bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct transcriptomic profile of satellite cells contributes to preservation of neuromuscular junctions in extraocular muscles of ALS mice
Authors: Li Ang , Yi Jianxun , Li Xuejun , Dong Li , Ostrow Lyle W. , Ma Jianjie , Zhou Jingsong 
Published: February 2023

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder characterized by progressive weakness of almost all skeletal muscles, whereas extraocular muscles (EOMs) are comparatively spared. While hindlimb and diaphragm muscles of end-stage SOD1G93A (G93A) mice (a familial ALS mouse model) exhibit severe denervation and depletion of Pax7+satellite cells (SCs), we found that the pool of SCs and the integrity of neuromuscular junctions (NMJs) are maintained in EOMs. In cell sorting profiles, SCs derived from hindlimb and diaphragm muscles of G93A mice exhibit denervation-related activation, whereas SCs from EOMs of G93A mice display spontaneous (non-denervation-related) activation, similar to SCs from wild-type mice. Specifically, cultured EOM SCs contain more abundant transcripts of axon guidance molecules, includingCxcl12, along with more sustainable renewability than the diaphragm and hindlimb counterparts under differentiation pressure. In neuromuscular co-culture assays, AAV-delivery ofCxcl12to G93A-hindlimb SC-derived myotubes enhances motor neuron axon extension and innervation, recapitulating the innervation capacity of EOM SC-derived myotubes. G93A mice fed with sodium butyrate (NaBu) supplementation exhibited less NMJ loss in hindlimb and diaphragm muscles. Additionally, SCs derived from G93A hindlimb and diaphragm muscles displayed elevated expression ofCxcl12and improved renewability following NaBu treatmentin vitro. Thus, the NaBu-induced transcriptomic changes resembling the patterns of EOM SCs may contribute to the beneficial effects observed in G93A mice. More broadly, the distinct transcriptomic profile of EOM SCs may offer novel therapeutic targets to slow progressive neuromuscular functional decay in ALS and provide possible "response biomarkers" in pre-clinical and clinical studies.
Aerobic exercise reverses aging-induced depth-dependent decline in cerebral microcirculation
Authors: Shin Paul , Pian Qi , Ishikawa Hidehiro , Hamanaka Gen , Mandeville Emiri T , Shuzhen Guo , Buyin Fu , Alfadhel Mohammed , Allu Srinivasa Rao , Şencan-Eğilmez Ikbal , Li Baoqiang , Ran Chongzhao , Vinogradov Sergei A , Ayata Cenk , Lo Eng H , Arai Ken , Devor Anna , Sakadžić Sava 
Published: February 2023

AbstractAging is a major risk factor for cognitive impairment. Aerobic exercise benefits brain function and may promote cognitive health in older adults. However, underlying biological mechanisms across cerebral gray and white matter are poorly understood. Selective vulnerability of the white matter to small vessel disease and a link between white matter health and cognitive function suggests a potential role for responses in deep cerebral microcirculation. Here, we tested whether aerobic exercise modulates cerebral microcirculatory changes induced by aging. To this end, we carried out a comprehensive quantitative examination of changes in cerebral microvascular physiology in cortical gray and subcortical white matter in mice (3-6 vs. 19-21 months old), and asked whether and how exercise may rescue age-induced deficits. In the sedentary group, aging caused a more severe decline in cerebral microvascular perfusion and oxygenation in deep (infragranular) cortical layers and subcortical white matter compared with superficial (supragranular) cortical layers. Five months of voluntary aerobic exercise partly renormalized microvascular perfusion and oxygenation in aged mice in a depth-dependent manner, and brought these spatial distributions closer to those of young adult sedentary mice. These microcirculatory effects were accompanied by an improvement in cognitive function. Our work demonstrates the selective vulnerability of the deep cortex and subcortical white matter to aging-induced decline in microcirculation, as well as the responsiveness of these regions to aerobic exercise.
Ubiquitination is a novel post-translational modification of VMP1 in autophagy of human tumor cells
Authors: Renna Felipe J. , Enriqué Steinberg Juliana H. , Gonzalez Claudio D. , Manifava Maria , Tadic Mariana S. , Orquera Tamara , Vecino Carolina V. , Ropolo Alejandro , Guardavaccaro Daniele , Rossi Mario , Ktistakis Nicholas T. , Vaccaro Maria I. 
Published: February 2023

