bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stab Wound Injury Elicits Transit Amplifying Progenitor-like Phenotype in Parenchymal Astrocytes
Authors: Maddhesiya Priya , Berger Finja , Koupourtidou Christina , Zambusi Alessandro , Novoselc Klara Tereza , Fischer-Sternjak Judith , Simon Tatiana , Olpe Cora , Jessberger Sebastian , Götz Magdalena , Ninkovic Jovica 
Published: September 2024

AbstractAstrocytes exhibit dual roles in central nervous system (CNS) recovery, offering both beneficial and detrimental effects. Following CNS injury, a subset of astrocytes undergoes proliferation, de-differentiation, and acquires self-renewal and neurosphere-forming capabilitiesin vitro.This subset of astrocytes represents a promising target for initiating brain repair processes and holds potential for neural recovery. However, studying these rare plastic astrocytes is challenging due to the absence of distinct markers. In our study, we characterized these astrocytic subpopulations using comparative single-cell transcriptome analysis. By leveraging the regenerative properties observed in radial glia of zebrafish, we identified and characterized injury-induced plastic astrocytes in mice. These injury-induced astrocytic subpopulations were predominantly proliferative and demonstrated the capacity for self-renewal and neurosphere formation, ultimately differentiating exclusively into astrocytes. Integration with scRNAseq data of the subependymal zone (SEZ) allowed us to trace the origins of these injury-induced plastic astrocytic subpopulations to parenchymal astrocytes. Our analysis revealed that a subset of these injury-induced astrocytes shares transcriptional similarities with endogenous transient amplifying progenitors (TAPs) within the SEZ, rather than with neural stem cells (NSCs). Notably, these injury-induced TAP-like cells exhibit distinct differentiation trajectories, favoring gliogenic over neurogenic differentiation. In summary, our study identifies a rare subset of injury-induced, proliferative plastic astrocytes with neurosphere-forming capacities. These cells originate from reactive astrocytes and resemble TAPs in their transcriptional profile. This study enhances our understanding of astrocyte plasticity post-injury.HighlightsSingle-cell transcriptomics and cross-species comparisons reveal proliferative and de-differentiated plastic astrocytes following CNS injury.Injury-induced de-differentiated astrocytes exhibit remarkablein vitroself-renewal and neurosphere formation but favor glial differentiation.De-differentiated astrocytes exhibit transcriptional similarities to transit-amplifying progenitors (TAPs) over neural stem cells (NSCs)Injury-induced TAP-like progenitors exhibit limited spontaneous neuronal differentiation.
Reduction of RAD23A extends lifespan and mitigates pathology in TDP-43 mice
Authors: Xueshui Guo , Prajapati Ravindra , Chun Jiyeon , Byun Insuk , Gebis Kamil K , Wang Yi-Zhi , Ling Karen , Dalton Casey , Blair Jeff A. , Hamidianjahromi Anahid , Bachmann Gemma , Rigo Frank , Jafar-nejad Paymaan , Savas Jeffrey N. , Lee Min Jae , Sreedharan Jemeen , Kalb Robert G. 
Published: September 2024

AbstractProtein misfolding and aggregation are cardinal features of neurodegenerative disease (NDD) and they contribute to pathophysiology by both loss-of-function (LOF) and gain-of-function (GOF) mechanisms. This is well exemplified by TDP-43 which aggregates and mislocalizes in several NDDs. The depletion of nuclear TDP-43 leads to reduction in its normal function in RNA metabolism and the cytoplasmic accumulation of TDP-43 leads to aberrant protein homeostasis. A modifier screen found that loss ofrad23suppressed TDP-43 pathology in invertebrate and tissue culture models. Here we show in a mouse model of TDP-43 pathology that genetic or antisense oligonucleotide (ASO)-mediated reduction inrad23aconfers benefits on survival and behavior, histological hallmarks of disease and reduction of mislocalized and aggregated TDP-43. This results in improved function of the ubiquitin-proteasome system (UPS) and correction of transcriptomic alterations evoked by pathologic TDP-43. RAD23A-dependent remodeling of the insoluble proteome appears to be a key event driving pathology in this model. As TDP-43 pathology is prevalent in both familial and sporadic NDD, targetingRAD23Amay have therapeutic potential.
Synthetic G-quadruplex components for predictable, precise two-level control of mammalian recombinant protein expression
Authors: Pohle Melinda , Curry Edward , Gibson Suzanne , Brown Adam 
Published: September 2024

AbstractControl of mammalian recombinant protein expression underpins thein vitromanufacture andin vivoperformance of all biopharmaceutical products. However, routine optimization of protein expression levels in these applications is hampered by a paucity of genetic elements that function predictably across varying molecular formats and host cell contexts. Herein, we describe synthetic genetic components that are specifically built to simplify bioindustrial expression cassette design processes. Synthetic G-quadruplex elements with varying sequence feature compositions were systematically designed to exhibit a wide-range of regulatory activities, and inserted into identified optimal positions within a standardized, bioindustry compatible core promoter-5’UTR control unit. The resulting library tuned protein production rates over two orders of magnitude, where DNA and RNA G-quadruplexes could be deployed individually, or in combination to achieve synergistic two-level regulatory control. We demonstrate these components can predictably and precisely tailor protein expression levels in i) varying gene therapy and biomanufacturing cell hosts, and ii) both plasmid DNA and synthetic mRNA contexts. As an exemplar use-case, a vector design platform was created to facilitate rapid optimization of polypeptide expression ratios for difficult-to-express multichain products. Permitting simple, predictable titration of recombinant protein expression, this technology should prove useful for gene therapy and biopharmaceutical manufacturing applications.
Platelet PI3Kβ regulates breast cancer metastasis
Authors: Graff Ryan C , Haimowitz Adam , Aguilan Jennifer T , Levine Adriana , Zhang Jinghang , Yuan Wenlin , Roose-Girma Merone , Seshagiri Somasekar , Porcelli Steven A , Gamble Matthew J , Sidoli Simone , Bresnick Anne R , Backer Jonathan M 
Published: September 2024

