bluuebunny/crossref_metadata_2025_split huggingface dataset:
Specific interaction between Group BStreptococcusCC17 hypervirulent clone and phagocytes
Authors: Bourrel Anne-Sophie , Picart Amandine , Fernandez Jose-Carlos , Hays Constantin , Mignon Virginie , Saubaméa Bruno , Poyart Claire , Fouet Agnès , Tazi Asmaa , Guignot Julie 
Published: December 2022

ABSTRACTStreptococcus agalactiaealso named Group BStreptococcus(GBS) is the most significant pathogen causing invasive infections, such as bacteremia and meningitis, in neonates. Worldwide epidemiological studies have shown that a particular clonal complex (CC) of capsular serotype III, the CC17, is strongly associated with meningitis in neonates and is therefore designated as the hypervirulent clone. Macrophages are a permissive niche for intracellular bacteria of all GBS clones. In this study we deciphered the specific interaction of GBS CC17 strains with macrophages. Our study revealed that CC17 strains are phagocytosed at a higher rate than GBS non-CC17 strains by human monocytes and macrophages both in cellular models and primary cells. CC17 enhanced phagocytosis is due to an initial enhanced-attachment step to macrophages mediated by the CC17 specific surface protein HvgA and the PI-2b pilus (Spb1). We showed that two different inhibitors of scavenger receptors (fucoidan and poly(I)) specifically inhibited CC17 adhesion and phagocytosis while not affecting those of non-CC17 strains. Once phagocytosed, both CC17 and non-CC17 strains remained in a LAMP-1 positive vacuole that ultimately fuses with lysosomes where they can survive at similar rates. Finally, both strains displayed a basal egress which occurs independently from actin and microtubule networks. Our findings provide new insights into the interplay between the hypervirulent GBS CC17 and major players of the host’s innate immune response. This enhanced adhesion leading to higher phagocytosis could reflect a peculiar capacity of the CC17 lineage to subvert the host immune defenses, establish a niche for persistence or disseminate.
Leaf ontogeny steers ethylene and auxin crosstalk to regulate leaf epinasty during waterlogging of tomato
Authors: Geldhof B. , Pattyn J. , Mohorović P. , Van den Broeck K. , Everaerts V. , Novák O. , Van de Poel B. 
Published: December 2022

AbstractDeveloping leaves undergo a vast array of age-related changes as they mature. These include physiological, hormonal and morphological changes that determine their adaptation plasticity towards adverse conditions. Waterlogging induces leaf epinasty in tomato, and the magnitude of leaf bending is intricately related to the age-dependent cellular and hormonal response. We now show that ethylene, the master regulator of epinasty, is differentially regulated throughout leaf development, giving rise to age-dependent epinastic responses. Young leaves have a higher basal ethylene production, but are less responsive to waterlogging-induced epinasty, as they have a higher capacity to convert the root-borne and mobilized ACC into the inactive conjugate MACC. Ethylene stimulates cell elongation relatively more at the adaxial petiole side, by activating auxin biosynthesis and locally inhibiting its transport through PIN4 and PIN9 in older and mature leaves. As a result, auxins accumulate in the petiole base of these leaves and enforce partially irreversible epinastic bending upon waterlogging. Young leaves maintain their potential to transport auxins, both locally and through the vascular tissue, leading to enhanced flexibility to dampen the epinastic response and a faster upwards repositioning during reoxygenation. This mechanism also explains the observed reduction of epinasty during and its recovery after waterlogging in theanthocyanin reduced(are) andNever ripe(Nr) mutants, both characterized by higher auxin flow. Our work has demonstrated that waterlogging activates intricate hormonal crosstalk between ethylene and auxin, controlled in an age-dependent way.
Mechanisms that promote the evolution of cross-reactive antibodies upon vaccination with designed influenza immunogens
Authors: Yang Leerang , Caradonna Timothy M. , Schmidt Aaron G. , Chakraborty Arup K. 
Published: December 2022

