bluuebunny/crossref_metadata_2025_split huggingface dataset:
The blast pathogen effector AVR-Pik binds and stabilizes rice heavy metal-associated (HMA) proteins to co-opt their function in immunity
Authors: Oikawa Kaori , Fujisaki Koki , Shimizu Motoki , Takeda Takumi , Nemoto Keiichiro , Saitoh Hiromasa , Hirabuchi Akiko , Hiraka Yukie , Miyaji Naomi , Białas Aleksandra , Langner Thorsten , Kellner Ronny , Bozkurt Tolga O , Cesari Stella , Kroj Thomas , Banfield Mark J , Kamoun Sophien , Terauchi Ryohei 
Published: December 2020

AbstractIntracellular nucleotide-binding domain and leucine-rich repeat-containing (NLR) receptors play crucial roles in immunity across multiple domains of life. In plants, a subset of NLRs contain noncanonical integrated domains that are thought to have evolved from host targets of pathogen effectors to serve as pathogen baits. However, the functions of host proteins with similarity to NLR integrated domains and the extent to which they are targeted by pathogen effectors remain largely unknown. Here, we show that the blast fungus effector AVR-Pik binds a subset of related rice proteins containing a heavy metal-associated (HMA) domain, one of the domains that has repeatedly integrated into plant NLR immune receptors. We find that AVR-Pik binding stabilizes the rice small HMA (sHMA) proteins OsHIPP19 and OsHIPP20. Knockout ofOsHIPP20causes enhanced disease resistance towards the blast pathogen, indicating thatOsHIPP20is a susceptibility gene (S-gene). We propose that AVR-Pik has evolved to bind HMA domain proteins and co-opt their function to suppress immunity. Yet this binding carries a trade-off, it triggers immunity in plants carrying NLR receptors with integrated HMA domains.Significance StatementRice blast disease, caused by the fungusMagnaporthe oryzae, is one of the most devastating diseases of rice. Therefore, understanding the mechanisms of blast fungus infection and resistance of rice against the disease is important for global food security. In this study, we show that theM. oryzaeeffector protein AVR-PikD binds rice sHMA proteins and stabilizes them, presumably to enhance pathogen infection. We show that loss-of-function mutants in one rice sHMA, OsHIPP20, reduced the level of susceptibility against a compatible isolate ofM. oryzae, suggesting thatM. oryzaerequires host sHMA to facilitate invasion. Remarkably,OsHIPP20knockout rice line showed no growth defect, suggesting editing sHMA genes may present a novel source of resistance against blast disease.
Cumulative impacts across Australia’s Great Barrier Reef: A mechanistic evaluation
Authors: Bozec Yves-Marie , Hock Karlo , Mason Robert A. B. , Baird Mark E. , Castro-Sanguino Carolina , Condie Scott A. , Puotinen Marji , Thompson Angus , Mumby Peter J. 
Published: December 2020

ABSTRACTCumulative impacts assessments on marine ecosystems have been hindered by the difficulty of collecting environmental data and identifying drivers of community dynamics beyond local scales. On coral reefs, an additional challenge is to disentangle the relative influence of multiple drivers that operate at different stages of coral ontogeny. We integrated coral life history, population dynamics and spatially-explicit environmental drivers to assess the relative and cumulative impacts of multiple stressors across 2,300 km of the world’s largest coral reef ecosystem, Australia’s Great Barrier Reef (GBR). Using literature data, we characterized relationships between coral life history processes (reproduction, larval dispersal, recruitment, growth and mortality) and environmental variables. We then simulated coral demographics and stressor impacts at the organism (coral colony) level on >3,800 individual reefs linked by larval connectivity, and exposed to temporally- and spatially-realistic regimes of acute (crown-of-thorns starfish outbreaks, cyclones and mass coral bleaching) and chronic (water quality) stressors. Model simulations produced a credible reconstruction of recent (2008–2020) coral trajectories consistent with monitoring observations, while estimating the impacts of each stressor at reef and regional scales. Overall, corals declined by one third across the GBR, from an average ∼29% to ∼19% hard coral cover. By 2020, less than 20% of the GBR had coral cover higher than 30%. Global annual rates of coral mortality were driven by bleaching (48%) ahead of cyclones (41%) and starfish predation (11%). Beyond the reconstructed status and trends, the model enabled the emergence of complex interactions that compound the effects of multiple stressors while promoting a mechanistic understanding of coral cover dynamics. Drivers of coral cover growth were identified; notably, water quality (suspended sediments) was estimated to delay recovery for at least 25% of inshore reefs. Standardized rates of coral loss and recovery allowed the integration of all cumulative impacts to determine the equilibrium cover for each reef. This metric, combined with maps of impacts, recovery potential, water quality thresholds and reef state metrics, facilitates strategic spatial planning and resilience-based management across the GBR.
PPalign: Optimal alignment of Potts models representing proteins with direct coupling information
Authors: Talibart Hugo , Coste François 
Published: December 2020

