bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural Mechanism Underlying Ligand Binding and Activation of PPARγ
Authors: Shang Jinsai , Kojetin Douglas J. 
Published: September 2020

ABSTRACTLigands bind to an occluded orthosteric pocket within the nuclear receptor (NR) ligand-binding domain (LBD). Molecular simulations have revealed several theoretical ligand entry/exit pathways to the orthosteric pocket, but experimentally it remains unclear whether ligand binding proceeds through induced fit or conformational selection mechanisms. Using NMR spectroscopy lineshape analysis, we show that ligand binding to the peroxisome proliferator-activated receptor gamma (PPARγ) LBD involves a two-step induced fit mechanism including an initial fast step followed by slow conformational change. Surface plasmon resonance and isothermal titration calorimetry heat capacity analysis support the fast kinetic binding step and the conformational change after binding step, respectively. The putative initial ligand binding pose is suggested in several crystal structures of PPARγ LBD where a ligand is bound to a surface pore formed by helix 3, the β-sheet, and the Ω-loop—one of several ligand entry sites suggested in previous targeted and unbiased molecular simulations. These findings, when considered with a recent NMR study showing the activation function-2 (AF-2) helix 12 exchanges in and out of the orthosteric pocket in apo/ligand-free PPARγ, suggest an activation mechanism whereby agonist binding occurs through an initial encounter complex with the LBD followed by transition of the ligand into the orthosteric pocket concomitant with a conformational change resulting in a solvent-exposed active helix 12 conformation.
Intercontinental prediction of soybean phenology via hybrid ensemble of knowledge-based and data-driven models
Authors: McCormick Ryan F. , Truong Sandra K. , Rotundo Jose , Gaspar Adam P. , Kyle Don , van Eeuwijk Fred , Messina Carlos D. 
Published: September 2020

AbstractThe timing of crop development has significant impacts on management decisions and subsequent yield formation. A large intercontinental dataset recording the timing of soybean developmental stages was used to establish ensembling approaches that leverage both discrete-time dynamical system models of soybean phenology and data-driven, machine-learned models to achieve accurate and interpretable predictions. We demonstrate that the knowledge-based, dynamical models can improve machine learning by generating expert-engineered features. Combining the predictions of the diverse component models via super learning resulted in a mean absolute error of 4.12 and 4.55 days to flowering (R1) and physiological maturity (R7), providing an improvement relative to the best benchmark model error of 6.90 and 15.47 days, respectively. The hybrid intercontinental model applies to a much wider range of management and temperature conditions than previous mechanistic models, enabling improved decision support as alternative cropping systems arise, farm sizes increase, and changes in the global climate continue to accelerate.
First high-quality reference genome ofAmphicarpaea edgeworthii
Authors: Song Tingting , Zhou Mengyan , Yuan Yuying , Yu Jinqiu , Cai Hua , Li Jiawei , Chen Yajun , Bai Yan , Zhou Gang , Cui Guowen 
Published: September 2020

AbstractAmphicarpaea edgeworthii, an annual twining herb, is a widely distributed species and an ideal model for studying complex flowering types and evolutionary mechanisms of species. Herein, we generated a high-quality assembly ofA. edgeworthiiby using a combination of PacBio, 10× Genomics libraries, and Hi-C mapping technologies. The final 11 chromosome-level scaffolds covered 90.61% of the estimated genome (343.78 Mb), which is the first chromosome-scale assembled genome of an amphicarpic plant. These data will be beneficial for the discovery of genes that control major agronomic traits, spur genetic improvement of and functional genetic studies in legumes, and supply comparative genetic resources for other amphicarpic plants.
A novel small molecule LLL12B inhibits STAT3 signaling and sensitizes ovarian cancer cell to paclitaxel and cisplatin
Authors: Zhang Ruijie , Yang Xiaozhi , Roque Dana M. , Li Chenglong , Lin Jiayuh 
Published: September 2020