SUMMARYImmunogens that elicit broadly neutralizing antibodies targeting the conserved receptor-binding site (RBS) on influenza hemagglutinin (HA) may serve as a universal influenza vaccine candidate. Here, we developed a computational model to interrogate antibody evolution by affinity maturation after immunization with two types of immunogens: a chimeric heterotrimeric ‘HAtCh’ antigen that is enriched for the RBS epitope relative to other B cell epitopes, and a cocktail composed of three non-epitope-enriched homotrimeric antigens that comprise the HAtCh. Experiments in mice (Caradonna et al.) find that the chimeric antigen outperforms the cocktail for eliciting RBS-directed antibodies. We show that this result follows from an interplay between how B cells engage these antigens and interact with diverse T helper cells, and requires T cell-mediated selection of germinal center B cells to be a stringent constraint. Our results shed new light on antibody evolution, and highlight how immunogen design and T cells modulate vaccination outcomes.
Dimerization thermodynamics govern biological phase separation
Authors: Dubach J. Matthew 
Published: December 2022

SummaryMany intrinsically disordered proteins/regions (IDR) can phase separate into a liquid state (biomolecular condensates) and/or a solid state (aggregates and amyloids). De-mixing in liquid-like phase separation carries an entropic cost that must be balanced by an energetic advantage of condensing. Yet, the mechanism of this energetic advantage remains unclear. Here, it is shown that an increase in dimerization binding interactions through liquid-like condensation can create overall energetic minimums when a system phase separates. Yet, the dimer binding interactions must be rapid explaining why IDRs are so prominent in phase separations. Numerous experimental examples that can only be described through dimer interactions support the dimer model presented here. The transition from condensates to aggregates and amyloids under certain conditions also appears to be driven by dimer abundance. Overall, the dimer model provides a novel theory that solves the thermodynamic mechanism of protein phase separation into biomolecular condensates, aggregates and amyloids.
High-sensitivity calcium biosensor on the mitochondrial surface reveals that IP3R channels participate in the reticular Ca2+leak towards mitochondria
Authors: Gouriou Yves , Gonnot Fabrice , Gomez Ludovic , Bidaux Gabriel 
Published: December 2022

SummaryGenetically encoded biosensors based on fluorescent proteins (FPs) are widely used to monitor dynamics and sub-cellular spatial distribution of calcium ion (Ca2+) fluxes and their role in intracellular signaling pathways. The development of different mutations in the Ca2+-sensitive elements of the cameleon probes has allowed sensitive range of Ca2+measurements in almost all cellular compartments. Region of the endoplasmic reticulum (ER) tethered to mitochondria, named as the mitochondrial-associated membranes (MAMs), has received an extended attention since the last 5 years. Indeed, as MAMs are essential for calcium homeostasis and mitochondrial function, molecular tools have been developed to assess quantitatively Ca2+levels in the MAMs. However, sensitivity of the first generation Ca2+biosensors on the surface of the outer-mitochondrial membrane (OMM)do not allow to measure μM or sub-μM changes in Ca2+concentration which prevents to measure the native activity (unstimulated exogenously) of endogenous channels. In this study, we assembled a new ratiometric highly sensitive Ca2+biosensor expressed on the surface of the outer-mitochondrial membrane (OMM). It allows the detection of smaller differences than the previous biosensor in or at proximity of the MAMs. Noteworthy, we demonstrated that IP3-receptors have an endogenous activity which participate to the Ca2+leak channel on the surface of the OMM during hypoxia or when SERCA activity is blocked.
The E-cadherin-ESR1-GRPR axis defines a sex-specific metastatic pathway in melanoma
Authors: Raymond Jérémy H. , Pouteaux Marie , Petit Valérie , Aktary Zackie , Luciani Flavie , Wehbe Maria , Gizzi Patrick , Bourban Claire , Martianov Igor , Davidson Irwin , Tomasetto Catherine-Laure , Betzer Florence-Mahuteau , Vergier Béatrice , Larue Lionel , Delmas Véronique 
Published: December 2022