AbstractAutophagy is a tightly regulated catabolic process involved in the degradation and re-cycling of proteins and organelles. Ubiquitination plays an important role in the regulation of autophagy. Vacuole Membrane Protein 1 (VMP1) is an essential autophagy protein. The expression of VMP1 in pancreatic cancer stem cells carrying the activated Kirsten rat sarcoma viral oncogene homolog (KRAS) triggers autophagy and enables therapy resistance. Using biochemical and cellular approaches, we identified ubiquitination as a post-translational modification of VMP1 from the initial steps in autophagosome biogenesis. VMP1 remains ubiquitinated as part of the autophagosome membrane throughout autophagic flux until autolysosome formation. However, VMP1 is not degraded by autophagy, nor by the ubiquitin–proteasomal system. Mass spectrometry and immunoprecipitation showed that the cell division cycle protein cdt2 (Cdt2), the substrate recognition subunit of the E3 ligase complex associated with cancer, cullin–RING ubiquitin ligase complex 4 (CRL4), is a novel interactor of VMP1 and is involved in VMP1 ubiquitination. VMP1 ubiquitination decreases under the CRL inhibitor MLN4924 and increases with Cdt2 overexpression. Moreover, VMP1 recruitment and autophagosome formation is significantly affected by CRL inhibition. Our results indicate that ubiquitination is a novel post-translational modification of VMP1 during autophagy in human tumor cells. VMP1 ubiquitination may be of clinical relevance in tumor cell therapy resistance.
Optimizing Xenium In Situ data utility by quality assessment and best practice analysis workflows
Authors: Salas Sergio Marco , Czarnewski Paulo , Kuemmerle Louis B. , Helgadottir Saga , Matsson-Langseth Christoffer , Tismeyer Sebastian , Avenel Christophe , Rehman Habib , Tiklova Katarina , Andersson Axel , Chatzinikolaou Maria , Theis Fabian J. , Luecken Malte D. , Wählby Carolina , Ishaque Naveed , Nilsson Mats 
Published: February 2023

AbstractThe Xenium In Situ platform is a new spatial transcriptomics product commercialized by 10X Genomics capable of mapping hundreds of transcriptsin situat a subcellular resolution. Given the multitude of commercially available spatial transcriptomics technologies, recommendations in choice of platform and analysis guidelines are increasingly important. Herein, we explore eight preview Xenium datasets of the mouse brain and two of human breast cancer by comparing scalability, resolution, data quality, capacities and limitations with eight other spatially resolved transcriptomics technologies. In addition, we benchmarked the performance of multiple open source computational tools when applied to Xenium datasets in tasks including cell segmentation, segmentation-free analysis, selection of spatially variable genes and domain identification, among others. This study serves as the first independent analysis of the performance of Xenium, and provides best-practices and recommendations for analysis of such datasets.
MiR-302-Induced anti-aging neural stem cells enhance cognitive function and extend lifespan
Authors: Li Yuanyuan , Sun Jing , Zheng Yuanyuan , Xu Tingting , Zhang Yanan , Wang Yuesi 
Published: February 2023

ABSTRACTNeural stem cells play a vital role in maintaining tissue stability and extending lifespan. Transplanting these cells to treat neurodegenerative diseases faces challenges like cellular aging, low viability, and immune rejection. We have effectively reprogrammed human fibroblasts into induced neural stem cells (iNSCs) via a single-factor miR-302a strategy, which converted skin fibroblasts into human-induced neural stem cells (hiNSCs) within 2-3 days. These cells showed delayed aging and increased resistance to oxidative stress compared to wild-type cells. Implanting them into the hippocampus of senescence-accelerated mice improved cognitive performance in severe Alzheimer’s, prolonged lifespan by 34%, increased fatigue resistance, and improved hair regeneration and reproductive capacity. Our findings suggest that miR-302a-hiNSCs can improve functional recovery in Alzheimer’s and promote healthy aging.
Probing the ligand binding specificity of FNBP4 WW domains and interaction with FH1 domain of FMN1
Authors: Das Shubham , Maiti Sankar 
Published: February 2023

