bluuebunny/crossref_metadata_2025_split huggingface dataset:
Conformations of a Low-Complexity Protein in Homogeneous and Phase-Separated Frozen Solutions
Authors: Wilson C. Blake , Lee Myungwoon , Yau Wai-Ming , Tycko Robert 
Published: July 2024

AbstractSolutions of the intrinsically disordered, low-complexity domain of the FUS protein (FUS-LC) undergo liquid-liquid phase separation (LLPS) below temperatures TLLPSin the 20-40° C range. To investigate whether local conformational distributions are detectably different in the homogeneous and phase-separated states of FUS-LC, we performed solid state nuclear magnetic resonance (ssNMR) measurements on solutions that were frozen on sub-millisecond time scales after equilibration at temperatures well above (50° C) or well below (4° C) TLLPS. Measurements were performed at 25 K with signal enhancements from dynamic nuclear polarization. Crosspeak patterns in two-dimensional (2D) ssNMR spectra of rapidly frozen solutions in which FUS-LC was uniformly15N,13C-labeled were found to be nearly identical for the two states. Similar results were obtained for solutions in which FUS-LC was labeled only at Thr, Tyr, and Gly residues, as well as solutions of a FUS construct in which five specific residues were labeled by ligation of synthetic and recombinant fragments. These experiments show that local conformational distributions are nearly the same in the homogeneous and phase-separated solutions, despite the much greater protein concentrations and more abundant intermolecular interactions within phase-separated, protein-rich “droplets”. Comparison of the experimental results with simulations of the sensitivity of 2D crosspeak patterns to an enhanced population of β-strand-like conformations suggests that changes in conformational distributions are no larger than 5-10%.Statement of SignificanceLiquid-liquid phase separation (LLPS) in solutions of proteins with intrinsically disordered domains has attracted recent attention because of its relevance to multiple biological processes and its inherent interest from the standpoint of protein biophysics. The high protein concentrations and abundant intermolecular interactions within protein-rich, phase-separated “droplets” suggests that conformational distributions of intrinsically disordered proteins may differ in homogeneous and phase-separated solutions. To investigate whether detectable differences exist, we performed experiments on the low-complexity domain of the FUS protein (FUS-LC) in which FUS-LC solutions were first equilibrated at temperatures well above or well below their LLPS transition temperatures, then rapidly frozen and examined at very low temperatures by solid state nuclear magnetic resonance (ssNMR) spectroscopy. The ssNMR data for homogeneous and phase-separated frozen solutions of FUS-LC were found to be nearly identical, showing that LLPS is not accompanied by substantial changes in the local conformational distributions of this intrinsically disordered protein.
Bursts of rapid diversification, dispersals out of southern Africa, and two origins of dioecy punctuate the evolution ofAsparagus
Authors: Bentz Philip C. , Burrows John E. , Burrows Sandra M. , Mizrachi Eshchar , Liu Zhengjie , Yang Jun-Bo , Mao Zichao , Popecki Margot , Seberg Ole , Petersen Gitte , Leebens-Mack Jim 
Published: July 2024

AbstractThe genusAsparagusarose approximately 9–15 million years ago (Ma) and transitions from hermaphroditism to dioecy (separate sexes) occurred ∼3–4 Ma. Roughly 27% of extantAsparagusspecies are dioecious, while the remaining are bisexual with monoclinous flowers. As such,Asparagusis an ideal model taxon for studying early stages of dioecy and sex chromosome evolution in plants. Until now, however, understanding of diversification and shifts from hermaphroditism to dioecy inAsparagushas been hampered by the lack of robust species tree estimates for the genus. In this study, a genus-wide phylogenomic analysis including 1726 nuclear loci and comprehensive species sampling supports two independent origins of dioecy inAsparagus—first in a widely distributed Eurasian clade, then again in a clade restricted to the Mediterranean Basin. Modeling of ancestral biogeography indicates that both dioecy origins were associated with range expansion out of southern Africa. Our findings also revealed several bursts of diversification across the phylogeny, including an initial radiation in southern Africa that gave rise to 12 major clades in the genus, and more recent radiations that have resulted in paraphyly and polyphyly among closely related species, as expected given active speciation processes. Lastly, we report that the geographic origin of domesticated garden asparagus (Asparagus officinalisL.) was likely in western Asia near the Mediterranean Sea. The presented phylogenomic framework forAsparagusis foundational for ongoing genomic investigations of diversification and functional trait evolution in the genus and contributes to its utility for understanding the origin and early evolution of dioecy and sex chromosomes.Significance StatementAsparagusis an important model system for studying dioecy (separate sexes) evolution in plants.Asparagustaxonomy has been challenging, likely due to rapid species diversifications leading to highly variable species with complicated relationships that are impossible to resolve with limited DNA-sequence data. Using phylogenomics and the largest species sampling to date, we show that allAsparaguslineages originated from an initial radiation in southern Africa and that separate range expansions out of southern Africa set the stage for two distinct origins of dioecy inAsparagus. Our findings provide a deeper understanding of species diversification and the role of long-distance dispersals in the evolution of dioecy. This study also illustrates the utility of phylogenomics for elucidating past and present speciation processes.
Evaluation of AlphaFold3 for the fatty acids docking to human fatty acid-binding proteins
Authors: Nam Ki Hyun 
Published: July 2024