SummaryAlthough tremendous progress has been made in understanding the mechanisms leading to cancer, those governing metastases are still poorly understood. E-cadherin (Ecad) is a cell-cell adhesion molecule essential for tissue homeostasis, and its loss often correlates with the dissemination of human cancers. However, whether and how the loss of Ecad triggers the full metastatic program is largely unknown. Here, we show that the loss of Ecad promotes melanoma lung metastases in females. The loss of Ecad, after the induction of estrogen receptor α (ERα) expression, activates gastrin-releasing peptide receptor (GRPR) expression. GRPR promotes cellular processes essential for metastasis formation through G□qand YAP1 signaling and its pharmacological inhibition reduces metastasisin vivo. This study reveals an Ecad-ERα-GRPR metastatic sex dimorphism axis in melanoma that is conserved in human breast cancer and provides proof of concept that the G-coupled receptor GRPR is a therapeutic target for metastasis.
Phen2Disease: A Phenotype-driven Semantic Similarity-based Integrated Model for Disease and Gene Prioritization
Authors: Zhai Weiqi , Huang Xiaodi , Shen Nan , Zhu Shanfeng 
Published: December 2022

ABSTRACTBy utilizing the Human Phenotype Ontology (HPO), recent approaches to prioritizing disease-causing genes for patients become popular. However, these approaches do not comprehensively use information about phenotypes of diseases and patients. We present a new method called Phen2Disease that calculates similarity scores between two phenotype sets of patients and diseases by which to prioritize diseases and genes. Specifically, we calculate three scores of information content-based similarities using the phenotypes, and their combination as the respective benchmarks, and integrate them as a final score. Comprehensive experiments were conducted on six real data cohorts with 2051 cases and two simulated data cohorts with 1000 cases. Compared with the three state-of-the-art methods, if we only use phenotype information and HPO knowledge base, Phen2Disease outperformed all of them, particularly in cohorts with the less average numbers of HPO terms. We have found that patients with higher information content scores had more specific information so their predictions would be more accurate. In addition, Phen2Disease has high interpretability with ranked diseases and patient HPO terms provided.
Viral burdens are associated with age and viral variant in a population-representative study of SARS-CoV-2 that accounts for time-since-infection related sampling bias
Authors: Fryer Helen R. , Golubchik Tanya , Hall Matthew , Fraser Christophe , Hinch Robert , Ferretti Luca , Thomson Laura , Nurtay Anel , Pellis Lorenzo , MackIntyre-Cockett George , Trebes Amy , Buck David , Piazza Paolo , Green Angela , Lonie Lorne J , Smith Darren , Bashton Matthew , Crown Matthew , Nelson Andrew , McCann Clare M. , Tariq Adnan Mohammed , Dos Santos Rui Nunes , Richards Zack ,   The COVID-19 Genomics UK (COG-UK) consortium, Bonsall David , Lythgoe Katrina A. 
Published: December 2022

AbstractIn this study, we evaluated the impact of viral variant, in addition to other variables, on within-host viral burdens, by analysing cycle threshold (Ct) values derived from nose and throat swabs, collected as part of the UK COVID-19 Infection Survey. Because viral burden distributions determined from community survey data can be biased due to the impact of variant epidemiology on the time-since-infection of samples, we developed a method to explicitly adjust observed Ct value distributions to account for the expected bias. Analysing the adjusted Ct values using partial least squares regression, we found that among unvaccinated individuals with no known prior infection, the average Ct value was 0.94 lower among Alpha variant infections, compared those with the predecessor strain, B.1.177. However, among vaccinated individuals, it was 0.34 lower among Delta variant infections, compared to those with the Alpha variant. In addition, the average Ct value decreased by 0.20 for every 10 year age increment of the infected individual. In summary, within-host viral burdens are associated with age, in addition to the interplay of vaccination status and viral variant.
Water shortage reducesPHYTOCHROME INTERACTING FACTOR 4, 5and3expression and shade avoidance in Arabidopsis
Authors: Semmoloni Mariana , Rojas Cecilia Costigliolo , Yan Yan , Cao Xiaofeng , Casal Jorge J. 
Published: December 2022