AbstractFormins are a group of actin-binding proteins that mediate nascent actin filament polymerization, filament elongation, and barbed end capping function, thereby regulating different cellular and developmental processes. Developmental processes like vertebrate gastrulation, neural growth cone dynamics, and limb development require formins to function in a regulated manner. Formin binding proteins like Rho GTPase regulates activation of auto-inhibited conformation of diaphanous formins. Unlike other diaphanous formins, Formin1 (FMN1), a non-diaphanous formin, is not regulated by Rho GTPase. FMN1 acts as an antagonist of the BMP signaling pathway during limb development. Several previous reports demonstrated that WW domain-containing proteins can interact with poly-proline-rich amino acid stretches of formins and play a crucial role in developmental processes. WW domain-containing FNBP4 protein plays an essential role in limb development. It has been hypothesized that the interaction between FNBP4 and FMN1 can further attribute to the role in limb development through the BMP signaling pathway. In this study, we have elucidated the binding kinetics of FNBP4 and FMN1 using surface plasmon resonance and enzyme-linked immunosorbent assays. Our findings confirm that the FNBP4 exhibits interaction with the poly-proline-rich formin homology 1 (FH1) domain of FMN1. Furthermore, only the first WW1 domains is involved in the interaction between the two domains. Thus, this study sheds light on the binding potentialities of WW domains of FNBP4 and their possible contribution to the regulation of FMN1 function.
Deep evolution of MADS-box genes in Archaeplastida
Authors: Gramzow Lydia , Tessari Chiara , Rümpler Florian , Theißen Günter 
Published: February 2023

AbstractMADS-box genes represent a paneukaryotic gene family encoding transcription factors. Given its importance for essential functions in plants, animals and fungi, such as development of organ identity and mating type determination, the phylogeny of MADS-box genes is of great biological interest. It has been well established that a gene duplication in the stem group of extant eukaryotes generated two clades of MADS-box genes, termed Type I and Type II genes. Almost all Type II genes of land plants contain a keratin-like (K) domain in addition to the family-defining, DNA-binding MADS (M) domain and are also termed MIKC-type genes. Due to a lack of sampling of MADS-box genes in Archaeplastida (rhodophytes, glaucophytes, chlorophytes, and streptophytes) except land plants, the deep evolution of MADS-box genes in plants remains poorly understood, however. Here we use the genomic and transcriptomic ressources that have become available in recent years to answer longstanding questions of MADS-box gene evolution in Archaeplastida. Our results reveal that archaeplastid algae likely do not harbour Type I MADS-box genes. However, rhodophytes, glaucophytes, prasinodermophytes and chlorophytes possess Type II MADS-box genes without a K domain. Type II MADS-box genes with a K domain are found only in streptophytes. This corroborates previous views that some Type II gene acquired a K domain in the stem group of extant streptophytes, generating MIKC-type genes. Interestingly, we found both variants of Type II genes - with (MIKC) and without a K domain - in streptophyte algae, but not in land plants (embryophytes), suggesting that Type II genes without a K domain (ancestral Type II genes) were lost in the stem group of land plants. Our data reveal that the deep evolution of MADS-box genes in “plants” (Archaeplastida) was more complex than has previously been thought.
The intraosseous expansion of primary chondrosarcoma is achieved by osteoclasts expressing GnTase V (MGAT5) activity to drive neoangiogenesis
Authors: McClure John , McClure Sheena F 
Published: February 2023

ABSTRACTWe have studied the impact of primary central conventional chondrosarcoma on the bone tissues (trabecular, endosteal and cortical) of the proximal femur. A combination of macroscopy, contact radiography, histology, lectin histochemistry and immunohistochemistry techniques were employed. The tumours expanded by driving the resorption of bone tissue progressively removing trabecular, endosteal and cortical bone ultimately causing pathological fracture of the latter. Resorption of all tissue types was by osteoclasts invariably accompanied by companion mesenchymal tissue containing capillaries, mononuclear cells and mast cells. There were no new pathological mechanisms in play, rather the usurpation of normal physiological mechanisms of bone tissue remodelling and modelling. Lectin histochemistry showed that osteoclasts, endothelial cells and mast cells expressed GnTase V (MGAT5) which has been implicated in neoangiogenesis. The linkage of osteoclasts and new blood vessels we believe is key to successful bone resorption.
Social play behavior shapes the development of prefrontal inhibition in a region-specific manner
Authors: Bijlsma Ate , Vanderschuren Louk J.M.J. , Wierenga Corette J. 
Published: February 2023

