morphotype and consequently reduces their capacity to optimally conduct water in normal conditions, and to recover from drought. Altogether, lignin chemistry is differently controlled for each sap conducting cell types during their maturation to dynamically adjust their biomechanics and hydraulic properties to adapt to developmental and environmental constraints.
The extra-embryonic space is a geometric constraint regulating cell arrangement in nematodes
Authors: Seirin-Lee Sungrim , Kimura Akatsuki 
Published: June 2021

AbstractIn multicellular systems, cells communicate with adjacent cells to decide their positions and fates. Cellular arrangement in space is thus important for development. Orientation of cell division, cell-cell interaction (i.e., attraction and repulsion), and geometrical constraints are the three major factors that define cell arrangement. Here we found that the amount and location of extra-embryonic space (ES), the empty space within the eggshell not occupied by embryonic cells, are critical to define cell arrangement in the 4-cell stage embryo of nematodes. This discovery was motivated by observations of a T-reversed-type arrangement, which was not explained by a model assuming simplified shapes of the eggshell, in our previous experiments. In this study, we incorporated the precise shape of the C. elegans eggshell in our newly developed multicellular morphology model based on the phase-field method. The new model succeeded in reproducing the T-reverse arrangement, demonstrating the importance of the precise shape of the eggshell. Further analyses revealed that the amount and location of ES is critical to develop various cell arrangements. Overall, our analyses characterized the roles of new geometrical contributors to cell arrangements, which should be considered for any multicellular system.
Pharmacologic and genetic inhibition of cholesterol esterification reduces tumour burden: a pan-cancer systematic review and meta-analysis of preclinical models
Authors: Websdale Alex , Kiew Yi , Chalmers Philip , Chen Xinyu , Cioccoloni Giorgia , Hughes Thomas A , Luo Xinyu , Mwarzi Rufaro , Poirot Marc , Røberg-Larsen Hanne , Wu Ruoying , Xu Mengfan , Zulyniak Michael A. , Thorne James L 
Published: June 2021

AbstractCholesterol esterification proteins Sterol-O acyltransferases (SOAT) 1 and 2 are emerging prognostic markers in many cancers. These enzymes utilise fatty acids conjugated to coenzyme A to esterify cholesterol. Cholesterol esterification is tightly regulated and enables formation of lipid droplets that act as storage organelles for lipid soluble vitamins and minerals, and as cholesterol reservoirs. In cancer, this provides rapid access to cholesterol to maintain continual synthesis of the plasma membrane. In this systematic review and meta-analysis, we summarise the current depth of understanding of the role of this metabolic pathway in pan-cancer development. A systematic search of PubMed, Scopus, and Web of Science for preclinical studies identified eight studies where cholesteryl ester concentrations were compared between tumour and adjacent-normal tissue, and 24 studies where cholesterol esterification was blocked by pharmacological or genetic approaches. Tumour tissue had a significantly greater concentration of cholesteryl esters than non-tumour tissue (p<0.0001). Pharmacological or genetic inhibition of SOAT was associated with significantly smaller tumours of all types (p≤0.002). SOAT inhibition increased tumour apoptosis (p=0.007), CD8+ lymphocyte infiltration and cytotoxicity (p≤0.05), and reduced proliferation (p=0.0003) and metastasis (p<0.0001). Significant risk of publication bias was found and may have contributed to a 32% overestimation of the meta-analysed effect size was overestimated. Avasimibe, the most frequently used SOAT inhibitor, was effective at doses equivalent to those previously reported to be safe and tolerable in humans. This work indicates that SOAT inhibition should be explored in clinical trials as an adjunct to existing anti-neoplastic agents.
Multimodal Single-Cell Characterization of the Human Granulocyte Lineage
Authors: Qi Jingjing , D’Souza Darwin , Dawson Travis , Geanon Daniel , Stefanos Hiyab , Marvin Robert , Walker Laura , Rahman Adeeb H. 
Published: June 2021

