bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nitrogen assimilation plays a role in balancing the chloroplastic glutathione redox state under high-light conditions
Authors: Gilad Gal , Sapir Omer , Hipsch Matanel , Waiger Daniel , Ben-Ari Julius , Lampl Nardy , Rosenwasser Shilo 
Published: March 2023

AbstractNitrate reduction and subsequent ammonium assimilation require reducing equivalents directly produced by the photosynthetic electron transport chain. Therefore, it has been suggested that nitrate assimilation provides a valuable sink for excess electrons under high-light (HL) conditions, which protects the photosynthetic apparatus from excessive harmful reactive oxygen species. This work experimentally tested this hypothesis by monitoring photosynthetic efficiency and the chloroplastic glutathione redox state (chl-EGSH) of plant lines with mutated glutamine synthetase 2 (GS2) and ferredoxin-dependent glutamate synthase 1 (GOGAT1), two key enzymes of the nitrogen assimilation pathway. Unlike wild-type (WT) plants, mutant lines incorporated significantly less isotopically-labeled nitrate into amino acids, demonstrating impaired nitrogen assimilation. When nitrate assimilation was compromised, photosystem II (PSII) proved more vulnerable to photodamage, as shown by the low PSII quantum yields recorded in the mutant lines. High temporal resolution monitoring of the redox state of chloroplast-targeted reduction-oxidation sensitive green fluorescent protein 2 (chl-roGFP2), expressed in the background of the mutant lines, enabled assessment of the effect of the nitrate assimilation pathway on the chl-EGSH. Remarkably, while oxidation followed by reduction of chl-roGFP2 was detected in WT plants in response to HL, oxidation values were stable in the mutant lines, suggesting that the relaxation of chl-EGSHafter HL-induced oxidation is achieved by diverting excess electrons to the nitrogen assimilation pathway. Together, these findings indicate that the nitrogen assimilation pathway serves as a sustainable energy dissipation route, ensuring efficient photosynthetic activity and fine-tuning redox metabolism under light-saturated conditions.
TemStaPro: protein thermostability prediction using sequence representations from protein language models
Authors: Pudžiuvelytė Ieva , Olechnovič Kliment , Godliauskaite Egle , Sermokas Kristupas , Urbaitis Tomas , Gasiunas Giedrius , Kazlauskas Darius 
Published: March 2023

AbstractMotivationReliable prediction of protein thermostability from its sequence is valuable for both academic and industrial research. This prediction problem can be tackled using machine learning and by taking advantage of the recent blossoming of deep learning methods for sequence analysis. These methods can facilitate training on more data and, possibly, enable development of more versatile thermostability predictors for multiple ranges of temperatures.ResultsWe applied the principle of transfer learning to predict protein thermostability using embeddings generated by protein language models (pLMs) from an input protein sequence. We used large pLMs that were pre-trained on hundreds of millions of known sequences. The embeddings from such models allowed us to efficiently train and validate a high-performing prediction method using over one million sequences that we collected from organisms with annotated growth temperatures. Our method, TemStaPro (Temperatures of Stability for Proteins), was used to predict thermostability of CRISPR-Cas Class II effector proteins (C2EPs). Predictions indicated sharp differences among groups of C2EPs in terms of thermostability and were largely in tune with previously published and our newly obtained experimental data.Availability and ImplementationTemStaPro software and the related data are freely available fromhttps://github.com/ievapudz/TemStaProandhttps://doi.org/10.5281/zenodo.7743637.
Dynamics of the rice yellow mottle disease in western Burkina Faso: epidemic monitoring, spatio-temporal variation of viral diversity and pathogenicity in a disease hotspot
Authors: Billard Estelle , Barro Mariam , Sérémé Drissa , Bangratz Martine , Wonni Issa , Koala Moustapha , Kassankogno Abalo Itolou , Hébrard Eugénie , Thébaud Gaël , Brugidou Christophe , Poulicard Nils , Tollenaere Charlotte 
Published: March 2023