AbstractExperience-dependent organization of neuronal connectivity is critical for brain development. We recently demonstrated the importance of social play behavior for the developmental fine-tuning of inhibitory synapses in the medial prefrontal cortex (mPFC) in rats. When these effects of play experience exactly occur and if this happens uniformly throughout the prefrontal cortex is currently unclear. Here we report important temporal and regional heterogeneity in the impact of social play on the development of excitatory and inhibitory neurotransmission in the mPFC and the orbitofrontal cortex (OFC). We recorded in layer 5 pyramidal neurons from juvenile (postnatal day (P)21), adolescent (P42) and adult (P85) rats after social play deprivation (SPD; between P21-P42). The development of these PFC subregions followed different trajectories. On P21, inhibitory and excitatory synaptic input was multiple times higher in the OFC than in the mPFC. SPD did not affect excitatory currents, but reduced inhibitory transmission in both mPFC and OFC. Intriguingly, the reduction occurred in the mPFC during SPD, while the reduction in the OFC only became manifested after SPD. These data reveal a complex interaction between social play experience and the specific developmental trajectories of prefrontal subregions.
Energetics and proton release in Photosystem II fromThermosynechococcus elongatuswith a D1 protein encoded by either thepsbA2orpsbA3gene
Authors: Boussac Alain , Sellés Julien , Sugiura Miwa 
Published: February 2023

AbstractIn the cyanobacteriumThermosynechococcus elongatus, there are threepsbAgenes coding for the Photosystem II (PSII) D1 subunit that interacts with most of the main cofactors involved in the electron transfers. Recently, the 3D crystal structures of both PsbA2-PSII and PsbA3-PSII have been solved [Nakajima et al., J. Biol. Chem. 298 (2022) 102668.]. It was proposed that the loss of one hydrogen bond of PheD1due to the D1-Y147F exchange in PsbA2-PSII resulted in a more negativeEmof PheD1in PsbA2-PSII when compared to PsbA3-PSII. In addition, the loss of two water molecules in the Cl-1 channel was attributed to the D1-P173M substitution in PsbA2-PSII. This exchange, by narrowing the Cl-1 proton channel, could be at the origin of a slowing down of the proton release. Here, we have continued the characterization of PsbA2- PSII by measuring the thermoluminescence from the S2QA-/DCMU charge recombination and by measuring proton release kinetics using time-resolved absorption changes of the dye bromocresol purple. It was found thati) theEmof PheD1−•/PheD1was decreased by ∼ 30 mV in PsbA2-PSII when compared to PsbA3-PSII andii) the kinetics of the proton release into the bulk was significantly slowed down in PsbA2-PSII in the S2TyrZ•to S3TyrZand S3TyrZ•→ (S3TyrZ•)’ transitions. This slowing down was partially reversed by the PsbA2/M173P mutation and induced by the PsbA3/P173M mutation thus confirming a role of the D1-173 residue in the egress of protons trough the Cl-1 channel.
CRISPR interference screens reveal tradeoffs between growth rate and robustness inSynechocystissp. PCC 6803 across trophic conditions
Authors: Miao Rui , Jahn Michael , Shabestary Kiyan , Hudson Elton Paul 
Published: February 2023

