bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sauna-like conditions or menthol treatment reduce tau phosphorylation through mild hyperthermia
Authors: Guisle Isabelle , Pétry Séréna , Morin Françoise , Kérauden Rémi , Whittington Robert A. , Calon Frédéric , Hébert Sébastien S. , Planel Emmanuel 
Published: January 2021

AbstractIn Alzheimer’s disease (AD), hyper-phosphorylation and aggregation of tau correlates with clinical progression and represents a valid therapeutic target. A recent 20-year prospective study revealed an association between moderate to high frequency of Finnish sauna bathing and a lower incidence of dementia and AD, but the molecular mechanisms underlying these benefits remain uncertain. Here, we tested the hypothesis that sauna-like conditions could lower tau phosphorylation by increasing body temperature. We observed a decrease in tau phosphorylation in wild-type and hTau mice as well as in neuron-like cells when exposed to higher temperatures. These effects were correlated with specific changes in phosphatase and kinase activities, but not with inflammatory or heat-shock responses. We also used a drug strategy to promote thermogenesis. Topical application of menthol led to a sustained increase in body temperature in hTau mice concomitant with a significant decrease in tau phosphorylation. Our results suggest that sauna-like conditions or menthol treatment could lower tau pathology through mild hyperthermia, and may provide promising therapeutic strategies for AD and other tauopathies.
Discovery of an IKK2 Site that Allosterically Controls Its Activation
Authors: Hotchkiss Sonjiala Jackson , Mulero Maria Carmen , Chan Garrett J. , Biswas Tapan , Polley Smarajit , Ohn Christine , Konduri Srihari , Siegel Dionicio , Demir Özlem , Amaro Rommie E. , Ghosh Gourisankar 
Published: January 2021

ABSTRACTIκB kinase 2/β (IKK2) is a critical regulator of inflammation which is inducibly activated by a host of stimuli. Aberrant activation of IKK2 is the leading cause of most inflammatory diseases and many associated cancers. Efforts to prevent these diseases by small-molecule inhibitors of IKK2 activity have not been successful. Most inhibitors developed for IKK2 are ATP-competitive, and they are toxicin vivodue to their off-target effects. Here we focused on identifying inhibitors to block IKK2 activity from an allosteric site, not the ATP-binding pocket. Using virtual screening, we first identified several candidate allosteric sites and screened for potential small-molecule binders, and then selected candidates inhibitory to IKK2 activity using cell-based functional assays. Hydrogen deuterium exchange coupled to mass-spectrometry (HDX-MS) and MS-MS assays revealed that a class of benzoyl conjugates of pyrrolidinedione covalently bound to a site located at the interface of the kinase domain (KD) and the helical domain (SDD), and inhibited IKK2 activation allosterically by preventing phosphorylation of its activation loop serines. Additionally, this class of inhibitor partially blocks IKK2’s catalytic activity by enhancing dynamics within the ATP binding pocket and likely the general active site. Hydrogen deuterium exchange (HDX) experiments further revealed that while binding of substrate ATP perturbs only the local structure surrounding its binding site, binding to ATP-competitive or allosteric inhibitors induces structural perturbations in an expansive area including the helical domain. We propose that these allosteric sites can act as specific targets for the development of novel potent IKK inhibitors.SIGNIFICANCEAberrant activation of IKK2 is the leading cause of most inflammatory diseases and many associated cancers. Most inhibitors developed for IKK2 are ATP-competitive, and they are toxicin vivodue to their off-target effects. By combination of virtual screening and cell-based functional assays, we identified small-molecule binders of the class of benzoyl conjugates of pyrrolidinedione that block IKK2 activity from an allosteric site through covalent attachment and could be specific only for IKK2. HDX-MS and MS-MS assays identified a binding pocket with a ‘Cys-Cys motif’ for these inhibitors, and revealed specific differences in IKK2 dynamics upon binding to substrate ATP vs ATP-competitive and allosteric inhibitors. Present work provides a framework for the development of allosteric inhibitors to combat IKK2-induced diseases inhibitors.
Revealing the human mucinome
Authors: Malaker Stacy A. , Riley Nicholas M. , Shon D. Judy , Pedram Kayvon , Krishnan Venkatesh , Dorigo Oliver , Bertozzi Carolyn R. 
Published: January 2021