ABSTRACTThe rice yellow mottle virus (RYMV) is a model in plant virus molecular epidemiology and phylogeography, with the reconstruction of historical introduction routes at the scale of the African continent. However, information on patterns of viral prevalence and viral diversity over multiple years at local scale remain scarce, in spite of potential implications for crop protection.Here we describe a five-years monitoring of RYMV prevalence in six sites from western Burkina Faso. This study confirmed one irrigated site as a disease hotspot, and found two rainfed lowland sites with occasional high prevalence levels. Within studied field, a pattern of disease aggregation was evidenced at a five-meter distance, as expected for a mechanically transmitted virus.Next, we monitored RYMV genetic diversity in the irrigated disease hotspot site, revealing a high viral diversity, with the current coexistence of various distinct genetic groups at the site-scale (irrigated perimeter of ca. 520 ha), and also within various specific fields (25 meters side). One genetic lineage, named S1bzn, is the most recently introduced group and increased in frequency over the studied period. Its genome results from a recombination between two other lineages.Finally, experimental work evidenced no differences between three rice varieties cultivated in Burkina Faso in terms of resistance level, and no statistical effect of RYMV genetic group on symptom expression and viral load. We found however, that infection outcome depended on the specific RYMV isolate, with various isolates from the lineage S1bzn found to be particularly aggressive, including one accumulating at highest level.Overall, this study documents a case of high viral prevalence and high viral diversity, with the co-occurrence of divergent genetic lineages at small geographic scale. A recently introduced lineage, that includes viral isolates with high symptoms and accumulation in controlled conditions, could be recently rising though natural selection. Following up the monitoring of RYMV genetic and pathogenic diversity in the area is required to confirm this trend and further understand the factors driving the maintenance of viral diversity at local scale.
Exploring the Effects of Ecological Parameters on the Spatial Structure of Genealogies
Authors: Ianni-Ravn Mariadaria K. , Petr Martin , Racimo Fernando 
Published: March 2023

1AbstractGeographic space is a fundamental dimension of evolutionary change, determining how individuals disperse and interact with each other. Consequently, space has an important influence on the structure of genealogies and the distribution of genetic variants over time. Recently, the development of highly flexible simulation tools and computational methods for genealogical inference has greatly increased the potential for incorporating space into models of population genetic variation. It is now possible to explore how spatial ecological parameters can influence the distribution of genetic variation among individuals in unprecedented detail. In this study, we explore the effects of three specific parameters (the dispersal distance, competition distance and mate choice distance) on the spatial structure of genealogies. We carry out a series ofin silicoexperiments using forwards-in-time simulations to determine how these parameters influence the distance between closely- and distantly-related individuals. We also assess the accuracy of the maximum likelihood estimation of the dispersal distance in a Gaussian model of dispersal from tree-sequence data, and highlight how it is affected by realistic factors such as finite habitat size and limited data. We find overall that the scale of mate choice in particular has marked patterns on short and long terms patterns of dispersal, as well as on the positions of individuals within a habitat. Our results showcase the potential for linking phylogeography, population genetics and ecology, in order to answer fundamental questions about the nature of spatial interactions across a landscape.
Therapeutic targeting of ACLY in T-ALLin vivo
Authors: da Silva-Diz Victoria , Singh Amartya , Aleksandrova Maya , Kim Oekyung , Thai Christopher , Lancho Olga , Nunes Patricia Renck , Affronti Hayley , Su Xiaoyang , Wellen Kathryn E. , Herranz Daniel 
Published: March 2023

AbstractT-cell Acute Lymphoblastic Leukemia (T-ALL) is a hematological malignancy in need of novel therapeutic approaches. Here, we identify the ATP-citrate lyase ACLY as overexpressed and as a novel therapeutic target in T-ALL. To test the effects of ACLY in leukemia progression, we developed an isogenic model of NOTCH1-inducedAclyconditional knockout leukemia. Importantly, we observed intrinsic antileukemic effects upon loss of ACLY, which further synergized with NOTCH1 inhibitionin vivo.Metabolomic profiling upon ACLY loss revealed a metabolic crisis with reduced acetyl-CoA levels, as well as a decreased oxygen consumption rate. Gene expression profiling analyses showed that the transcriptional signature of ACLY loss very significantly correlates with the signature of MYC lossin vivo. Mechanistically, the decrease in acetyl-CoA led to reduced H3K27ac levels inMyc, resulting in transcriptional downregulation ofMycand drastically reduced MYC protein levels. Interestingly, our analyses also revealed a reciprocal relationship wherebyACLYitself is a direct transcriptional target of MYC, thus establishing a feedforward loop that is important for leukemia progression. Overall, our results identified a relevant ACLY-MYC axis and unveiled ACLY as a novel promising target for T-ALL treatment.
Image-based temporal profiling of autophagy-related phenotypes
Authors: Beesabathuni Nitin Sai , Thilakaratne Eshan , Shah Priya S. 
Published: March 2023