AbstractBarcoded mutant libraries are a powerful tool for elucidating gene function in microbes, particularly when screened in multiple growth conditions. Here, we screened a pooled CRISPR interference library of the model cyanobacteriumSynechocystis sp. PCC 6803 in 11 bioreactor-controlled conditions, spanning multiple light regimes and carbon sources. This gene repression library contained 21,705 individual mutants with high redundancy over all open reading frames and non-coding RNAs. Comparison of the derived gene fitness scores revealed multiple instances of gene repression being beneficial in one condition while generally detrimental in others, particularly for genes within light harvesting and conversion, such as antennae components at high light and PSII subunits during photoheterotrophy. Suboptimal regulation of such genes likely represents a tradeoff of reduced growth speed for enhanced robustness to perturbation. The extensive dataset assigns condition-specific importance to many previously unannotated genes, and suggests new functions for central metabolic enzymes. Prk, GAPDH, and CP12 were critical for mixotrophy and photoheterotrophy, which implicates the ternary complex as important for redirecting metabolic flux in these conditions in addition to inactivation of the Calvin cycle in the dark. To predict the potency of sgRNA sequences, we applied machine learning on sgRNA sequences and gene repression data, which showed the importance of C enrichment and T depletion in the first 12 bp proximal to the PAM site. Fitness data for all genes in all conditions is compiled in an interactive web application.
A comparative study of low-pH tolerance and chitinase activity between toxigenic and non-toxigenic strains ofVibrio cholerae
Authors: Jayaraman Vijay , Khan Shafqat Ali , Perinbam Kumar , Rakheja Isha , Vadakkepat Abhinav Koyamangalath , Chaudhary Santosh Kumar , Pandey Asheesh Kumar , Mitra Joydeep 
Published: February 2023

AbstractCholera toxin, encoded by thectxgene, is a key virulence factor in toxigenicVibrio cholerae(ctx+) strains. However, some non-toxigenicV. cholerae(ctx-) strains are also pathogenic to humans and the mechanism involved in low-pH tolerance and pathogenicity in these strains remains unclear. To address this, we profiled the growth and chitinase activity in different pH of two clinical isolates ofV. cholerae: VC20, actx+strain, and WO5, actx-strain. We also compared the expression level of key genes involved in pathogenesis between the strains. WO5, the non-toxigenic strain had robust growth and greater chitinase activity across a wide pH range, in comparison to VC20. Additionally, WO5 expressed higher levels of transcripts from genes implicated in host cell adhesion and virulence, namelyompKandtoxT, respectively. Notably, we propose that lowerhapRlevels in WO5 contrary to VC20 is key to its low-pH tolerance. To systematically identify genes involved in low pH tolerance, we used a sequence-based homology search and found a widespread presence of low-pH adaptation modules, lysine-cadaverine, and ornithine-putrescine in multiple representative species of theVibriophylum. Furthermore, our analysis suggests that the loss of a gene encoding nitrite reductase that confers low pH tolerance is specific toV. choleraeandV. mimicus. Together, these findings reveal that the low-pH tolerance enhances the chitinase activity of the non-toxigenic strain that could helpV. choleraeto survive the acidic environment of the stomach and readily colonize the intestine.
Maternal infection causes dysfunctional BCR signaling in male offspring due to aberrant Xist expression
Authors: Gibbs Lisa C. , Oviedo Juan M. , Ondigo Bartholomew N. , Fairfax Keke C. 
Published: February 2023

AbstractInfections during pregnancy with pathogens such as helminths correlate with altered immune responses to common childhood immunizations. However, the molecular mechanisms that underlie this remain unknown. Using our murine model of maternal schistosomiasis, when immunized, males from infected mothers had a lower frequency of antigen-specific germinal center B cells and downregulation of transcripts downstream of BCR signaling compared to males from uninfected mothers. This is driven by a reduction in developing B cell populations within the bone marrow of pups from infected mothers. Males from infected mothers were impacted to a greater extent than their female littermate counterparts. We found this defect to be caused by aberrant expression of the long non-coding RNAXistin males leading to dysregulated Igα expression on developing B cells. This, for the first time, links dysfunctional BCR signaling withXistexpression, while also proposing a detrimental function forXistexpression in males.One sentence summaryXistexpression in males decreases BCR reactivity.
Higher-order co-mutation interactions in mitochondrial genomes
Authors: Verma Rahul K , Shinde Pramod , Mishra Ankit , Jalan Sarika 
Published: February 2023

AbstractPair-wise co-mutation networks of the mitochondrial genome have already provided ample evidences about the roles of genetic interactions in the manifestation of phenotype under altered environmental conditions. Here, we present a method to construct and analyze higher-order interactions, namely, 3-uniform hypergraphs of the mitochondrial genome for different altitude populations to decipher the role of co-mutating variable sites beyond pair-wise interactions. While the weights distribution of such gene hyperedges manifested power-law for all the altitudes, we identified altitude-specific genes based on gene hyperedge weight. This framework of hypergraphs serves a promising avenue for future investigation of nuclear genomes in context of phenotypic association and genetic disorders.