AbstractBackgroundTo assign structural and functional annotations to the ever increasing amount of sequenced proteins, the main approach relies on sequence-based homology search methods, e.g. BLAST or the current state-of-the-art methods based on profile Hidden Markov Models (pHMM), which rely on significant alignments of query sequences to annotated proteins or protein families. While powerful, these approaches do not take coevolution between residues into account. Taking advantage of recent advances in the field of contact prediction, we propose here to represent proteins by Potts models, which model direct couplings between positions in addition to positional composition, and to compare proteins by aligning these models. Due to non-local dependencies, the problem of aligning Potts models is hard and remains the main computational bottleneck for their use.ResultsWe introduce here an Integer Linear Programming formulation of the problem and PPalign, a program based on this formulation, to compute the optimal pairwise alignment of Potts models representing proteins in tractable time. The approach is assessed with respect to a non-redundant set of reference pairwise sequence alignments from SISYPHUS benchmark which have lowest sequence identity (between 3% and 20%) and enable to build reliable Potts models for each sequence to be aligned. This experimentation confirms that Potts models can be aligned in reasonable time (1′37″ in average on these alignments). The contribution of couplings is evaluated in comparison with HHalign and PPalign without couplings. Although Potts models were not fully optimized for alignment purposes and simple gap scores were used, PPalign yields a better meanF1score and finds significantly better alignments than HHalign and PPalign without couplings in some cases.ConclusionsThese results show that pairwise couplings from protein Potts models can be used to improve the alignment of remotely related protein sequences in tractable time. Our experimentation suggests yet that new research on the inference of Potts models is now needed to make them more comparable and suitable for homology search. We think that PPalign’s guaranteed optimality will be a powerful asset to perform unbiased investigations in this direction.
Chemical inhibition of ENL/AF9 YEATS domains in acute leukemia
Authors: Garnar-Wortzel Leopold , Bishop Timothy R. , Kitamura Seiya , Milosevich Natalia , Asiaban Joshua N. , Zhang Xiaoyu , Zheng Qinheng , Chen Emily , Ramos Anissa R. , Ackerman Christopher J. , Hampton Eric N. , Chatterjee Arnab K. , Young Travis S. , Hull Mitchell V. , Sharpless K. Barry , Cravatt Benjamin F. , Wolan Dennis W. , Erb Michael A. 
Published: December 2020

AbstractTranscriptional co-regulators, which mediate chromatin-dependent transcriptional signaling, represent tractable targets to modulate tumorigenic gene expression programs with small molecules. Genetic loss-of-function studies have recently implicated the transcriptional co-activator, ENL, as a selective requirement for the survival of acute leukemia and highlighted an essential role for its chromatin reader YEATS domain. Motivated by these discoveries, we executed a screen of nearly 300,000 small molecules and identified an amido-imidazopyridine inhibitor of the ENL YEATS domain (IC50= 7 µM). Leveraging a SuFEx-based high-throughput approach to medicinal chemistry optimization, we discovered SR-0813 (IC50= 25 nM), a potent and selective ENL/AF9 YEATS domain inhibitor that exclusively inhibits the growth of ENL-dependent leukemia cell lines. Armed with this tool and a first-in-class ENL PROTAC, SR-1114, we detailed the response of AML cells to pharmacological ENL disruption for the first time. Most notably, displacement of ENL from chromatin by SR-0813 elicited a strikingly selective suppression of ENL target genes, includingHOXA9/10, MYB, MYCand a number of other leukemia proto-oncogenes. Our study reproduces a number of key observations previously made by CRISPR/Cas9 loss of function and dTAG-mediated degradation, and therefore, both reinforces ENL as an emerging leukemia target and validates SR-0813 as a high-quality chemical probe.
Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension
Authors: Lakk Monika , Hoffmann Grace F. , Gorusupudi Aruna , Enyong Eric , Lin Amy , Bernstein Paul S. , Toft-Bertelsen Trine , MacAulay Nanna , Elliott Michael H. , Križaj David 
Published: December 2020