AbstractOvarian cancer is the fifth most common cause of cancer deaths among American women. Platinum and taxane combination chemotherapy represents the first-line approach for ovarian cancer, but treatment success is often limited by chemoresistance. Therefore, it is necessary to find new drugs to sensitize ovarian cancer cells to chemotherapy. Persistent activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling plays an important role in oncogenesis. Using a novel approach called advanced multiple ligand simultaneous docking (AMLSD), we developed a novel nonpeptide small molecule, LLL12B, which targets the STAT3 pathway. In this study, LLL12B inhibited STAT3 phosphorylation (tyrosine 705) and the expression of its downstream targets, which are associated with cancer cell proliferation and survival. We showed that LLL12B also inhibits cell viability, migration, and proliferation in human ovarian cancer cells. LLL12B combined with either paclitaxel or with cisplatin demonstrated synergistic inhibitory effects relative to monotherapy in inhibiting cell viability and LLL12B-paclitaxel or LLL12B-cisplatin combination exhibited greater inhibitory effects than cisplatin- paclitaxel combination in ovarian cancer cells. Furthermore, LLL12B-paclitaxel or LLL12B-cisplatin combination showed more significant in inhibiting cell migration and growth than monotherapy in ovarian cancer cells. In summary, our results support the novel small molecule LLL12B as a potent STAT3 inhibitor in human ovarian cancer cellsand suggest that LLL12B in combination with the current front-line chemotherapeutic drugs cisplatin and paclitaxel may represent a promising approach for ovarian cancer therapy.
MANF regulates unfolded protein response and neuronal survival through its ER-located receptor IRE1α
Authors: Kovaleva Vera , Yu Li-Ying , Ivanova Larisa , Nam Jinhan , Eesmaa Ave , Kumpula Esa-Pekka , Huiskonen Juha , Lindholm Päivi , Voutilainen Merja , Karelson Mati , Saarma Mart 
Published: September 2020

AbstractMesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-located protein with cytoprotective effects in numerous cell typesin vitroand in models of neurodegeneration and diabetesin vivo. So far, the exact mode of its action has remained elusive and plasma membrane or ER-located receptors of MANF have not been identified. We have found that MANF can directly interact with transmembrane unfolded protein response (UPR) receptor IRE1α and compete with the major ER chaperone BiP (GRP78) for the interaction with IRE1α. With lower affinities MANF can also interact with other UPR receptors, PERK and ATF6. Using molecular modeling and mutagenesis analysis, we have identified the exact structural MANF regions involved in its binding to the luminal domain of IRE1α. MANF attenuates UPR signaling by decreasing IRE1α oligomerization and IRE1α phosphorylation. MANF mutant deficient in IRE1α binding cannot regulate IRE1α oligomerization and fails to protect neurons from ER stress induced death. Importantly, we found that MANF-IRE1α interaction is also crucial for the survival promoting action of MANF for dopamine neurons in an animal model of Parkinson’s disease. Our data reveal a novel mechanism of IRE1α regulation during ER stress and demonstrate the intracellular mode of action of MANF as a modulator of UPR and neuronal cell survival through the direct interaction with IRE1α and regulation of its activity. Furthermore, our data explain why MANF in contrast to other growth factors has no effects on naive cells and rescues only ER stressed or injured cells.
Amplicons and isolates:Rhizobiumdiversity in fields under conventional and organic management
Authors: Moeskjær Sara , Tausen Marni , Andersen Stig U. , Young J. Peter W. 
Published: September 2020

AbstractBackgroundThe influence of farming on plant, animal and microbial biodiversity has been carefully studied and much debated. Here, we compare an isolate-based study of 196Rhizobiumstrains to amplicon-based MAUI-seq analysis of rhizobia from 17,000 white clover root nodules. We use these data to investigate the influence of soil properties, geographic distance, and field management onRhizobiumnodule populations.ResultsOverall, there was good agreement between the two approaches and the precise allele frequency estimates from the large-scale MAUI-seq amplicon data allowed detailed comparisons of rhizobium populations between individual plots and fields. A few specific chromosomal core-gene alleles were significantly correlated with soil clay content, and core-gene allele profiles became increasingly distinct with geographic distance. Field management was associated with striking differences inRhizobiumdiversity, where organic fields showed significantly higher diversity levels than conventionally managed trials.ConclusionsOur results indicate that MAUI-seq is suitable and robust for assessing noduleRhizobiumdiversity. We further observe possible profound effects of field management on microbial diversity, which could impact plant health and productivity and warrant further investigation.
HiCRes: a computational method to estimate and predict the resolution of HiC libraries
Authors: Marchal Claire , Singh Nivedita , Corso-Díaz Ximena , Swaroop Anand 
Published: September 2020

