bluuebunny/crossref_metadata_2025_split huggingface dataset:
G6PD deficiency mediated impairment of iNOS and lysosomal acidification affecting phagocytotic clearance in microglia in response to SARS-CoV-2
Authors: Mondal Abir , Munan Subrata , Saxena Isha , Mukherjee Soumyadeep , Upadhyay Prince , Gupta Nutan , Dar Waseem , Samanta Animesh , Singh Shailja , Pati Soumya 
Published: December 2023

AbstractThe glucose-6-phosphate dehydrogenase (G6PD) deficiency is X-linked and is the most common enzymatic deficiency disorder globally. It is a crucial enzyme for the pentose phosphate pathway and produces NADPH, which plays a vital role in the regulation of oxidative stress of many cell types. The deficiency of G6PD causes hemolytic anemia, diabetes, cardiovascular and neurological disorders. Notably, the patient with G6PD deficiency was severely affected by SARS-CoV-2 and showed prolonged COVID-19 symptoms, neurological impacts, and high mortality. However, the mechanism of COVID-19 severity in G6PD deficient patients is still ambiguous. Here, using a CRISPR-edited G6PD deficient human microglia cell culture model, we observed a significant reduction in NADPH and an increase in basal reactive oxygen species (ROS) in microglia. Interestingly, the deficiency of the G6PD-NAPDH axis impairs induced nitric oxide synthase (iNOS) mediated nitric oxide (NO) production which plays a fundamental role in inhibiting viral replication. Surprisingly, we also observed that the deficiency of the G6PD-NADPH axis reduced lysosomal acidification, which further abrogates the lysosomal clearance of viral particles. Thus, impairment of NO production and lysosomal acidification as well as redox dysregulation in G6PD deficient microglia altered innate immune response, promoting the severity of SARS-CoV-2 pathogenesis.
Lumbosacral spinal cord functional connectivity at rest: From feasibility to reliability
Authors: Ricchi Ilaria , Kinany Nawal , Van De Ville Dimitri 
Published: December 2023

AbstractIn the past decade, exploration of spontaneous blood-oxygen-level-dependent (BOLD) signal fluctuations has expanded beyond the brain to include the spinal cord. While most studies have predominantly focused on the cervical region, the lumbosacral segments play a crucial role in motor control and sensory processing of the lower limbs. Addressing this gap, the aims of the current study were two-fold: first, confirming the presence and nature of organized spontaneous BOLD signals in the human lumbosacral spinal cord; second, systematically assessing the impact of various denoising strategies on signal quality and functional connectivity (FC) patterns. Given the susceptibility of spinal cord fMRI to noise, this step is pivotal to ensure the robustness of intrinsic FC. Our findings uncovered bilateral FC between the ventral horns. Importantly, these patterns were consistently observed across denoising methods and demonstrating fair to excellent reliability. Conversely, no other significant connectivity patterns were identified across the remaining horns. Importantly, the evaluation of diverse denoising strategies highlighted the efficacy of PNM-based pipelines in cleaning the signal while preserving the strength and reliability of connectivity estimates. Together, our results provide evidence of robust FC patterns in the lumbosacral spinal cord, thereby paving the way for future studies probing caudal spinal activity.
Adaptive LDA classifier enhances real-time control of an EEG Brain-computer interface for imagined-speech decoding
Authors: Wu Shizhe , Bhadra Kinkini , Giraud Anne-Lise , Marchesotti Silvia 
Published: December 2023

AbstractBrain-Computer Interfaces (BCI) aim to establish a pathway between the brain and an external device without the involvement of the motor system, relying exclusively on neural signals. Such systems have the potential to provide a means of communication for patients who have lost the ability to speak due to a neurological disorder. Traditional methodologies for decoding imagined speech directly from brain signals often deploy static classifiers, that is, decoders that are computed once at the beginning of the experiment and that remain unchanged throughout the BCI use. However, this approach might be inadequate in effectively handling the non-stationary nature of electroencephalography (EEG) signals and the learning that accompanies BCI use as parameters are expected to change, all the more in a real-time setting. To address this limitation, we have developed an adaptive classifier that updates its parameters based on the incoming data in real time. We first identified optimal parameters (the update coefficient, UC) to be used in an adaptive Linear Discriminant Analysis (LDA) classifier, using a previously recorded EEG dataset, acquired while healthy participants controlled a binary BCI based on imagined syllable decoding. We subsequently tested the effectiveness of this optimization in a real-time BCI-control setting. Twenty healthy participants performed two BCI-control sessions based on the imagery of two syllables, using a static LDA and the other the adaptive LDA classifier, in randomized order. In this real-time BCI-control task, the adaptive classifier led to better performances than the static one. Furthermore, the optimal parameters for the adaptive classifier were closely aligned in both datasets acquired with the same syllable imagery task. These findings highlight the effectiveness and re-liability of adaptive LDA classifiers for real-time imagined speech decoding, and its interest for non-invasive EEG-based BCI notably characterized by low decoding accuracies.
Validation of a non-appetitive effort-based foraging task as a measure of motivational state in male mice
Authors: Xeni Foteini , Marangoni Caterina , Jackson Megan G 
Published: December 2023

