bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene Expression Meta-Analysis Reveals Interferon-induced Genes
Authors: Park Amber , Harris Laura K. 
Published: November 2020

AbstractBackgroundSevere Acute Respiratory Syndrome (SARS) corona virus (CoV) infections are a serious public health threat because of their pandemic-causing potential. This work analyzes mRNA expression data from SARS infections through meta-analysis of gene signatures, possibly identifying therapeutic targets associated with major SARS infections.MethodsThis work defines 37 gene signatures representing SARS-CoV, Middle East Respiratory Syndrome (MERS)-CoV, and SARS-CoV2 infections in human lung cultures and/or mouse lung cultures or samples and compares them through Gene Set Enrichment Analysis (GSEA). To do this, positive and negative infectious clone SARS (icSARS) gene panels are defined from GSEA-identified leading-edge genes between two icSARS-CoV derived signatures, both from human cultures. GSEA then is used to assess enrichment and identify leading-edge icSARS panel genes between icSARS gene panels and 27 other SARS-CoV gene signatures. The meta-analysis is expanded to include five MERS-CoV and three SARS-CoV2 gene signatures. Genes associated with SARS infection are predicted by examining the intersecting membership of GSEA-identified leading-edges across gene signatures.ResultsSignificant enrichment (GSEA p<0.001) is observed between two icSARS-CoV derived signatures, and those leading-edge genes defined the positive (233 genes) and negative (114 genes) icSARS panels. Non-random significant enrichment (null distribution p<0.001) is observed between icSARS panels and all verification icSARSvsmock signatures derived from human cultures, from which 51 over- and 22 under-expressed genes are shared across leading-edges with 10 over-expressed genes already associated with icSARS infection. For the icSARSvsmock mouse signature, significant, non-random significant enrichment held for only the positive icSARS panel, from which nine genes are shared with icSARS infection in human cultures. Considering other SARS strains, significant, non-random enrichment (p<0.05) is observed across signatures derived from other SARS strains for the positive icSARS panel. Five positive icSARS panel genes, CXCL10, OAS3, OASL, IFIT3, and XAF1, are found across mice and human signatures regardless of SARS strains.ConclusionThe GSEA-based meta-analysis approach used here identifies genes with and without reported associations with SARS-CoV infections, highlighting this approach’s predictability and usefulness in identifying genes that have potential as therapeutic targets to preclude or overcome SARS infections.
Mimicking the Human Tympanic Membrane: the Significance of Geometry
Authors: Anand Shivesh , Stoppe Thomas , Lucena Mónica , Rademakers Timo , Neudert Marcus , Danti Serena , Moroni Lorenzo , Mota Carlos 
Published: November 2020

AbstractThe human tympanic membrane (TM) captures sound waves reaching the outer ear from the environment and transforms them into mechanical motion. The successful transmission of these acoustic vibrations in varying frequency ranges is attributed to the structural architecture of the TM. However, a limited knowledge is available on the contribution of its discrete anatomical features, which is important to fabricate functional biomimetic TM replacements. This work synergizes theoretical and experimental approaches toward understanding the significance of geometry in tissue engineered TM scaffolds. Three test designs along with a plain control were chosen to decouple some of the dominant structural attributes, such as, the radial and circumferential alignment of the collagen fibrils.In silicomodels suggested a geometrical dependency of their mechanical and acoustical responses, where the presence of radially aligned fibers was observed to have a more prominent effect compared to their circumferential counterparts. Following which, a hybrid fabrication strategy combining electrospinning and additive manufacturing was optimized to manufacture hierarchical scaffolds within the dimensions of the native TM. The experimental characterizations conducted using macro-indentation and laser Doppler vibrometry were in line with the computational models. Finally, biological studies performed with human dermal fibroblasts and human mesenchymal stromal cells, revealed a favorable influence of scaffold hierarchy on cellular alignment and subsequent collagen deposition.Abstract FigureGraphical abstract.Schematic diagram illustrating the overall flowchart of the work. 3D: three-dimensional; ES: electrospinning; FDM: fused deposition modeling; TM: tympanic membrane.
Non-coding variants upstream ofMEF2Ccause severe developmental disorder through three distinct loss-of-function mechanisms
Authors: Wright Caroline F , Quaife Nicholas M , Ramos-Hernández Laura , Danecek Petr , Ferla Matteo P , Samocha Kaitlin E , Kaplanis Joanna , Gardner Eugene J , Eberhardt Ruth Y , Chao Katherine R , Karczewski Konrad J , Morales Joannella , Balasubramanian Meena , Banka Siddharth , Gompertz Lianne , Kerr Bronwyn , Kirby Amelia , Lynch Sally A , Morton Jenny EV , Pinz Hailey , Sansbury Francis H , Stewart Helen , Zuccarelli Britton D ,   Genomics England Research Consortium, Cook Stuart A , Taylor Jenny C , Juusola Jane , Retterer Kyle , Firth Helen V , Hurles Matthew E , Lara-Pezzi Enrique , Barton Paul JR , Whiffin Nicola 
Published: November 2020

