bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extracellular vesicle molecular signatures characterize metastatic dynamicity in ovarian cancer
Authors: Gonda Amber , Zhao Nanxia , Shah Jay V. , Siebert Jake N. , Gunda Srujanesh , Inan Berk , Kwon Mijung , Libutti Steven K. , Moghe Prabhas V. , Francis Nicola L. , Ganapathy Vidya 
Published: April 2021

AbstractLate-stage diagnosis of ovarian cancer drastically lowers 5-year survival rate from 90% to 30%. Early screening tools that use non-invasive sampling methods combined with high specificity and sensitivity can significantly increase survival. Emerging research employing blood-based screening tools have shown promise in non-invasive detection of cancer. Our findings in this study show the potential of a small extracellular vesicle (sEV)-derived signature as a non-invasive longitudinal screening tool in ovarian cancer. We identified a 7-gene panel in these sEVs that overlapped with an established tissue-derived metastatic ovarian carcinoma signature. We found the 7-gene panel to be differentially expressed with tumor development and metastatic spread. While there were quantifiable changes in genes from the 7-gene panel in plasma-derived sEVs from ovarian cancer patients, we were unable to establish a definitive signature due to low sample number. The most notable finding was a significant change in the ascites-derived sEV gene signature that overlapped with that of the plasma-derived sEV signature at varying stages of disease progression. Taken together our findings show that differential expression of metastatic genes derived from circulating sEVs present a minimally invasive screening tool for ovarian cancer detection and longitudinal monitoring of molecular changes associated with progression and metastatic spread.
Multiple morphogens and rapid elongation promote segmental patterning during development
Authors: Qiu Yuchi , Fung Lianna , Schilling Thomas F. , Nie Qing 
Published: April 2021

ABSTRACTThe vertebrate hindbrain is segmented into rhombomeres (r) initially defined by distinct domains of gene expression. Previous studies have shown that noise-induced gene regulation and cell sorting are critical for the sharpening of rhombomere boundaries, which start out rough in the forming neural plate (NP) and sharpen over time. However, the mechanisms controlling simultaneous formation of multiple rhombomeres and accuracy in their sizes are unclear. We have developed a stochastic multiscale cell-based model that explicitly incorporates dynamic morphogenetic changes (i.e. convergent-extension of the NP), multiple morphogens, and gene regulatory networks to investigate the formation of rhombomeres and their corresponding boundaries in the zebrafish hindbrain. During pattern initiation, the short-range signal, fibroblast growth factor (FGF), works together with the longer-range morphogen, retinoic acid (RA), to specify all of these boundaries and maintain accurately-sized segments with sharp boundaries. At later stages of patterning, we show a nonlinear change in the shape of rhombomeres with rapid left-right narrowing of the NP followed by slower dynamics. Rapid initial convergence improves boundary sharpness and segment size by regulating cell sorting and cell fate both independently and coordinately. Overall, multiple morphogens and tissue dynamics synergize to regulate the sizes and boundaries of multiple segments during development.Author SummaryIn segmental pattern formation, chemical gradients control gene expression in a concentration-dependent manner to specify distinct gene expression domains. Despite the stochasticity inherent to such biological processes, precise and accurate borders form between segmental gene expression domains. Previous work has revealed synergy between gene regulation and cell sorting in sharpening borders that are initially rough. However, it is still poorly understood how size and boundary sharpness ofmultiplesegments are regulated in a tissue that changes dramatically in its morphology as the embryo develops. Here we develop a stochastic multiscale cell-base model to investigate these questions. Two novel strategies synergize to promote accurate segment formation, a combination of long- and short-range morphogens plus rapid tissue convergence, with one responsible for pattern initiation and the other enabling pattern refinement.
HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts
Authors: Pipalia Nina H. , Saad Syed Z. , Subramanian Kanagaraj , Cross Abigail , al-Motawa Aisha , Garg Kunal , Blagg Brian S.J. , Neckers Len , Helquist Paul , Wiest Olaf , Ory Daniel S. , Maxfield Frederick R. 
Published: April 2021