AbstractMucin domains are densely O-glycosylated modular protein domains found in a wide variety of cell surface and secreted proteins. Mucin-domain glycoproteins are key players in a host of human diseases, especially cancer, but the scope of the mucinome remains poorly defined. Recently, we characterized a bacterial mucinase, StcE, and demonstrated that an inactive point mutant retains binding selectivity for mucins. In this work, we leveraged inactive StcE to selectively enrich and identify mucins from complex samples like cell lysate and crude ovarian cancer patient ascites fluid. Our enrichment strategy was further aided by an algorithm to assign confidence to mucin-domain glycoprotein identifications. This mucinomics platform facilitated detection of hundreds of glycopeptides from mucin domains and highly overlapping populations of mucin-domain glycoproteins from ovarian cancer patients. Ultimately, we demonstrate our mucinomics approach can reveal key molecular signatures of cancer fromin vitroandex vivosources.
SARS-CoV-2 variant B.1.1.7 is susceptible to neutralizing antibodies elicited by ancestral Spike vaccines
Authors: Shen Xiaoying , Tang Haili , McDanal Charlene , Wagh Kshitij , Fischer Will , Theiler James , Yoon Hyejin , Li Dapeng , Haynes Barton F. , Sanders Kevin O. , Gnanakaran Sandrasegaram , Hengartner Nick , Pajon Rolando , Smith Gale , Dubovsky Filip , Glenn Gregory M. , Korber Bette , Montefiori David C. 
Published: January 2021

ABSTRACTThe SARS-CoV-2 Spike glycoprotein mediates virus entry and is a major target for neutralizing antibodies. All current vaccines are based on the ancestral Spike with the goal of generating a protective neutralizing antibody response. Several novel SARS-CoV-2 variants with multiple Spike mutations have emerged, and their rapid spread and potential for immune escape have raised concerns. One of these variants, first identified in the United Kingdom, B.1.1.7 (also called VUI202012/01), contains eight Spike mutations with potential to impact antibody therapy, vaccine efficacy and risk of reinfection. Here we employed a lentivirus-based pseudovirus assay to show that variant B.1.1.7 remains sensitive to neutralization, albeit at moderately reduced levels (~2-fold), by serum samples from convalescent individuals and recipients of two different vaccines based on ancestral Spike: mRNA-1273 (Moderna), and protein nanoparticle NVX-CoV2373 (Novavax). Some monoclonal antibodies to the receptor binding domain (RBD) of Spike were less effective against the variant while others were largely unaffected. These findings indicate that B.1.1.7 is not a neutralization escape variant that would be a major concern for current vaccines, or for an increased risk of reinfection.
Cortical representation variability aligns with in-class variances and can help one-shot learning
Authors: Shang Jiaqi , Shea-Brown Eric , Mihalas Stefan 
Published: January 2021

AbstractLearning invariance across a set of transformations is an important step in mapping high-dimensional inputs to a limited number of classes. After understanding the set of\ invariances, can a new class be learned from one element? We propose a representation which can facilitate such learning: if the variability in representing individual elements across trials aligns with the variability among different elements in a class, then class boundaries learned from the variable representations of one element should be representative of the entire class. In this study, we test whether such a representation occurs in mouse visual systems. We use Neuropixels probes recording single unit activity in mice observing 200 repeats of natural movies taken from a set of 9 continuous clips. We observe that the trial-by-trial variability in the representation of individual frames is well aligned to the variability in representation of multiple frames from the same clip, but not well aligned to the variability among frames from different clips. Thus, the variable representations of images in the mouse cortex can be efficiently used to classify images into their clips. We compare these representations to those in artificial neural networks. We find that, when introducing noise in networks trained for classification (both feed-forward and recurrent networks), the variability in the representation of elements aligns with the in-class variance. The networks which best reproduce the in-vivo observed directions of variability were those trained on a hierarchical classification task. Taken together, these results point to a solution which the cortex can use for one-shot learning of a class: by using noise as a mechanism for generalization. This is a potential computational explanation for the high level of noise observed in the cortex.
A Human Accelerated Region is a Leydig cellGLI2Enhancer that Affects Male-Typical Behavior
Authors: Norman Andrew R. , Ryu Ann H. , Jamieson Kirsty , Thomas Sean , Shen Yin , Ahituv Nadav , Pollard Katherine S. , Reiter Jeremy F. 
Published: January 2021

