bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disease-associated programming of cell memory in glycogen storage disorder type 1a
Authors: Sprecher U , D’Souza J , Mishra K , Muchtar N , Shalev O , Eliassaf A , Morshina A , Canella Miliano A , Mithieux G , Rajas F , Avraham S , Castellani Moses F , Kauffman H , Bergman Y , Garti N , Garti S , Linial M , Anikster Y , Kakhlon O , Weil M 
Published: February 2023

SummaryGlycogen storage disorder type 1a (GSD1a) is caused by loss-of-function mutations in the catalytic subunit of glucose-6-phosphatase enzyme (G6PC1) in the liver, kidney and intestine exclusively. Here we show the surprising results that while not expressingG6PC1, primary skin fibroblasts isolated from GSD1a patients’ skin biopsies preserve a distinctive disease phenotype irrespective of the different culture conditions under which they grow. This discovery was initially made by phenotypic image-based high content analysis (HCA). Deeper analysis into this disease phenotype, revealed impaired lysosomal and mitochondrial functions in GSD1a cells, which were driven by a transcriptional dysregulation of the NAD+/NADH-Sirt-1-TFEB regulatory axis. This dysregulation impacts the normal balance between mitochondrial biogenesis and mitophagy in the patients’ cells. The distinctive GSD1a fibroblasts phenotype involves elevated H3 histone acetylation, global DNA hypomethylation, differences in the chromatin accessibility and different RNA-seq and metabolomic profiles, all of which suggesting that in some way a distinctive disease cell phenotype is programmed in these cellsin vivoand that this phenotype is maintainedin vitro. Supporting this notion, reversing H3 acetylation in these cells erased the original cellular phenotype in GSD1a cells. Remarkably, GHF201, an established glycogen reducing molecule, which ameliorated GSD1a pathology in a liver-targeted inducibleL.G6pc-knockout mouse model, also reversed impaired cellular functions in GSD1a patients’ fibroblasts. Altogether, this experimental evidence strongly suggests that GSD1a fibroblasts express a strong and reversible disease phenotype without expressing the causalG6PC1gene.
A globalCorynebacterium diphtheriaegenomic framework sheds light on current diphtheria reemergence
Authors: Hennart Melanie , Crestani Chiara , Bridel Sebastien , Armatys Nathalie , Brémont Sylvie , Carmi-Leroy Annick , Landier Annie , Passet Virginie , Fonteneau Laure , Vaux Sophie , Toubiana Julie , Badell Edgar , Brisse Sylvain 
Published: February 2023

AbstractBackgroundDiphtheria, caused byCorynebacterium diphtheriae, reemerges in Europe since 2022. Genomic sequencing can inform on transmission routes and genotypes of concern, but currently, no standard approach exists to detect clinically important genomic features and to interpret emergence in the globalC. diphtheriaepopulation framework.MethodsWe developed the bioinformatics pipeline DIPHTOSCAN (available athttps://gitlab.pasteur.fr/BEBP/diphtoscan) to extract from genomes of Corynebacteria of thediphtheriaespecies complex, medically relevant features includingtoxgene presence and disruption. We analyzed 101 humanC. diphtheriaeisolates collected in 2022 in metropolitan and overseas France (France-2022). To define the population background of this emergence, we sequenced 379 additional isolates (mainly from France, 2018-2021) and collated 870 publicly-available genomes.ResultsThe France-2022 isolates comprised 45tox-positive (44 toxigenic) isolates, mostly imported, belonging to 10 sublineages (<500 distinct core genes). The global dataset comprised 245 sublineages and 33.9%tox-positive genomes, with DIPHTOSCAN predicting non-toxigenicity in 16.0% of these. 12% of the global isolates, and 43.6% of France-2022 ones, were multidrug resistant. Convergence of toxigenicity with penicillin and erythromycin resistance was observed in 2 isolates from France-2022. Phylogenetic lineages Gravis and Mitis contrasted strikingly in their pathogenicity-associated genes.ConclusionsThis work provides a bioinformatics tool and global population framework to analyzeC. diphtheriaegenomes, revealing important heterogeneities in virulence and resistance features. Emerging genotypes combining toxigenicity and first-line antimicrobial resistance represent novel threats. Genomic epidemiology studies ofC. diphtheriaeshould be intensified globally to improve understanding of reemergence and spatial spread.
A sweeter future: Using protein language models for exploring sweeter brazzein homologs
Authors: Chua Bryan Nicholas , Guo Wei Mei , Wong Han Teng , Ow Dave Siak-Wei , Ho Pooi Leng , Koh Winston , Koay Ann , Wong Fong Tian 
Published: February 2023