SUMMARYIn agricultural crops, forests and grasslands, water deficit often occurs in the presence of cues from neighbouring vegetation. However, most studies have addressed separately the mechanisms of plant growth responses to these two aspects of the environment. Here we show that transferringArabidopsis thalianaseedlings to agar containing polyethylene glycol (PEG) to restrict water availability reduces hypocotyl growth responses to shade without simultaneous affecting cotyledon expansion or its response to shade. Water restriction diminished the activity of thePHYTOCHROME INTERACTING FACTOR 4 (PIF4), PIF5, PIF3andPIF3-LIKE 1gene promoters, particularly in seedlings exposed to simulated shade. The response ofPIF4expression to PEG required the presence of its positive morning regulatorsCIRCADIAN CLOCK ASSOCIATED 1 (CCA1)andLATE ELONGATED HYPOCOTYL (LHY), which also reduced their expression in response to PEG. Water restriction diminished the nuclear abundance of PIF4 in hypocotyl cells only in the seedlings exposed to shade. In addition to the changes inPIF4levels, post-transcriptional processes also contributed to the response to PEG. Hypocotyl growth showed significant triple interaction among water availability, shade and the presence of PIF4, PIF5 and PIF3. Collectively, these results unveil PIFs as a hub that interlinks shade and drought information to control growth.
The dynamic linkage between intact provirus integration sites and the host functional genome property alongside HIV-1 infections associated with antiretroviral therapy
Authors: Chen Heng-Chang 
Published: December 2022

AbstractThe HIV-1 latent reservoir harboring replication-competent proviruses, is the major barrier in the quest for a HIV-1 infection cure. HIV-1 infection at all stages of disease progression is associated with immune activation and dysfunctional production of proinflammatory soluble factors (cytokines and chemokines) and it is expected that during HIV-1 infection different immune components and immune cells, in turn, participate in immune responses, subsequently activating downstream biological pathways. However, whether HIV-1 infections activate only specific pathways or result in the global activation of functional pathways is presently not fully understood. Therefore, in this work, I used genes targeted by intact proviruses from published datasets to seek enriched immunologic signatures and host biological pathways alongside HIV-1 infections. I observed that different compositions of immune cell types and proinflammatory soluble factors appeared alongside HIV-1 infections associated with antiretroviral therapy based on the over-representation analysis. Moreover, KEGG pathways relevant to “cancer specific type”, “immune system”, “infectious disease viral” and “signal transduction” were frequently enriched in HIV-1-infected individuals subjected to antiretroviral therapy.
Photoactivatable Large Stokes Shift Fluorophores for Multicolor Nanoscopy
Authors: Likhotkin Ilya , Lincoln Richard , Bossi Mariano L. , Butkevich Alexey N. , Hell Stefan W. 
Published: December 2022

ABSTRACTWe designed caging-group-free photoactivatable live-cell permeant dyes with red fluorescence emission and ∼100 nm Stokes shifts based on a 1-vinyl-10-silaxanthone imine core structure. The proposed fluorophores undergo byproduct-free one- and two-photon activation, are suitable for multicolor fluorescence microscopy in fixed and living cells and are compatible with super-resolution techniques such as STED (stimulated emission depletion) and PALM (photoactivated localization microscopy). Use of photoactivatable labels for strain-promoted azide-alkyne cycloaddition and self-labeling protein tags (HaloTag, SNAP-tag), and duplexing of imaging channel with another large Stokes shift dye have been demonstrated.
Impacts of ocean acidification and warming on post-larval growth and metabolism in two populations of the great scallop (Pecten maximusL.)
Authors: Harney E. , Rastrick S.P.S. , Artigaud S. , Pisapia J. , Bernay B. , Miner P. , Pichereau V. , Strand Ø. , Boudry P. , Charrier G. 
Published: December 2022

AbstractOcean acidification and warming are key stressors for many marine organisms. Some organisms display physiological acclimatisation or plasticity, but this may vary across species ranges, especially if populations are adapted to local climatic conditions. Understanding how acclimatisation potential varies among populations is therefore important in predicting species responses to climate change. We carried out a common garden experiment to investigate how different populations of the economically important great scallop (Pecten maximus) from France and Norway responded to variation in temperature andpCO2concentration. After acclimation, post-larval scallops (spat) were reared for 31 days at one of two temperatures (13°C and 19°C) under either ambient or elevatedpCO2(pH 8.0 and pH 7.7). We combined measures of proteomic, metabolic, and phenotypic traits to produce an integrative picture of how physiological plasticity varies between the populations. The proteome of French spat showed significant sensitivity to environmental variation, with 12 metabolic, structural and stress-response proteins responding to temperature and/orpCO2. Principal component analysis revealed seven energy metabolism proteins in French spat that were consistent with countering ROS stress under elevated temperature. Oxygen uptake in French spat did not change under elevated temperature, but increased under elevatedpCO2. In contrast, Norwegian spat reduced oxygen uptake under both elevated temperature andpCO2. Metabolic plasticity seemingly allowed French scallops to maintain greater energy availability for growth than Norwegian spat. However, increased physiological plasticity and growth in French spat may come at a cost, as French (but not Norwegian) spat showed reduced survival under elevated temperature.Summary StatementJuvenile scallops from France and Norway differ in their response to warming and acidification. French scallops show more physiological plasticity, adjusting their proteome and metabolism in order to maintain growth.
PSIP1/LEDGF reduces R-loops at transcription sites to maintain genome integrity
Authors: Jayakumar Sundarraj , Patel Manthan , Boulet Fanny , Aziz Hadicha , Brooke Greg N. , Tummala Hemanth , Pradeepa Madapura M 
Published: December 2022

