bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel splice variant of human TGF-β type II receptor encodes a soluble protein and its Fc-tagged version prevents liver fibrosisin vivo
Authors: Bertolio Marcela Soledad , Colla Anabela La , Carrea Alejandra , Romo Ana , Canziani Gabriela , Echarte Stella Maris , Campisano Sabrina , Barletta German Patricio , Monzon Alexander Miguel , Rodríguez Tania Melina , Chisari Andrea Nancy , Dewey Ricardo Alfredo 
Published: March 2021

AbstractWe describe, for the first time, a new splice variant of the human TGF-β type II receptor (TβRII). The new transcript lacks 149 nucleotides, causing a frameshift with the appearance of an early stop codon, rendering a truncated mature protein of 57 amino acids. The predicted protein, lacking the transmembrane domain and with a distinctive 13 amino acid stretch in the C-terminus, was named TβRII-Soluble Endogenous (TβRII-SE). Binding predictions indicated that the novel 13 amino acid stretch interacts with all three TGF-β cognate ligands and generate a more extensive protein-protein interface than TβRII. TβRII-SE and human IgG1 Fc-domain, were fused in frame in a lentiviral vector (Lv) for further characterization. With this vector, we transduced 293T cells and purified TβRII-SE/Fc by A/G protein chromatography from conditioned medium. Immunoblotting revealed homogeneous bands of approximately 37 kDa (reduced) and 75 kD (non-reduced), indicating that TβRII-SE/Fc is secreted as a disulphide-linked homodimer. Moreover, high affinity binding of TβRII-SE to the three TGF-β isoforms was confirmed by Surface Plasmon Resonance (SPR) analysis. Also, intrahepatic delivery of Lv.TβRII-SE/Fc in a carbon tetrachloride-induced liver fibrosis model revealed amelioration of liver injury and fibrosis. Our results indicate that TβRII-SE is a novel member of the TGF-β signaling pathway with distinctive characteristics. This novel protein offers an alternative for the prevention and treatment of pathologies caused by the overproduction of TGF-β ligands.
Evolutionary Analysis of Transcriptional Regulation Mediated by Cdx2 in Rodents
Authors: Liang Weizheng , Li Guipeng , Cui Huanhuan , Wang Yukai , Wei Wencheng , Sun Siyue , Gan Diwen , Chen Rui , Yi Hongyang , Schaefke Bernhard , Hu Yuhui , Zhou Qi , Li Wei , Chen Wei 
Published: March 2021

AbstractDifferences in gene expression, which can arise from divergence incis-regulatory elements or alterations in transcription factors binding specificity, are one of the most important causes of phenotypic diversity during evolution. By protein sequence analysis, we observed high sequence conservation in the DNA binding domain (DBD) of the transcription factor Cdx2 across many vertebrates, whereas three amino acid changes were exclusively found in mouse Cdx2 (mCdx2), suggesting potential positive selection in the mouse lineage. Multi-omics analyses were then carried out to investigate the effects of these changes. Surprisingly, there were no significant functional differences between mCdx2 and its rat homologue (rCdx2), and none of the three amino acid changes had any impact on its function. Finally, we used rat-mouse allodiploid embryonic stem cells (RMES) to study theciseffects of Cdx2-mediated gene regulation between the two rodents. Interestingly, whereas Cdx2 binding is largely divergent between mouse and rat, the transcriptional effect induced by Cdx2 is conserved to a much larger extent.Author summaryOur study 1) represented a first systematic analysis of species-specific adaptation in DNA binding pattern of transcription factor. Although the mouse-specific amino acid changes did not manifest functional impact in our system, several explanations may account for it (See Discussion part for the detail); 2) represented a first study of cis-regulation between two reproductively isolated species by using a novel allodiploid system; 3) demonstrated a higher conservation of transcriptional output than that of DNA binding, suggesting the evolvability/plasticity of the latter; 4) finally provided a rich data resource for Cdx2 mediated regulation, including gene expression, chromatin accessibility and DNA binding etc.
Biotransformation of agro-industrial waste to wealth in Africa through mushroom farming
Authors: Ekun Victor S. , Adenipekun Clementina O. , Idowu Olufunmilayo , Etaware Peter M. 
Published: March 2021