AbstractMotivational disorders such as apathy syndrome are highly prevalent across neurological disorders but do not yet have an agreed treatment approach. The use of translational behavioural models can provide a route through which to meaningfully screen novel drug targets. Methods that utilise food deprivation in contrived environments may lack the sensitivity to detect deficits in self-initiated or self-driven behaviour. Animals monitored in more naturalistic environments may display more ethologically-relevant behaviours of greater translational value. Here, we aimed to validate a novel, non-appetitive effort-based foraging task as a measure of motivational state in mice. In this task, the mouse can freely choose to exert effort to forage bedding material and shuttle it back to a safe and enclosed environment. The amount of bedding material foraged is used as a readout of motivational state. Acute dopaminergic modulation with haloperidol, amphetamine and methylphenidate, and two phenotypic models known to induce motivational deficits (healthy ageing and chronic administration of corticosterone) were used to validate this task. Consistent with other effort-based decision-making tasks we find that foraging behaviour is sensitive to acute modulation of dopaminergic transmission. We find that both phenotypic models induce differing deficits in various aspects of foraging behaviour suggesting that the task may be used to parse different behavioural profiles from distinct disease phenotypes. Thus, without requiring extended training periods or physiological deprivation, this task may represent a refined and translational preclinical measure of motivation.
Serine hydroxymethyl transferase is a binding target of caprylic acid: Uncovering a novel molecular target for a herbicide and for producing caprylic acid-tolerant crops
Authors: Li Zuren , Wang Mugui , Bai Haodong , Wang Hongzhi , Han Jincai , An Likun , Luo Dingfeng , Wang Yingying , Kuang Wei , Nie Xiaoyi , Bai Lianyang 
Published: December 2023

AbstractIdentification of new binding targets is essential for the development of herbicides and phytotoxin-tolerant crops. Caprylic acid (CAP) is a safe and non-selective bio-herbicide in uncultivated areas. However, the herbicidal action of CAP remains unclear. Herein, metabolomic and proteomic profiling indicated that a serine hydroxymethyl transferase inConyza canadensis(CcSHMT1) is a promising candidate binding targeted for CAP. The protein abundance and activity ofCcSHMT1 were decreased in a time- and dosage-dependent manners after CAP treatment. CAP competes with phenyl-serine at the binding sites, decreasing the enzymatic activity ofCcSHMT1. Overexpression ofCcSHMT1, AtSHMT1andOsSHMT1inArabidopsisor rice endowed plants with high tolerance to CAP treatment, whereas the knockout ofosshmt1led to death of plants under normal atmospheric conditions. Furthermore, T194A, T194A/ M195V and D209NOsshmt1mutant plants derived from base editing exhibited tolerance to CAP. CAP bound toCcSHMT1 with high affinity, and Ala191 in the key domains of N-terminus was identified to be critical for the binding site of CAP. Collectively, our findings demonstrate thatCcSHMT1 is a binding target for herbicidal activity of CAP. This study marks a key step in the druggability of SHMT inhibitors and represents an attractive target for phytotoxin-tolerant crops.
A modeling analysis of whole-body potassium regulation on a high potassium diet: Proximal tubule and tubuloglomerular feedback effects
Authors: Stadt Melissa M. , Layton Anita T. 
Published: December 2023