AbstractHuman fatty acid-binding proteins (FABPs) are involved in many aspects of lipid metabolism, such as the uptake, transport, and storage of lipophilic molecules, as well as cellular functions. Understanding how FABPs recognize fatty acids (FAs) is crucial for identifying FABP function and applications, such as in inhibitor design or biomarker development. The recently developed AlphaFold3 (AF3) demonstrates significantly higher accuracy than other prediction tools, particularly in predicting protein–ligand interactions with state-of-the-art docking tools. Studies on whether AF3 can be used to identify the FAs of FABP are lacking. To assess the accuracy of FA docking to FABPs using AF3, models of FA docked into FABP generated using AF3 were compared with experimentally determined FA-bound FABP structures. FA ligands in AF3 structures docked reliably into the FA-binding pocket of FABPs; however, the detailed binding configuration of most FA ligands docked into FABPs and the interaction between FA and FABP determined using AF3 and experimentally differed. These results will aid in understanding FA docking to FABPs and other FA-binding proteins using AF3.
History-dependent spiking facilitates efficient encoding of polarization angles in neurons of the central complex
Authors: Rother Lisa , Stöckl Anna , Pfeiffer Keram 
Published: July 2024

AbstractMany insects use the polarization pattern of the sky for spatial orientation. Since flying insects perform rapid maneuvers, including saccadic yaw turns which alternate with translational flight, they perceive highly dynamic polarization input to their navigation system. The tuning of compass-neurons in the central complex of insects, however, has been mostly investigated with polarized-light stimuli that rotated at slow and constant velocities, and thus were lacking these natural dynamics. Here we investigated the dynamic response properties of compass-neurons, using intracellular recordings in the central complex of bumblebees. We generated naturalistic stimuli by rotating a polarizer either according to a sequence of head orientations that have been reported from freely flying bumblebees, or at constant velocities between 30°/s and 1920°/s, spanning almost the entire range of naturally occurring rotation velocities. We found that compass neurons responded reliably across the entire range of the presented stimuli. In their responses, we observed a dependency on spiking history. We further investigated this dependency using a rate code model taking spiking history into account. Extending the model to a neuronal population with different polarization tuning, which mirrored the neuronal architecture of the central complex, suggests that spiking history has a directly impact on the overall population activity, which has two effects: First, it facilitates faster responses to stimulus changes during highly dynamic flight maneuvers, and increases sensitivity for course deviations during straight flight. Second, population activity during phases of constant polarization input is reduced, which might conserve energy during straight flight.Significance StatementMany insects use the pattern of polarized light, which arises from scattering of sunlight, for spatial orientation. Neurons in the central complex, a brain structure, which governs spatial orientation, encode the orientation of the insect’s head with respect to polarized light. To investigate the dynamic properties of these neurons, we recorded intracellularly in the central complex of bumblebees and stimulated with naturalistic polarized-light stimuli. We found that neuronal activity was not only dictated by the angle of polarization, but also by the amount of previous activity. Using a modelling approach we show, that this dependency on spiking history can facilitate faster adjustment of the heading signal and leads to reduced overall activity and therefore reduced energy consumption during straight flight.
Chromatin Remodeling by the Histone Methyltransferase SETD2 Drives Lipotoxic Injury in Cardiometabolic Heart Failure with Preserved Ejection Fraction
Authors: Ambrosini Samuele , Costantino Sarah , Mohammed Shafeeq A. , Gorica Era , Herwig Melissa , van Heerebeek Loek , Mengozzi Alessandro , Karsai Gergely , Hornemann Thorsten , Dzemali Omer , Ruschitzka Frank , Hamdani Nazha , Paneni Francesco 
Published: July 2024