AbstractAutophagy is a dynamic process that is critical in maintaining cellular homeostasis. Dysregulation of autophagy is linked to many diseases and is emerging as a promising therapeutic target. High-throughput methods to characterize autophagy are essential for accelerating drug discovery and characterizing mechanisms of action. In this study, we developed a highly scalable image-based profiling approach to characterize ∼900 morphological features at a single cell level with high temporal resolution. We differentiated drug treatments based on morphological profiles using a random forest classifier with ∼90% accuracy and identified the key features that govern the classification. Additionally, temporal morphological profiles accurately predicted biologically relevant changes in autophagy after perturbation, such as total cargo degradation. Therefore, this study acts as proof-of-principle for using image-based profiling to differentiate autophagy perturbations in a high-throughput manner and identify biologically relevant autophagy phenotypes, which can accelerate drug discovery.
Myofibrillar malformations that arise in mdx muscle fibers are driven by detyrosinated microtubules
Authors: Harriot Anicca , Altair-Morris Tessa , Venegas Camilo , Kallenbach Jacob , Pinto Kaylie , Joca Humberto C. , Moutin Marie-Jose , Shi Guoli , Ursitti Jeanine , Grosberg Anna , Ward Christopher W. 
Published: March 2023

AbstractIn Duchenne muscular dystrophy (DMD), alterations in the myofibrillar structure of skeletal muscle fibers that impair contractile function and increase injury susceptibility arise as a consequence of dystrophic pathology. In murine DMD (mdx), myofibrillar alterations are abundant in advanced pathology (>4 months), an age where we formerly established the densification of microtubules (MTs) post-translationally modified by detyrosination (deTyr-MTs) as a negative disease modifier. Given the essential role of MTs in myofibrillar growth, maintenance, and repair, we examined the increased abundance of deTyr-MTs as a potential mechanism for these myofibrillar alterations. Here we find increased levels of deTyr-MTs as an early event in dystrophic pathology (4 weeks) with no evidence of myofibrillar alterations. At 16 weeks, we show the level of deTyr-MTs is significantly increased and co-localized to areas of myofibrillar malformation. Profiling the enzyme complexes responsible for deTyr-tubulin, we identify vasohibin 2 (VASH2) and small vasohibin binding protein (SVBP) significantly elevated in themdxmuscle at 4 wks. We then use the genetic increase in VASH2/SVBP expression in 4 wk wild-type mice and find densified deTyr-MTs that co-segregate with myofibrillar malformations similar to those in the 16 wkmdx. Given that no changes were identified in fibers expressing EGFP as a control, we conclude that disease dependent densification of deTyr-MTs underscores the altered myofibrillar structure in dystrophic skeletal muscle fibers.
Replicative stress in gastroesophageal adenocarcinoma is associated with chromosomal instability and sensitivity to DNA damage response inhibitors
Authors: Sahgal Pranshu , Patil Deepa T. , Sztupinszki Zsofia M. , Tisza Viktoria , Spisak Sandor , Huffman Brandon , Prosz Aurel , Singh Harshabad , Lazaro Jean-Bernard , Szallasi Zoltan , Cleary James M. , Sethi Nilay S. 
Published: March 2023

SUMMARYGastroesophageal adenocarcinoma (GEA) is an aggressive, often lethal, malignancy that displays marked chromosomal instability (CIN). To understand adaptive responses that enable CIN, we analyzed paired normal, premalignant, and malignant gastric lesions from human specimens and a carcinogen-induced mouse model, observing activation of replication stress, DNA damage response (DDR), and cell cycle regulator p21 in neoplastic progression. In GEA cell lines, expression of DDR markers correlated with ploidy abnormalities, including high-level focal amplifications and whole-genome duplication (WGD). Moreover, high expression of DNA damage markerH2AXcorrelated with CIN, WGD, and inferior patient survival. By developing and implementing a composite diagnostic score that incorporatesTP53mutation status, ploidy abnormalities, andH2AXexpression, among other genomic information, we can identify GEA cell lines with enhanced sensitivity to DDR pathway inhibitors targeting Chk1/2 and Wee1. Anti-tumor properties were further augmented in combination with irinotecan (SN38) but not gemcitabine chemotherapy. These results implicate specific DDR biomarkers and ploidy abnormalities as diagnostic proxy that may predict premalignant progression and response to DDR pathway inhibitors.
Five years later, with double the demographic data, naked mole-rat mortality rates continue to defy Gompertzian laws by not increasing with age
Authors: Ruby J. Graham , Smith Megan , Buffenstein Rochelle 
Published: March 2023