AbstractDiscarding Waste in open drainages, water bodies and unauthorized dumpsites is a common practice in Africa that is deleterious to the global ecosystem. Global warming, flooding and land encroachment are direct impact of these actions. Therefore, a proposed eco-friendly solution to efficient waste management in Africa is “Mushroom Farming”. The region between Latitude 6.43–7.95°N and Longitude 2.88–5.24°E (Nigeria) was the research focus. Mushroom samples were collected, identified, coded and geo-tagged in the field, while Laboratory analyses and mushroom cultivation was conducted in NIHORT and University of Ibadan. The result showed that postharvest waste (rice straw) was best for spawning (Ek1-8→23days, LA1-8→21days, OG1-8→20days, and OY1-8→22days), while agro-waste fromGliricidium sepiumfacilitated early pin head emergence (26days) and fruiting (28days). Also, agro-waste fromCedrela odoratafacilitated early maturation (3days after fruiting), and those fromMangifera indica, G. sepiumandC. odorata, improved yield (9.05g), pileus size (4.24g) and dry matter (3.01g), respectively. The Laboratory analyses showed that LA1-8 had the best N2, Na and Ca contents (13.59, 70.49 and 61.90mg/100g, respectively), while fat, fibre and carbohydrate contents were highest in samples from EK1-8 (6.60%), OS1-8 (25.13%) and OG1-8 (54.23%), respectively. Mushroom farming is the key to efficient transformation of waste to wealth in Africa.
The impact of mutations on the structural and functional properties of SARS-CoV-2 proteins: A comprehensive bioinformatics analysis
Authors: Ikram Aqsa , Naz Anam , Awan Faryal Mehwish , Rauff Bisma , Obaid Ayesha , Hakim Mohamad S. , Malik Arif 
Published: March 2021

AbstractAn in-depth analysis of first wave SARS-CoV-2 genome is required to identify various mutations that significantly affect viral fitness. In the present study, we have performed comprehensive in-silico mutational analysis of 3C-like protease (3CLpro), RNA dependent RNA polymerase (RdRp), and spike (S) proteins with the aim of gaining important insights into first wave virus mutations and their functional and structural impact on SARS-CoV-2 proteins. Our integrated analysis gathered 3465 SARS-CoV-2 sequences and identified 92 mutations in S, 37 in RdRp, and 11 in 3CLpro regions. The impact of those mutations was also investigated using various in silico approaches. Among these 32 mutations in S, 15 in RdRp, and 3 in 3CLpro proteins are found to be deleterious in nature and could alter the structural and functional behavior of the encoded proteins. D614G mutation in spike and P323L in RdRp are the globally dominant variants with a high frequency. Most of them have also been found in the binding moiety of the viral proteins which determine their critical involvement in the host-pathogen interactions and drug targets. The findings of the current study may facilitate better understanding of COVID-19 diagnostics, vaccines, and therapeutics.
Modeling gene x environment interactions in PTSD using glucocorticoid-induced transcriptomics in human neurons
Authors: Breen Michael S. , Rusielewicz Tom , Bader Heather N. , Seah Carina , Xu Changxin , Hunter Christopher J. , McCarthy Barry , Chattopadhyay Mitali , Desarnaud Frank , Makotkine Iouri , Flory Janine D. , Bierer Linda M. , Staniskyte Migle ,   NYSCF Global Array Team, Noggle Scott A. , Paull Daniel , Brennand Kristen J. , Yehuda Rachel 
Published: March 2021