AbstractNiemann Pick type C1 (NPC1) disease is a lysosomal lipid storage disorder caused by mutations of theNPC1gene. More than 300 disease-associated mutations are reported in patients, resulting in abnormal accumulation of unesterified cholesterol, glycosphingolipids and other lipids in late endosomes and lysosomes (LE/Ly) of many cell types. Previously, we showed that treatment of many differentNPC1mutant fibroblasts with histone deacetylase inhibitors resulted in reduction of cholesterol storage, and we found that this was associated with enhanced exit of the NPC1 protein from the endoplasmic reticulum and delivery to LE/Ly. This suggested that histone deacetylase inhibitors may work through changes in protein chaperones to enhance the folding of NPC1 mutants, allowing them to be delivered to LE/Ly. In this study we evaluated the effect of several HSP90 inhibitors on NPC1I1061Tskin fibroblasts. We found that HSP90 inhibition resulted in clearance of cholesterol from LE/Ly, and this was associated with enhanced delivery of the mutant NPC1I1061Tprotein to LE/Ly. We also observed that inhibition of HSP90 increased the expression of HSP70, and overexpression of HSP70 also reduced cholesterol storage inNPC1I1061Tfibroblasts. However, we did not see correction of cholesterol storage by arimoclomol, a drug that is reported to increase HSP70 expression, at doses up to 0.5 mM. These results indicate that manipulation of molecular chaperones may lead to effective treatments for NPC1 disease, but further investigation of mechanisms will be required.
Sick and Tired: Polyparasitism, Food Stress and Sickness Behaviour in a Gregarious Mammal
Authors: Blersch Rosemary , Bonnell Tyler R. , Ganswindt Andre , Young Christopher , Barrett Louise , Peter Henzi S. 
Published: April 2021

AbstractAlthough sickness behaviour in response to non-lethal parasites has been documented in wild animals, it remains unclear how social and environmental stress might also shape an animal’s behavioural response to parasitism, nor do we know whether simultaneous infection with more than one parasite changes the way animals respond. Here, we combine physiological, environmental, behavioural and parasite measures to investigate behavioural responses to infection in wild vervet monkeys (Chlorocebus pygerythrus) living in a semi-arid region of South Africa. We quantified both activity budget and behavioural predictability to investigate the occurrence of sickness behaviour and infection with two non-lethal gastrointestinal parasite genera. Higher parasite load was linked to an increase in the time spent resting. However, the nature of the relationship with other behaviours was contingent on both the parasite genus in question, and how parasite species interacted, highlighting the importance of considering co-infection. Overall, food availability was the dominant predictor of behavioural change suggesting that, for monkeys living in a more extreme environment, coping with ecological stress may override the ability to modulate behaviour in response to other physiological stressors. Our findings provide insight into how animals living in harsh environments find ways to cope with parasite infection, avoidance, and transmission.
Lipid droplets modulate proteostasis, SQST-1/SQSTM1 dynamics, and lifespan inC. elegans
Authors: Kumar Anita V. , Mills Joslyn , Parker Wesley M. , Leitão Joshua A. , Rodriguez Diego I. , Ng Celeste , Patel Rishi , Aguilera Joseph L. , Johnson Joseph R. , Wong Shi Quan , Lapierre Louis R. 
Published: April 2021

