bluuebunny/crossref_metadata_2025_split huggingface dataset:
COMPUTATIONAL IDENTIFICATION VALIDATION AND STRUCTURAL CHARACTERIZATION OF SOME POTENTIAL CANDIDATE GENES FOR DIABETES MELLITUS
Authors: Tanty Dhananjay Kumar , Sahu Prachi Rani , Behera Swagatika , Mohapatra Ranjit , Behera Pabitra Mohan , Sahu Susanta Kumar 
Published: August 2022

AbstractDiabetes mellitus seems to be a complex metabolic disorder due to its association with several complications like cardiovascular, ocular, neurologic, skeletal, hepatic and renal abnormalities etc. Current estimations by WHO suggest that most of the low and middle-income countries of the world are worst affected by this disorder with a prediction that the prevalence may double between 2020 and 2030. Thus both doctors and scientists across the globe are involved in research to disclose the complex genetics of this disorder associated with several environmental and demographic factors. In the last 10 years, several predictions have been made in the lane of omics approaches and computational biology which makes the process quite generous. In the current work, we present a computational analysis of potential candidate genes for diabetes mellitus and their differential expressions in targeted human tissue systems. About 220 reported genes for diabetes mellitus were selected for the study and their protein-protein interaction network (5090 nodes) was extracted using medium-confidence interactions of the HIPPIE database. From the network, the top 10% (509) genes were categorised as hub genes after calculation of about 11 centralities, their consensus ranking and rank correlations. The same set of 220 genes was used for gene ontology enrichment analysis featuring about 1483 genes. About 89 candidate genes were predicted for diabetes mellitus and their differential expressions were studied in adipose, pancreas, skeletal, hepatic and renal tissue systems using the information from NCBI GEOdatabase. Then the differentially expressed gene sets for each tissue system were further validated by fetching them in the potential clusters of the PPI network designed earlier with their functional enrichment analysis using information from the STRINGS database. About 77 genes were prioritized with help of our scoring system and their structural characterization was done with protein centric annotations from UniProtKB database information and molecular model building. We hope our findings are helpful in understanding the expression of diabetes-related genes in different human tissue systems which may lead to the design of newer therapeutic strategies.
Orthogonal Shared Basis Factorization: Cross-species gene expression analysis using a common expression subspace
Authors: Thomas Amal 
Published: August 2022

AbstractOne of the main challenges in analyzing gene expression profiles across species is the dependence on determining corresponding genes between species. Homology-based approaches fail to account for the contribution of non-homologous genes to the phenotype, genes’ functional divergence, and rewiring of pathways. Homology-independent methods based on joint matrix factorization provide a potential solution, but biological interpretations with existing approaches are difficult. We developed a novel joint matrix factorization method that we call the orthogonal shared basis factorization (OSBF) to compare functionally similar phenotypes across species. OSBF utilizes a similar correlation structure within individual datasets to estimate interpretable matrix factors. This homology-independent approach places cellular phenotypes in a common coordinate system that can summarize gene expression patterns shared by different organisms and quantifies the role of all genes in the phenotype independent of their homology relationships and annotation. OSBF is available on GitHub.
Disruption of lysosomal proteolysis in astrocytes facilitates midbrain proteostasis failure in an early-onset PD model
Authors: Parfitt Gustavo Morrone , Coccia Elena , Goldman Camille , Whitney Kristen , Reyes Ricardo , Sarrafha Lily , Nam Ki Hong , Sohail Soha , Jones Drew , Crary John F , Ordureau Alban , Blanchard Joel , Ahfeldt Tim D 
Published: August 2022

SUMMARYAccumulation of advanced glycation end products (AGEs) on biopolymers accompany cellular aging and drives poorly understood disease processes. Here, we studied how AGEs contribute to development of early on-set Parkinson’s Disease (PD) caused by loss-of-function of DJ1, a protein deglycase. In induced pluripotent stem cell (iPSC)-derived midbrain organoid models deficient for DJ1 activity, we find that lysosomal proteolysis is impaired, causing AGEs to accumulate, α-synuclein (α-syn) phosphorylation to increase, and proteins to aggregate. These processes are at least partly driven by astrocytes, as DJ1 loss reduces their capacity to provide metabolic support and triggers acquisition of a pro-inflammatory phenotype. Consistently, in co-cultures, we find that DJ1-expressing astrocytes are able to reverse the proteolysis deficits of DJ1 knockout midbrain neurons. In conclusion, astrocytes’ capacity to clear toxic damaged proteins is critical to preserve neuronal function and their dysfunction contributes to the neurodegeneration observed in PD.
Harmonized single-cell landscape, intercellular crosstalk and tumor architecture of glioblastoma
Authors: Ruiz-Moreno Cristian , Salas Sergio Marco , Samuelsson Erik , Brandner Sebastian , Kranendonk Mariette E.G. , Nilsson Mats , Stunnenberg Hendrik G. 
Published: August 2022