AbstractThe naked mole-rat (Heterocephalus glaber) is a mouse-sized rodent species, notable for its eusociality and long lifespan. Previously, we reported that demographic aging, i.e., the exponential increase of mortality hazard that accompanies advancing age in mammals and other organisms, does not occur in naked mole-rats (Ruby et al, 2018). The demographic data supporting that conclusion had taken over three decades to accumulate, starting with the original rearing ofH.glaberin captivity. In the five years following that study, we ∼doubled our quantity of demographic data. Here, we re-evaluated our prior conclusions in light of these new data and found them to be supported and indeed strengthened. We additionally provided insight into the social dynamics of captiveH.glaberwith data and analyses of body weight and colony size versus mortality. Finally, we provide a phylogenetically-proximal comparator in the form of lifespan data from our Damaraland mole-rat (Fukomys damarensis) colony and demographic meta-analysis of those data along with published data from Ansell’s mole-rat (Fukomys anselli). We foundFukomysmortality hazard to increase gradually with age, an observation with implications on the evolution of exceptional lifespan among mole-rats and the ecological factors that may have accompanied that evolution.
Terrestrial Support of Aquatic Food Webs via an Overlooked Pathway—Inorganic Carbon and its Significance to Global Carbon Cycle
Authors: Wang Junna , Durand John R. , Lawler Sharon P. , Chen Pinyuan , Dong Xiaoli 
Published: March 2023

AbstractFreshwater ecosystems receive substantial terrestrial organic matter (t-OM) from surrounding landscapes. How the t-OM is transferred affects aquatic food webs and global carbon budgets. Previous studies have emphasized terrestrial support of aquatic ecosystems via direct organic carbon subsidy, overlooking the dissolved inorganic carbon (DIC) pathway, that is, DIC from t-OM decomposition is used by aquatic primary producers, supporting higher trophic levels. Using 2-year13C and15N measurements of phytoplankton, zooplankton, terrestrial plants, sediments, dissolved and particulate organic matter from seasonal wetlands, we found that while zooplankton (mid-trophic consumers) used t-OM directly in January, in March and May zooplankton were mainly supported by phytoplankton that used DIC recycled from t-OM mineralization and methanogenesis. The dominance of this DIC pathway is tightly coupled with the characteristics of these systems. Mineralization and methanogenesis of rich fresh t-OM resulted in supersaturated CO2with high CO2and CH4emissions. Atmospheric CO2diffusion and methanogenesis significantly enrichedδ13Cof DIC, leading to wide variations inδ13Cof DIC between -12.4 and 6.7 ‰, which provided ideal conditions to quantify carbon cycling in these widespread but understudied ecosystems. Our findings draw attention to potentially high carbon emissions from temporary freshwater ecosystems that are being increasingly common under warming climate.
Phage-Antibiotic Combination: An Effective Method for Eradication ofStaphylococcus aureus
Authors: Loganathan Archana , Manohar Prasanth , Nachimuthu Ramesh 
Published: March 2023

AbstractIncreasing antibiotic resistance poses a serious threat, especially in patients admitted to ICUs. The use of phages in combination with antibiotics as compassionate therapy has become a choice of treatment for pan-drug-resistant bacteria. Here, we studied the cumulative effect of phages with four antibiotics, fosfomycin, ciprofloxacin, vancomycin and oxacillin using three different treatment orders againstS. aureus. The antibiotic disc synergy method showed that the plaque size of the phage increased in the subinhibitory antibiotic zone. The sub-inhibitory antibiotic amended in the agar media showed that the plaque size increased between 0.25 μg/mL and 1 μg/mL of antibiotics. It increases from 0.5 ± 0.1 mm (phage-alone control) to 4 ± 0.2 mm, 1.6 ± 0.1 mm, and 1.6 ± 0.4 mm with fosfomycin, ciprofloxacin, and oxacillin, respectively. Checkerboard analysis showed that phages and antibiotics were synergistic with the FIC index of less than 0.5. So, phage-antibiotic combination treatment appeared to be effective. However, the highest efficiency was observed when the antibiotics were administered after phage treatment. A maximum of 39.4-, 39.4-, and 37.0-fold reduction relative to untreated bacterial culture was observed with fosfomycin, oxacillin, and ciprofloxacin. Vancomycin antibiotic had a least 14.7-fold reduction. Finally, our findings emphasize the potential benefits of phage-antibiotic combination therapy compared with phage-alone therapy to treatS. aureusinfections.
Exploring the Impact of the Covid-19 Pandemic on Health-Related Behaviours: A Person-Centred Analysis of Two British Longitudinal Cohort Studies
Authors: Kiri Janet , Brandt Valerie 
Published: March 2023

