bluuebunny/crossref_metadata_2025_split huggingface dataset:
Task-Free Recovery and Spatial Characterization of a P3-Like Global Network from Resting-State EEG
Authors: Tang Akaysha C. , Privitera Adam John 
Published: September 2020

AbstractDiagnosis of mental illness, testing of treatment effects, and design of prevention strategies all require brain-based biomarkers that can serve as effective targets of evaluation. The search for such markers often starts with a search for neural correlates from brain imaging studies with measures of functions and behavior of interest. Yet such an approach can produce erroneous results for correlations do not guarantee causation. Only when the markers map onto neurocomputationally-relevant parameters can such markers best serve the intended function. Here we take an alternative approach to begin with targeting the neuroanatomically and neurophysiologically well-defined neuromoduatory systems that are well positioned to serve the computational role of generating globally synchronized neural activity for the purpose of functional integration [1]. By applying second-order blind identification (SOBI) [2], a blind source separation algorithm (BSS), to five minutes of resting-state EEG data (n=13), we provide evidence to support our conclusion that neuroelectrical signals associated with synchronized global network activity can be extracted using the detailed temporal information in the on-going continuously recorded EEG, instead of event-related potentials (ERPs). We report reliable extraction of a SOBI component, which we refer to as the P3-like component, in every individual studied, replicating our earlier report on data from a single participant [3]. We show that individual differences in the neural networks underlying this P3-like component can be revealed in high dimensional space by a vector of hits-based measures [4] for each of the P3-like network’s constituent structures. Given that resting-state EEG can be obtained with greater ease at natural non-hospital settings and at much lower cost in comparison with fMRI, and that mobile EEG systems have become increasingly available, the present work offers an enabling technology to support rapid and low-cost assessment of much larger and diverse populations of individuals, addressing several methodological limitations in our current investigation of brain function. Future opportunities and current limitations will be discussed.
Discovery and Development of Human SARS-CoV-2 Neutralizing Antibodies using an Unbiased Phage Display Library Approach
Authors: Cao Xia , Maruyama Junki , Zhou Heyue , Kerwin Lisa , Sattler Rachel , Manning John T. , Johnson Sachi , Richards Susan , Li Yan , Shen Weiqun , Blair Benjamin , Du Na , Morais Kyndal , Lawrence Kate , Lu Lucy , Pai Chin-I , Li Donghui , Brunswick Mark , Zhang Yanliang , Ji Henry , Paessler Slobodan , Allen Robert D. 
Published: September 2020

ABSTRACTSARS-CoV-2 neutralizing antibodies represent an important component of the ongoing search for effective treatment of and protection against COVID-19. We report here on the use of a naïve phage display antibody library to identify a panel of fully human SARS-CoV-2 neutralizing antibodies. Following functional profilingin vitroagainst an early pandemic isolate as well as a recently emerged isolate bearing the D614G Spike mutation, the clinical candidate antibody, STI-1499, and the affinity-engineered variant, STI-2020, were evaluated forin vivoefficacy in the Syrian golden hamster model of COVID-19. Both antibodies demonstrated potent protection against the pathogenic effects of the disease and a dose-dependent reduction of virus load in the lungs, reaching undetectable levels following a single dose of 500 micrograms of STI-2020. These data support continued development of these antibodies as therapeutics against COVID-19 and future use of this approach to address novel emerging pandemic disease threats.
A genomic variant of ALPK2 is associated with increased liver fibrosis risk in HIV/HCV coinfected women
Authors: McIntosh Alec T. , Wei Renhuizi , Ahn Jaeil , Aouizerat Brad E. , Kassaye Seble G. , Augenbraun Michael H. , Price Jennifer C. , French Audrey L. , Gange Stephen J. , Anastos Kathryn M. , Goldman Radoslav 
Published: September 2020