SUMMARYGlioblastoma, isocitrate dehydrogenase (IDH)-wildtype (hereafter, GB), is an aggressive brain malignancy associated with a dismal prognosis and poor quality of life. Single-cell RNA sequencing has helped to grasp the complexity of the cell states and dynamic changes in GB. Large-scale data integration can help to uncover unexplored tumor pathobiology. Here, we resolved the composition of the tumor milieu and created a cellular map of GB (‘GBmap’), a curated resource that harmonizes 26 datasets gathering 240 patients and spanning over 1.1 million cells. We showcase the applications of our resource for reference mapping, transfer learning, and biological discoveries. Our results uncover the sources of pro-angiogenic signaling and the multifaceted role of mesenchymal-like cancer cells. Reconstructing the tumor architecture using spatially resolved transcriptomics unveiled a high level of well-structured neoplastic niches. The GBmap represents a framework that allows the streamlined integration and interpretation of new data and provides a platform for exploratory analysis, hypothesis generation and testing.
Long non-coding RNA RGMB-AS1 as a novel modulator of Bone Morphogenetic Protein Receptor 2 signaling in pulmonary arterial hypertension
Authors: Ali Md Khadem , Liu Yu , Zhao Lan , Wu Joseph C. , de Jesus Perez Vinicio , Rhodes Christopher J. , Cao Aiqin , Wilkins Martin R. , Nicolls Mark R. , Spiekerkoetter Edda F. 
Published: August 2022

AbstractThis study shows that the long non-coding RNA RGMB-AS1 is upregulated in the blood and pulmonary vascular cells of PAH patient and that it regulates BMPR2 signaling. Inhibiting RGMB-AS1 increases BMPR2 signaling and improves pulmonary vascular cell function.
Lipid droplets are intracellular mechanical stressors that promote hepatocyte dedifferentiation
Authors: Loneker Abigail E. , Alisafaei Farid , Kant Aayush , Janmey Paul A. , Shenoy Vivek B. , Wells Rebecca G. 
Published: August 2022

AbstractMatrix stiffening and external mechanical stress have been linked to disease and cancer development in multiple tissues, including the liver, where cirrhosis (which increases stiffness markedly) is the major risk factor for hepatocellular carcinoma. Patients with non-alcoholic fatty liver disease and lipid-droplet-filled hepatocytes, however, can develop cancer in non-cirrhotic, relatively soft tissue. Here, we show that lipid droplets are intracellular mechanical stressors with similar effects to tissue stiffening, including nuclear deformation, chromatin condensation, and hepatocyte dedifferentiation. Mathematical modelling of lipid droplets as inclusions that have only mechanical interactions with other cellular components generated results consistent with our experiments. These data show that lipid droplets are intracellular sources of mechanical stress and suggest that nuclear membrane tension integrates cell responses to combined internal and external stresses.Significance StatementDeformation of the nucleus as a result of extracellular sources of stress, including increased substrate stiffness, constricted migration, and compression, has been well documented to lead to increased nuclear rupture, changes in gene expression, and accumulation of DNA damage. Lipid droplet accumulation in hepatocytes provides a unique scenario to investigate potential intracellular mechanical stresses and sources of nuclear deformation. Our results show that lipid droplets are significant mechanical elements in the cell, deforming the nucleus in a way that promotes hepatocyte dedifferentiation and resisting cytoskeletal contraction and alignment.
Histone Tail Electrostatics Modulate E2-E3 Enzyme Dynamics: A Gateway to Regulate Ubiquitination Machinery
Authors: Ranathunga Dineli T. S. , Torabifard Hedieh 
Published: August 2022