ABSTRACTHuman accelerated regions (HARs) are sequences that have evolved at an accelerated rate in the human lineage. Some HARs are developmental enhancers. We used a massively parallel reporter assay (MPRA) to identify HARs with enhancer activity in a mammalian testis cell line. A subset of HARs exhibited differential activity between the human and chimpanzee orthologs, representing candidates for underlying unique human male reproductive biology. We further characterized one of these candidate testis enhancers, 2xHAR.238. CRISPR/Cas9-mediated deletion in a testis cell line and mice revealed that 2xHAR.238 enhances expression ofGli2, encoding a Hedgehog pathway effector, in testis Leydig cells. 4C-seq revealed that 2xHAR.238 contacts theGli2promoter, consistent with enhancer function. In adult male mice, deletion of 2xHAR.238 disrupted mouse male-typical behavior and male interest in female odor. Combined, our work identifies a HAR that promotes the expression ofGli2in Leydig cells and may have contributed to the evolution of human male reproductive biology.
Complexity and graded regulation of neuronal cell type-specific alternative splicing revealed by single-cell RNA sequencing
Authors: Feng Huijuan , Moakley Daniel F. , Chen Shuonan , McKenzie Melissa G. , Menon Vilas , Zhang Chaolin 
Published: January 2021

AbstractThe enormous neuronal cellular diversity in the mammalian brain, which is highly prototypical and organized in a hierarchical manner, is dictated by cell type-specific gene regulatory programs at the molecular level. Although prevalent in the brain, contribution of alternative splicing (AS) to the molecular diversity across neuronal cell types is just starting to emerge. Here we systematically investigated AS regulation across over 100 transcriptomically defined neuronal types of the adult mouse cortex using deep single cell RNA-sequencing (scRNA-seq) data. We found distinct splicing programs between glutamatergic and GABAergic neurons and between subclasses within each neuronal class, consisting of overlapping sets of alternative exons showing differential splicing at multiple hierarchical levels. Using an integrative approach, our analysis suggests that RNA-binding proteins (RBPs) Celf1/2, Mbnl2 and Khdrbs3 are preferentially expressed and more active in glutamatergic neurons, while Elavl2 and Qk are preferentially expressed and more active in GABAergic neurons. Importantly, these and additional RBPs also contribute to differential splicing between neuronal subclasses at multiple hierarchical levels, and some RBPs drive splicing dynamics that do not conform to the hierarchical structure defined by the transcriptional profiles. Thus, our results suggest graded regulation of AS across neuronal cell types, which provides a molecular mechanism orthogonal to, rather than downstream of, transcriptional regulation in specifying neuronal identity and function.SignificanceAlternative splicing (AS) is extensively used in the mammalian brain, but its contribution to the molecular and cellular diversity across neuronal cell types remains poorly understood. Through systematic and integrative analysis of AS regulation across over 100 transcriptomically defined cortical neuronal types, we found neuronal subclass-specific splicing regulatory programs consists of overlapping alternative exons showing differential splicing at multiple hierarchical levels. This graded AS regulation is controlled by unique combinations of RNA-binding proteins (RBPs). Importantly, these RBPs also drive splicing dynamics across neuronal cell types that do not conform to the hierarchical taxonomy established based on transcriptional profiles, suggesting that the graded AS regulation provides a molecular mechanism orthogonal to transcriptional regulation in specifying neuronal identity and function.
Crop modeling defines opportunities and challenges for drought escape, water capture, and yield increase using chilling-tolerant sorghum
Authors: Raymundo Rubí , Sexton-Bowser Sarah , Ciampitti Ignacio A. , Morris Geoffrey 
Published: January 2021