AbstractClinical genetic testing of protein-coding regions identifies a likely causative variant in only ∼35% of severe developmental disorder (DD) cases. We screened 9,858 patients from the Deciphering Developmental Disorders (DDD) study forde novomutations in the 5’untranslated regions (5’UTRs) of dominant haploinsufficient DD genes. We identify four single nucleotide variants and two copy number variants upstream ofMEF2Cthat cause DD through three distinct loss-of-function mechanisms, disrupting transcription, translation, and/or protein function. These non-coding variants represent 23% of disease-causing variants identified inMEF2Cin the DDD cohort. Our analyses show that non-coding variants upstream of known disease-causing genes are an important cause of severe disease and demonstrate that analysing 5’UTRs can increase diagnostic yield, even using existing exome sequencing datasets. We also show how non-coding variants can help inform both the disease-causing mechanism underlying protein-coding variants, and dosage tolerance of the gene.
ToRQuEMaDA: Tool for Retrieving Queried Eubacteria, Metadata and Dereplicating Assemblies
Authors: Léonard Raphaël R. , Leleu Marie , Van Vlierberghe Mick , Kerff Frédéric , Baurain Denis 
Published: November 2020

AbstractTQMD is a tool which downloads, stores and produces lists of dereplicated prokaryotic genomes. It has been developed to counter the ever-growing number of prokaryotic genomes and their uneven taxonomic distribution. It is based on word-based alignment-free methods (k-mers), an iterative single-linkage approach and a divide-and-conquer strategy to remain both efficient and scalable. We studied the performance of TQMD by verifying the influence of its parameters and heuristics on the clustering outcome. We further compared TQMD to two other dereplication tools (dRep and Assembly-Dereplicator). Our results showed that TQMD is optimized to dereplicate at high taxonomic levels (phylum/class), whereas the other dereplication tools are optimized for lower taxonomic levels (species/strain), making TQMD complementary to the existing dereplicating tools. TQMD is available at <https://bitbucket.org/phylogeno/tqmd>.
A novel human fetal liver-derived model reveals that MLL-AF4 drives a distinct fetal gene expression program in infant ALL
Authors: Rice Siobhan , Jackson Thomas , Crump Nicholas T , Fordham Nicholas , Elliott Natalina , O’Byrne Sorcha , Inglott Sarah , Ladon Dariusz , Wright Gary , Bartram Jack , Ancliff Philip , Mead Adam J , Halsey Christina , Roberts Irene , Milne Thomas A , Roy Anindita 
Published: November 2020