AbstractReducing sugar intake lowers the risk of obesity and associated metabolic disorders. Currently, this is achieved using artificial non-nutritive sweeteners, where their safety is widely debated and their contributions in various diseases is controversial. Emerging research suggests that these sweeteners may even increase the risk of cancer and cardiovascular problems, and some people experience gastrointestinal issues as a result of using them. A safer alternative to artificial sweeteners could be sweet-tasting proteins, such as brazzein, which do not appear to have any adverse health effects.In this study, protein language models were explored as a new method for protein design of brazzein. This innovative approach resulted in the identification of unexpected mutations, which opened up new possibilities for engineering thermostable and potentially sweeter versions of brazzein. To facilitate the characterization of the brazzein mutants, a simplified procedure was developed for expressing and analyzing related proteins. This process involved an efficient purification method usingLactococcus lactis(L. lactis), a generally recognized as safe (GRAS) bacterium, as well as taste receptor assays to evaluate sweetness. The study successfully demonstrated the potential of computational design in producing a more heat-resistant and potentially more palatable brazzein variant, V23.
Fusogenic Structural Changes in Arenavirus Glycoproteins are Associated with Viroporin Activity
Authors: Zhang You , York Joanne , Brindley Melinda A. , Nunberg Jack H. , Melikyan Gregory B. 
Published: February 2023

AbstractMany enveloped viruses enter host cells by fusing with acidic endosomes. The fusion activity of multiple viral envelope glycoproteins does not generally affect viral membrane permeability. However, fusion induced by the Lassa virus (LASV) glycoprotein complex (GPc) is always preceded by an increase in viral membrane permeability and the ensuing acidification of the virion interior. Here, systematic investigation of “leaky” LASV fusion using single pseudoparticle tracking in live cells reveals that the change in membrane barrier function is associated with the fusogenic conformational reorganization of GPc. We show that a small- molecule fusion inhibitor or mutations that impair viral fusion by interfering with GPc refolding into the post-fusion structure prevent the increase in membrane permeability. We find that the increase in virion membrane permeability occurs early during endosomal maturation and is facilitated by virus-cell contact. This increase is observed using diverse arenavirus glycoproteins, whether presented on lentivirus-based pseudoviruses or arenavirus-like particles, and in multiple different cell types. Collectively, these results suggest that conformational changes in GPc triggered by low pH and cell factor binding are responsible for virion membrane permeabilization and acidification of the virion core prior to fusion. We propose that this viroporin-like activity may augment viral fusion and/or post-fusion steps of infection, including ribonucleoprotein release into the cytoplasm.Authors summaryFusion of enveloped virus with host cell membranes is mediated by extensive conformational changes in viral glycoproteins, triggered by binding to cognate receptors and/or by exposure to acidic pH in the maturing endosome. We have previously reported that, unlike many other viral glycoproteins, pH-triggered endosomal fusion by the Lassa virus viral glycoprotein complex (GPc) is preceded by a mild permeabilization of the viral membrane. Here, we provide evidence that this activity is associated with early fusogenic changes in the GPc and is markedly enhanced by virus-cell contact. Permeabilization is induced by the glycoproteins of diverse arenaviruses and occurs in multiple target cell types. Based on these observations, we propose that, by analogy to the influenza virus M2 channel, membrane permeabilization and the resultant acidification of the arenavirus interior facilitate viral fusion and/or post-fusion steps of infection.
Co-chaperone-mediated post-translational control of efflux pump induction underlies adaptive β-lactam resistance inCaulobacter crescentus
Authors: Costafrolaz Jordan , Panis Gaël , Casu Bastien , Ardissone Silvia , Degeorges Laurence , Pilhofer Martin , Viollier Patrick H. 
Published: February 2023