AbstractBRCA1 (BReast Cancer-Associated protein 1), a human tumor suppressor, plays a key role in genome stability and DNA repair. Heterodimerization of BRCA1 with BARD1 is important for its stability, maximal Ub ligase (E3) activity and cooperative activation of UbcH5c (E2). Recent studies demonstrate the importance of ubiquitination of the nucleosomal H2A C-terminal tail by BRCA1/BARD1-UbcH5c (E3-E2) in which its mutations inhibit ubiquitination, predispose cells to chromosomal instability and greatly increase the likelihood of breast and ovarian cancer development. Due to the lack of molecular-level insight on the flexible and disordered H2A C-tail, its ubiquitination mechanism by BRCA1/BARD1-UbcH5c and its function and relationship to cancer susceptibility remain elusive. Here, we use molecular dynamics simulations to provide molecular-level insights into the dynamics of the less-studied H2A C-tail and BRCA1/BARD1-UbcH5c on the nucleosome surface. Our results precisely identify the key interactions and residues that trigger conformational transitions of BRCA1/BARD1-UbcH5c, and characterize the important role of histone electrostatics in their dynamics. We show that the dynamics of the H2A C-tail, combined with the highly mobile UbcH5c, define the ubiquitination capacity. Furthermore, our data demonstrate a mechanistic basis for the probability of ubiquitination of C-tail lysines in the ordered and disordered regions. Altogether, the findings of this study will provide unrevealed insights into the mechanism of H2A C-tail ubiquitination and help us understand the communication between E2-E3 enzymes and nucleosome to regulate ubiquitination machinery, paving the way for the development of effective treatments for cancer and chronic pain.Abstract Figure
Genome sequencing and de novo and reference-based genome assemblies of Bos indicus breeds
Authors: Chakraborty Abhisek , Bisht Manohar S. , Saxena Rituja , Mahajan Shruti , Pulikkan Joby , Sharma Vineet K. 
Published: August 2022

ABSTRACTBos indicus is a domestic cattle species with many indigenous breeds found in India and is important for dairy, draught work, and other household activities. Distinct phenotypic differences are observed among the breeds of this species; however, their whole genome sequences were not available. Therefore, in this study, we performed the whole genome sequencing using Illumina short-read technology to construct draft genome assemblies of four B. indicus breeds; Ongole, Kasargod Dwarf, Kasargod Kapila, and Vechur, of which Vechur is known as the smallest cow of the world. We also report the first de novo genome assemblies of these native B. indicus breeds. Further, we constructed the 18S rRNA marker gene sequences of these B. indicus breeds, which were not yet known. Genomic analysis helped to identify the distinct bovine phenotypic characteristics-related and other biological process-related genes in this species compared to B. taurus, and to gain comparative genomic insights between the dwarf and non-dwarf breeds of this species.
Cell-type-specific whole-genome landscape of ΔFOSB binding in nucleus accumbens after chronic cocaine exposure
Authors: Yeh Szu-Ying , Estill Molly , Lardner Casey K. , Browne Caleb J. , Minier-Toribio Angelica , Futamura Rita , Beach Katherine , McManus Catherine A. , Xu Song-jun , Zhang Shuo , Heller Elizabeth A. , Shen Li , Nestler Eric J. 
Published: August 2022

AbstractThe ability of neurons to respond to external stimuli involves adaptations of gene expression. The transcription factor, ΔFOSB, is important for the development of drug addiction, however, its gene targets have not been identified. Here we use CUT&RUN to map the genome-wide enrichment of ΔFOSB binding in the two major neuronal cell types of the nucleus accumbens, a key brain reward region, after cocaine exposure. The binding landscape shows that the majority of ΔFOSB peaks occur outside of promoter regions, including intergenic regions, and are surrounded by epigenetic marks indicative of active enhancers. BRG1, the core subunit of the SWI/SNF chromatin remodeling complex, overlaps with ΔFOSB peaks, consistent with earlier studies of ΔFOSB’s interacting proteins. In addition, in silico analyses predict that ΔFOSB cooperatively regulates gene expression with homeobox and T-box transcription factors. These novel findings uncover key elements of ΔFOSB’s molecular mechanisms in transcriptional regulation.
Vector acquisition and co-inoculation of two plant viruses influences transmission, infection, and replication in new hosts
Authors: McLaughlin Autumn A. , Hanley-Bowdoin Linda , Kennedy George G. , Jacobson Alana L. 
Published: August 2022

