bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Remarkable Genetic Shift in a Transmitted/Founder Virus Broadens Antibody Responses Against HIV-1
Authors: Jain Swati , Uritskiy Gherman , Mahalingam Marthandan , Batra Himanshu , Chand Subhash , Trinh Hung V. , Beck Charles , Shin Woong-Hee , AlSalmi Wadad , Kijak Gustavo , Eller Leigh A. , Kim Jerome , Kihara Daisuke , Tovanabutra Sodsai , Ferrari Guido , Robb Merlin L. , Rao Mangala , Rao Venigalla B. 
Published: June 2021

AbstractA productive HIV-1 infection in humans is often established by transmission and propagation of a single transmitted/founder (T/F) virus, which then evolves into a complex mixture of variants during the lifetime of infection. An effective HIV-1 vaccine should elicit broad immune responses in order to block the entry of diverse T/F viruses. Currently, no such vaccine exists. An in-depth study of escape variants emerging under host immune pressure during very early stages of infection might provide insights into such a HIV-1 vaccine design. Here, in a rare longitudinal study involving HIV-1 infected individuals just days after infection in the absence of antiretroviral therapy, we discovered a remarkable genetic shift that resulted in near complete disappearance of the original T/F virus and appearance of a variant with H173Y mutation in the variable V2 domain of the HIV-1 envelope protein. This coincided with the disappearance of the first wave of strictly H173-specific antibodies and emergence of a second wave of Y173-specific antibodies with increased breadth. Structural analyses indicated conformational dynamism of the envelope protein which likely allowed selection of escape variants with a conformational switch in the V2 domain from an α-helix (H173) to a β-strand (Y173) and induction of broadly reactive antibody responses. This differential breadth due to a single mutational change was also recapitulated in a mouse model. Rationally designed combinatorial libraries containing 54 conformational variants of V2 domain around position 173 further demonstrated increased breadth of antibody responses elicited to diverse HIV-1 envelope proteins. These results offer new insights into designing broadly effective HIV-1 vaccines.
Age-related decline of the unfolded protein response in the heart promotes protein misfolding and cardiac pathology
Authors: Hofmann Christoph , Blackwood Erik A. , Jakobi Tobias , Sandmann Clara , Groß Julia , Herzog Nicole , Kaufman Randal J. , Katus Hugo A. , Völkers Mirko , Glembotski Christopher C. , Doroudgar Shirin 
Published: June 2021

AbstractCardiac myocyte death during heart failure is particularly detrimental, given that cardiac muscle exhibits limited regenerative potential. Protein aggregation was previously observed in end-stage heart failure, suggesting protein-misfolding in cardiac myocytes as a contributor to the disease process. However, the relationship between protein-misfolding, cardiac myocyte death, and myocardial dysfunction is yet to be clearly established. Here, we showed that protein synthesis and the unfolded protein response (UPR) declined as a function of mammalian postnatal development, especially in tissues with low mitotic activity, such as the heart. A deeper examination in animals models showed that compared to neonatal cardiac myocytes, adult cardiac myocytes expressed lower levels of the adaptive UPR transcription factor, ATF6, as well as lower levels of numerous ATF6-regulated genes, which was associated with susceptibility to ER stress-induced cell death. Further reduction of the ATF6-dependent gene program in ATF6 knock-out mice led to the accumulation of misfolded proteins in the myocardium and impaired myocardial function in response to cardiac stress, indicating that ATF6 plays a critical adaptive role in the setting of cardiac disease. Thus, strategies to increase ATF6 aimed at balancing proteostasis in cardiac myocytes might be a fruitful avenue for the development of novel therapies for heart disease and other age-associated diseases.HighlightsThe unfolded protein response (UPR) declines as a function of age in adult mammalian tissues with low mitotic activity, such as the heartDecreases in the UPR in adult cardiac myocytes is associated with impaired survival during ER stressATF6 loss of function in adult hearts increases protein misfolding and cardiac disfunction during stress
HVEM structures and mutants reveal distinct functions of binding to LIGHT and BTLA/CD160
Authors: Liu Weifeng , Chou Ting-Fang , Garrett-Thomson Sarah C. , Seo Goo-Young , Fedorov Elena , Ramagopal Udupi A. , Bonanno Jeffrey B. , Kakugawa Kiyokazu , Cheroutre Hilde , Kronenberg Mitchell , Almo Steven C. 
Published: June 2021