SUMMARYThe acquisition of multi-drug resistance (MDR) determinants jeopardizes treatment of bacterial infections with antibiotics. The tripartite efflux pump AcrAB-NodT confers adaptive MDR in the non-pathogenic α-proteobacteriumCaulobacter crescentusvia transcriptional induction by first-generation quinolone antibiotics. We discovered that overexpression of AcrAB-NodT by mutation or exogenous inducers confers resistance to cephalosporin and penicillin (β-lactam) antibiotics. Combining two-step mutagenesis-sequencing (Mut-Seq) and cephalosporin-resistant point mutants, we dissected how TipR uses a common operator of the divergenttipRandacrAB-nodTpromoter for adaptive and/or potentiated AcrAB-NodT-directed efflux. Chemical screening identified compounds that interfere with DNA-binding by TipR or induce its dependent proteolytic turnover. We found that long-term induction of AcrAB-NodT disfigures the envelope and that homeostatic control by TipR includes co-induction of the DnaJ-like co-chaperone DjlA, to boost pump assembly and/or capacity in anticipation of envelope stress. Thus, the adaptive MDR regulatory circuitry reconciles drug efflux with co-chaperone function for trans-envelope assemblies and maintenance.
Kaempferol suppresses the activation of mast cells by modulating the expression of FcεRI and SHIP1
Authors: Nagata Kazuki , Araumi Sanae , Ando Daisuke , Ando Miki , Ito Naoto , Ikeda Yuki , Takahashi Miki , Noguchi Sakura , Yashiro Takuya , Hachisu Masakazu , Nishiyama Chiharu 
Published: February 2023

AbstractIn the present study, we evaluated the effects of kaempferol on bone marrow-derived mast cells (BMMCs). Kaempferol treatment significantly and dose-dependently inhibited IgE-induced degranulation, and cytokine production of BMMCs under the condition that cell viability was maintained. Kaempferol downregulated the surface expression levels of FcεRI on BMMCs, but the mRNA levels of FcεRIα, β, and γ-chains were not changed by kaempferol treatment. Furthermore, the kaempferol-mediated downregulation of surface FcεRI on BMMCs was still observed in the presence of a protein-synthesis inhibitor. These results suggest that kaempferol reduced the surface FcεRI on BMMCs, independently of transcription and translation. We also found that kaempferol inhibited both LPS- and IL-33-induced IL-6 production from BMMCs, without affecting the expression levels of their receptors, TLR4 and ST2. Although kaempferol treatment increased the protein amount of NRF2, a master transcription factor of antioxidant stress, in BMMCs, inhibition of NRF2 did not alter the suppressive effect of kaempferol on degranulation. Finally, we observed that kaempferol treatment increased the levels of mRNA and protein of a phosphatase SHIP1 in BMMCs. These results indicate that kaempferol inhibited the IgE-induced activation of BMMCs by downregulating FcεRI and upregulating SHIP1, and the SHIP1 increase is involved in the suppression of various signaling-mediated stimulations of BMMCs, such as those associated with TLR4 and ST2.
Assessment of long-term trends in genetic mean and variance after the introduction of genomic selection in layers: a simulation study
Authors: Pocrnic Ivan , Obšteter Jana , Gaynor R. Chris , Wolc Anna , Gorjanc Gregor 
Published: February 2023

ABSTRACTNucleus-based breeding programs are characterized by intense selection that results in high genetic gain, which inevitably means reduction of genetic variation in the breeding population. Therefore, genetic variation in such breeding systems is typically managed systematically, for example, by avoiding mating the closest relatives to limit progeny inbreeding. However, intense selection requires maximum effort to make such breeding programs sustainable in the long-term. The objective of this study was to use simulation to evaluate the long-term impact of genomic selection on genetic mean and variance in an intense layer chicken breeding program. We developed a large-scale stochastic simulation of an intense layer chicken breeding program to compare conventional truncation selection to genomic truncation selection optimized with either minimization of progeny inbreeding or full-scale optimal contribution selection. We compared the programs in terms of genetic mean, genic variance, conversion efficiency, rate of inbreeding, effective population size, and accuracy of selection. Our results confirmed that genomic truncation selection has immediate benefits compared to conventional truncation selection in all specified metrics. A simple minimization of progeny inbreeding after genomic truncation selection did not provide any significant improvements. Optimal contribution selection was successful in having better conversion efficiency and effective population size compared to genomic truncation selection, but it must be fine-tuned for balance between loss of genetic variance and genetic gain. In our simulation, we measured this balance using trigonometric penalty degrees between truncation selection and a balanced solution and concluded that the best results were between 45° and 65°. This balance is specific to the breeding program and depends on how much immediate genetic gain a breeding program may risk vs. save for the future. Furthermore, our results show that the persistence of accuracy is better with optimal contribution selection compared to truncation selection. In general, our results show that optimal contribution selection can ensure long-term success in intensive breeding programs using genomic selection.
A purely visual adaptation to motion can differentiate between perceptual timing and interval timing
Authors: Bruno Aurelio , Segala Federico G. , Baker Daniel H. 
Published: February 2023

