bluuebunny/crossref_metadata_2025_split huggingface dataset:
Widespread diversity in the transcriptomes of functionally divergent limb tendons
Authors: Disser Nathaniel P , Ghahramani Gregory C , Swanson Jacob B , Wada Susumu , Chao Max L , Rodeo Scott A , Oliver David J , Mendias Christopher L 
Published: December 2019

AbstractTendon is a functionally important connective tissue that transmits force between skeletal muscle and bone. Previous studies have evaluated the architectural designs and mechanical properties of different tendons throughout the body. However, less is known about the underlying transcriptional differences between tendons which may dictate their designs and properties. Therefore, our objective was to develop a comprehensive atlas of the transcriptome of limb tendons in adult mice and rats using systems biology techniques. We selected the Achilles, forepaw digit flexor, patellar, and supraspinatus tendons due to their divergent functions and high rates of injury and tendinopathies in patients. Using RNA sequencing data, we generated the Comparative Tendon Transcriptional Database (CTTDb) that identified substantial diversity in the transcriptomes of tendons both within and across species. Approximately 30% of transcripts were differentially regulated between tendons of a given species, and nearly 60% of the transcripts present in anatomically similar tendons were different between species. Many of the genes that differed between tendons and across species are important in tissue specification and limb morphogenesis, tendon cell biology and tenogenesis, growth factor signaling, and production and maintenance of the extracellular matrix. This study indicates that tendon is a surprisingly heterogenous tissue with substantial genetic variation based on anatomical location and species.Key PointsTendon is a hypocellular, matrix-rich tissue that has been excluded from comparative transcriptional atlases. These atlases have provided important knowledge about biological heterogeneity between tissues, and our manuscript addresses this important gap.We performed measures on four of the most studied tendons, the Achilles, forepaw flexor, patellar, and supraspinatus tendons of both mice and rats. These tendons are functionally distinct and are also among the most commonly injured, and therefore of important translational interest.Approximately one-third of the transcriptome was differentially regulated between Achilles, forepaw flexor, patellar, and supraspinatus tendons within either mice or rats. Nearly two thirds of the transcripts that are expressed in anatomically similar tendons were different between mice and rats.The overall findings from this study identified that although tendons across the body share a common anatomical definition based on their physical location between skeletal muscle and bone, tendon is a surprisingly genetically heterogeneous tissue.
Polygenic Risk for Skin Autoimmunity Impacts Immune Checkpoint Blockade in Bladder Cancer
Authors: Khan Zia , Di Nucci Flavia , Kwan Antonia , Hammer Christian , Mariathasan Sanjeev , Rouilly Vincent , Carroll Jonathan , Fontes Magnus , Acosta Sergio Ley , Guardino Ellie , Chen-Harris Haiyin , Bhangale Tushar , Mellman Ira , Rosenberg Jonathan , Powles Thomas , Hunkapiller Julie , Chandler G. Scott , Albert Matthew L. 
Published: December 2019

AbstractPD-1 and PD-L1 act to restrict T-cell responses in cancer and contribute to self-tolerance. Consistent with this role, PD-1 checkpoint inhibitors have been associated with immune-related adverse events (irAEs), immune toxicities thought to be autoimmune in origin. Analyses of dermatological irAEs have identified an association with improved overall survival (OS) following anti-PD-(L)1 therapy, but the factors that contribute to this relationship are poorly understood. We collected germline whole genome sequencing data from IMvigor211, a recent phase 3 randomized controlled trial comparing atezolizumab (anti-PD-L1) monotherapy to chemotherapy in bladder cancer. We found that high vitiligo, high psoriasis, and low atopic dermatitis polygenic risk scores (PRSs) were associated with longer OS under anti-PD-L1 monotherapy as compared to chemotherapy, reflecting the Th17 polarization of these diseases. PRSs were not correlated with tumor mutation burden, PD-L1 immunohistochemistry, nor T-effector gene signatures. Shared genetic factors impact risk for dermatological autoimmunity and anti-PD-L1 monotherapy in bladder cancer.
Finding a suitable library size to call variants in RNA-seq
Authors: Quaglieri Anna , Flensburg Christoffer , Speed Terence P , Majewski Ian J 
Published: December 2019