AbstractThree-dimensional (3D) conformation of the chromatin is crucial to stringently regulate gene expression patterns and DNA replication in a cell-type specific manner. HiC is a key technique for measuring 3D chromatin interactions genome wide. Estimating and predicting the resolution of a library is an essential step in any HiC experimental design. Here, we present the mathematical concepts to estimate the resolution of a library and predict whether deeper sequencing would enhance the resolution. We have developed HiCRes, a docker pipeline, by applying these concepts to human and mouse HiC libraries.
Mass cytometry and artificial intelligence define CD169 as a specific marker of SARS-CoV2-induced acute respiratory distress syndrome
Authors: Roussel M. , Ferrant J. , Reizine F. , Le Gallou S. , Dulong J. , Carl S. , Lesouhaitier M. , Gregoire M. , Bescher N. , Verdy C. , Latour M. , Bézier I. , Cornic M. , Leonard S. , Feuillard J. , Tiwari V.K. , Tadié J.M. , Cogné M. , Tarte K. 
Published: September 2020

AbstractAcute respiratory distress syndrome (ARDS) is the main complication of COVID-19, requiring admission to Intensive Care Unit (ICU). Despite recent immune profiling of COVID-19 patients, to what extent COVID-19-associated ARDS specifically differs from other causes of ARDS remains unknown, To address this question, we built 3 cohorts of patients categorized in COVID-19negARDSpos, COVID-19posARDSpos, and COVID-19posARDSneg, and compared their immune landscape analyzed by high-dimensional mass cytometry on peripheral blood followed by artificial intelligence analysis. A cell signature associating S100A9/calprotectin-producing CD169posmonocytes, plasmablasts, and Th1 cells was specifically found in COVID-19posARDSpos, unlike COVID-19negARDSpospatients. Moreover, this signature was shared by COVID-19posARDSnegpatients, suggesting severe COVID-19 patients, whatever they experienced or not ARDS, displayed similar immune dysfunctions. We also showed an increase in CD14posHLA-DRlowand CD14lowCD16posmonocytes correlated to the occurrence of adverse events during ICU stay. Our study demonstrates that COVID-19-associated ARDS display a specific immune profile, and might benefit from personalized therapy in addition to standard ARDS management.One Sentence SummaryCOVID-19-associated ARDS is biologically distinct from other causes of ARDS.
Multilocus phylogeny and historical biogeography ofHypostomusshed light on the processes of fish diversification in La Plata Basin
Authors: Cardoso Yamila P. , de Queiroz Luiz Jardim , Bahechar Ilham A. , Posadas Paula E. , Montoya-Burgos Juan I. 
Published: September 2020

AbstractDistribution history of the widespread Neotropical genusHypostomusto shed light on the processes that shaped species diversity. We inferred a calibrated phylogeny; ancestral habitat preference, ancestral areas distribution, and the history of dispersal and vicariance events of this genus. The phylogenetic and distributional analyses indicate thatHypostomusspecies inhabiting La Plata Basin do not form a monophyletic clade, suggesting that several unrelated ancestral species colonized this basin in the Miocene (∼17 Mya). Dispersal to other rivers of La Plata Basin started about 8 Mya, followed by habitat shifts and an increased rate of cladogenesis. AmazonianHypostomusspecies colonized La Plata Basin several times in the Middle Miocene, probably via the Upper Paraná and the Paraguay rivers that acted as biogeographic corridors. During the Miocene, La Plata Basin experienced marine incursions; and geomorphological and climatic changes that reconfigured its drainage pattern, driving the dispersal and diversification ofHypostomus. The Miocene marine incursion was a strong barrier and its retraction triggeredHypostomusdispersal, increased speciation rate and ecological diversification. The timing of hydrogeological changes in La Plata Basin coincides well withHypostomuscladogenetic events, indicating that the history of this basin has acted on the diversification of its biota.
Higher-order sensorimotor circuit of the brain’s global network supports human consciousness
Authors: Qin Pengmin , Wu Xuehai , Wu Changwei , Wu Hang , Zhang Jun , Huang Zirui , Weng Xuchu , Qi Zengxin , Tang Weijun , Hiromi Tanikawa , Tan Jiaxing , Tanabe Sean , Fogel Stuart , Hudetz Anthony G. , Yang Yihong , Stamatakis Emmanuel A , Mao Ying , Northoff Georg 
Published: September 2020