AbstractDespite the association of cholesterol with debilitating pressure-related diseases, its role in mechanotransduction is not well understood. We investigated the relationship between mechanical strain, free membrane cholesterol, actin cytoskeleton, and activation of stretch- activated TRPV4 (transient receptor potential vanilloid isoform 4) channel in human trabecular meshwork (TM) cells. Physiological levels of cyclic stretch resulted in time- dependent decreases in membrane cholesterol/phosphatidylcholine ratio and upregulation of stress fibers. Depletion of free membrane cholesterol with m-β-cyclodextrin (MβCD) augmented TRPV4 activation by the agonist GSK1016790A, swelling and strain, with the effects reversed by cholesterol supplementation. MβCD increased membrane expression of TRPV4, caveolin-1 and flotillin. Caveolin-1 antibody partially precipitated a truncated ∼75 kDa variant whereas the majority of TRPV4 did not colocalize or interact with caveolae or lipid rafts, indicating that TRPV4 is mainly localized outside of cholesterol-enrichedmembrane domains. MβCD induced currents in TRPV4-expressingXenopus laevisoocytes. Thus, while the membrane C/P ratio reflects the biomechanical milieu, trabecular transduction of mechanical information is modulated by the membrane cholesterol content. Diet, cholesterol metabolism and mechanical stress might modulate the conventional outflow pathway and intraocular pressure in glaucoma and diabetes.
Scaling effects of temperature on parasitism from individuals to host–parasite systems
Authors: Kirk Devin , O’Connor Mary I. , Mordecai Erin A. 
Published: December 2020

ABSTRACTParasitism is expected to change in a warmer future, but whether warming leads to substantial increases in parasitism remains unclear. Understanding how warming effects on parasitism in individual hosts (e.g., parasite load) translate to effects on population-level parasitism (e.g., prevalence, R0) remains a major knowledge gap. We analyzed the temperature dependence of parasitism at both host and population levels in thirteen empirical vector-borne host–parasite systems and found a strong, significant positive correlation between the thermal optima of individual- and population-level parasitism. We also found a significant, positive correlation in eleven environmentally-transmitted parasite systems, though several of these systems exhibited thermal optima >5ºC apart between individual and population levels. Similarly, parasitism thermal optima were close to host performance thermal optima in vector-borne systems but not in environmentally-transmitted systems. We then adapted and simulated simple models for both transmission modes and found a similar pattern to the empirical systems: thermal optima in vector-borne systems were more strongly correlated across scales compared to environmentally-transmitted systems. Generally, our results suggest that information on the temperature-dependence, and specifically the thermal optimum, at either the individual- or population-level should provide a useful—though not quantitatively exact—baseline for predicting temperature dependence at the other level, especially in vector-borne parasite systems. Environmentally-transmitted parasitism may operate by a different set of rules, in which temperature-dependence is decoupled in some systems, requiring the need for trait-based studies of temperature-dependence at individual and population levels.
MTX-COVAB, a human-derived antibody with potent neutralizing activity against SARS-CoV-2 infectionin vitroand in a hamster model of COVID-19
Authors: Schmitt Simone , Weber Marcel , Hillenbrand Matthias , Seidenberg Jemima , Zingg Andreas , Townsend Catherine , Eicher Barbara , Rutkauskaite Justina , Riese Peggy , Guzman Carlos A. , Fischer Karsten , Esslinger Christoph 
Published: December 2020

AbstractFast track microfluidic screening of the antibody repertoires of 12 convalescent COVID-19 donors comprising 2.8mio antibodies yielded MTX-COVAB, a human-derived monoclonal antibody with low picomolar neutralization IC50 of SARS-CoV-2. COVAB neutralization potency is on par with the Regeneron cocktail as demonstrated in a comparative neutralization assay. MTX-COVAB shows strong efficacyin vivoand binds to all currently identified clinically relevant variants of SARS-CoV-2. MTX-COVAB completes GMP manufacturing by the end of this year and will be tested in the clinic in March 2021.
Humans optimally anticipate and compensate for an uneven step during walking
Authors: Darici Osman , Kuo Arthur D. 
Published: December 2020