AbstractBackgroundRNA-Seq allows the study of both gene expression changes and transcribed mutations, providing a highly effective way to gain insight into cancer biology. When planning the sequencing of a large cohort of samples, library size is a fundamental factor affecting both the overall cost and the quality of the results. While several studies analyse the effect that library size has on differential expression analyses, sensitivity analysis for variant detection has received far less attention.ResultsWe simulated shallower sequencing depths by downsampling 45 AML samples that are part of the Leucegene project, which were originally sequenced at high depth. We compared the sensitivity of six methods of recovering validated mutations on the same samples. The methods compared are a combination of three popular callers (MuTect, VarScan, and VarDict) and two filtering strategies. We observed an incremental loss in sensitivity when simulating libraries of 80M, 50M, 40M, 30M and 20M fragments, with the largest loss detected with less than 30M fragments (below 90%). The sensitivity in recovering indels varied markedly between callers, with VarDict showing the highest sensitivity (60%). Single nucleotide variant sensitivity is relatively consistent across methods, apart from MuTect, whose default filters need adjustment when using RNA-Seq. We also analysed 136 RNA-Seq samples from the TCGA-LAML cohort, assessing the change in sensitivity between the initial libraries (average 59M fragments) and after downsampling to 40M fragments. When considering single nucleotide variants in recurrently mutated myeloid genes we found a comparable performance, with a 3% average loss in sensitivity using 40M fragments.ConclusionsBetween 30M and 40M fragments are needed to recover 90%-95% of the initial variants on recurrently mutated myeloid genes. To extend this result to another cancer type, an exploration of the characteristics of its mutations and gene expression patterns is suggested.
Anin situatlas of mitochondrial DNA in mammalian tissues reveals high content in stem/progenitor cells
Authors: Chen Jiayu , Zheng Qizhi , Peiffer Lauren B. , Hicks Jessica L. , Haffner Michael C. , Rosenberg Avi Z. , Levi Moshe , Wang Xiaoxin X. , Ozbek Busra , Yegnasubramanian Srinivasan , De Marzo Angelo M. 
Published: December 2019

ABSTRACTMitochondria regulate ATP production, metabolism and cell death. Alterations in mitochondrial DNA (mtDNA) sequence and copy number are implicated in aging and organ dysfunction in diverse inherited and sporadic diseases. Since most measurements of mtDNA use homogenates of complex tissues, little is known about cell type-specific mtDNA copy number heterogeneity in normal physiology, aging and disease. Thus, the precise cell types whose loss of mitochondrial activity and altered mtDNA copy number that result in organ dysfunction in aging and disease have often not been clarified. Here, we validated anin situhybridization approach to generate a single cell resolution atlas of mtDNA content in mammalian tissues. In hierarchically organized self-renewing tissues, higher levels of mtDNA were observed in stem/proliferative compartments compared to differentiated compartments. Striking zonal patterns of mtDNA levels in the liver reflected the known oxygen tension gradient. In the kidney, proximal and distal tubules had markedly higher mtDNA levels compared to cells within glomeruli and collecting duct epithelial cells. Decreased mtDNA levels were visualized in renal tubules as a function of aging, which was prevented by calorie restriction. We provide a novel approach for quantifying species- and cell type-specific mtDNA copy number and dynamics in any normal or diseased tissue and can be used for monitoring the effects of interventions in animal and human studies.
Correlation ofp53and DNA repair gene mutation patterns in human malignancies indicates different tumour suppression mechanisms of p53
Authors: Xue Xuemin , Dong Lin , Xue Liyan , Lu Yong-jie 
Published: December 2019