AbstractPotassium (K+) is an essential electrolyte that plays a key role in many physiological processes, including mineralcorticoid action, systemic blood-pressure regulation, as well as hormone secretion and action. Indeed, maintaining K+balance is critical for normal cell function, as too high or too low K+levels can have serious and potentially deadly health consequences. K+homeostasis is achieved by an intricate balance between the intracellular and extracellular fluid as well as balance between K+intake and excretion. This is achieved via the coordinated actions of regulatory mechanisms such as the gastrointestinal feedforward effect, insulin and aldosterone upregulation of Na+-K+-ATPase uptake, and hormone and electrolyte impacts on renal K+handling. We recently developed a mathematical model of whole-body K+regulation to unravel the individual impacts of regulatory mechanisms. In this study, we extend our mathematical model to incorporate recent experimental findings that showed decreased fractional proximal tubule reabsorption under a high K+diet. We conducted model simulations and sensitivity analyses to unravel how these renal alterations impact whole-body K+regulation. Our results suggest that the reduced proximal tubule K+reabsorption under a high K+diet could achieve K+balance in isolation, but the resulting tubuloglomerular feedback reduces filtration rate and thus K+excretion. Model predictions quantify the sensitivity of K+regulation to various levels of proximal tubule K+reabsorption adaptation and tubuloglomerular feedback. Additionally, we predict that without the hypothesized muscle-kidney cross talk signal, intracellular K+stores can exceed normal range under a high K+diet.
III. Geometrical framework for thinking about globular proteins: turns in proteins
Authors: Škrbić Tatjana , Giacometti Achille , Hoang Trinh X. , Maritan Amos , Banavar Jayanth R. 
Published: December 2023

AbstractWe have shown recently that the notion of poking pairwise interactions along a chain provides a unifying framework for understanding the formation of both secondary and the tertiary protein structure based on symmetry and geometry. α-helices and β-sheets are found to be special geometries that have systematic poking contacts in a repetitive manner with the contacts being local along the α-helix and non-local along a pair of adjacent strands within a β-sheet. Pairwise poking interactions also govern tertiary structure formation, but they are weaker and there are no special geometrical constraints as in secondary structure formation. Here we demonstrate that protein turns, the most prevalent non-repetitive structural element in proteins, are instances of local (as in α-helices) and isolated (non-repetitive) poking pairwise contacts for which the geometrical constraints are partially relaxed. This simple and purely geometrical definition of protein turns (also sometimes known as reverse turns, β-turns, β-bends, hairpin bends, 310bends, kinks, widgets, …) provides a simple framework for unifying them. We present the results of a systematic analysis and identify their structural classes as well as their respective amino acid preferences.Statement for broader audiencePoking interaction along a discrete chain signals the affinity of one part of the chain with another. It has been shown that a simple and purely geometrical model based on poking interactions is able to capture the essential features of complex protein chains, especially their building blocks and their assembly. We demonstrate that poking interactions also provide a simple framework to describe protein turns as isolated (not coordinated) local poking interactions. This framework allows one to comprehend the structural variety of protein turns that have been extensively studied in the past.
Genotype imputation in F2 crosses of inbred lines
Authors: Pierotti Saul , Welz Bettina , Lopez Mireia Osuna , Fitzgerald Tomas , Wittbrodt Joachim , Birney Ewan 
Published: December 2023

AbstractMotivationCrosses among inbred lines are a fundamental tool for the discovery of genetic loci associated with phenotypes of interest. In organisms for which large reference panels or SNP chips are not available, imputation from low-pass whole-genome sequencing is an effective method for obtaining genotype data from a large number of individuals. To date, a structured analysis of the conditions required for optimal genotype imputation has not been performed.ResultsWe report a systematic exploration of the effect of several design variables on imputation performance in F2 crosses of inbred medaka lines using the imputation software STITCH. We determined that, depending on the number of samples, imputation performance reaches a plateau when increasing the per-sample sequencing coverage. We also systematically explored the trade-offs between cost, imputation accuracy, and sample numbers. We developed a computational pipeline to streamline the process, enabling other researchers to perform a similar cost-benefit analysis on their population of interest.Availability and implementationThe source code for the pipeline is available athttps://github.com/birneylab/stitchimpute. While our pipeline has been developed and tested for an F2 population, the software can also be used to analyse populations with a different structure.
Transcription Factor NRF2 is Activated by Erythrophagocytosis of Oxidized Red Blood Cell Products and Suppresses the IL-12-IFNg-IL-10 Axis in a Murine Model of Hyperinflammatory Disease
Authors: Gallo Paul M. , Elliott Em , Ford Grace , Biswas Chhanda , Kim Jihwan , Wheaton Jadyn , Jiang Connie , Chu Niansheng , Kreiger Portia A. , Lambert Michele , Behrens Edward M. 
Published: December 2023