AbstractHVEM is a TNF (tumor necrosis factor) receptor contributing to a broad range of immune functions involving diverse cell types. It interacts with a TNF ligand, LIGHT, and immunoglobulin (Ig) superfamily members BTLA and CD160. Assessing the functional impact of HVEM binding to specific ligands in different settings has been complicated by the multiple interactions of HVEM and HVEM binding partners. To dissect the molecular basis for multiple functions, we determined crystal structures that reveal the distinct HVEM surfaces that engage LIGHT or BTLA/CD160, including the human HVEM:LIGHT:CD160 ternary complex, with HVEM interacting simultaneously with both binding partners. Based on these structures, we generated mouse HVEM mutants that selectively recognized either the TNF or Ig ligands in vitro. Knock-in mice expressing these muteins maintain expression of all the proteins in the HVEM network, yet they demonstrate selective functions for LIGHT in the clearance of bacteria in the intestine and for the Ig ligands in the amelioration of liver inflammation.
Reduced light access promotes hypocotyl growth via autophagy-mediated recycling
Authors: Ince Yetkin Çaka , Fiorucci Anne Sophie , Trevisan Martine , Galvão Vinicius Costa , Krahmer Johanna , Wigger Leonore , Pradervand Sylvain , Fouillen Laeticia , Delft Pierre Van , Mongrand Sebastien , Gallart-Ayala Hector , Ivanisevic Julijana , Fankhauser Christian 
Published: June 2021

SUMMARYPlant growth ultimately depends on fixed carbon, thus the available light for photosynthesis. Due to canopy light absorption properties, vegetative shade combines reduced light and a low red to far-red ratio (LRFR). In shade-avoiding plants, these two conditions independently promote growth adaptations to enhance light access. However, how these conditions, differing in photosynthetically-available light, similarly promote growth remains unknown. Here, we show that Arabidopsis seedlings adjust metabolism according to light conditions to supply resources for hypocotyl growth enhancement. Transcriptome analyses indicate that reduced light induces starvation responses, suggesting a switch to a catabolic state to promote growth. Accordingly, reduced light promotes autophagy. In contrast, LRFR promotes anabolism including biosynthesis of plasma-membrane sterols downstream of PHYTOCHROME-INTERACTING FACTORs (PIFs) acting in hypocotyls. Furthermore, sterol biosynthesis and autophagy are indispensable for shade-induced hypocotyl growth. We conclude that vegetative shade enhances hypocotyl growth by combining autophagy-mediated recycling and promotion of specific anabolic processes.HIGHLIGHTSReduced light and LRFR induce catabolism and anabolism, respectivelyReduced light promotes autophagy to enhance hypocotyl growth in vegetative shadeLRFR enhances hypocotyl growth by promoting plasma membrane lipid biosynthesisIn LRFR, PIFs promote sterol biosynthesis specifically in the hypocotyl
GBS-SBG - GBS Serotyping by Genome Sequencing
Authors: Tiruvayipati Suma , Ying Tan Wen , Barkham Timothy , Chen Swaine L. 
Published: June 2021