ABSTRACTThe simple task of walking up a sidewalk curb is actually a dynamic prediction task. The curb is a disturbance that causes a loss of momentum, to be anticipated and compensated for. For example, the compensation might regain momentum and ensure undisturbed time of arrival. But without a selection criterion, there are infinite possible strategies. Here we show that humans compensate with an anticipatory pattern of forward speed adjustments, with a criterion of minimizing mechanical energy input. This is predicted by optimal control for a simple model of walking dynamics, with each leg’s push-off work as input. Optimization predicts a tri-phasic trajectory of speed (and thus momentum) adjustments, including an anticipatory, feedforward phase. In experiment, human subjects successfully regain time relative to undisturbed walking, with the predicted tri-phasic trajectory. They also scale the pattern with up- or down-steps, and inversely with average speed, as also predicted by model. Humans can reason about the dynamics of walking to plan anticipatory and economical control, even with a sidewalk curb in the way.
PhenoBR: a model to phenotype body condition dynamics in meat sheep
Authors: Macé Tiphaine , González-García Eliel , Kövér György , Hazard Dominique , Taghipoor Masoomeh 
Published: December 2020

AbstractIn situations of negative energy balance (NEB) due to feed scarcity or high physiological demands, body energy reserves (BR), mainly stored in adipose tissues, become the main sources of energy for ruminants. The capacity to mobilize and restore such BRs in response to different challenges is of major concern in the current context of breeding for resilience. Body condition score (BCS) is a common, practical indicator of BR variations throughout successive productive cycles, and quantitative tools for characterizing such dynamics at the individual level are still lacking. The main objective of this work was to characterize body condition dynamics in terms of BR mobilization and accretion capacities of meat sheep during their productive lifespan through a modelling approach.The animal model used in this work was the reproductive meat ewe (n= 1478) reared in extensive rangeland. Regular measurements of BCS for each productive cycle were used as the indicator of BR variations. A hybrid mathematical model and a web interface, called PhenoBR, was developed to characterize ewes’ BCS variations through four synthetic and biologically meaningful parameters for each productive cyclei: BR accretion rate, BR mobilization rate, plus the time of onset and the duration of the BR mobilization,and ΔTi, respectively.The model converged for all the ewes included in the analysis. Estimation of the parameters indicated the inter-individual variability for BR accretion and mobilization rates, and for the length of the mobilization period. Body reserve mobilization rates were closely correlated between productive cycles. Significant correlations between BR mobilization and accretion rates suggest that the two processes are biologically linked. Parameterskpandkbdecreased as parity increased. BR mobilization rate and duration increased as litter size increased, while BR accretion rate decreased.Individual characterization of animals by these parameters makes it possible to rank them for their efficiency in the use of body reserves when facing NEB challenges. Such parameters could contribute to better management and decision-making by farmers and advisors, e.g. by adapting feeding systems to the individual characteristics of BR dynamics, or by geneticists as criteria to develop future animal breeding programs including BR dynamics for more robust and resilient animals.
Atomic force microscopy reveals the role of vascular smooth muscle cell elasticity in hypertension
Authors: Zhu Yi 
Published: December 2020

AbstractThe vascular smooth muscle cell (VSMC) mechanical properties not only provide intrinsic cellular functions, but also influence many vascular and circulation functions in physiology. In this report, the VSMCs of thoracic aorta from 16 week age Wistar-Kyoto normotensive rats (WKY) and spontaneously hypertensive rats (SHR) were used as research subjects to reveal hypertension mechanism at a single cell level using atomic force microscopy (AFM). The apparent elastic modulus was significantly increased in VSMCs from SHRs compared to those from WKYs. Treatment with cytochalasin D (CD), ML7, Y27632 and lysophosphatidic acid (LPA) modulated VSMC stiffness of WKYs and SHRs. A spectral analysis approach was applied to further investigate the time-dependent change in VSMC elasticity of WKYs and SHRs. This report demonstrated the efficacy of real-time analysis of VSMC elasticity by AFM nano-indentation, and revealed real-time functional differences in biomechanical characteristics of VSMCs with drug treatments.
Mitochondrial fusion mediated by mitofusin 1 regulates macrophage mycobactericidal activity by enhancing autophagy
Authors: Ning Yuping , Cai Yi , Dai Youchao , Mo Siwei , Werz Oliver , Chen Xinchun 
Published: December 2020