AbstractBackgroundCardiometabolic heart failure with preserved ejection fraction (cHFpEF) is highly prevalent and associates with a poor outcome. Pathological gene expression in heart failure is accompanied by changes in active histone marks without major alterations in DNA methylation. Histone 3 trimethylation at lysine 36 (H3k36me3) - a chromatin signature induced by the histone methyltransferase SETD2 - strongly correlates with changes in gene expression in human failing hearts; however, its role is poorly understood. Here we investigate the role of SETD2 in cHFpEF.MethodsMice with cardiomyocyte-specific deletion of SETD2 (c-SETD2-/-) were generated and subjected to high fat diet feeding and L-NAME treatment for 15 weeks to induce cHFpEF. Cardiac function and exercise tolerance were assessed by echocardiography and Treadmill exhaustion test. Chromatin immunoprecipitation assays (ChIP) were performed to investigate SETD2/H3k36me3 enrichment on gene promoters. SETD2 gain- and loss-of-function experiments were performed in cultured cardiomyocytes (CMs) exposed to palmitic acid (PA). SETD2 expression was also investigated in left ventricular (LV) myocardial specimens from patients with cHFpEF and control donors.ResultsSETD2 was upregulated in cHFpEF mouse hearts and its chromatin mark H3k36me3 was enriched on the promoter of sterol regulatory element-binding transcription factor 1 (SREBP1) gene. SETD2 activation in cHFpEF led to SREBP1 upregulation, triglyceride accumulation and lipotoxic damage. Of note, cardiomyocyte-specific deletion of SETD2 in mice prevented HFpEF-related hypertrophy, diastolic dysfunction and lung congestion while improving exercise tolerance. SETD2 deletion blunted H3K36me3 enrichment on SREBP1 promoter thus leading to a marked rewiring of the cardiac lipidome and restoration of autophagic flux. SETD2 depletion in PA-treated CMs prevented SREBP1 upregulation, whereas SETD2 overexpression recapitulated lipotoxic damage. Finally, SETD2 was upregulated in LV specimens from cHFpEF patients and its pharmacological inhibition by EZM0414 attenuated CM stiffness.ConclusionsTherapeutic modulation of SETD2/H3k36me3 axis might prevent lipotoxic injury and cardiac dysfunction in cHFpEF.
Engineering anti-amyloid antibodies with transferrin receptor targeting improves brain biodistribution and mitigates ARIA
Authors: Pizzo Michelle E. , Plowey Edward D. , Khoury Nathalie , Kwan Wanda , Abettan Jordan , DeVos Sarah L. , Discenza Claire B. , Earr Timothy , Joy David , Lye-Barthel Ming , Roche Elysia , Chan Darren , Dugas Jason C. , Gadkar Kapil , Meisner René , Sebalusky Jennifer , Amaral Ana Claudia Silva , Becerra Isabel , Chau Roni , Chow Johann , Clemens Allisa J. , Dennis Mark S. , Duque Joseph , Fusaro Laura , Getz Jennifer A. , Kariolis Mihalis S. , Kim Do Jin , Leung Amy Wing-Sze , Nguyen Hoang N. , Thomsen Elliot R. , Sanchez Pascal E. , Shan Lu , Silverman Adam P. , Solanoy Hilda , Tong Raymond , Calvert Meredith E. , Watts Ryan J. , Thorne Robert G. , Weinreb Paul H. , Walsh Dominic M. , Lewcock Joseph , Bussiere Thierry , Zuchero Y. Joy Yu 
Published: July 2024