ABSTRACTPost-traumatic stress disorder (PTSD) results from severe trauma exposure, but the extent to which genetic and epigenetic risk factors impact individual clinical outcomes is unknown. We assessed the impact of genomic differences following glucocorticoid administration by examining the transcriptional profile of human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons and live cultured peripheral blood mononuclear cells from combat veterans with PTSD (n=5) and without PTSD (n=5). This parallel examination in baseline and glucocorticoid-treated conditions resolves cell-type specific and diagnosis-dependent elements of stress response, and permits discrimination of gene expression signals associated with PTSD risk from those induced by stress. Computational analyses revealed neuron-specific glucocorticoid-response expression patterns that were enriched for transcriptomic patterns observed in clinical PTSD samples. PTSD-specific signatures, albeit underpowered, accurately stratify veterans with PTSD relative to combat-exposed controls. Overall,in vitroPTSD and glucocorticoid response signatures in blood and brain cells represent exciting new platforms with which to test the genetic and epigenetic mechanisms underlying PTSD, identify biomarkers of PTSD risk and onset, and conduct drug-screening to identify novel therapeutics to prevent or ameliorate clinical phenotypes.
Delineating the complex mechanistic interplay between autophagy and monocyte to macrophage differentiation: a functional perspective
Authors: Bhattacharya Anindita , Ghosh Purnam , Singh Arpana , Ghosh Arnab , Bhowmick Arghya , Sinha Deepak Kumar , Ghosh Abhrajyoti , Sen Prosenjit 
Published: March 2021

AbstractAutophagy is an extremely essential cellular process aimed to clear redundant and damaged materials. In this study, we demonstrated that mTOR dependent classical autophagy is ubiquitously triggered in differentiating monocytes. Moreover, autophagy plays a decisive role in sustaining the process of monocyte to macrophage differentiation. We have delved deeper into understanding the underlying mechanistic complexities that trigger autophagy during differentiation. We have also shown that autophagy directs monocyte differentiation via protein degradation. Further, we delineated the complex cross-talk between autophagy and cell-cycle arrest in differentiating monocytes. This study also inspects the contribution of adhesion on various steps of autophagy and its ultimate impact on monocyte differentiation. Our study reveals new mechanistic insights into the process of autophagy associated with monocyte differentiation and would undoubtedly help to understand the intricacies of the process better for the effective design of therapeutics as autophagy and autophagy-related processes have enormous importance in human patho-physiology.Graphical Abstract
Polymer physics and machine learning reveal a combinatorial code linking chromatin 3D architecture to 1D epigenetics
Authors: Esposito Andrea , Bianco Simona , Chiariello Andrea M. , Abraham Alex , Fiorillo Luca , Conte Mattia , Campanile Raffaele , Nicodemi Mario 
Published: March 2021

ABSTRACTThe mammalian genome has a complex 3D organization, serving vital functional purposes, yet it remains largely unknown how the multitude of specific DNA contacts, e.g., between transcribed and regulatory regions, is orchestrated by chromatin organizers, such as Transcription Factors. Here, we implement a method combining machine learning and polymer physics to infer from only Hi-C data the genomic 1D arrangement of the minimal set of binding sites sufficient to recapitulate, through only physics, 3D contact patterns genome-wide in human and mouse cells. The inferred binding sites are validated by their predictions on how chromatin refolds in a set of duplications at theSox9locus against available independent cHi-C data, showing that their different phenotypes originate from distinct enhancer hijackings in their 3D structure. Albeit derived from only Hi-C, our binding sites fall in epigenetic classes that well match chromatin states from epigenetic segmentation studies, such as active, poised and repressed states. However, the inferred binding domains have an overlapping, combinatorial organization along chromosomes, missing in epigenetic segmentations, which is required to explain Hi-C contact specificity with high accuracy. In a reverse approach, the epigenetic profile of binding domains provides a code to derive from only epigenetic marks the DNA binding sites and, hence, the 3D architecture, as validated by successful predictions of Hi-C matrices in an independent set of chromosomes. Overall, our results shed light on how complex 3D architectural information is encrypted in 1D epigenetics via the related, combinatorial arrangement of specific binding sites along the genome.
Identification of the Rigid Core for Aged Liquid Droplets of the TDP-43 Low Complexity Domain
Authors: Fonda Blake D. , Jami Khaled M. , Boulos Natalie R. , Murray Dylan T. 
Published: March 2021