AbstractMitochondria as a highly dynamic organelle continuously changes morphology and position during its life cycle. Mitochondrial dynamics including fission and fusion play a critical role in maintaining functional mitochondria for ATP production, which is directly linked to host defense against Mtb infection. However, how macrophages regulate mitochondrial dynamics duringMycobacterium tuberculosis(Mtb) infection remains elusive. In this study, we found that Mtb infection induced mitochondrial fusion through enhancing the expression of mitofusin 1 (MFN1), which resulted in increased ATP production. SilencingMFN1inhibited mitochondrial fusion and subsequently reduced ATP production, which, in turn, severely impaired macrophage mycobactericidal activity by inhibiting autophagy. Impairment of mycobactericidal activity and autophagy was replicated using oligomycin, an inhibitor of ATP synthase. In summary, our study revealed MFN1-mediated mitochondrial fusion is essential for macrophage mycobactericidal activity through the regulation of ATP dependent autophagy. MFN1-mediated metabolism pathway might be targets for development of host direct therapy (HDT) strategy against TB.ImportanceHow mitochondrial dynamic is regulated in attempt to fight against Mtb remains elusive. Our study revealed that the fission/fusion dynamics of mitochondria during Mtb infection is regulated by MFN1, through which mitochondrial respiration and autophagy activity are affected. Our findings suggested that intervention of energy metabolism by targeting MFN1 might be a strategy against Mtb infection.
Regulation of pancreatic fibrosis by acinar cell-derived exosomal miR-130a-3p via targeting of stellate cell PPAR-γ
Authors: Wang Qiang , Wang Hao , Jing Qingxu , Yang Yang , Xue Dongbo , Hao Chen jun , Zhang Weihui 
Published: December 2020

ABSTRACTAs endogenous miRNA carriers,exosomes play a role in the pathophysiological process of various diseases. However, their functions and regulation mechanisms in pancreatic fibrosis remain unclear. In this study, an RNA microarray was used to detect differentially expressed exosomal miR-130a-3p in AR42J cells after taurolithocholate (TLC) treatment. mRNA-seq was used to screen the differentially expressed PPAR-γ after pancreatic stellate cell (PSC) activation. Fluorescence labeling of exosomes and dynamic tracing showed that exosomes can fuse with the cell membrane of PSCs and transport miR-130a-3p into PSCs. A luciferase reporter gene assay was used to confirm that miR-130a can bind to PPAR-γ to inhibit PPAR-γ expression. In vitro and in vivo functional experiments were performed for gain-of-function studies and loss-of-function studies, respectively. These studies showed that acinar cell-derived exosomal miR-130a-3p promotes PSC activation and collagen formation through targeting of cellular PPAR-γ. Knockdown of miR-130a-3p significantly improved pancreatic fibrosis. Notably, miR-130a-3p knockdown reduced serum levels of hyaluronic acid (HA) and β-amylase and increased the C-peptide to protect endocrine and exocrine pancreatic functions and the function of endothelial cells. The exosomal miR-130a-3p/PPAR-γ axis participates in the activation of PSCs and the mechanism of CP fibrosis, thus providing a potential new target for the treatment of chronic pancreatitis fibrosis.
Spatio-temporal Dynamics of the Patterning ofArabidopsisFlower Meristem
Authors: Díaz José , Álvarez-Buylla Elena R. 
Published: December 2020

AbstractThe qualitative model presented in this work recovers the onset of the four fields that correspond to those of each floral organ whorl ofArabidopsisflower, suggesting a mechanism for the generation of the positional information required for the differential expression of the A, B and C identity genes according to the ABC model for organ determination during early stages of flower development. Our model integrates a previous model for the emergence of WUS pattern in the apical meristem, and shows that this pre-pattern is a necessary but not sufficient condition for the posterior information of the four fields predicted by the ABC model. Furthermore, our model predicts that LFY diffusion along the L1 layer of cells is not a necessary condition for the patterning of the floral meristem.