AbstractThe current study explored the impact of the Covid-19 pandemic on health-related behaviours in the United Kingdom. We conducted a repeated measures latent class analysis with five indicators of health-related behaviours; frequency of alcohol consumption, binge drinking, smoking, BMI and sleep, to identify distinct subgroups of individuals with similar patterns of change across three timepoints during the first 9 months of the pandemic. We hypothesised that various psychosocial risk factors, such as a history of adverse childhood experiences would predict membership in latent classes with a higher probability of engaging in risky health behaviours, and that protective factors, like social support, would be associated with membership in classes with less risky health behaviours. We identified 5 latent classes, and multinomial logistic regression analyses revealed multiple predictors of class membership. Our findings did not support the relationship between poor mental health and the adoption of risky health behaviours.
Insomnia and early incident atrial fibrillation: A 16-year cohort study of younger men and women Veterans
Authors: Gaffey Allison E. , Rosman Lindsey , Lampert Rachel , Yaggi Henry K. , Haskell Sally G. , Brandt Cynthia A. , Enriquez Alan D. , Mazzella Anthony J. , Burg Matthew M. 
Published: March 2023

AbstractBackgroundThere is growing consideration of sleep disturbances and disorders in early cardiovascular risk, including atrial fibrillation (AF). Obstructive sleep apnea (OSA) confers risk for AF but is highly comorbid with insomnia, another common sleep disorder. The objectives of this investigation were first to determine the association of insomnia and early incident AF risk and second, to determine if AF onset is earlier among those with insomnia.MethodsThis retrospective analysis used electronic health records from a cohort study of U.S. Veterans who were discharged from military service as of October 1, 2001 (i.e., post-9/11) and received Veterans Health Administration (VA) healthcare, 2001-2017. Time-varying, multivariate Cox proportional hazard models were used to examine the independent contribution of insomnia diagnosis to AF incidence while serially adjusting for demographics, lifestyle factors, clinical comorbidities including OSA, psychiatric disorders, and healthcare utilization.ResultsOverall, 1,063,723 post-9/11 Veterans (Mage=28.2 years, 12% women) were followed for 10 years on average. There were 4168 cases of AF (0.42/1000 person-years). Insomnia was associated with a 32% greater, adjusted risk of AF (95% CI, 1.21-1.43), and Veterans with insomnia showed AF onset up to two years earlier. Insomnia-AF associations were similar after accounting for healthcare utilization, excluding Veterans with OSA, and among those with a sleep study (adjusted hazard ratios [aHR]: 1.29-1.34).ConclusionsIn younger adults, insomnia was independently associated with incident AF even when accounting for OSA. Additional studies should determine if this association differs by sex and if behavioral or pharmacological treatment for insomnia attenuates AF risk.Clinical Perspective1.What is new?In more than one million younger men and women Veterans with 16 years of follow-up, a history of insomnia conferred a 32% increase in risk for atrial fibrillation (AF).The insomnia-AF association persisted despite accounting for obstructive sleep apnea, a well-known risk factor for AF, and other demographic, lifestyle, and clinical factors.Veterans with insomnia may also present with AF up to 2 years earlier compared to those without insomnia.2.What are the clinical implications?Insomnia is a potentially modifiable risk factor for AF and sleep should be a focus for AF prevention.Screening and referral for insomnia and other sleep symptoms is critical, particularly among patients with an elevated risk for cardiovascular disease, as observed in the Veteran population.Although sex-specific associations could not be examined, insomnia is more prevalent among women, and it is possible that insomnia-AF associations may differ by sex.