ABSTRACTGroup B Streptococcus agalactiae (GBS; Streptococcus agalactiae) is the most common cause of neonatal meningitis and a rising cause of sepsis in adults. Recently, it has also been shown to cause foodborne disease. As with many other bacteria, the polysaccharide capsule of GBS is antigenic, enabling its use for strain serotyping. Recent advances in DNA sequencing have made sequence-based typing attractive (as has been implemented for several other bacteria, including Escherichia coli, Klebsiella pneumoniae species complex, Streptococcus pyogenes, and others). For GBS, existing WGS-based serotyping systems do not provide complete coverage of all known GBS serotypes (specifically including subtypes of serotype III), and none are simultaneously compatible with the two most common data types, raw short reads and assembled sequences. Here, we create a serotyping database (GBS-SBG, GBS Serotyping by Genome Sequencing), with associated scripts and running instructions, that can be used to call all currently described GBS serotypes, including subtypes of serotype III, using both direct short-read- and assembly-based typing. We achieved higher concordance using GBS-SBG on a previously reported data set of 790 strains. We further validated GBS-SBG on a new set of 572 strains, achieving 99.8% concordance with PCR-based molecular serotyping using either short-read- or assembly-based typing. The GBS-SBG package is publicly available and will accelerate and simplify serotyping by sequencing for GBS.DATA SUMMARYThe GBS-SBG package is open source and available for at Github under the MIT license (URL - https://github.com/swainechen/GBS-SBG)Accession numbers of the sequencing reads and reference sequences used in the study from earlier reports have been provided within the article and the supplementary dataThe WGS data for the 572 isolates used in the study is available at https://www.ncbi.nlm.nih.gov/bioproject/PRJNA293392
Long-term quality assessment and monitoring of light microscope performance through accessible and reliable protocols, tools and metrics
Authors: Faklaris Orestis , Bancel-Vallée Leslie , Dauphin Aurélien , Monterroso Baptiste , Frère Perrine , Geny David , Manoliu Tudor , de Rossi Sylvain , Cordelières Fabrice P. , Schapman Damien , Nitschke Roland , Cau Julien , Guilbert Thomas 
Published: June 2021

AbstractReliable, reproducible and comparable results are what biology requires from microscopy. To achieve that level of confidence, monitoring the stability of the microscope performance over time with standardized quality testing routines is essential for mining quantitative data. Three levels of microscope quality control procedures should be considered: i) usage of accessible and affordable tools and samples, ii) execution of easy and fast, preferably automatized, acquisition protocols, iii) analysis of data in the most automated way possible with adequate metrics for long-term monitoring. In this paper, we test the acquisition protocols on the mainly used microscope techniques (wide-field, spinning disk and confocal microscopy) with simple quality control tools. Seven protocols specify metrics on measuring the lateral and axial resolution (Point-Spread Function) of the system, field flatness, chromatic aberrations and co-registration, illumination power monitoring and stability, stage drift and positioning repeatability and finally temporal and spatial noise sources of camera detectors. We designed an ImageJ/FiJi java plugin named MetroloJ_QC to incorporate the identified metrics and automatize the data processing for the analysis. After processing and comparing the data of microscopes from more than ten imaging facilities, we test the robustness of the metrics and the protocols by determining experimental limit values. Our results give a first extensive characterization of the quality control procedures of a light microscope, with an automated data processing and experimental limit values that can be used by core facility staff and researchers to monitor the microscope performance over time.
Ceylon cinnamon and its major compound Cinnamaldehyde can limit overshooting inflammatory signaling and angiogenesisin vitro: implications for COVID-19 treatment
Authors: Lucas Kurt , Ackermann Maximilian , Leifke Anna Lena , Li William W. , Pöschl Ulrich , Fröhlich-Nowoisky Janine 
Published: June 2021

AbstractOvershooting immune reactions can occur during inflammatory responses that accompany severe infections, such as COVID-19. Cytokines, damage-associated molecular patterns (DAMPs), and reactive oxygen and nitrogen species can generate positive feedback loops of inflammation, leading to long-term complications such as vascular endothelialitis, thrombosis, endothelial dysfunction, neurological impairments, and chronic fatigue. Dexamethasone can limit inflammation by inhibiting the activation of pro-inflammatory transcription factors. High dose dexamethasone, however, has undesirable side effects. Here, we show that Ceylon cinnamon and its major compound cinnamaldehyde can mitigate inflammatory signalingin vitro. Cinnamaldehyde interferes with the dimerization of toll-like receptor 4 (TLR4), which can be activated by DAMPs like HSP60 and HMGB1. Our results suggest that supplementary treatment with Ceylon cinnamon may allow administration of lower doses of dexamethasone to avoid high dose steroid side effects. Moreover, preliminary results indicate that Ceylon cinnamon modulates angiogenesis, which is a reactive phenomenon in COVID-19.
Maturation of persistent and hyperpolarization-activated inward currents shapes the differential activation of motoneuron subtypes during postnatal development
Authors: Sharples Simon A. , Miles Gareth B. 
Published: June 2021