AbstractThis study investigated the role of vector acquisition and transmission on the propagation of single and co-infections of tomato yellow leaf curl virus (TYLCV,) and tomato mottle virus (ToMoV) (Family: Geminiviridae, Genus: Begomovirus) by the whitefly vector Bemisia tabaci MEAM1 (Gennadius) in tomato. The aim of this research was to determine if how viruses are co-acquired and co-transmitted changes the probability of acquisition, transmission and new host infections. Whiteflies acquired virus by feeding on singly infected plants, co-infected plants, or by sequential feeding on singly infected plants. Viral titers were also quantified by qPCR in vector cohorts, in artificial diet, and plants after exposure to viruliferous vectors. Differences in transmission, infection status of plants, and titers of TYLCV and ToMoV were observed among treatments. All vector cohorts acquired both viruses, but co-acquisition/co-inoculation generally reduced transmission of both viruses as single and mixed infections. Co-inoculation of viruses by the vector also altered virus accumulation in plants regardless of whether one or both viruses were propagated in new hosts. These findings highlight the complex nature of vector-virus-plant interactions that influence the spread and replication of viruses as single and co-infections.
A pharmacoproteomic landscape of organotypic intervention responses in Gram-negative sepsis
Authors: Mohanty Tirthankar , Karlsson Christofer A. Q. , Chao Yashuan , Malmström Erik , Bratanis Eleni , Grentzmann Andrietta , Mørch Martina , Nizet Victor , Malmström Lars , Linder Adam , Shannon Oonagh , Malmström Johan 
Published: August 2022

AbstractSepsis is the major cause of mortality across intensive care units globally, yet details of accompanying pathological molecular events remains unclear. This knowledge gap has resulted in ineffective development of sepsis-specific biomarkers and therapies, and suboptimal treatment regimens to prevent or reverse organ damage. Here, we used pharmacoproteomics to score treatment effects in a murineEscherichia colisepsis model based on changes in the organ, cell, and plasma proteome landscapes. A combination of pathophysiological read-outs and time-resolved proteome maps of organs and blood enabled us to define time-dependent and organotypic proteotypes of dysfunction and damage upon administration of several combinations of the broad-spectrum beta-lactam antibiotic meropenem (Mem) and/or the immunomodulatory glucocorticoid methylprednisolone (Gcc). Three distinct response patterns were identified, defined as intervention-specific reversions, non-reversions, and specific intervention-induced effects, which depended on the underlying proteotype and varied significantly across organs. In the later stages of the disease, Gcc enhanced some positive treatment effects of Mem with superior reduction of the inflammatory response in the kidneys and partial restoration of sepsis-induced metabolic dysfunction. Unexpectedly, Mem introduced sepsis-independent perturbations in the mitochondrial proteome that were to some degree counteracted by Gcc. In summary, this study provides a pharmacoproteomic resource describing the time-resolved septic organ failure landscape across organs and blood, coupled to a novel scoring strategy that captures unintended secondary drug effects as an important criterion to consider when assessing therapeutic efficacy. Such information is critical for quantitative, objective, and organotypic assessment of benefits and unintended effects of candidate treatments in relationship to dosing, timing, and potential synergistic combinations in murine sepsis models.
Spatial transcriptomics reveals ovarian cancer subclones with distinct tumour microenvironments
Authors: Denisenko Elena , de Kock Leanne , Tan Adeline , Beasley Aaron B. , Beilin Maria , Jones Matthew E. , Hou Rui , Muirí Dáithí Ó , Bilic Sanela , Mohan G. Raj K. A. , Salfinger Stuart , Fox Simon , Hmon Khaing , Yeow Yen , Gray Elin S. , Cohen Paul A. , Yu Yu , Forrest Alistair R. R. 
Published: August 2022