ABSTRACTHIV coinfection is associated with more rapid liver fibrosis progression in hepatitis C (HCV) infection. Recently, much work has been done to improve outcomes of liver disease and to identify targets for pharmacological intervention in coinfected patients. In this study, we analyzed clinical data of 1,858 participants from the Women’s Interagency HIV Study (WIHS) to characterize risk factors associated with changes in the APRI and FIB-4 surrogate measurements for advanced fibrosis. We assessed 887 non-synonymous single nucleotide variants (nsSNV) in a subset of 661 coinfected participants for genetic associations with changes in liver fibrosis risk. The variants utilized produced amino acid substitutions that either altered an N-linked glycosylation (NxS/T) sequon or mapped to a gene related to glycosylation processes. Seven variants were associated with an increased likelihood of liver fibrosis. The most common variant, ALPK2 rs3809973, was associated with liver fibrosis in HIV/HCV coinfected patients; individuals homozygous for the rare C allele displayed elevated APRI (0.61, 95% CI, 0.334 to 0.875) and FIB-4 (0.74, 95% CI, 0.336 to 1.144) relative to those coinfected women without the variant. Although warranting replication, ALPK2 rs3809973 may show utility to detect individuals at increased risk for liver disease progression.
The influence of socioeconomic deprivation on dementia mortality, age at death and quality of diagnosis: a nationwide death records study in England and Wales 2001-2017
Authors: Jitlal Mark , Amirthalingam Guru NK , Karania Tasvee , Parry Eve , Neligan Aidan , Dobson Ruth , Noyce Alastair J , Marshall Charles R 
Published: September 2020

AbstractBackgroundSocioeconomic deprivation is postulated to be an important determinant of dementia risk, mortality, and access to diagnostic services. Nevertheless, premature mortality from other causes and under-representation of deprived individuals in research cohorts may lead to this effect being overlooked.MethodsWe obtained Office of National Statistics (ONS) mortality data where dementia was recorded as a cause of death in England and Wales from 2001 to 2017, stratified by age, diagnosis code and UK Index of Multiple Deprivation (IMD) decile. We calculated standardised mortality ratios (SMR) for each IMD decile, adjusting for surviving population size in each IMD decile and age stratum. In those who died of dementia, we used ordinal logistic regression to examine the effect of deprivation on likelihood of being older at death. We used logistic regression to test the effect of deprivation on likelihood of receiving a diagnosis of unspecified dementia, a proxy for poor access to specialist diagnostic care.Results578,623 deaths due to dementia in people over the age of 65 were identified between 2001-2017. SMRs were similar across the three most deprived deciles (1-3) but progressively declined through deciles 4-10 (Mean SMR [95%CI] in decile 1: 0.528 [0.506 to 0.550], decile 10: 0.369 [0.338 to 0.400]). This effect increased over time with improving ascertainment of dementia. In 2017, 14,837 excess dementia deaths were attributable to deprivation (21.5% of the total dementia deaths that year). There were dose-response effects of deprivation on likelihood of being older at death with dementia (odds ratio [95%CI] for decile 10 (least deprived): 1.31 [1.28 to 1.33] relative to decile 1), and on likelihood of receiving a diagnosis of unspecified dementia (odds ratio [95%CI] for decile 10: 0.78 [0.76 to 0.80] relative to decile 1).ConclusionsSocioeconomic deprivation in England and Wales is associated with increased dementia mortality, younger age at death with dementia, and poorer access to specialist diagnosis. Reducing social inequality may be an important strategy for prevention of dementia mortality.
Extracellular hyaluronate pressure shaped by cellular tethers drives tissue morphogenesis
Authors: Munjal Akankshi , Hannezo Edouard , Mitchison Timothy J. , Megason Sean G. 
Published: September 2020

SummaryHow tissues acquire complex shapes is a fundamental question in biology and regenerative medicine. Zebrafish semicircular canals form from invaginations in the otic epithelium (buds) that extend and fuse to form the hubs of each canal. We find that conventional actomyosin-driven behaviors are not required. Instead, local secretion of hyaluronan, made by the enzymesugdhandhas3, drives canal morphogenesis. Charged hyaluronate polymers osmotically swell with water and generate isotropic extracellular pressure to deform the overlying epithelium into buds. The mechanical anisotropy needed to shape buds into tubes is conferred by a polarized distribution of cellular protrusions, linked between cells, that we term cytocinches. Most work on tissue morphogenesis ascribes actomyosin contractility as the driving force, while the extracellular matrix shapes tissues through differential stiffness. Our work inverts this expectation. Hyaluronate-pressure shaped by anisotropic tissue stiffness may be a widespread mechanism for powering morphological change in organogenesis and tissue engineering.
Regulation of lipid accumulation-induced ROS in myeloid-derived suppressor cells via targeting fatty-acid transport protein 2 enhanced anti-PD-L1 tumor immunotherapy
Authors: Adeshakin Adeleye Oluwatosin , Liu Wan , Adeshakin Funmilayo O. , Afolabi Lukman O. , Zhang Mengqi , Zhang Guizhong , Wang Lulu , Li Zhihuan , Lin Lilong , Yan Dehong , Wan Xiaochun 
Published: September 2020