AbstractThe neural correlates of consciousness, defined as the minimum neuronal mechanisms sufficient for any conscious percept, are usually subject to different interpretations depending on whether one uses measures of local or global brain activities. We argue that the local regions may support consciousness by serving as hubs within the brain’s global network. We adopt a unique functional magnetic resonance imaging resting state dataset that encompasses various conscious states, including non-rapid eye movement (NREM)-sleep, rapid eye movement (REM)-sleep, anesthesia, and brain injury patients. Using a graph-theoretical measure for detecting local hubs within the brain’s global network, we identify various higher-order sensory and motor regions as hubs with significantly reduced degree centrality during unconsciousness. Additionally, these regions form a sensorimotor circuit which correlates with levels of consciousness. Our findings suggest that integration of higher-order sensorimotor function may be a key mechanism of consciousness. This opens novel perspectives for therapeutic modulation of unconsciousness.
A Modular Approach to Active Focus Stabilization for Fluorescence Microscopy
Authors: van den Berg Birthe , Van den Eynde Robin , Amouroux Baptiste , Müller Marcel , Dedecker Peter , Vandenberg Wim 
Published: September 2020

AbstractFluorescent time-lapse experiments often suffer from focus drift, regularly rendering long measurements partially unusable. Frequently, this instability can be traced back to the specific mechanical components of the setup, but even in highly robust implementations z-drift occurs due to small temperature fluctuations which are hard to avoid. To resolve this issue, microscope manufacturers often offer their own interpretation of out-of-focus correction modules for their flagship instruments. However, self-assembled or older systems typically have to fend for their own or adapt their measurements to circumvent drift effects. In this manuscript, we propose a cost-efficient z-drift detection- and correction system that, due to its modular design, can be attached to any fluorescence microscope with an actuated stage or objective, be it in a custom or commercial setup. The reason for this wide applicability is specific to the design, which has a straightforward alignment procedure and allows sharing optics with the fluorescent emission path. Our system employs an infrared (IR) laser that is passed through a double-hole mask to achieve two parallel beams which are made to reflect on the coverslip and subsequently detected on an industrial sCMOS camera. The relative position of these beams is then uniquely linked to the z-position of a microscope-mounted sample. The system was benchmarked by introducing temperature perturbations, where it was shown to achieve a stable focus, and by scanning different positions while simulating a perturbation in the z-position of the stage, where we show that a lost focus can be recovered within seconds.
ADAR2 deaminase activity promotes Th17 effector function and protects against intestine inflammation
Authors: Ma Shengyun , Hao Yajing , Cho Benjamin S. , Chen Nicholas , Zheng Anna , Zhang Shuyang , Sun Ge , Patel Parth R. , Li Yuxin , Yee Brian A , Yeo Gene W , Zhou Bing , Fu Xiang-Dong , Huang Wendy Jia Men 
Published: September 2020