ABSTRACTMany crop species, particularly those of tropical origin, are chilling sensitive so improved chilling tolerance can enhance production of these crops in temperate regions. For the cereal crop sorghum (Sorghum bicolor L.) early planting and chilling tolerance have been investigated for >50 years, but the potential value or tradeoffs of this genotype × management change has not been formally evaluated with modeling. To assess the potential of early-planted chilling-tolerant grain sorghum in the central US sorghum belt, we conducted CERES-Sorghum simulations and characterized scenarios under which this change would be expected to enhance (or diminish) drought escape, water capture, and yield. We conducted crop growth modeling for full- and short-season hybrids under rainfed systems that were simulated to be planted in very early (April), early (May 15), and normal (June 15) planting dates over 1986–2015 in four locations in Kansas representative of the central US sorghum belt. Simulations indicated that very early planting will generally lead to lower initial soil moisture, longer growing periods, and higher evapotranspiration. Very early planting is expected to extend the growing period by 20% for short- or full-season hybrids, reduce evaporation during fallow periods, and increase plant transpiration in the two-thirds of years with the highest precipitation (mean > 428 mm), leading to 11% and 7% increase grain yield for short- and full-season hybrids, respectively. Thus, in this major sorghum growing region very early and early planting could reduce risks of terminal droughts, extend seasons, and increase rotation options, suggesting that further development of chilling tolerant hybrids is warranted.
Nodal Modulator is required to sustain endoplasmic reticulum morphology
Authors: Amaya Catherine , Cameron Christopher JF , Devarkar Swapnil C. , Gerstein Mark B. , Xiong Yong , Schlieker Christian 
Published: January 2021

AbstractNodal Modulator (NOMO) is a widely conserved type I transmembrane protein of unknown function, with three nearly identical orthologs specified in the human genome. We identified NOMO1 in a proteomics approach aimed at the identification of proteins that support the structural integrity of the endoplasmic reticulum (ER). Overexpression of NOMO1 imposes a sheet morphology on the ER, while depletion of NOMO1 and its orthologs causes a collapse of ER morphology concomitant with the formation of membrane-delineated holes in the ER network. These structures are positive for the autophagy marker LAMP1, and LC3 is profoundly upregulated upon NOMO depletion.In vitroreconstitution of NOMO1 revealed a dimeric state that is mediated by the cytosolic tail domain, with each monomer featuring a “beads on a string” structure likely representing bacterial Ig-like folds. Based on these observations and a genetic epistasis analysis including the known ER-shaping proteins Atlastin2 and Climp63, we propose a role for NOMO1 in the functional network of ER-shaping proteins.
Modeling mutational effects on biochemical phenotypes using convolutional neural networks: application to SARS-CoV-2
Authors: Wang Bo , Gamazon Eric R. 
Published: January 2021

ABSTRACTBiochemical phenotypes are major indexes for protein structure and function characterization. They are determined, at least in part, by the intrinsic physicochemical properties of amino acids and may be reflected in the protein three-dimensional structure. Modeling mutational effects on biochemical phenotypes is a critical step for understanding protein function and disease mechanism as well as enabling drug discovery. Deep Mutational Scanning (DMS) experiments have been performed on SARS-CoV-2’s spike receptor binding domain and the human ACE2 zinc-binding peptidase domain – both central players in viral infection and evolution and antibody evasion - quantifying how mutations impact binding affinity and protein expression. Here, we modeled biochemical phenotypes from massively parallel assays, using convolutional neural networks trained on protein sequence mutations in the virus and human host. We found that neural networks are significantly predictive of binding affinity, protein expression, and antibody escape, learning complex interactions and higher-order features that are difficult to capture with conventional methods from structural biology. Integrating the intrinsic physicochemical properties of amino acids, including hydrophobicity, solvent-accessible surface area, and long-range non-bonded energy per atom, significantly improved prediction (empirical p<0.01) though there was such a strong dependence on the sequence data alone to yield reasonably good prediction. We observed concordance of the DMS data and our neural network predictions with an independent study on intermolecular interactions from molecular dynamics (multiple 500 ns or 1 μs all-atom) simulations of the spike protein-ACE2 interface, with critical implications for the use of deep learning to dissect molecular mechanisms. The mutation- or genetically-determined component of a biochemical phenotype estimated from the neural networks has improved causal inference properties relative to the original phenotype and can facilitate crucial insights into disease pathophysiology and therapeutic design.
AnnoMiner: a new web-tool to integrate epigenetics, transcription factor occupancy and transcriptomics data to predict transcriptional regulators
Authors: Meiler Arno , Marchiano Fabio , Weikunat Michaela , Schnorrer Frank , Habermann Bianca H. 
Published: January 2021