ABSTRACTThe ability of organisms to live long depends largely on the maintenance of proteome stability via proteostatic mechanisms including translational regulation, protein chaperoning and degradation machineries. In several long-livedCaenorhabditis elegansstrains, such as insulin/IGF-1 receptordaf-2mutants, enhanced proteostatic mechanisms are accompanied by elevated intestinal lipid stores, but the role of lipid droplets in longevity has remained obscure. Here, while determining the regulatory network of the selective autophagy receptor SQST-1/SQSTM1, we unexpectedly uncovered a novel role for lipid droplets in proteostasis and longevity. Using an unbiased genome-wide RNAi screening approach, we identified several SQST-1 modulators, including proteins found on lipid droplets and those prone to aggregate with age. SQST-1 accumulated on lipid droplets when autophagy was inhibited, suggesting that lipid droplets may serve a role in facilitating selective autophagy. Expansion of intestinal lipid droplets by silencing the conserved cytosolic triacylglycerol lipase geneatgl-1/ATGLenhanced autophagy, and extended lifespan in an HSF-1/HSF1-dependent and CDC-48/VCP-dependent manner. Silencingatgl-1mitigated the age-related accumulation of SQST-1 and reduced overall ubiquitination of proteins. Reducingatgl-1also improved proteostasis in proteotoxicity models of neurodegenerative diseases. Subcellular analyses revealed that lipid droplets unexpectedly harbor more soluble ubiquitinated proteins than the cytosol. Accordingly, low lipid droplet levels exacerbated the proteostatic collapse when autophagy or proteasome function was compromised. Altogether, our study uncovers a key role for lipid droplets inC. elegansas a proteostatic mediator that reduces protein ubiquitination, facilitates autophagy, and promotes longevity.
Fauxcurrence: simulating multi-species occurrences for null models in species distribution modelling and biogeography
Authors: Osborne Owen G. , Fell Henry G. , Atkins Hannah , van Tol Jan , Phillips Daniel , Herrera-Alsina Leonel , Mynard Poppy , Bocedi Greta , Gubry-Rangin Cécile , Lancaster Lesley T. , Creer Simon , Nangoy Meis , Fahri Fahri , Lupiyaningdyah Pungki , Sudiana I Made , Juliandi Berry , Travis Justin M.J. , Papadopulos Alexander S.T. , Algar Adam C. 
Published: April 2021

ABSTRACTDefining appropriate null expectations for species distribution hypotheses is important because sampling bias and spatial autocorrelation can produce realistic, but ecologically meaningless, geographic patterns. Generating null species occurrences with similar spatial structure to observed data can help overcome these problems, but existing methods focus on single or pairs of species and do not incorporate between-species spatial structure that may occlude comparative biogeographic analyses. Here, we describe an algorithm for generating randomised species occurrence points that mimic the within- and between-species spatial structure of real datasets and implement it in a new R package -fauxcurrence. The algorithm can be implemented on any geographic domain for any number of species, limited only by computing power. To demonstrate its utility, we apply the algorithm to two common analysis-types: testing the fit of species distribution models (SDMs) and evaluating niche-overlap. The method works well on all tested datasets within reasonable timescales. We found that many SDMs, despite a good fit to the data, were not significantly better than null expectations and identified only two cases (out of a possible 32) of significantly higher niche divergence than expected by chance. The package is user-friendly, flexible and has many potential applications beyond those tested here, such as joint SDM evaluation and species co-occurrence analysis, spanning the areas of ecology, evolutionary biology and biogeography.
ME-VAE: Multi-Encoder Variational AutoEncoder for Controlling Multiple Transformational Features in Single Cell Image Analysis
Authors: Ternes Luke , Dane Mark , Gross Sean , Labrie Marilyne , Mills Gordon , Gray Joe , Heiser Laura , Chang Young Hwan 
Published: April 2021

AbstractImage-based cell phenotyping relies on quantitative measurements as encoded representations of cells; however, defining suitable representations that capture complex imaging features is challenged by the lack of robust methods to segment cells, identify subcellular compartments, and extract relevant features. Variational autoencoder (VAE) approaches produce encouraging results by mapping an image to a representative descriptor, and outperform classical hand-crafted features for morphology, intensity, and texture at differentiating data. Although VAEs show promising results for capturing morphological and organizational features in tissue, single cell image analyses based on VAEs often fail to identify biologically informative features due to uninformative technical variation. Herein, we propose a multi-encoder VAE (ME-VAE) in single cell image analysis using transformed images as a self-supervised signal to extract transform-invariant biologically meaningful features, including emergent features not obvious from prior knowledge. We show that the proposed architecture improves analysis by making distinct cell populations more separable compared to traditional VAEs and intensity measurements by enhancing phenotypic differences between cells and by improving correlations to other analytic modalities.
Cerebrovascular responses to O2-CO2 exchange ratio under brief breath-hold challenge in patients with chronic mild traumatic brain injury
Authors: Chan Suk Tak , Ordway Cora , Calvanio Ronald J. , Buonanno Ferdinando S. , Rosen Bruce R. , Kwong Kenneth K. 
Published: April 2021