AbstractR-loops that accumulate at transcription sites pose a persistent threat to genome integrity. PSIP1 is a chromatin protein associated with transcriptional elongation complex, possesses histone chaperone activity, and is implicated in recruiting RNA processing and DNA repair factors to transcription sites. Here, we show that PSIP1 interacts with R-loops and other proteins involved in R-loop homeostasis, including PARP1. Genome-wide mapping of PSIP1, R-loops and γ-H2AX in PSIP1-depleted human and mouse cell lines revealed an accumulation of R-loops and DNA damage at gene promoters in the absence of PSIP1. R-loop accumulation causes local transcriptional arrest and transcription-replication conflict, leading to DNA damage. PSIP1 depletion increases 53BP1 foci and reduces RAD51 foci, suggesting altered DNA repair choice. Furthermore, PSIP1 depletion increases the sensitivity of cancer cells to PARP1 inhibitors and DNA-damaging agents that induce R-loop-induced DNA damage. These findings provide fresh insights into the mechanism through which PSIP1 maintains genome integrity at the site of transcription.
Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mousePkd2model gene expression reversion
Authors: Wilk Elizabeth J. , Howton Timothy C. , Fisher Jennifer L. , Oza Vishal H. , Brownlee Ryan T. , McPherson Kasi C. , Cleary Hannah L. , Yoder Bradley K. , George James F. , Mrug Michal , Lasseigne Brittany N. 
Published: December 2022

AbstractAutosomal dominant polycystic kidney disease (ADPKD) is one of the most prevalent monogenic human diseases. It is mostly caused by pathogenic variants inPKD1orPKD2genes that encode interacting transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). Among many pathogenic processes described in ADPKD, those associated with cAMP signaling, inflammation, and metabolic reprogramming appear to regulate the disease manifestations. Tolvaptan, a vasopressin receptor-2 antagonist that regulates cAMP pathway, is the only FDA-approved ADPKD therapeutic. Tolvaptan reduces renal cyst growth and kidney function loss, but it is not tolerated by many patients and is associated with idiosyncratic liver toxicity. Therefore, additional therapeutic options for ADPKD treatment are needed. As drug repurposing of FDA-approved drug candidates can significantly decrease the time and cost associated with traditional drug discovery, we used the computational approach signature reversion to detect inversely related drug response gene expression signatures from the Library of Integrated Network-Based Cellular Signatures (LINCS) database and identified compounds predicted to reverse disease-associated transcriptomic signatures in three publicly availablePkd2kidney transcriptomic data sets of mouse ADPKD models. We focused on a pre-cystic model for signature reversion, as it was less impacted by confounding secondary disease mechanisms in ADPKD, and then compared the resulting candidates’ target differential expression in the two cystic mouse models. We further prioritized these drug candidates based on their known mechanism of action, FDA status, targets, and by functional enrichment analysis. With this in-silico approach, we prioritized 29 unique drug targets differentially expressed inPkd2ADPKD cystic models and 16 prioritized drug repurposing candidates that target them, including bromocriptine and mirtazapine, which can be further tested in-vitro and in-vivo. Collectively, these indicate drug targets and repurposing candidates that may effectively treat pre-cystic as well as cystic ADPKD.Abstract FigureGraphical abstract of the study created with Biorender.com.