AbstractGene expression regulation requires precise transcriptional programs, led by transcription factors in combination with epigenetic events. Recent advances in epigenomic and transcriptomic techniques provided insight into different gene regulation mechanisms. However, to date it remains challenging to understand how combinations of transcription factors together with epigenetic events control cell-type specific gene expression. We developed the AnnoMiner web-server and introduce an innovative and flexible way to annotate and integrate epigenetic, and transcription factor occupancy data. First, AnnoMiner annotates user-provided peaks with gene features. Second, AnnoMiner can integrate genome binding data from two different transcriptional regulators together with gene features. Third, AnnoMiner offers to explore the transcriptional deregulation of 10 genes nearby a user-provided peak. AnnoMiner’s fourth function performs transcription factor or histone mark enrichment analysis for user-provided gene lists by utilizing hundreds of public, high-quality datasets from ENCODE for the model organisms human, mouse,DrosophilaandC. elegans. Thus, AnnoMiner can predict transcriptional regulators for a studied process without the strict need for chromatin data from the same process. We compared AnnoMiner to existing tools and experimentally validated several transcriptional regulators predicted by AnnoMiner to indeed contribute to muscle morphogenesis inDrosophila. AnnoMiner is freely available athttp://chimborazo.ibdm.univ-mrs.fr/AnnoMiner/.
Legume proteins are smart carriers to encapsulate hydrophilic and hydrophobic bioactive compounds and probiotic bacteria: A review
Authors: Gharibzahedi Seyed Mohammad Taghi , Smith Brennan 
Published: January 2021

AbstractEncapsulation is a promising technological process enabling the protection of bioactive compounds against harsh storage, processing, and gastrointestinal tract (GIT) conditions. Legume proteins (LPs) are unique carriers that can efficiently encapsulate these unstable and highly reactive ingredients. Stable LPs‐based microcapsules loaded with active ingredients can thus develop to be embedded into processed functional foods. The recent advances in micro‐ and nanoencapsulation process of an extensive span of bioactive health‐promoting probiotics and chemical compounds such as marine and plant fatty acid‐rich oils, carotenoid pigments, vitamins, flavors, essential oils, phenolic and anthocyanin‐rich extracts, iron, and phytase by LPs as single wall materials were highlighted. A technical summary of the use of single LP‐based carriers in designing innovative delivery systems for natural bioactive molecules and probiotics was made. The encapsulation mechanisms, encapsulation efficiency, physicochemical and thermal stability, as well as the release and absorption behavior of bioactives were comprehensively discussed. Protein isolates and concentrates of soy and pea were the most common LPs to encapsulate nutraceuticals and probiotics. The microencapsulation of probiotics using LPs improved bacteria survivability, storage stability, and tolerance in the in vitro GIT conditions. Moreover, homogenization and high‐pressure pretreatments as well as enzymatic cross‐linking of LPs significantly modify their structure and functionality to better encapsulate the bioactive core materials. LPs can be attractive delivery devices for the controlled release and increased bioaccessibility of the main food‐grade bioactives.
Plant growth‐promoting rhizobacteria isolation from rhizosphere of submerged macrophytes and their growth‐promoting effect onVallisneria natansunder high sediment organic matter load
Authors: Wang Chuan , Wang Huihui , Li Yahua , Li Qianzheng , Yan Wenhao , Zhang Yi , Wu Zhenbin , Zhou Qiaohong 
Published: January 2021

SummarySediment organic matter is a key stressor for submerged macrophyte growth, which negatively impacts the ecological restoration of lakes. Plant growth‐promoting rhizobacteria (PGPR) were screened from the rhizosphere of submerged macrophytes and used due to their promoting effect onVallisneria natansunder a high sediment organic matter load. Root exudates were used as the sole carbon source to obtain the root affinity strains. Eight isolates were selected from the 61 isolated strains, based on the P solubilization, IAA production, cytokinins production and ACC deaminase activity. The analysis of the 16S rDNA indicated that one strain wasStaphylococcussp., while the other seven bacterial strains wereBacillussp. They were all listed in low‐risk groups for safety use in agricultural practices. The plant height significantly increased after inoculation with PGPR strains, with the highest rate of increase reaching 96%. This study provides an innovative technique for recovering submerged macrophytes under sediment organic matter stress.