AbstractDespite the remarkable success and efficacy of immune checkpoint blockade (ICB) therapy against the PD-1/PD-L1 axis, it induces sustained responses in a sizeable minority of cancer patients due to the activation of immunosuppressive factors such as myeloid-derived suppressor cells (MDSCs). Inhibiting the immunosuppressive function of MDSCs is critical for successful cancer ICB therapy. Interestingly, lipid metabolism is a crucial factor in modulating MDSCs function. Fatty acid transport protein 2 (FATP2) conferred the function of PMN-MDSCs in cancer via the upregulation of arachidonic acid metabolism. However, whether regulating lipid accumulation in MDSCs by targeting FATP2 could block MDSCs reactive oxygen species (ROS) production and enhance PD-L1 blockade-mediated tumor immunotherapy remains unexplored. Here we report that FATP2 regulated lipid accumulation, ROS, and immunosuppressive function of MDSCs in tumor-bearing mice. Tumor cells-derived granulocyte macrophage-colony stimulating factor (GM-CSF) induced FATP2 expression in MDSCs by activation of STAT3 signaling pathway. Pharmaceutical blockade of FATP2 expression in MDSCs by lipofermata decreased lipid accumulation, reduced ROS, blocked immunosuppressive activity, and consequently inhibited tumor growth. More importantly, lipofermata inhibition of FATP2 in MDSCs enhanced anti-PD-L1 tumor immunotherapy via the upregulation of CD107a and reduced PD-L1 expression on tumor-infiltrating CD8+T-cells. Furthermore, the combination therapy blocked MDSC’s suppressive role on T-cells thereby enhanced T-cell’s ability for the production of IFN-γ. These findings indicate that FATP2 plays a key role in modulating lipid-induced ROS in MDSCs and targeting FATP2 in MDSCs provides a novel therapeutic approach to enhance anti-PD-L1 cancer immunotherapy.Research highlightsFATP2 inhibition in MDSCs blocked ROS-mediated immunosuppressive function and promoted MDSCs differentiation to immune-stimulatory phenotype.GM-CSF mediated FATP2 expression via activation of STAT3 signaling leading to lipid accumulation-induced ROS in MDSCs.FATP2 inhibition enhanced anti-PD-L1 tumor immunotherapy by reducing MDSCs immunosuppressive activity in blocking T-cell’s ability to produce IFN-γ.Combination of anti-PD-L1 antibody and FATP2 inhibitor decreased MDSCs accumulation and PD-L1 surface expression in the spleens of LLC-bearing mice.Combined treatment of FATP2 inhibitor and PD-L1 blockade-mediated tumor immunotherapy enhanced tumor-infiltrating CD8+T cells activation via increased CD107a and reduced PD-L1 surface expression.
DEELIG: A Deep Learning-based approach to predict protein-ligand binding affinity
Authors: Ahmed Asad , Mam Bhavika , Sowdhamini Ramanathan 
Published: September 2020

AbstractProtein-ligand binding prediction has extensive biological significance. Binding affinity helps in understanding the degree of protein-ligand interactions and has wide protein applications. Protein-ligand docking using virtual screening and molecular dynamic simulations are required to predict the binding affinity of a ligand to its cognate receptor. In order to perform such analyses, it requires intense computational power and it becomes impossible to cover the entire chemical space of small molecules. Recent developments using deep learning has enabled us to make sense of massive amounts of complex datasets where the ability of the model to “learn” intrinsic patterns in a complex plane of data is the strength of the approach. Here, we have incorporated Convolutional Neural Networks to find spatial relationships amongst data to help us predict affinity of binding of proteins in whole superfamilies towards a diverse set of ligands without the need of a docked pose or complex as input. The models were trained and validated using a detailed methodology for feature extraction. We have also tested DEELIG on protein complexes relevant to the current public health scenario. Our approach to network construction and training on protein-ligand dataset prepared in-house has yielded novel insights.
Deciphering the Genome Protection Roles of Autophagy in Primary Human Dermal Fibroblasts (HDFs) against Ultraviolet-(B) –Induced Skin Photodamage
Authors: Umar Sheikh Ahmad , Tasduq Sheikh Abdullah 
Published: September 2020