SUMMARYADAR1 and ADAR2 catalyze adenosine-to-inosine (A-to-I) editing, the most common post-transcriptional modification in RNA. While ADAR1 is ubiquitously expressed and plays a critical role in preventing activation of the host immune system, ADAR2 exhibits tissue-specific and inducible expression patterns, and its function in the immune system is not known. Here, we identify an intragenic super-enhancer involved in the dramatic induction of ADAR2 when naïve helper T cells differentiate toward the Th17 lineage. By editing the inverted repeat sequences at the 3’ untranslated region (UTR) ofMalt1, which encodes a component of the NF-κB activation complex, ADAR2 promotes MALT1 expression and Th17 effector function. Interference with the ADAR2-MALT1 pathway dampens the production of Th17 cytokines and promotes T cell-mediated colitis. This study expands our understanding of RNA editing in adaptive immunity and identifies the ADAR2-MALT1-IL-17A axis as a potential therapeutic target for inflammatory conditions in the intestine.
Integrative genomic strategies applied to a lymphoblast cell line model reveal specific transcriptomic signatures associated with clozapine response
Authors: de With SAJ , Ori APS , Wang T , Pulit SL , Strengman E , Viana J , Mill J , de Jong S , Ophoff RA 
Published: September 2020

AbstractClozapine is an important antipsychotic drug. However, its use is often accompanied by metabolic adverse effects and, in rare instances, agranulocytosis. The molecular mechanisms underlying these adverse events are unclear. To gain more insights into the response to clozapine at the molecular level, we exposed lymphoblastoid cell lines (LCLs) to increasing concentrations of clozapine and measured genome-wide gene expression and DNA methylation profiles. We observed robust and significant changes in gene expression levels due to clozapine (n = 463 genes at FDR < 0.05) affecting cholesterol and cell cycle pathways. At the level of DNA methylation, we find significant changes upstream of the LDL receptor, in addition to global enrichments of regulatory, immune and developmental pathways. By integrating these data with human tissue gene expression levels obtained from the Genotype-Tissue Expression project (GTEx), we identified specific tissues, including liver and several tissues involved in immune, endocrine and metabolic functions, that clozapine treatment may disproportionately affect. Notably, differentially expressed genes were not enriched for genome-wide disease risk of schizophrenia or for known psychotropic drug targets. However, we did observe a nominally significant association of genetic signals related to total cholesterol and low-density lipoprotein levels. Together, these results shed light on the biological mechanisms through which clozapine functions. The observed associations with cholesterol pathways, its genetic architecture and specific tissue effects may be indicative of the metabolic adverse effects observed in clozapine users. LCLs may thus serve as a useful tool to study these molecular mechanisms further.
The genetic landscape for amyloid beta fibril nucleation accurately discriminates familial Alzheimer’s disease mutations
Authors: Seuma Mireia , Faure Andre , Badia Marta , Lehner Ben , Bolognesi Benedetta 
Published: September 2020

AbstractAmyloid fibrils are associated with many human diseases but how mutations alter the propensity of proteins to form fibrils has not been comprehensively investigated and is not well understood. Alzheimer’s Disease (AD) is the most common form of dementia with amyloid plaques of the amyloid beta (Aß) peptide a pathological hallmark of the disease. Mutations in Aß also cause familial forms of AD (fAD). Here we use deep mutational scanning to quantify the effects of >14,000 mutations on the aggregation of Aß. The resulting genetic landscape reveals fundamental mechanistic insights into fibril nucleation, including the importance of charge and gatekeeper residues in the disordered region outside of the amyloid core in preventing nucleation. Strikingly, unlike computational predictors and previous measurements, the in vivo nucleation scores accurately identify all known dominant fAD mutations, validating this simple cell-based assay as highly relevant to the human genetic disease and suggesting accelerated fibril nucleation is the ultimate cause of fAD. Our results provide the first comprehensive map of how mutations alter the formation of any amyloid fibril and a validated resource for the interpretation of genetic variation in Aß.HighlightsFirst comprehensive map of how mutations alter the propensity of a protein to form amyloid fibrils.Charge and gatekeeper residues in the disordered N-terminus of amyloid beta prevent fibril nucleation.Rates of nucleation in a cell-based assay accurately identify the mutations that cause dominant familial Alzheimer’s disease.The combination of deep mutational scanning and human genetics provides a general strategy to quantify the disease-relevance of in vitro and in vivo assays.