AbstractHyperinflammatory diseases including macrophage activation syndrome (MAS) and hemophagocytic lymphohistocytosis (HLH) are characterized by multi-lineage cytopenias, hypercytokinemia, and tissue hemophagocytosis. However, the mechanisms by which erythrophagocytosis mediates iron metabolism and regulates the hyperactive immune response remain unclear. The transcription factor NRF2 is an important sensor for inflammatory and redox distress. The targets of NRF2 are antioxidant response elements responsible for transcription of genes related to restoration of redox homeostasis within the cell. Here we demonstrate that mice with CpG-induced MAS have evidence of systemic oxidative and nitrosative distress – including increased serum nitric oxide and elevated systemic lipid peroxidation. In this model, NRF2 knockout mice develop significantly worse organomegaly, hypercytokinemia, and reticulocytosis. NRF2 knockout mice have unexpected exacerbation in the cytokines that are central to hyperinflammatory physiology – namely IL-12, IFN gamma (IFNg), and IL-10.In vitrowe demonstrate that oxidized red blood cell products and heme itself suppress IL-12 protein production and transcription from bone marrow derived dendritic cells in a NRF2-dependent manner. Together our studies demonstrate that erythrophagocytosis of oxidized red blood cell products suppresses the Il-12-IFNg-IL-10 axis which drives hyperinflammation in murine hyperinflammation.Graphical abstractCreated with BioRender
Single-nucleotide-resolution genomic maps ofO6-methylguanine from the glioblastoma drug temozolomide
Authors: Büchel Jasmina , Mingard Cécile , Takhaveev Vakil , Reinert Patricia B. , Keller Giulia , Kloter Tom , Huber Sabrina M. , McKeague Maureen , Sturla Shana J. 
Published: December 2023

ABSTRACTTemozolomide kills cancer cells by formingO6-methylguanine (O6-MeG), which leads to apoptosis due to mismatch-repair overload. However,O6-MeG repair byO6-methylguanine-DNA methyltransferase (MGMT) contributes to drug resistance. Characterizing genomic profiles ofO6-MeG could elucidate howO6-MeG accumulation is influenced by repair, but there are no methods to map genomic locations ofO6-MeG. Here, we developed an immunoprecipitation- and polymerase-stalling-based method, termedO6-MeG-seq, to locateO6-MeG across the whole genome at single-nucleotide resolution. We analyzedO6-MeG formation and repair with regards to sequence contexts and functional genomic regions in glioblastoma-derived cell lines and evaluated the impact of MGMT.O6-MeG signatures were highly similar to mutational signatures from patients previously treated with temozolomide. Furthermore, MGMT did not preferentially repairO6-MeG with respect to sequence context, chromatin state or gene expression level, however, may protect oncogenes from mutations. Finally, we found an MGMT-independent strand bias inO6-MeG accumulation in highly expressed genes, suggesting an additional transcription-associated contribution to its repair. These data provide high resolution insight on howO6-MeG formation and repair is impacted by genome structure and regulation. Further,O6-MeG-seq is expected to enable future studies of DNA modification signatures as diagnostic markers for addressing drug resistance and preventing secondary cancers.GRAPHICAL ABSTRACT
Differential developmental blueprints of organ-intrinsic nervous systems
Authors: Hsu I-Uen , Lin Yingxin , Guo Yunshan , Xu Qian J. , Shao Yuancheng , Wang Ruiqi L. , Yin Dominic , Zhao Jia , Young Lawrence H. , Zhao Hongyu , Zhang Le , Chang Rui B. 
Published: December 2023