AbstractUltraviolet-B (UV-B) exposure to skin causes photo-damage and acts as the primary etiological agent in photo-carcinogenesis. UV-B exposure induces photodamage in epidermal cells and is the major factor that challenges skin homeostasis. Autophagy allows fundamental adaptation of cells to metabolic needs and stresses. Cellular dysfunction is observed in aged tissues and in toxic insults to cells that undergo through stress. Conversely, promising anti-aging strategies aimed at inhibiting the mTOR pathway has been found to significantly improve the aging related disorders. Recently, autophagy has been found to positively regulate skin homeostasis by enhancing DNA damage recognition. Here we investigated the Geno-protective roles of autophagy in UV-B exposed primary HDFs. We found that improving autophagy levels in HDFs regulates UV-B mediated cellular stress by decreasing the formation of DNA photo adducts, alleviates oxidative and ER stress response and by regulating the expression levels of cell cycle regulatory proteins P21 and P27. Autophagy also prevents HDFs from UV-B -induced nuclear damage as is evident from Tunnel assay and Acridine Orange/Ethidium Bromide co-staining. Salubrinal, (an eIf2α inhibitor) significantly decreases the DNA damage response in HDFs. P62 silenced HDFs show enhanced DNA damage response and disturbs the tumor suppressor axis PTEN/pAKT towards damage whereas ATG7 silenced HDFs reveal an unexpected consequence by decreasing the UV-B -induced DNA damage compared to UV-B treated HDFs. Together, our results suggest that autophagy is essential in protecting skin cells from UV-B radiation -induced photo-damage and holds great promise in devising it as a suitable therapeutic strategy against skin photo-damage.HighlightsAutophagy is an immediate molecular event induced following exposure of primary HDFs to UV-B –irradiationAutophagy offers pro-survival capacity to HDFs under UV-B induced genotoxic stressAutophagy regulates DNA Damage Response via regulation of oxidative and ER stress in UV-B exposed HDFsRelieving ER stress response offers significant protection to primary HDFs from UV-B by decreasing the DNA damageAutophagy deprivation to HDFs via P62 silencing potentiates UV-B -induced DNA damage responseATG7 silencing in UV-B exposed HDFs unexpectedly alleviates the DNA Damage Response in primary HDFs
Parietal cell-Specific SLC26A9 Deletion induces spontaneous Gastric Carcinogenesis in Mice
Authors: Liu Xuemei , Li Taolang , Yuan Dumin , Riederer Brigitte , Ma Zhiyuan , Zhu Jiaxing , Li Yunhua , An Jiaxing , Wen Guorong , Jin Hai , Hu Chunli , Zhang Minglin , Yang Xiao , Seidler Ursula , Tuo Biguang 
Published: September 2020

AbstractPrevious study showed that Slc26a9 loss impairs parietal cell function and survival. We investigated whether Slc26a9 loss causes spontaneous gastric carcinogenesis in mice and plays a role in the development and progression in human gastric cancer (GC). Gastric histopathology and potential molecular mechanism were explored in Slc26a9 knockout mice and wild-type littermates as well as Slc26a9fl/fl/Atp4b-Cre and Slc26a9fl/fl mice from 8 days to 18 months by histological and immunohistochemical analyses, quantitative PCR, in situ hybridization, and RNA microarray analysis, respectively. We demonstrated that loss of parietal cell expression of Slc26a9 is the key event to induce spontaneous gastric carcinogenesis in mice, and clarified the sequence of events leading to malignant transformation, including Slc26a9 deficiency in parietal cells resulted in dysregulated differentiation of stem cells in an inflammatory environment, activated Wnt signaling pathway to induce gastric epithelia cell hyperproliferation and apoptosis inhibition, as well as spontaneous epithelial to mesenchymal transition-induced cancer stem cell phenotypes. Downregulation of SLC26A9 correlated with GC patient’s short survival.Graphical AbstractLoss of parietal cell expression of Slc26a9 is the key event to induce spontaneous gastric carcinogenesis in transgenic mice.
Structural and dynamical heterogeneity of water trapped inside Na+-pumping KR2 rhodopsin in the dark state
Authors: Santra Mantu , Seal Aniruddha , Bhattacharjee Kankana , Chakrabarty Suman 
Published: September 2020