AbstractThe biomolecular condensation of proteins with low complexity sequences plays a functional role in RNA metabolism and a pathogenic role in neurodegenerative diseases. The formation of dynamic liquid droplets brings biomolecules together to achieve complex cellular functions. The rigidification of liquid droplets into β-strand-rich hydrogel structures composed of protein fibrils is thought to be purely pathological in nature. However, low complexity sequences often harbor multiple fibril-prone regions with delicately balanced functional and pathological interactions. Here, we investigate the maturation of liquid droplets formed by the low complexity domain of the TAR DNA-binding protein 43 (TDP-43). Solid state nuclear magnetic resonance measurements on the aged liquid droplets identify a structured core region distinct from the region thought to be most important for pathological fibril formation and aggregation. The results of this study show that multiple segments of this low complexity domain are prone to form fibrils, and that stabilization of β-strand-rich structure in one segment precludes the other region from adopting rigid fibril structure.Table of Contents Graphic
Distinct sub-cellular autophagy impairments occur independently of protein aggregation in induced neurons from patients with Huntington’s disease
Authors: Pircs Karolina , Drouin-Ouellet Janelle , Gil Jeovanis , Rezeli Melinda , Grassi Daniela A. , Garza Raquel , Sharma Yogita , St-Amour Isabelle , Jönsson Marie E. , Johansson Pia A. , Harris Kate , Vuono Romina , Stoker Thomas , Hersbach Bob A. , Sharma Kritika , Lagerwall Jessica , Lagerström Stina , Storm Petter , Horváth Vivien , Hébert Sébastien S. , Marko-Varga György , Parmar Malin , Barker Roger A. , Jakobsson Johan 
Published: March 2021

AbstractHuntington’s disease (HD) is a neurodegenerative disorder caused by CAG expansions in the huntingtin (HTT) gene. Modelling HD has remained challenging, as rodent and cellular models poorly recapitulate the disease. To address this, we generated induced neurons (iNs) through direct reprogramming of human skin fibroblasts, which retain age-dependent epigenetic characteristics. HD-iNs displayed profound deficits in autophagy, characterised by reduced transport of late autophagic structures from the neurites to the soma. The neurite-specific alterations in autophagy resulted in shorter, thinner and fewer neurites presented by HD-iNs. CRISPRi-mediated silencing ofHTTdid not rescue this phenotype but rather resulted in additional autophagy alterations in ctrl-iNs, highlighting the importance of wild typeHTTin neuronal autophagy. In summary, our work identifies a distinct subcellular autophagy impairment in aged patient derived HD-neurons and provides a new rational for future development of autophagy activation therapies.
Arabidopsis ROOT UV-B SENSITIVE 1 and 2 Interact with Aminotransferases to Regulate Vitamin B6 Homeostasis
Authors: Tong Hongyun , Leasure Colin D. , Yen Robert , Hou Xuewen , O’Neil Nathan , Ting Dylan , Sun Ying , Zhang Shengwei , Tan Yanping , Duarte Elias Michael , Phan Stacey , Ibarra Cinthya , Chang Jo-Ting , Black Danielle , McCray Tyra , Perry Nate , Peng Xinxiang , Lee Jesi , Turcios Keirstinne , Guliaev Anton , He Zheng-Hui 
Published: March 2021

AbstractPyridoxal-5’-phosphate (PLP), the enzymatic cofactor form of Vitamin B6 (vitB6), is a versatile compound that has essential roles in metabolism. Cellular PLP homeostasic regulation is currently not well understood. Here we report that in Arabidopsis, biosynthesized PLP is sequestered by specific aminotransferases (ATs), and that the proteins ROOT UV-B SENSITIVE 1 (RUS1) and RUS2 function with ATs to regulate PLP homeostasis. The stunted growth phenotypes ofrus1andrus2mutants were previously shown to be rescuable by exogenously supplied vitB6. Specific residue changes near the PLP-binding pocket in ASPARTATE AMINOTRANSFERASE2 (ASP2) also rescuedrus1andrus2phenotypes. In this study, saturated suppressor screens identified 14 additionalsuppressor of rus(sor) alleles in four aminotransferase genes (ASP1,ASP2,ASP3, orALANIN AMINOTRANSFERASE1(AAT1)), which suppressed therusphenotypes to varying degrees. Each of thesormutations altered an amino acid in the PLP-binding pocket of the protein, and sor proteins were found to have reduced levels of PLP conjugation. Genetic data revealed that the availability of PLP normally requires both RUS1 and RUS2, and that increasing the number ofsormutants additively enhanced the suppression ofrusphenotypes. Biochemical results showed that RUS1 and RUS2 physically interacted with ATs. Our studies suggest a mechanism in which RUS1, RUS2 and specific ATs work together to regulate PLP homeostasis in Arabidopsis.
Capturing the interplay of membrane lipids and structural transitions in human ABCA7
Authors: Le Le Thi My , Thompson James R. , Dehghani-Ghahnaviyeh Sepehr , Pant Shashank , Dang Phuoc X. , Kanikeyo Takahisa , Tajkhorshid Emad , Alam Amer 
Published: March 2021