AbstractThe organ-intrinsic nervous system is a major interface between visceral organs and the brain, mediating important sensory and regulatory functions in the body-brain axis and serving as critical local processors for organ homeostasis. Molecularly, anatomically, and functionally, organ-intrinsic neurons are highly specialized for their host organs. However, the underlying mechanism that drives this specialization is largely unknown. Here, we describe the differential strategies utilized to achieve organ-specific organization between the enteric nervous system (ENS)1and the intrinsic cardiac nervous system (ICNS)2, a neuronal network essential for heart performance but poorly characterized. Integrating high-resolution whole-embryo imaging, single-cell genomics, spatial transcriptomics, proteomics, and bioinformatics, we uncover that unlike the ENS which is highly mobile and colonizes the entire gastrointestinal (GI) tract, the ICNS uses a rich set of extracellular matrix (ECM) genes that match with surrounding heart cells and an intermediate dedicated neuronal progenitor state to stabilize itself for a ‘beads-on-the-necklace’ organization on heart atria. While ICNS- and ENS-precursors are genetically similar, their differentiation paths are influenced by their host-organs, leading to distinct mature neuron types. Co-culturing ENS-precursors with heart cells shifts their identity towards the ICNS and induces the expression of heart-matching ECM genes. Our cross-organ study thus reveals fundamental principles for the maturation and specialization of organ-intrinsic neurons.
Rv0687 a Putative Short-Chain Dehydrogenase is indispensable for pathogenesis ofMycobacterium tuberculosis
Authors: Bhargavi Gunapati , Mallakuntla Mohan Krishna , Kale Deepa , Tiwari Sangeeta 
Published: December 2023

AbstractMycobacterium tuberculosis (Mtb),a successful human pathogen, resides in host sentinel cells and combats the stressful intracellular environment induced by reactive oxygen and nitrogen species during infection.Mtbemploys several evasion mechanisms in the face of the host as a survival strategy, including detoxifying enzymes as short-chain dehydrogenases/ reductases (SDRs) to withstand host-generated insults. In this study, using specialized transduction we have generated a Rv0687 deletion mutant and its complemented strain and investigated the functional role of Rv0687, a member of SDRs family genes inMtbpathogenesis. Wildtype (WT) and mutantMtbstrain lacking Rv0687 (RvΔ0687) were tested forin-vitrostress response andin-vivosurvival in macrophages and mice models of infection. The study demonstrates that Rv0687 is crucial for sustaining bacterial growth in nutrition-limited conditions. The deletion of Rv0687 elevated the sensitivity ofMtbto oxidative and nitrosative stress-inducing agents. Furthermore, the lack of Rv0687 compromised the survival ofMtbin primary bone marrow macrophages and led to an increase in the levels of the secreted proinflammatory cytokines TNF-α, and MIP-1α. Interestingly, the growth of WT and RvΔ0687 was similar in the lungs of infected immunocompromised mice however, a significant reduction in RvΔ0687 growth was observed in the spleen of immunocompromised Rag-/-mice at 4 weeks post-infection. Moreover Rag-/-mice infected with RvΔ0687 survived longer compared to WTMtbstrain. Additionally, we observed significant reduction in bacterial burden in spleens and lungs of immunocompetent C57BL/6 mice infected with RvΔ0687 compared to complemented and WTMtbstrains. Collectively, this study reveals that Rv0687 plays a role inMtbpathogenesis.
Staphylococcus aureuscan use an alternative pathway to be internalized by osteoblasts in absence of β1 integrins
Authors: Mouton William , Tricou Léo-Paul , Cara Andréa , Trouillet-Assant Sophie , Bouvard Daniel , Laurent Frédéric , Diot Alan , Josse Jérôme 
Published: December 2023

ABSTRACTStaphylococcus aureusmain internalization mechanism in osteoblasts relies on a tripartite interaction between bacterial fibronectin-binding proteins, extracellular matrix soluble fibronectin, and osteoblasts’ β1 integrins. Caveolins, and particularly caveolin-1, have shown to limit the plasma membrane microdomain mobility, and consequently reduce the uptake ofS. aureusin keratinocytes. In this study, we aimed to deepen our understanding of the molecular mechanisms underlyingS. aureusinternalization in osteoblasts. Mechanistically,S. aureusinternalization requires endosomal recycling β1 integrins as well as downstream effectors such as Src, Rac1, and PAK1. Surprisingly, in β1 integrin deficient osteoblasts,S. aureusinternalization is restored when Caveolin-1 is absent and requires αvβ3/αvβ5 integrins as backup fibronectin receptors. Altogether, our data support that β1 integrins regulate the level of detergent-resistant membrane at the plasma membrane in a an endosomal and Caveolin-1 dependent manner.SUMMARY STATEMENTStaphylococcus aureuscan be internalized by osteoblasts via a different mechanism than the main α5β1/fibronectin/fibronectin-binding protein that likely involves αvβ3 or αvβ5 integrin.