AbstractPhotoisomerisation in retinal leads to a channel opening in the rhodopsins that triggers translocation or pumping of an ion/proton. Crystal structures of rhodopsins contain several structurally conserved water molecules. It has been suggested that water plays an active role in facilitating the ion pumping/translocation process by acting as a lubricant in these systems. In this work, we systematically investigate the localisation, structure, dynamics and energetics of the water molecules along the channel for the resting/dark state of KR2 rhodopsin. Employing several microseconds long atomistic molecular dynamics (MD) simulation of this trans-membrane protein system, we demonstrate the presence of five distinct water containing pockets/cavities separated by gateways controlled by the protein side-chains. There exists a strong hydrogen bonded network involving these buried water molecules and functionally important key residues. We present evidence of significant structural and dynamical heterogeneity in the water molecules present in these cavities with very rare exchange between them. The exchange time-scale of these buried water with bulk has an extremely wide range from tens of nanoseconds to > 1.5μs! The translational and rotational dynamics of buried water are found to be strongly dependent on the protein cavity size and local interactions with classic signature of trapped diffusion and rotational anisotropy.
The impact of size on particle drainage dynamics and antibody response
Authors: Zinkhan Simon , Ogrina Anete , Balke Ina , Reseviča Gunta , Zeltins Andris , de Brot Simone , Lipp Cyrill , Chang Xinyue , Zha Lisha , Vogel Monique , Bachmann Martin F. , Mohsen Mona O. 
Published: September 2020

AbstractVaccine-induced immune response can be greatly enhanced by mimicking pathogen properties. The size and the repetitive geometric shape of virus-like particles (VLPs) influence their immunogenicity by facilitating drainage to secondary lymphoid organs and enhancing interaction with and activation of B-cells and other innate humoral immune components. VLPs derived from the plant Bromovirus genus, specifically cowpea chlorotic mottle virus (CCMV), are T=3 icosahedron particles. They can be easily expressed in anE. coli host system and package ssRNA during the expression process. Recently, we have engineered CCMV-VLPs by incorporating the universal tetanus toxoid (TT) epitope at the N-terminus. The modified CCMVTT-VLPs successfully form icosahedral particlesT=3, with a diameter of ∼30nm analogous to the parental VLPs. Interestingly, incorporating TT epitope at the C-terminus of CCMVTT-VLPs results in the formation of Rod-shaped VLPs, ∼1µm in length and ∼30nm in width. In this study, we have investigated the draining kinetics and immunogenicity of both engineered forms (termed as Round-shaped CCMVTT-VLPs and Rod-shaped CCMVTT-VLPs) as potential B cell immunogens using differentin vitroandin vivoassays. Our results reveal that Round-shaped CCMVTT-VLPs are more efficient in draining to secondary lymphoid organs to charge antigen-presenting cells as well as B-cells. Furthermore, compared to Rod-shaped CCMVTT-VLPs, Round-shaped CCMVTT-VLPs led to more than 100-fold increased systemic IgG and IgA responses accompanied by prominent formation of splenic germinal centers. Round-shaped CCMVTT-VLPs could also polarize the induced immune response towards TH1. Up to our knowledge, this is the first study investigating and comparing the draining kinetics and immunogenicity of one and the same VLP monomer forming nano-sized icosahedrons or rods in the micrometer size.
ISRIB blunts the integrated stress response by allosterically antagonising the inhibitory effect of phosphorylated eIF2 on eIF2B
Authors: Zyryanova Alisa F. , Kashiwagi Kazuhiro , Rato Claudia , Harding Heather P. , Crespillo-Casado Ana , Perera Luke A. , Sakamoto Ayako , Nishimoto Madoka , Yonemochi Mayumi , Shirouzu Mikako , Ito Takuhiro , Ron David 
Published: September 2020

AbstractThe small molecule ISRIB antagonises the activation of the integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(αP). ISRIB and eIF2(αP) bind distinct sites in their common target, eIF2B, a guanine nucleotide exchange factor (GEF) for eIF2. We have found that ISRIB-mediated acceleration of eIF2B activity in vitro is observed preferentially in the presence of eIF2(αP) and is attenuated by mutations that desensitise eIF2B to the inhibitory effects of eIF2(αP). ISRIB’s efficacy as an ISR inhibitor in cells also depends on presence of eIF2(αP). Cryo-EM showed that engagement of both eIF2B regulatory sites by two eIF2(αP) molecules remodels both the ISRIB-binding pocket and the pockets that would engage eIF2α during active nucleotide exchange, thereby discouraging both binding events. In vitro, eIF2(αP) and ISRIB reciprocally opposed each other’s binding to eIF2B. These findings point to antagonistic allostery in ISRIB action on eIF2B, culminating in inhibition of the ISR.