AbstractPhospholipid extrusion by ABC subfamily A (ABCA) exporters is central to cellular physiology, although the specifics of the underlying substrate interactions and transport mechanisms remain poorly resolved at the molecular level. Here we report cryo-EM structures of lipid-embedded human ABCA7 in an open state and a nucleotide-bound, closed state at resolutions between 3.6-4.0 Å. The former reveals an ordered patch of bilayer lipids traversing the transmembrane domain (TMD), while the latter reveals a lipid-free, closed TMD with a small extracellular opening. These structures offer a structural framework for both substrate entry and exit from the ABCA7 TMD and highlight conserved rigid-body motions that underlie the associated conformational transitions. Combined with functional analysis and molecular dynamics (MD) simulations, our data also shed light on lipid partitioning into the ABCA7 TMD and localized membrane perturbations that underlie ABCA7 function and have broader implications for other ABCA family transporters.
Spontaneous neural oscillations influence behavior and sensory representations by suppressing neuronal excitability
Authors: Iemi Luca , Gwilliams Laura , Samaha Jason , Auksztulewicz Ryszard , Cycowicz Yael M , King Jean-Remi , Nikulin Vadim V , Thesen Thomas , Doyle Werner , Devinsky Orrin , Schroeder Charles E , Melloni Lucia , Haegens Saskia 
Published: March 2021

AbstractThe ability to process and respond to external input is critical for adaptive behavior. Why, then, do neural and behavioral responses vary across repeated presentations of the same sensory input? Spontaneous fluctuations of neuronal excitability are currently hypothesized to underlie the trial-by-trial variability in sensory processing. To test this, we capitalized on invasive electrophysiology in neurosurgical patients performing an auditory discrimination task with visual cues: specifically, we examined the interaction between prestimulus alpha oscillations, excitability, task performance, and decoded neural stimulus representations. We found that strong prestimulus oscillations in the alpha+ band (i.e., alpha and neighboring frequencies), rather than the aperiodic signal, correlated with a low excitability state, indexed by reduced broadband high-frequency activity. This state was related to slower reaction times and reduced neural stimulus encoding strength. We propose that the alpha+ rhythm modulates excitability, thereby resulting in variability in behavior and sensory representations despite identical input.
Memory CD8+T cells mediate early pathogen-specific protection through localized delivery of chemokines and IFNγ to clusters of inflammatory monocytes
Authors: Boutet Marie , Benet Zachary , Guillen Erik , Koch Caroline , Soudja Saidi M’Homa , Delahaye Fabien , Fooksman David , Lauvau Grégoire 
Published: March 2021

SummaryWhile cognate antigen drives clonal expansion of memory CD8+T cells to achieve sterilizing immunity in immunized hosts, not much is known on how cognate antigen contributes to early mechanisms of protection before clonal expansion occurs. Herein, using distinct models of immunization, we establish that cognate antigen recognition by CD8+TMcells on dendritic cells initiates their rapid and coordinated production of a burst of CCL3, CCL4 and XCL1 chemokines under the transcriptional control of IRF4. Using intravital microscopy imaging andin vivomonoclonal antibody labelling, we reveal that memory CD8+T cells undergo antigen-mediated arrest in splenic red pulp clusters of CCR2+monocytes where they locally deliver both IFNγ- and chemokine-potentiating microbicidal activities to achieve early protection. Thus, rapid and effective memory CD8+T cell responses require a complex series of spatially and temporally coordinated stepwise molecular and cellular events that quickly restrict microbial pathogen growth and optimize the local delivery of effector molecules before clonal expansion occurs.