AbstractThe size principle underlies the orderly recruitment of motor units; however, motoneuron size is a poor predictor of recruitment amongst functionally defined motoneuron subtypes. Whilst intrinsic properties are key regulators of motoneuron recruitment, the underlying currents involved are not well defined. Whole-cell patch-clamp electrophysiology was deployed to study intrinsic properties, and the underlying currents, that contribute to the differential activation of delayed and immediate firing motoneuron subtypes. Motoneurons were studied during the first three postnatal weeks in mice to identify key properties that contribute to rheobase and may be important to establish orderly recruitment. We find that delayed and immediate firing motoneurons are functionally homogeneous during the first postnatal week and are activated based on size, irrespective of subtype. The rheobase of motoneuron subtypes become staggered during the second postnatal week, which coincides with the differential maturation of passive and active properties, particularly persistent inward currents. Rheobase of delayed firing motoneurons increases further in the third postnatal week due to the development of a prominent resting hyperpolarization-activated inward current. Our results suggest that motoneuron recruitment is multifactorial, with recruitment order established during postnatal development through the differential maturation of passive properties and sequential integration of persistent and hyperpolarization-activated inward currents.Impact StatementElectrophysiological recordings from mouse spinal motoneurons reveal key roles for ion channels in establishing the differential activation of motoneuron subtypes during postnatal development.
The role of epistasis in determining the fitness landscape of HIV proteins
Authors: Biswas Avik , Haldane Allan , Levy Ronald M 
Published: June 2021

AbstractThe rapid evolution of HIV is constrained by interactions between mutations which affect viral fitness. In this work, we explore the role of epistasis in determining the fitness landscape of HIV for multiple drug target proteins, including Protease, Reverse Transcriptase, and Integrase. Epistatic interactions between residues modulate the mutation patterns involved in drug resistance with unambiguous signatures of epistasis best seen in the comparison of a maximum entropy sequence co-variation (Potts) model predicted and experimental HIV sequence “prevalences” when expressed as higher-order marginals (beyond triplets) of the sequence probability distribution. In contrast, the evidence for epistasis based on experimental measures of fitness such as replicative capacity is weak; the correspondence with Potts model “prevalence”-based predictions is obscured by site conservation and limited precision. Double mutant cycles provide in principle one of the best ways to probe epistatic interactions experimentally without reference to a particular background, and we find they reveal that the most strongly interacting mutations in HIV involve correlated sets of drug-resistance-associated residues, however the analysis is complicated by the small dynamic range of measurements. The use of correlated models for the design of experiments to probe viral fitness can help identify the epistatic interactions involved in mutational escape, and lead to better inhibitor therapies.Author summaryProtein covariation models provide an alternative to experimental measures for estimating the fitness of mutations in proteins from across a variety of organisms. Yet, for viral proteins, it has been shown that models including epistatic couplings between residues, or other machine learning models perform no better or even worse than a simpler independent model devoid of such epistatic couplings in estimating viral fitness measurements such as replicative capacities, providing weak or ambiguous evidence for epistasis. We show that the evidence for long-range epistasis is strong by the analysis of the high-order marginals of the MSA distribution (up to subsequences of length 14), which are accurately captured by a correlated Potts sequence-covariation model but not by an independent model. While double mutant cycles in principle provide well-established biophysical probes for epistatic interactions, we demonstrate that the analysis and comparison between model and experiment is difficult due to the much smaller dynamic range of the measurements, making them more susceptible to noise.
Amyloid-β, p-tau, and reactive microglia load are correlates of MRI cortical atrophy in Alzheimer’s disease
Authors: Frigerio Irene , Boon Baayla DC , Lin Chen-Pei , Graaf Yvon Galis-de , Bol John GJM , Preziosa Paolo , Twisk Jos , Barkhof Frederik , Hoozemans Jeroen JM , Bouwman Femke H , Rozemuller Annemieke JM , van de Berg Wilma DJ , Jonkman Laura E 
Published: June 2021