ABSTRACTAlthough 90% of children with acute lymphoblastic leukemia (ALL) are now cured1, the prognosis of infant-ALL (diagnosis within the first year of life) remains dismal2. Infant-ALL is usually caused by a single genetic hit that arisesin utero: rearrangement of theMLL/KMT2Agene (MLL-r). This is sufficient to give rise to a uniquely aggressive and treatment-refractory leukemia compared to older children with the sameMLL-r3–5. The reasons for disparate outcomes in patients of different ages with identical driver mutations are unknown. This paper addresses the hypothesis that fetal-specific gene expression programs co-operate with MLL-AF4 to initiate and maintain infant-ALL. Using direct comparison of fetal and adult HSC and progenitor transcriptomes we identify fetal-specific gene expression programs in primary human cells. We show thatMLL-AF4-driven infant-ALL, but notMLL-AF4childhood-ALL, displays expression of fetal-specific genes. In a direct test of this observation, we find that CRISPR-Cas9 gene editing of primary human fetal liver cells to produce a t(4;11)/MLL-AF4translocation replicates the clinical features of infant-ALL and drives infant-ALL-specific and fetal-specific gene expression programs. These data strongly support the hypothesis that fetal-specific gene expression programs co-operate with MLL-AF4 to initiate and maintain the distinct biology of infant-ALL.
Iron can be microbially extracted from Lunar and Martian regolith simulants and 3D printed into tough structural materials
Authors: Castelein Sofie M. , Aarts Tom F. , Schleppi Juergen , Hendrikx Ruud , Böttger Amarante J. , Benz Dominik , Marechal Maude , Makaya Advenit , Brouns Stan J. , Schwentenwein Martin , Meyer Anne S. , Lehner Benjamin A.E. 
Published: November 2020

AbstractIn-situresource utilization (ISRU) is increasingly acknowledged as an essential requirement for the construction of sustainable extra-terrestrial colonies. Even with decreasing launch costs, the ultimate goal of establishing colonies must be the usage of resources found at the destination of interest. Typical approaches towards ISRU are often constrained by the mass and energy requirements of transporting processing machineries, such as rovers and massive reactors, and the vast amount of consumables needed. Application of self-reproducing bacteria for the extraction of resources is a promising approach to avoid these pitfalls. In this work, the bacteriumShewanella oneidensiswas used to reduce three different types of Lunar and Martian regolith simulants, allowing for the magnetic extraction of iron-rich materials. The quantity of bacterially extracted material was up to 5.8 times higher and the total iron concentration was up to 43.6% higher in comparison to untreated material. The materials were 3D printed into cylinders and the mechanical properties were tested, resulting in a 396 ± 115% improvement in compressive strength in the bacterially treated samples. This work demonstrates a proof of concept for the on-demand production of construction and replacement parts in space exploration.
Androgen responsiveness to simulated territorial intrusions inAllobates femoralismales: evidence supporting the challenge hypothesis in a territorial frog
Authors: Rodríguez Camilo , Fusani Leonida , Raboisson Gaëlle , Hödl Walter , Ringler Eva , Canoine Virginie 
Published: November 2020

AbstractTerritorial behaviour has been widely described across many animal taxa, where the acquisition and defence of a territory are critical for the fitness of an individual. Extensive evidence suggests that androgens (e.g. testosterone) are involved in the modulation of territorial behaviour in male vertebrates. Short-term increase of androgen following a territorial encounter appears to favour the outcome of a challenge. The “Challenge Hypothesis” proposed by Wingfield and colleagues outlines the existence of a positive feedback relationship between androgen and social challenges (e.g. territorial intrusions) in male vertebrates. Here we tested the challenge hypothesis in the highly territorial poison frog,Allobates femoralis, in its natural habitat by exposing males to simulated territorial intrusions in form of acoustic playbacks. We quantified repeatedly androgen concentrations of individual males via a non-invasive water-borne sampling approach. Our results show thatA. femoralismales exhibited a positive behavioural and androgenic response after being confronted to simulated territorial intrusions, providing support for the Challenge Hypothesis in a territorial frog.
Hematological parameters of high and low altitude Tibetan populations
Authors: Basak Nipa , Norboo Tsering , Mustak Mohammed S. , Thangaraj Kumarasamy 
Published: November 2020