AbstractHigh-grade serous ovarian carcinoma (HGSOC) is characterised by recurrence, chemotherapy resistance and overall poor prognosis. Genetic heterogeneity of tumour cells and the microenvironment of the tumour have been hypothesised as key determinants of treatment resistance and relapse. Here, using a combination of spatial and single cell transcriptomics (10x Visium and Chromium platforms), we examine tumour genetic heterogeneity and infiltrating populations of HGSOC samples from eight patients with variable response to neoadjuvant chemotherapy. By inferring gross copy number alterations (CNAs), we identified distinct tumour subclones co-existing within individual tumour sections. These tumour subclones have unique CNA profiles and spatial locations within each tumour section, which were further validated by ultra-low-pass whole genome sequencing. Differential expression analysis between subclones within the same section identified both tumour cell intrinsic expression differences and markers indicative of different infiltrating cell populations. The gene sets differentially expressed between subclones were significantly enriched for genes encoding plasma membrane and secreted proteins, indicative of subclone-specific microenvironments. Furthermore, we identified tumour derived ligands with variable expression levels between subclones that correlated or anticorrelated with various non-malignant cell infiltration patterns. We highlight several of these that are potentially direct tumour-stroma/immune cell relationships as the non-malignant cell type expresses a cognate receptor for the tumour derived ligand. These include predictions of CXCL10-CXCR3 mediated recruitment of T and B cells to associate with the subclones of one patient and CD47-SIRPA mediated exclusion of macrophages from association with subclones of another. Finally, we show that published HGSOC molecular subtype signatures associated with prognosis are heterogeneously expressed across tumour sections and that areas containing different tumour subclones with different infiltration patterns can match different subtypes. Our study highlights the high degree of intratumoural subclonal and infiltrative heterogeneity in HGSOC which will be critical to better understand resistance and relapse.
Histone variant H2A.Z modulates nucleosome dynamics to promote DNA accessibility
Authors: Li Shuxiang , Wei Tiejun , Panchenko Anna R. 
Published: August 2022

AbstractNucleosomes containing the histone variant H2A.Z are important for gene transcription initiation and termination, chromosome segregation and DNA double-strand break repair, among other functions. However, the underlying mechanism of how H2A.Z influences nucleosome stability, dynamics and DNA accessibility remains elusive as experimental and computational evidence are inconclusive. Our modeling efforts of nucleosome stability and dynamics, along with comparisons with experimental data show that the incorporation of H2A.Z results in a substantial decrease of the energy barrier for DNA unwrapping. This leads to spontaneous DNA unwrapping of about forty base pairs in total, enhanced DNA accessibility, nucleosome gapping and histone plasticity, which otherwise is not observed for canonical nucleosomes. We demonstrate that both N- and C-terminal tails of H2A.Z play major roles in these events, whereas H3.3 variant exerts a negligible impact in modulating the DNA end unwrapping. In summary, our results indicate that H2A.Z deposition makes nucleosomes more mobile and DNA more accessible to transcriptional machinery and other chromatin components.
High throughput expression-based phenotyping and RNAi screening reveals novel regulators of planarian stem cells
Authors: Schad Erik G. , Petersen Christian P. 
Published: August 2022

AbstractThe complexity of cell types and states revealed by single-cell RNAseq atlases presents a challenge for the systematic analysis of fate determinants using traditional screening methodologies. Differentiation in the planarian Schmidtea mediterranea exemplifies this problem, as these animals continuously produce over 100 differentiated cell types for homeostasis and regeneration using neoblast adult pluripotent stem cells. The signaling factors enabling neoblast self-renewal and selective differentiation of these many fates are still incompletely understood. We developed a method using high-throughput expression profiling by qPCR and whole-animal RNAseq to simultaneously assess numerous cell fate markers as the phenotypic readout in large-scale RNAi screens. Applying this method, we performed an RNAi screen of 400 kinases, receptors, and other regulatory molecules to reveal specific functions for 30 previously unknown factors in neoblast biology. 17 genes were required for neoblast maintenance, including factors likely involved in cell-cycle regulation, nutrient sensing, and chromatin modification. Multidimensional expression information additionally revealed several specific regulators of other neoblast activities, including a mink1 kinase regulating global neoblast differentiation, the energy responsive kinase adenylate kinase-2 regulating intestine specification within the neoblast population, an RNA acetyl transferase nat10 regulating epidermal differentiation, and a pak1 kinase restricting neoblast localization to prevent tissue outgrowths. These results identify several new regulators of neoblast activities and demonstrate the applicability of expression-based screening for systematic analysis of stem cell phenotypes in whole animals.