AbstractAlthough the first generation of immunotherapies for Alzheimer’s disease (AD) are now clinically approved, amyloid-related imaging abnormalities (ARIA) remain a major safety problem for this class of drugs. Here, we report an antibody transport vehicle (ATV) targeting the transferrin receptor (TfR) for brain delivery of amyloid beta (Aý) antibodies that significantly reduced ARIA-like lesions and improved plaque target engagement in a mouse model of amyloid deposition. Asymmetrical Fc mutations (ATVcisLALA) allowed the molecule to selectively retain effector function only when bound to Aý while mitigating TfR-related hematology liabilities. Mice treated with ATVcisLALA:Aý exhibited broad brain parenchymal antibody distribution; in contrast, anti-Aý IgG was highly enriched at arterial perivascular spaces where vascular Aý localizes and likely plays a role in induction of ARIA. Importantly, ATVcisLALA: Aý almost completely eliminated ARIA-like lesions and vascular inflammation associated with anti-Aý treatment. Taken together, ATVcisLALAhas the potential to significantly improve both safety and efficacy of Aý immunotherapy through enhanced biodistribution mediated by transport across the blood-brain barrier.
Contrast-dependent response modulation in convolutional neural networks captures behavioral and neural signatures of visual adaptation
Authors: Brands Amber Marijn , Oz Zilan , Vukšić Nikolina , Ortiz Paulo , Groen Iris Isabelle Anna 
Published: July 2024

AbstractHuman perception remains robust under challenging viewing conditions. Robust perception is thought to be facilitated by nonlinear response properties, including temporal adaptation (reduced responses to re-peated stimuli) and contrast gain (shift in the contrast response function with pre-exposure to a stimulus). Temporal adaptation and contrast gain have both been shown to aid object recognition, however, their joint effect on perceptual and neural responses remains unclear. Here, we collected behavioural measurements and electrocorticography (EEG) data while human participants (both sexes) classified objects embedded within temporally repeated noise patterns, whereby object contrast was varied. Our findings reveal an in-teraction effect, with increased categorization performance as a result of temporal adaptation for higher but not lower contrast stimuli. This increase in behavioral performance after adaptation is associated with more pronounced contrast-dependent modulation of evoked neural responses, as well as better decoding of object information from EEG activity. To elucidate the neural computations underlying these effects, we endowed deep convolutional neural networks (DCNN) with various temporal adaptation mechanisms, including intrinsic suppression and temporal divisive normalisation. We demonstrate that incorporating a biologically-inspired contrast response function to modify temporal adaptation helps DCNNs to accurately capture human behaviour and neural activation profiles. Moreover, we find that networks with multiplicative temporal adaptation mechanisms, such as divisive normalization, show higher robustness against spatial shifts in the inputs compared to DCNNs employing additive mechanisms. Overall, we reveal how interaction effects between nonlinear response properties influence human perception in challenging viewing contexts and investigate potential computations that mediate these effects.Significance statementHumans are able to perceive the environment even when viewing conditions are suboptimal. This robust perception has been linked to nonlinear neural processing of incoming visual information. Here, we examine the joint impact of two neural response properties, temporal adaptation and contrast gain, during object recognition, demonstrating interaction effects on categorization performance and in evoked neural responses. Using convolutional neural networks, we investigate various temporal adaptation mechanisms mediating the neural responses and perception, demonstrating that introducing contrast-dependent modulation of the unit activations captures human behaviour and neural object representations. Our findings shed light on how neural response properties give rise to robust perception and offer a framework to study the underlying neural dynamics and their impact on perception.
CD6 Regulates CD4 T Follicular Helper Cell Differentiation and Humoral Immunity During Murine Coronavirus Infection
Authors: Cardani-Boulton Amber , Lin Feng , Bergmann Cornelia C 
Published: July 2024