ABSTRACTINTRODUCTIONThe aim of this study was to identify the histopathological correlates of MRI cortical atrophy in (a)typical Alzheimer’s disease (AD) donors.METHODS19 AD and 10 control donors underwent post-mortem in-situ 3T-3DT1-MRI, from which cortical thickness was calculated. Upon subsequent autopsy, 21 cortical brain regions were selected and immunostained for amyloid-beta, phosphorylated-tau, and reactive microglia. MRI-pathology associations were assessed using linear mixed models. Post-mortem MRI was compared to ante-mortem MRI when available.RESULTSHigher amyloid-beta load weakly correlated with a higher cortical thickness globally. Phosphorylated-tau strongly correlated with cortical atrophy in temporo-frontal regions. Reactive microglia load strongly correlated with cortical atrophy in the parietal region. Post-mortem scans showed high concordance with ante-mortem scans acquired <1 year before death.DISCUSSIONDistinct histopathological markers differently correlate with cortical atrophy, highlighting their different roles in the neurodegenerative process. This study contributes in understanding the pathological underpinnings of MRI atrophy patterns.
EPAC1 inhibition protects the heart from doxorubicin-induced toxicity
Authors: Mazevet Marianne , Belhadef Anissa , Ribeiro Maxance , Dayde Delphine , Llach Anna , Laudette Marion , Belleville Tiphaine , Mateo Philippe , Gressette Mélanie , Lefebvre Florence , Chen Ju , Bachelot-Loza Christilla , Rucker-Martin Catherine , Lezoualc’h Frank , Crozatier Bertrand , Benitah Jean-Pierre , Vozenin Marie-Catherine , Fischmeister Rodolphe , Gomez Ana-Maria , Lemaire Christophe , Morel Eric 
Published: June 2021

AbstractAnthracyclines, such as doxorubicin (Dox), are widely used chemotherapeutic agents for the treatment of solid tumors and hematologic malignancies. However, they frequently induce cardiotoxicity leading to dilated cardiomyopathy and heart failure. This study sought to investigate the role of the Exchange Protein directly Activated by cAMP (EPAC) in Dox-induced cardiotoxicity and the potential cardioprotective effects of EPAC inhibition. We show that Dox induces DNA damage and cardiomyocyte cell death with apoptotic features. Dox also led to an increase in both cAMP concentration and EPAC1 activity. The pharmacological inhibition of EPAC1 (with CE3F4) but not EPAC2 alleviated the whole Dox-induced pattern of alterations. When administeredin vivo, Dox-treated WT mice developed a dilated cardiomyopathy which was totally prevented in EPAC1 KO mice. Moreover, EPAC1 inhibition potentiated Dox-induced cell death in several human cancer cell lines. Thus, EPAC1 inhibition appears as a potential therapeutic strategy to limit Dox-induced cardiomyopathy without interfering with its antitumoral activity.
Reactive Astrocytes Prevent Maladaptive Plasticity after Ischemic Stroke
Authors: Aswendt Markus , Wilhelmsson Ulrika , Wieters Frederique , Stokowska Anna , Schmitt Felix Johannes , Pallast Niklas , de Pablo Yolanda , Mohammed Lava , Hoehn Mathias , Pekna Marcela , Pekny Milos 
Published: June 2021

ABSTRACTRestoration of functional connectivity is a major contributor to functional recovery after stroke. We investigated the role of reactive astrocytes in functional connectivity and recovery after photothrombotic stroke in mice with attenuated reactive gliosis (GFAP−/−Vim−/−). Infarct volume and longitudinal functional connectivity changes were determined by in vivo T2-weighted MRI and resting-state functional MRI. Sensorimotor function was assessed with behavioral tests, and glial and neural plasticity responses were quantified in the peri-infarct region. Four weeks after stroke, GFAP−/−Vim−/− mice showed impaired recovery of sensorimotor function and aberrant restoration of global neuronal connectivity. These mice also exhibited maladaptive plasticity responses, shown by higher number of lost and newly formed functional connections between primary and secondary targets of cortical stroke regions and increased peri-infarct expression of the axonal plasticity marker Gap43. We conclude that reactive astrocytes are required for optimal recovery-promoting plasticity responses after ischemic stroke.