AbstractHigh altitude hypoxia is believed to be experienced at elevations more than 2500 meters. A few studies have shed light on the biochemical aspects of high altitude acclimatization that profoundly included the subjects sojourning to the high altitude from low altitude and observation of the transient changes. However, information regarding the difference between the adapted people in high altitude and their counterpart, who reside in the low altitude are lacking. To address that issue, we have measured various hematological parameters and level of serum erythropoietin (EPO) in Tibetan population, who are residing in both high and low altitudes. We observed significant difference (p value < 0.0001) between high and low altitude Tibetan, in various hematological parameters, including red blood cells (RBC) count, hematocrit (HCT) or packed cell volume (PCV), and hemoglobin concentration (Hb). In case of mean corpuscular volume (MCV), significant difference was observed only in females (p value < 0.0001). Mean corpuscular hemoglobin concentration (MCHC) was significantly different between both males and females, but age was a potential confounder. There was no significant difference in serum EPO level between these two groups, either in males or females, which might be due to blunted erythropoietin response in the Tibetan population. We have also analyzed correlation between serum EPO with Hb and serum EPO with HCT and found no significant correlation. In multiple regression analysis, low altitude and male-gender showed significant impact on both Hb and HCT. In conclusion, our study suggests significant perturbation of hematological parameters, when native high altitude populations migrated to low altitude and inhabited for a long period.
Sensitivity to Immune Checkpoint Blockade and Progression-Free Survival is associated with baseline CD8+T cell clone size and cytotoxicity
Authors: Watson RA , Tong O , Cooper R , Taylor CA , Sharma PK , Verge de Los Aires A , Mahé EA , Ruffieux H , Nassiri I , Middleton MR , Fairfax BP 
Published: November 2020

ABSTRACTImmune checkpoint blockers (ICB) exert their anti-cancer effects via CD8+T cells, although how responses vary over sub-populations and across clones is incompletely understood. We performed single-cell RNA-sequencing of CD8+T cells and their receptors pre- and post-ICB across eight patients, integrating results with bulk-sequencing data (n=209). We identify seven subsets with divergent responses to ICB, finding the effector cluster demonstrates the most pronounced changes. Likewise, transcriptomic response to ICB relates to clone size, with large clones demonstrating increased numbers of regulated genes of higher immunological pertinence. Cytotoxic effector clones were more likely to persist long-term following ICB and overlapped with public tumour-infiltrating lymphocyte clonotypes. Notably, pre-treatment CD8+cytotoxicity associated with progression-free survival, highlighting the importance of the baseline CD8+immune landscape in long-term response. This work further advances understanding of the molecular determinants of ICB response and assists in the search for peripheral prognostic biomarkers.ONE SENTENCE SUMMARYUsing single-cell and bulk RNA sequencing we explore checkpoint immunotherapy activity on peripheral CD8+T cells in metastatic melanoma; demonstrating that cell subset and clone size determine gene expression responses to treatment, and that pre-treatment cytotoxicity and clonality of peripheral CD8+T cells is clinically prognostic.
Active Participation of Membrane Lipids in Inhibition of Multidrug Transporter P-Glycoprotein
Authors: Kapoor Karan , Pant Shashank , Tajkhorshid Emad 
Published: November 2020

AbstractP-glycoprotein (Pgp) is a major efflux pump in humans, overexpressed in a variety of cancers and associated with the development of multi-drug resistance. Allosteric modulation by various ligands (e.g., transport substrates, inhibitors, and ATP) has been biochemically shown to directly influence structural dynamics, and thereby, the function of Pgp. However, the molecular details of such effects, particularly with respect to the role and involvement of the surrounding lipids, are not well established. Here, we employ all-atom molecular dynamics (MD) simulations to study the conformational landscape of Pgp in the presence of a high-affinity, third-generation inhibitor, tariquidar, in comparison to the nucleotide-free (APO) and the ATP-bound states, in order to characterize the mechanical effects of the inhibitor that might be of relevance to its blocking mechanism of Pgp. Simulations in a multi-component lipid bilayer show a dynamic equilibrium between open(er) and more closed inward-facing (IF) conformations in the APO state, with binding of ATP shifting the equilibrium towards conformations more prone to ATP hydrolysis and subsequent events in the transport cycle. In the presence of the inhibitor bound to the drug-binding pocket within the transmembrane domain (TMD), Pgp samples more open IF conformations, and the nucleotide binding domains (NBDs) become highly dynamic. Interestingly, and reproduced in multiple independent simulations, the inhibitor is observed to facilitate recruitment of lipid molecules into the Pgp lumen through the two proposed drug-entry portals, where the lipid head groups from the cytoplasmic leaflet penetrate into and, in some cases, translocate inside the TMD, while the lipid tails remain extended into the bulk lipid environment. These “wedge” lipids likely enhance the inhibitor-induced conformational restriction of the TMD leading to the differential modulation of coupling pathways observed with the NBDs downstream. We suggest a novel inhibitory mechanism for tariquidar, and potentially for related third-generation Pgp inhibitors, where lipids are seen to enhance the inhibitory role in the catalytic cycle of membrane transporters.
Evolutionary rates are correlated betweenBuchneraendosymbionts and mitochondrial genomes of their aphid hosts
Authors: Arab Daej A. , Lo Nathan 
Published: November 2020