AbstractHigh throughput single cell transcriptomics (scRNA-seq) has been successfully applied to characterize immune cell heterogeneity across a diverse range of settings; however, analysis of human granulocytes remains a significant challenge due to their low gene expression transcript detection. Consequently, granulocytes are typically either absent or highly under-represented and inaccurately enumerated in most human scRNA-seq datasets. Here, we apply multi-modal CITE-seq profiling to characterize granulocytes in human whole blood and bone marrow, and we show that these populations can be accurately detected and analyzed using the antibody-based modality, and that their frequencies and phenotype align well with antibody-based characterization of the same samples using CyTOF. These analyses also clearly highlight extremely low gene transcript detection across the entire granulocyte lineage including the earliest neutrophil progenitor populations when using the 10X Genomics platform. By contrast, when performing parallel analyses of the same samples using the BD Rhapsody platform, we recovered a much higher proportion of granulocyte gene transcripts, enabling true multi-modal characterization of human granulocyte heterogeneity.
Single-nucleus transcriptomes reveal functional and evolutionary properties of cell types in the Drosophila accessory gland
Authors: Majane Alex C. , Cridland Julie M. , Begun David J. 
Published: June 2021

ABSTRACTMany traits responsible for male reproduction evolve quickly, including gene expression phenotypes in germline and somatic male reproductive tissues. Rapid male evolution in polyandrous species is thought to be driven by competition among males for fertilizations and conflicts between male and female fitness interests that manifest in post-copulatory phenotypes. In Drosophila, seminal fluid proteins secreted by three major cell types of the male accessory gland and ejaculatory duct are required for female sperm storage and use, and influence female post-copulatory traits. Recent work has shown that these cell types have overlapping but distinct effects on female post-copulatory biology, yet relatively little is known about their evolutionary properties. Here we use single-nucleus RNA-Seq of the accessory gland and ejaculatory duct from Drosophila melanogaster and two closely related species to comprehensively describe the cell diversity of these tissues and their transcriptome evolution for the first time. We find that seminal fluid transcripts are strongly partitioned across the major cell types, and expression of many other genes additionally define each cell type. We also report previously undocumented diversity in main cells. Transcriptome divergence was found to be heterogeneous across cell types and lineages, revealing a complex evolutionary process. Furthermore, protein adaptation varied across cell types, with potential consequences for our understanding of selection on male post-copulatory traits.SIGNIFICANCE STATEMENTRapid evolution of male traits may result from competition among males or antagonistic interactions between the sexes over control of reproduction. In animals with internal fertilization, interactions may occur in the female reproductive tract. Drosophila seminal fluid proteins, which are secreted by three major cell types of the male accessory gland and ejaculatory duct, are required for female sperm storage and use, and influence female behavior and physiology. These cell types have distinct effects on females, yet relatively little is known about their evolutionary properties. Here we characterize diversity and transcriptome evolution of seminal fluid-producing tissues at the cell level. These data reveal new functional properties of these cells and complex evolutionary patterns that vary across cell types and lineages.
A PMMA bone cement composite that functions as a drug-refillable depot for localized, multi-window chemotherapeutic treatment of bone cancer
Authors: Cyphert Erika L. , Kanagasegar Nithya , Zhang Ningjing , Learn Greg D. , von Recum Horst A. 
Published: June 2021