AbstractBreath-by-breath O2-CO2exchange ratio (bER) is a respiratory gas exchange (RGE) metric, which is the ratio of the changes in the partial pressure of O2(ΔPO2) to CO2(ΔPCO2) between endinspiration and end-expiration, has been demonstrated to characterize the cerebrovascular responses to breath-hold challenge in healthy individuals. We aimed to explore if bER could characterize cerebrovascular responses in patients with chronic mild traumatic brain injury (mTBI) under breath-hold challenge. We also investigated the correlation between bER and the severity of post-concussion symptoms.Blood-oxygenation-level-dependent (BOLD) images were acquired using functional magnetic resonance imaging (fMRI) on eleven patients with chronic mTBI and eleven controls without brain injury history when performing a breath-hold task. Time series of RGE metrics of ΔPO2, ΔPCO2, and bER were computed, and their cross-correlation with regional change in BOLD (ΔBOLD) was calculated. Symptom burden was assessed using the Rivermead Post Concussion Questionnaire (RPQ), and its correlation with RGE changes was also measured.Compared with controls, a diffuse decrease in the correlation between regional ΔBOLD and bER was found in the brain of mTBI patients (pfdr<0.05). No significant difference was found between patients and controls for the correlation of regional ΔBOLD with ΔPO2and ΔPCO2. The averaged changes in bER (ρ=0.79, p=0.01) and ΔPO2(ρ=0.70, p=0.03) in breath-hold epochs decreased with increased symptom severity indicated by RPQ scores.Our imaging and symptom severity findings suggest that bER can be used to characterize cerebrovascular responses to breath-hold in mTBI patients. RGE may contribute to the post-concussive symptom severity.
Multicomponent nature underlies the extraordinary mechanical properties of spider dragline silk
Authors: Kono Nobuaki , Nakamura Hiroyuki , Mori Masaru , Yoshida Yuki , Ohtoshi Rintaro , Malay Ali D , Pedrazzoli Moran Daniel A , Tomita Masaru , Numata Keiji , Arakawa Kazuharu 
Published: April 2021

AbstractDragline silk of golden orb-weaver spiders (Nephilinae) is noted for its unsurpassed toughness, combining extraordinary extensibility and tensile strength, suggesting industrial application as a sustainable biopolymer material. To pinpoint the molecular composition of dragline silk and the roles of its constituents in achieving its mechanical properties, we report a multiomics approach combining high-quality genome sequencing and assembly, silk gland transcriptomics, and dragline silk proteomics of four Nephilinae spiders. We observed the consistent presence of the MaSp3B spidroin unique to this subfamily, as well as several non-spidroin SpiCE proteins. Artificial synthesis and combination of these components in vitro showed that the multicomponent nature of dragline silk, including MaSp3B and SpiCE, along with MaSp1 and MaSp2, is essential to realize the mechanical properties of spider dragline silk.
Simultaneous hybrid genome sequencing of Vermamoeba vermiformis and its Dependentiae endosymbiont Vermiphilus pyriformis
Authors: Delafont Vincent , Gasqué Mégane , Héchard Yann 
Published: April 2021

AbstractA hybrid sequencing approach, using short and long reads sequencing, was employed for characterizing the genomes of the free-living amoeba host Vermamoeba vermiformis, along with its Dependentiae endosymbiont Vermiphilus pyriformis. The amoeba host reconstructed nuclear genome is 39.5 Mb, and its full mitochondrial genome is 61.7 kb. The closed, circular genome of the Dependentiae endosymbiont Vermiphilus pyriformis, naturally infecting V. vermiformis is 1.1 Mb.
Topical TMPRSS2 inhibition prevents SARS-CoV-2 infection in differentiated primary human airway cells
Authors: Guo Wenrui , Porter Linsey M , Crozier Thomas WM , Coates Matthew , Jha Akhilesh , McKie Mikel , Nathan James A , Lehner Paul J , Greenwood Edward JD , McCaughan Frank 
Published: April 2021