AbstractThe evolution of bacterial endosymbiont genomes is strongly influenced by host-driven selection. Factors affecting host genome evolution will potentially affect endosymbiont genomes in similar ways. One potential outcome is correlations in molecular rates between the genomes of the symbiotic partners. Recently, we presented the first evidence of such a correlation between the mitochondrial genomes of cockroaches and the genome of their endosymbiont (Blattabacterium cuenoti). Here we investigate whether similar patterns are found in additional host-symbiont partners. We use partial genome data from multiple strains of bacterial endosymbionts,B. aphidicolaandSulcia mulleri, and the mitochondrial genomes of their sap-feeding insect hosts. Both endosymbionts show phylogenetic congruence with the mitochondria of their hosts, a result that is expected due to their identical mode of inheritance. We compared root-to-tip distances and branch lengths of phylogenetically independent species pairs. Both analyses show a highly significant correlation of molecular rates between genomes ofBuchneraand mitochondrial genomes of their hosts. A similar correlation was detected betweenSulciaand their hosts, but was not statistically significant. Our results indicate that evolutionary rate correlations between hosts and long-term symbionts may be a widespread phenomenon.
Anti-CRISPR RNAs: designing universal riboregulators with deep learning of Csy4-mediated RNA processing
Authors: Guo Haotian , Song Xiaohu , Lindner Ariel B. 
Published: November 2020

AbstractRNA-based regulation offers a promising alternative of protein-based transcriptional networks. However, designing synthetic riboregulators with desirable functionalities using arbitrary sequences remains challenging, due in part to insufficient exploration of RNA sequence-to-function landscapes. Here we report that CRISPR-Csy4 mediates a nearly all-or-none processing of precursor CRISPR RNAs (pre-crRNAs), by profiling Csy4 binding sites flanked by > 1 million random sequences. This represents an ideal sequence-to-function space for universal riboregulator designs. Lacking discernible sequence-structural commonality among processable pre-crRNAs, we trained a neural network for accurate classification (f1-score ≈ 0.93). Inspired by exhaustive probing of palindromic flanking sequences, we designed anti-CRISPR RNAs (acrRNAs) that suppress processing of pre-crRNAs via stem stacking. We validated machine-learning-guided designs with >30 functional pairs of acrRNAs and pre-crRNAs to achieve switch-like properties. This opens a wide range of plug-and-play applications tailored through pre-crRNA designs, and represents a programmable alternative to protein-based anti-CRISPRs.
The bone microenvironment invigorates metastatic seeds for further dissemination
Authors: Zhang Weijie , Bado Igor L. , Wang Hai , Singh Swarnima , Lo Hin-Ching , Niu Muchun , Xu Zhan , Liu Jun , Jiang Weiyu , Li Yi , Hu Jingyuan , Zhang Xiang H.-F. 
Published: November 2020

SUMMARYMetastasis has been considered as the terminal step of tumor progression. However, recent clinical studies suggest that many metastases are seeded from other metastases, rather than primary tumors. Thus, some metastases can further spread, but the corresponding pre-clinical models are lacking. By using several approaches including parabiosis and an evolving barcode system, we demonstrated that the bone microenvironment facilitates breast and prostate cancer cells to further metastasize and establish multi-organ secondary metastases. Importantly, dissemination from the bone microenvironment appears to be more aggressive compared to that from mammary tumors and lung metastases. We further uncovered that this metastasis-promoting effect is independent from genetic selection, as single cell-derived cancer cell populations (SCPs) exhibited enhanced metastasis capacity after being extracted from the bone microenvironment. Taken together, our work revealed a previously unappreciated effect of the bone microenvironment on metastasis evolution, and suggested a stable reprogramming process that engenders cancer cells more metastatic.