AbstractDuring activation the T cell transmembrane receptor CD6 becomes incorporated into the T cell immunological synapse where it can exert both co-stimulatory and co-inhibitory functions. Given the ability of CD6 to carry out opposing functions, this study sought to determine how CD6 regulates early T cell activation in response to viral infection. Infection of CD6 deficient mice with a neurotropic murine coronavirus resulted in greater activation and expansion of CD4 T cells in the draining lymph nodes. Further analysis demonstrated that there was also preferential differentiation of CD4 T cells into T follicular helper cells, resulting in accelerated germinal center responses and emergence of high affinity virus specific antibodies. Given that CD6 conversely supports CD4 T cell activation in many autoimmune models, we probed potential mechanisms of CD6 mediated suppression of CD4 T cell activation during viral infection. Analysis of CD6 binding proteins revealed that infection induced upregulation ofUbash3a,a negative regulator of T cell receptor signaling, was hindered in CD6 deficient lymph nodes. Consistent with greater T cell activation and reduced UBASH3a activity, the T cell receptor signal strength was intensified in CD6 deficient CD4 T cells. These results reveal a novel immunoregulatory role for CD6 in limiting CD4 T cell activation and deterring CD4 T follicular helper cell differentiation, thereby attenuating antiviral humoral immunity.ImportanceCD6 monoclonal blocking antibodies are being therapeutically administered to inhibit T cell activation in autoimmune disorders. However, the multifaceted nature of CD6 allows for multiple and even opposing functions under different circumstances of T cell activation. We therefore sought to characterize how CD6 regulates T cell activation in the context viral infections using anin vivomurine coronavirus model. In contrast to its role in autoimmunity, but consistent with its function in the presence of superantigens, we found that CD6 deficiency enhances CD4 T cell activation and CD4 T cell help to germinal center dependent antiviral humoral responses. Finally, we provide evidence that CD6 regulates transcription of its intracellular binding partner UBASH3a, which suppresses T cell receptor signaling and consequently T cell activation. These findings highlight the context dependent flexibility of CD6 in regulatingin vivoadaptive immune responses, which may be targeted to enhance anti-viral immunity.
MitoMAMMAL: a genome scale model of mammalian mitochondria predicts cardiac and BAT metabolism
Authors: Chapman Stephen P. , Brunet Theo , Mourier Arnaud , Habermann Bianca H. 
Published: July 2024

AbstractMitochondria perform several essential functions in order to maintain cellular homeostasis and mitochondrial metabolism is inherently flexible to allow correct function in a wide range of tissues. Dysregulated mitochondrial metabolism can therefore affect different tissues in different ways which presents experimental challenges in understanding the pathology of mitochondrial diseases. System-level metabolic modelling is therefore useful in gaining in-depth insights into tissue-specific mitochondrial metabolism, yet despite the mouse being a common model organism used in research, there is currently no mouse specific mitochondrial metabolic model available. In this work, building upon the similarity between human and mouse mitochondrial metabolism, we have created mitoMammal, a genome-scale metabolic model that contains human and mouse specific gene-product reaction rules. MitoMammal is therefore able to model mouse and human mitochondrial metabolism. To demonstrate this feature, using an adapted E-Flux2 algorithm, we first integrated proteomic data extracted from mitochondria of isolated mouse cardiomyocytes and mouse brown adipocyte tissue. We then integrated transcriptomic data fromin vitrodifferentiated human brown adipose cells and modelled the context specific metabolism using flux balance analysis. In all three simulations, mitoMammal made mostly accurate, and some novel predictions relating to energy metabolism in the context of cardiomyocytes and brown adipocytes. This demonstrates its usefulness in research relating to cardiac disease and diabetes in both mouse and human contexts.
Dynamics of influenza transmission in vampire bats revealed by longitudinal monitoring and a large-scale anthropogenic perturbation
Authors: Griffiths Megan E , Broos Alice , Morales Juan , Tu I-Ting , Bergner Laura , Behdenna Abdelkader , Valderrama William , Tello Carlos , Carrera Jorge E , Recuenco Sergio , Streicker Daniel G , Viana Mafalda 
Published: July 2024

AbstractInterrupting pathogen transmission between species is a priority strategy to mitigate zoonotic threats. However, avoiding counterproductive interventions requires knowing animal reservoirs of infection and the dynamics of transmission within them, neither of which are easily ascertained from the cross-sectional surveys which currently dominate investigations into newly discovered viruses. We used biobanked sera and metagenomic data to reconstruct the transmission of recently discovered bat-associated influenza virus (BIV) over 12 years in three zones of Peru. Mechanistic models fit under a Bayesian framework, which enabled joint inference from serological and molecular data, showed that common vampire bats maintain BIV independently of the currently assumed fruit bat reservoir through immune waning and seasonal transmission pulses. A large-scale vampire bat cull targeting rabies incidentally halved BIV transmission, confirming vampire bats as maintenance hosts. Our results show how combining field studies, perturbation responses and multi-data type models can elucidate pathogen dynamics in nature and reveal pathogen-dependent effects of interventions.