AbstractP53 suppresses tumorigenesis through multiple cellular functions/mechanisms. Recently, Janic A, et al. reported that DNA repair pathways are critical mediators of p53-dependent tumor suppression. We showed, by mining cBioPortal data of a range of human cancers, that the tendency of ‘mutual exclusivity’ of mutations inp53and DNA repair genes only exist in very limited human cancer types. In the majority of human cancers,p53mutations are equally distributed between DNA repair gene mutation positive and negative cases and in a number of human cancers, p53 and DNA repair gene mutations have a tendency of co-occurrence. These different correlation patterns ofp53and DNA repair gene mutations in human malignancies may reflect different critical molecular/cellular pathways activated by p53 in different organs or cell types to suppress tumorigenesis.
Physiological Adaptability and Parametric Versatility in a Simple Genetic Circuit
Authors: Chure Griffin , Kaczmarek Zofii A. , Phillips Rob 
Published: December 2019

ABSTRACTThe intimate relationship between the environment and cellular growth rate has remained a major topic of inquiry in bacterial physiology for over a century. Now, as it becomes possible to understand how the growth rate dictates the wholesale reorganization of the intracellular molecular composition, we can interrogate the biophysical principles underlying this adaptive response. Regulation of gene expression drives this adaptation, with changes in growth rate tied to the activation or repression of genes covering enormous swaths of the genome. Here, we dissect how physiological perturbations alter the expression of a circuit which has been extensively characterized in a single physiological state. Given a complete thermodynamic model, we map changes in physiology directly to the biophysical parameters which define the expression. Controlling the growth rate via modulating the available carbon source or growth temperature, we measure the level of gene expression from a LacI-regulated promoter where the LacI copy number is directly measured in each condition, permitting parameter-free prediction of the expression level. The transcriptional output of this circuit is remarkably robust, with expression of the repressor being largely insensitive to the growth rate. The predicted gene expression quantitatively captures the observations under different carbon conditions, indicating that the bio-physical parameters are indifferent to the physiology. Interestingly, temperature controls the expression level in ways that are inconsistent with the prediction, revealing temperature-dependent effects that challenge current models. This work exposes the strengths and weaknesses of thermodynamic models in fluctuating environments, posing novel challenges and utility in studying physiological adaptation.SignificanceCells adapt to changing environmental conditions by repressing or activating gene expression from enormous fractions of their genome, drastically changing the molecular composition of the cell. This requires the concerted adaptation of transcription factors to the environmental signals, leading to binding or releasing of their cognate sequences. Here, we dissect a well characterized genetic circuit in a number of physiological states, make predictions of the response, and measure how the copy number of a regulator and its gene target are affected. We find the parameters defining the regulators behavior are remarkably robust to changes in the nutrient availability, but are susceptible to temperature changes. We quantitatively explore these two effects and discuss how they challenge current models of transcriptional regulation.
Conserved function of ether lipids and sphingolipids in the early secretory pathway
Authors: Jiménez-Rojo Noemi , Leonetti Manuel D. , Zoni Valeria , Colom Adai , Feng Suihan , Iyengar Namrata R. , Matile Stefan , Roux Aurélien , Vanni Stefano , Weissman Jonathan S. , Riezman Howard 
Published: December 2019

ABSTRACTSphingolipids have been shown to play important roles in physiology and cell biology, but a systematic examination of their functions is lacking. We performed a genome-wide CRISPRi screen in sphingolipid-depleted cells and identified hypersensitive mutants in genes of membrane trafficking and lipid biosynthesis, including ether lipid synthesis. Systematic lipidomic analysis showed a coordinate regulation of ether lipids with sphingolipids, where depletion of one of these lipid types resulted in increases in the other, suggesting an adaptation and functional compensation. Biophysical experiments on model membranes show common properties of these structurally diverse lipids that also share a known function as GPI anchors in different kingdoms of life. Molecular dynamics simulations show a selective enrichment of ether phosphatidylcholine around p24 proteins, which are receptors for the export of GPI-anchored proteins and have been shown to bind a specific sphingomyelin species. Our results support a model of convergent evolution of proteins and lipids, based on their physico-chemical properties, to regulate GPI-anchored protein transport and maintain homeostasis in the early secretory pathway.
A model of bidirectional interactions between complementary learning systems for memory consolidation of sequential experiences
Authors: Howard Michael D. , Skorheim Steven W. , Pilly Praveen K. 
Published: December 2019