ABSTRACTStandard chemotherapy for primary and secondary bone tumors typically involves systemic administration of chemotherapeutic drugs, such as doxorubicin (DOX). However, non-targeted delivery increases dose requirements, and results in off-target toxicity and suboptimal chemotherapeutic efficacy. When chemotherapy is ineffective, substantial resection of tissue and/or total amputation become necessary – a debilitating outcome for any patient. In this work, we developed a proof-of-concept, non-biodegradable, mechanically robust, and refillable composite system for chemotherapeutic (i.e. DOX) delivery comprised of poly(methyl methacrylate) (PMMA) bone cement and insoluble polymeric γ-cyclodextrin (γ-CD) microparticles. The porosity and compressive strength of DOX-filled PMMA composites were characterized. DOX filling capacity, elution kinetics, cytotoxicity against primary osteosarcoma and lung cancer cells, and refilling capacity of composites were evaluated. PMMA composites containing up to 15wt% γ-CD microparticles provided consistent, therapeutically-relevant release of DOX with ~100% of the initial DOX released after 100 days. Over the same period, only ~6% of DOX was liberated from PMMA with free DOX. Following prolonged curing, PMMA composites with up to 15wt% γ-CD surpassed compressive strength requirements outlined by international standards for acrylic bone cements. Compared to DOX-filled PMMA, DOX-filled PMMA/γ-CD composites provided long-term release with decreased burst effect, correlating to long-term cytotoxicity against cancer cells. Refillable properties demonstrated by the PMMA composite system may find utility for treating local recurrences, limiting chemoresistance, and altering drug combinations to provide customized treatment regimens. Overall, findings suggest that PMMA composites have the potential to serve as a platform for the delivery of combinatorial chemotherapeutics to treat bone tumors.
Horizontal transfer and subsequent explosive expansion of a DNA transposon in sea kraits (Laticauda)
Authors: Galbraith James D. , Ludington Alastair J. , Sanders Kate L. , Suh Alexander , Adelson David L. 
Published: June 2021

AbstractTransposable elements (TEs) are self replicating genetic sequences and are often described as important “drivers of evolution”. This driving force is because TEs promote genomic novelty by enabling rearrangement, and through exaptation as coding and regulatory elements. However, most TE insertions will be neutral or harmful, therefore host genomes have evolved machinery to supress TE expansion. Through horizontal transposon transfer (HTT) TEs can colonise new genomes, and since new hosts may not be able to shut them down, these TEs may proliferate rapidly. Here we describe HTT of the Harbinger-Snek DNA transposon into sea kraits (Laticauda), and its subsequent explosive expansion within Laticauda genomes. This HTT occurred following the divergence of Laticauda from terrestrial Australian elapids ~15-25 Mya. This has resulted in numerous insertions into introns and regulatory regions, with some insertions into exons which appear to have altered UTRs or added sequence to coding exons. Harbinger-Snek has rapidly expanded to make up 8-12% of Laticauda spp. genomes; this is the fastest known expansion of TEs in amniotes following HTT. Genomic changes caused by this rapid expansion may have contributed to adaptation to the amphibious-marine habitat.
Oncogenic RAS sensitizes cells to drug-induced replication stress via transcriptional silencing of P53
Authors: Segeren Hendrika A. , van Liere Elsbeth A. , Riemers Frank M. , de Bruin Alain , Westendorp Bart 
Published: June 2021

AbstractCancer cells often experience high basal levels of DNA replication stress (RS), for example due to hyperactivation of oncoproteins like MYC or RAS. Therefore, cancer cells are considered to be sensitive to drugs that exacerbate the level of RS or block the intra S-phase checkpoint. Consequently, RS-inducing drugs including ATR and CHK1 inhibitors are used or evaluated as anti-cancer therapies. However, drug resistance and lack of biomarkers predicting therapeutic efficacy limit efficient use. This raises the question what determines sensitivity of individual cancer cells to RS. Here, we report that oncogenic RAS does not only enhance the sensitivity to ATR/CHK1 inhibitors by directly causing RS. Instead, we observed that HRASG12V dampens the activation of the P53-dependent transcriptional response to drug-induced RS, which in turn confers sensitivity to RS. We demonstrate that inducible expression of HRASG12V sensitized retina pigment epithelial (RPE-hTERT) as well as osteosarcoma (U2OS) cells to ATR and CHK1 inhibitors. Using RNA-sequencing of FACS-sorted cells we discovered that P53 signaling is the sole transcriptional response to RS. However, oncogenic RAS attenuates the transcription of P53 and its target genes. Accordingly, live cell imaging showed that HRASG12V exacerbates RS in S/G2-phase, which could be rescued by stabilization of P53. Thus, our results demonstrate that transcriptional control of P53 is a prime determinant in the response to ATR/CHK1 inhibitors and show that hyperactivation of the MAPK pathway impedes this response. Our findings suggest that the level of oncogenic MAPK signaling could predict sensitivity to intra-S-phase inhibition in cancers with intact P53.