AbstractIt is unclear whether our brain extracts and processes time information using a single centralized mechanism or through a network of distributed mechanisms, which are specific for modality and time range. Visual adaptation has previously been used to investigate the mechanisms underlying time perception for millisecond intervals. Here, we investigated whether a well-known duration aftereffect induced by motion adaptation in the sub-second range (referred to as ‘perceptual timing’), also occurs in the supra-second range (called ‘interval timing’), which is more accessible to cognitive control. Participants judged the relative duration of two intervals after spatially localized adaptation to drifting motion. Adaptation substantially compressed the apparent duration of a 600 ms stimulus in the adapted location, whereas it had a much weaker effect on a 1200 ms interval. Discrimination thresholds after adaptation improved slightly relative to baseline, implying that the duration effect cannot be ascribed to changes in attention or to noisier estimates. A novel computational model of duration perception can explain these results, and also bidirectional shifts of perceived duration after adaptation reported in other studies. We suggest that we can use adaptation to visual motion as a tool to investigate the mechanisms underlying time perception at different time scales.
Retinoic acid and proteotoxic stress induce AML cell death overcoming stromal cell protection
Authors: Liccardo Francesca , Śniegocka Martyna , Tito Claudia , Iaiza Alessia , Ottone Tiziana , Divona Mariadomenica , Travaglini Serena , Mattei Maurizio , Cicconi Rossella , Miglietta Selenia , Familiari Giuseppe , Nottola Stefania Annarita , Petrozza Vincenzo , Tamagnone Luca , Voso Maria Teresa , Masciarelli Silvia , Fazi Francesco 
Published: February 2023

AbstractAcute myeloid leukemia (AML) patients bearing the ITD mutation in the tyrosine kinase receptor FLT3 (FLT3-ITD) present a poor prognosis and a high risk of relapse. FLT3-ITD is retained in the endoplasmic reticulum (ER) and generates intrinsic proteotoxic stress. We devised a strategy based on proteotoxic stress, generated by the combination of low doses of the differentiating agent retinoic acid (R), the proteasome inhibitor bortezomib (B), and the oxidative stress inducer arsenic trioxide (A). It exerts strong cytotoxic activity on FLT3-ITD+AML cell lines and primary blasts isolated from patients, due to ER homeostasis imbalance and generation of oxidative stress. AML cells become completely resistant to the combination RBA when treated in co-culture with bone marrow stromal cells (BMSC). Nonetheless, we could overcome such protective effects by using high doses of ascorbic acid (Vitamin C) as an adjuvant. Importantly, the combination RBA plus ascorbic acid significantly prolongs the life span of a murine model of human FLT3-ITD+AML without toxic effects. Furthermore, we show for the first time that the cross-talk between AML cells and BMSC upon treatment involves disruption of the actin cytoskeleton and the actin cap, increased thickness of the nuclei, and relocalization of the transcriptional co-regulator YAP in the cytosol of the BMSC. Our findings strengthen our previous work indicating induction of proteotoxic stress as a possible strategy in FLT3-ITD+AML therapy and open to the possibility of identifying new therapeutic targets in the crosstalk between AML cells and BMSC, involving mechanotransduction and YAP signaling
Chronic industrial perturbation and seasonal change induces shift in the bacterial community from gammaproteobacteria to betaproteobacteria at Amlakhadi canal
Authors: Johnson Jenny , Jain Kunal R. , Patel Anand , Parmar Nidhi , Joshi Chaitanya , Madamwar Datta 
Published: February 2023