ABSTRACTThe standard theory of memory consolidation posits a dual-store memory system: a fast-learning fast-decaying hippocampus that transfers memories to slow-learning long-term cortical storage. Hippocampal lesions interrupt this transfer, so recent memories are more likely to be lost than more remote memories. Existing models of memory consolidation that simulate this temporally graded retrograde amnesia operate only on static patterns or unitary variables as memories. However, the mechanisms underlying the consolidation of episodes, which are sequential in nature and comprise multiple events, are not well understood. There is currently no computational theory for how memory replays of sequential experiences emerge dynamically during offline periods and how they are coordinated between the hippocampus and cortex to facilitate the stabilization of episodic memories. Further, there is evidence for a bi-directional interaction between the two memory systems during offline periods (Ji & Wilson, 2007), whereby the reactivation of waking neural patterns originating in the cortex triggers time-compressed sequential replays in the hippocampus, which in turn drive the consolidation of the pertinent sequence in the cortex. We have developed a computational model of memory encoding, consolidation, and recall for storing temporal sequences that explores the dynamics of this bi-directional interaction and time-compressed replays in four simulation experiments, providing novel insights into whether hippocampal learning needs to be suppressed for stable memory consolidation and into how new and old memories compete for limited replay opportunities during offline periods. The salience of experienced events, based on factors such as recency and frequency of use, is shown to have considerable impact on memory consolidation because it biases the relative probability that a particular event will be cued in the cortex during offline periods. In the presence of hippocampal learning during sleep, our model predicts that the fast-forgetting hippocampus can continually refresh the memory traces of a given episodic sequence if there are no competing experiences to be replayed.
Close range vocal interaction in the common marmoset (Callithrix Jacchus)
Authors: Landman R. , Sharma J. , Hyman J.B. , Fanucci-Kiss A. , Meisner O. , Parmar S. , Feng G. , Desimone R. 
Published: December 2019

AbstractVocal communication in animals often involves taking turns vocalizing. In humans, turn taking is a fundamental rule in conversation. Among non-human primates, the common marmoset is known to engage in antiphonal calling using phee calls and trill calls. Calls of the trill type are the most common, yet difficult to study, because they are not very loud and uttered in conditions when animals are in close proximity to one another. Here we recorded trill calls in captive pair-housed marmosets using wearable microphones, while the animals were together with their partner or separated, but within trill call range. Trills were exchanged mainly with the partner and not with other animals in the room. Animals placed outside the home cage increased their trill call rate and uttered more trills in response more to their partner. The fundamental frequency, F0, of trills increased when animals were placed outside the cage. Our results indicate that trill calls can be monitored using wearable audio equipment. Relatively minor changes in social context affect trill call interactions and spectral properties of trill calls, indicating that marmosets can communicate subtle information to their partner vocally.
Genome mining of the citrus pathogenElsinoë fawcettii; prediction and prioritisation of candidate effectors, cell wall degrading enzymes and secondary metabolite gene clusters
Authors: Jeffress Sarah , Arun-Chinnappa Kiruba , Stodart Ben , Vaghefi Niloofar , Tan Yu Pei , Ash Gavin 
Published: December 2019

Abstract:Elsinoë fawcettii, a necrotrophic fungal pathogen, causes citrus scab on numerous citrus varieties around the world. Known pathotypes ofE. fawcettiiare based on host range; additionally, cryptic pathotypes have been reported and more novel pathotypes are thought to exist.E. fawcettiiproduces elsinochrome, a non-host selective toxin which contributes to virulence. However, the mechanisms involved in potential pathogen-host interactions occurring prior to the production of elsinochrome are unknown, yet the host-specificity observed among pathotypes suggests a reliance upon such mechanisms. In this study we have generated a whole genome sequencing project forE. fawcettii,producing an annotated draft assembly 26.01 Mb in size, with 10,080 predicted gene models and low (0.37%) coverage of transposable elements. The assembly showed evidence of AT-rich regions, potentially indicating genomic regions with increased plasticity. Using a variety of computational tools, we mined theE. fawcettiigenome for potential virulence genes as candidates for future investigation. A total of 1,280 secreted proteins and 203 candidate effectors were predicted and compared to those of other necrotrophic (Botrytis cinerea,Parastagonospora nodorum,Pyrenophora tritici-repentis,Sclerotinia sclerotiorumandZymoseptoria tritici), hemibiotrophic (Leptosphaeria maculans,Magnaporthe oryzae,Rhynchosporium communeandVerticillium dahliae) and biotrophic (Ustilago maydis) plant pathogens. Genomic and proteomic features of known fungal effectors were analysed and used to guide the prioritisation of 77 candidate effectors ofE. fawcettii. Additionally, 378 carbohydrate-active enzymes were predicted and analysed for likely secretion and sequence similarity with known virulence genes. Furthermore, secondary metabolite prediction indicated nine additional genes potentially involved in the elsinochrome biosynthesis gene cluster than previously described. A further 21 secondary metabolite clusters were predicted, some with similarity to known toxin producing gene clusters. The candidate virulence genes predicted in this study provide a comprehensive resource for future experimental investigation into the pathogenesis ofE. fawcettii.
Modeling the efficiency of filovirus entry into cellsin vitro: Effects of SNP mutations in the receptor molecule
Authors: Kim Kwang Su , Kondoh Tatsunari , Asai Yusuke , Takada Ayato , Iwami Shingo 
Published: December 2019