AbstractBackgroundThere are limited effective prophylactic treatments for SARS-CoV-2 infection, and limited early treatment options. Viral cell entry requires spike protein binding to the ACE2 receptor and spike cleavage by TMPRSS2, a cell surface serine protease. Targeting of TMPRSS2 by either androgen blockade or direct inhibition is already in clinical trials in early SARS-CoV-2 infection.MethodsThe likely initial cells of SARS-CoV-2 entry are the ciliated cells of the upper airway. We therefore used differentiated primary human airway epithelial cells maintained at the air-liquid interface (ALI) to test the impact of targeting TMPRSS2 on the prevention of SARS-CoV-2 infection.ResultsWe first modelled the systemic delivery of compounds. Enzalutamide, an oral androgen receptor antagonist, had no impact on SARS-Cov-2 infection. By contrast, camostat mesylate, an orally available serine protease inhibitor, blocked SARS-CoV-2 entry. However, camostat is rapidly metabolised in the circulationin vivo, and systemic bioavailability after oral dosing is low. We therefore modelled local airway administration by applying camostat to the apical surface of the differentiated ALI cultures. We demonstrated that a brief exposure to topical camostat is effective at restricting SARS-CoV-2 viral infection.ConclusionThese experiments demonstrate a potential therapeutic role for topical camostat for pre- or post-exposure prophylaxis of SARS-CoV-2, which can now be evaluated in a clinical trial.
One more avenue for whale-watching contributions to science: the study of cetacean-cephalopod interactions
Authors: Suciu Stéphanie R.A. , Zereba Jasmine , Fiori Lorenzo , Azevedo José M.N. 
Published: April 2021

AbstractCephalopods are the primary source of food for several species of odontocetes. The unstable nature of this trophic resource is likely to affect the ecology of their cetacean predators, and this can be reflected on their conservation status but also on the tourist activities which target the observation of these animals. However, the study of the cetacean-cephalopod interaction is limited by the heavy logistics and expense of dedicated scientific campaigns. Fortunately, this gap can be filled by coupling modern molecular tools with indirect sampling methods. In this note we test if whale watching activities, which represent an intense observation effort worldwide, could be a source of material for studies of cetacean-cephalopod interactions. All contacted companies welcomed the invitation and received the sampling kit. Nine samples were collected, most of them in close association with sperm whales. All samples were determined as the seven-arm octopusHaliphron atlanticus(Octopoda, Alloposidae). We conclude that, although the Azores may have particularly favorable conditions for participatory science, similar programs can be replicated elsewhere
Recurrent fusions inPLAGL1define a distinct subset of pediatric-type supratentorial ependymoma
Authors: Sievers Philipp , Henneken Sophie C. , Blume Christina , Sill Martin , Schrimpf Daniel , Stichel Damian , Okonechnikov Konstantin , Reuss David E. , Benzel Julia , Maaß Kendra , Kool Marcel , Sturm Dominik , Kohlhof-Meinecke Patricia , Cruz Ofelia , Suñol Mariona , Lavarino Cinzia , Ruf Viktoria , Boldt Henning B. , Pagès Mélanie , Pouget Celso , Schweizer Leonille , Kranendonk Mariëtte E. G. , Akhtar Noreen , Schüller Ulrich , Mueller Wolf C. , Dohmen Hildegard , Acker Till , Harter Patrick N. , Mawrin Christian , Beschorner Rudi , Brandner Sebastian , Snuderl Matija , Abdullaev Zied , Aldape Kenneth , Gilbert Mark R. , Armstrong Terri S. , Ellison David W. , Capper David , Ichimura Koichi , Reifenberger Guido , Grundy Richard G. , Jabado Nada , Krskova Lenka , Zapotocky Michal , Vicha Ales , Varlet Pascale , Wesseling Pieter , Rutkowski Stefan , Korshunov Andrey , Wick Wolfgang , Pfister Stefan M. , Jones David T. W. , Deimling Andreas von , Pajtler Kristian W. , Sahm Felix 
Published: April 2021

AbstractEpendymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving thepleomorphic adenoma gene-like 1(PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion beingEWSR1:PLAGL1(n = 13). Five tumors showed aPLAGL1:FOXO1fusion and one aPLAGL1:EP300fusion. High transcript levels ofPLAGL1were noted in these tumors, with concurrent overexpression of the imprinted genesH19andIGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of largely ependymoma-like tumors. Immunohistochemically, tumors were GFAP-positive and OLIG2- and SOX10-negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. Consistent with other fusion-positive ependymal groups, all tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Analysis of time to progression or recurrence revealed survival times comparable to those of patients withZFTA:RELA-fused ependymoma. In summary, our findings suggest the existence of a novel group of supratentorial ependymomas that are characterized by recurrentPLAGL1fusions and enriched for pediatric patients.