AbstractEscalating proportions of industrially contaminated sites are one of the major catastrophes faced at the present time due to the industrial revolution. In the outlook of the obstacles associated with culturing the microbes, the direct metagenomic analysis of various complex niches is rapidly gaining attention. In this study, metagenomic approach using next generation sequencing technologies was applied to exemplify the taxonomic abundance and metabolic potential of the microbial community residing in Amlakhadi canal, Ankleshwar at two different seasons. All the metagenomes revealed a predominance of Proteobacteria phylum. However, difference was observed within class level where Gammaproteobacteria was relatively high in polluted metagenome in Summer while in Monsoon the abundance shifted to Betaproteobacteria. Similarly, significant statistical differences were obtained while comparing the genera amongst contaminated sites whereSerratia, Achromobacter, StenotrophomonasandPseudomonaswere abundant at one season and the dominance changed toThiobacillus, Thauera, Acidovorax, Nitrosomonas, Sulfuricurvum, Novosphingobium, HyphomonasandGeobacterat the next season. Further upon functional characterization, the microbiomes demonstrated diverse survival mechanisms adapted by the inherent microbial community such as degradation of aromatic compounds, heavy metal resistance, oxidative stress responses and multidrug resistance efflux pumps. The results have important implications in understanding and predicting the impacts of human-induced activities on microbial communities inhabiting natural niche and their responses in coping with the fluctuating pollution load.
Compensation to visual impairments and behavioral plasticity in navigating ants
Authors: Schwarz Sebastian , Clement Leo , Haalck Lars , Risse Benjamin , Wystrach Antoine 
Published: February 2023

AbstractDesert ants are known to rely heavily on vision while venturing for food and returning to the nest. During these foraging trips, ants memorize and recognize their visual surroundings, which enables them to recapitulate individually learnt routes in a fast and effective manner. The compound eyes are crucial for such visual navigation; however, it remains unclear how information from both eyes are integrated and how ants cope with visual impairment. Here we manipulated the ants’ visual system by covering one of the two compound eyes and analyzed their ability to recognize familiar views in various situations. Monocular ants showed an immediate disruption of their ability to recapitulate their familiar route. However, they were able to compensate for the visual impairment in a few hours by restarting a route-learning ontogeny, as naïve ants do. This re-learning process with one eye forms novel memories, without erasing the previous memories acquired with two eyes. Additionally, ants having learnt a route with one eye only are unable to recognize it with two eyes, even though more information is available. Together, this shows that visual memories are encoded and recalled in an egocentric and fundamentally binocular way, where the visual input as a whole must be matched to enable recognition. We show how this kind of visual processing fits with their neural circuitry.Significance StatementIf humans look at the world with both eyes, they have no problem to then recognize it with one eye only, and vice-versa. Thus, our way of encoding the world is robust to changes of the visual field. Yet ants do so very differently. Views learnt with two eyes can only be recognized with two eyes, and views learnt with one eye can only be recognized with one eyes (the same eye). However, this rigidity is compensated by a remarkable behavioral flexibility. Upon covering one eye, ants – which can no longer recognize their familiar surroundings – will restart a learning process to store these novel visual inputs in a parallel memory and resume their normal foraging activity.
Geometry-preserving Expansion Microscopy microplates enable high fidelity nanoscale distortion mapping
Authors: Seehra Rajpinder S. , Allouis Benjamin H.K. , Sheard Thomas M.D. , Spencer Michael E , Shakespeare Tayla , Cadby Ashley , Jayasinghe Izzy 
Published: February 2023

AbstractExpansion microscopy (ExM) is a versatile super-resolution microscopy pipeline, leveraging nanoscale biomolecular cross- linking and osmotically driven swelling of hydrogels. In its current implementation, ExM remains a laborious and skill-intensive technique, involving manual handling of the hydrogels that can compromise the integrity of the gel matrix and diminish reproducibility. The lack of protocols to constrain the gel orientation during this process lends to challenges in tracking gel isotropy during or after the swelling. We have developed a bespoke microplate system capable of carrying out the entire ExM workflow within each well. The microplates enablein situimage acquisition and eliminate the need for direct physical handling of the hydrogels. The preservation of the gel geometry and orientation by the design of the microplate wells also enables convenient tracking of gel expansion, pre- and post-ExM image acquisition, and distortion mapping of every cell or region of interest. We demonstrate the utility of this approach with both single-colour and multiplexed ExM of HeLa cells cultured within the microplate wells to reveal nuclear and sub-plasmalemmal regions as distortion-prone structures.