AbstractInteraction between filovirus glycoprotein (GP) and the Niemann-Pick C1 (NPC1) protein is essential for membrane fusion during virus entry. Some single-nucleotide polymorphism (SNPs) in two surface-exposed loops of NPC1 are known to reduce viral infectivity. However, the dependence of differences in entry efficiency on SNPs remains unclear. Using vesicular stomatitis virus pseudotyped with Ebola and Marburg virus GPs, we investigated the cell-to-cell spread of viruses in cultured cells expressing NPC1 or SNP derivatives. Eclipse and virus-producing phases were assessed byin vitroinfection experiments, and we developed a mathematical model describing spatial-temporal virus spread. This mathematical model fit the plaque radius data well from day 2 to day 6. Based on the estimated parameters, we found that SNPs causing the P424A and D508N substitutions in NPC1 most effectively reduced the entry efficiency of Ebola and Marburg viruses, respectively. Our novel approach could be broadly applied to other virus plaque assays.Author SummaryEbola virus belongs to the family Filoviridae, together with Marburg virus and Cueva virus. In 2015, the World Health Organization included Ebola and Marburg viruses among the infectious diseases that should be globally prioritized because these filoviruses can cause severe hemorrhagic fever in humans and nonhuman primates, and antiviral agents to these viruses are very limited. Filovirus particles bear the envelope glycoprotein (GP), which is the only viral surface protein and thus responsible for receptor binding and membrane fusion. Interaction between filovirus GP and the Niemann-Pick C1 (NPC1) protein is essential for membrane fusion during virus entry. Some single-nucleotide polymorphism (SNPs) in two surface-exposed loops of NPC1 are known to reduce viral infectivity. However, the dependence of differences in entry efficiency on SNPs remains unclear. In this study, combiningin vitroexperiments and mathematical models, we evaluated on the interaction between GP and wildtype and mutant NPC1, enabling us to estimate the cellular entry efficiency during plaque formation.
A portable, low-cost device for precise control of specimen temperature under stereomicroscopes
Authors: Testa Nicholas D. , Kaul Samiksha , Le Kim N. , Zhan Mei , Lu Hang , Paaby Annalise B. 
Published: December 2019

ABSTRACTTo facilitate precise and convenient control of biological sample temperature, we developed a low-cost device that can be used independently or with any stereomicroscope. The purpose of the device is to control the thermal environment during experimental intervals in which a specimen must be manipulated outside of an incubator, e.g. for dissection or slide-mounting in preparation for imaging. Sample temperatures can be both cooled to below and heated to above room temperatures, and stably maintained at a precision of +/− 0.1°C. To demonstrate the utility of this device, we report improved characterization of the penetrance of a short-acting temperature-sensitive allele inC. elegansembryos, and identification of the upper temperature threshold for embryonic viability for sixCaenorhabditisspecies. By controlling the temperature environment even as a specimen is manipulated, this device offers consistency and flexibility, reduces environmental noise, and enables precision timing in experiments requiring temperature shifts.