AbstractPlatelets promote tumor metastasis by several mechanisms. Platelet-tumor cell interactions induce the release of platelet cytokines, chemokines, and other factors that promote tumor cell epithelial-mesenchymal transition and invasion, granulocyte recruitment to circulating tumor cells (CTCs), and adhesion of CTCs to the endothelium, assisting in their extravasation at metastatic sites. Previous studies have shown that platelet activation in the context of thrombus formation requires the Class IA PI 3-kinase PI3Kβ. We now define a role for platelet PI3Kβ in breast cancer metastasis. Platelet PI3Kβ is essential for platelet-stimulated tumor cell invasion through Matrigel. Consistent with this finding,in vitroplatelet-tumor cell binding and tumor cell-stimulated platelet activation are reduced in platelets isolated from PI3Kβ mutant mice. RNAseq and proteomic analysis of human breast epithelial cells co-cultured with platelets revealed that platelet PI3Kβ regulates the expression of EMT and metastasis-associated genes in these cells. The EMT and metastasis-associated proteins PAI-1 and IL-8 were specifically downregulated in co-cultures with PI3Kβ mutant platelets. PI3Kβ mutant platelets are impaired in their ability to stimulate YAP and Smad2 signaling in tumor cells, two pathways regulating PAI-1 expression. Finally, we show that mice expressing mutant PI3Kβ show reduced spontaneous metastasis, and platelets isolated from these mice are less able to stimulate experimental metastasis in WT mice. Taken together, these data support a role for platelet PI3Kβ in promoting breast cancer metastasis and highlight platelet PI3Kβ as a potential therapeutic target.SignificanceWe demonstrate that platelet PI3Kβ regulates metastasis, broadening the potential use of PI3Kβ-selective inhibitors as novel agents to treat metastasis.
Identification and Validation of Mitophagy-Related Genes in Diabetic Retinopathy
Authors: Peng Wenxuan , Zou Yulin 
Published: September 2024

BackgroundDiabetic retinopathy is one of the common chronic complications of diabetes, characterized by retinal microvascular and neurodegenerative impairment, and it is the primary cause of vision impairment and blindness in adults. Many studies have demonstrated that mitophagy plays a significant role in the pathological mechanism of DR. however, its mechanism is not yet fully clear and requires further research.MethodsWe obtained relevant datasets of diabetic retinopathy from the GEO database and used R language to screen for differentially expressed genes. We intersected these genes with mitophagy-related genes and identified differentially expressed mitophagy-related genes. We performed GO and KEGG analysis on the differentially expressed mitophagy-related genes, followed by PPI network analysis. Using Cytoscape software, we selected mitophagy hub genes. Finally, we further validated the expression of the mitophagy hub genes in an in vitro cell culture high-glucose model using quantitative real-time polymerase chain reaction (qRT-PCR).ResultsWe identified 27 differentially expressed genes related to mitophagy by using R language, with 10 genes upregulated and 17 genes down regulated. We performed GO and KEGG enrichment analysis using R software to further study the potential biological functions of differentially expressed genes. Through PPI network analysis and Cytoscape software, we selected 10 hub genes associated with mitophagy. Finally, through qRT-PCR validation of these 10 hub genes, we found that the mRNA expression differences of MFN1, BNIP3L, GABARAPL1, and PINK1 genes were consistent with our bioinformatics analysis results.ConclusionWe consider that MFN1, BNIP3L, GABARAPL1, and PINK1 may serve as potential biomarkers for diabetic retinopathy. The upregulation and downregulation of these genes provide new insights for further exploration of the role of mitophagy in the pathological mechanism of diabetic retinopathy. These genes can serve as new potential therapeutic targets for the treatment of diabetic retinopathy.
The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain
Authors: Gerlach Jule , Pireddu Paola , Zhang Xiaoqun , Wetzel Simon , Mennuni Mara , Milenkovic Dusanka , Nolte Hendrik , Branzell Niclas , Kaya Ibrahim , Villegas Rodolfo Garcia , Rubalcava-Gracia Diana , Alsina David , Feederle Regina , Andrén Per E. , Langer Thomas , Svenningsson Per , Filograna Roberta 
Published: September 2024

AbstractThe highly conserved CHCHD2 and CHCHD10 are small mitochondrial proteins residing in the intermembrane space. Recently, mutations in theCHCHD2andCHCHD10genes have been linked to severe disorders, including Parkinson’s disease and amyotrophic lateral sclerosis. In cultured cells, a small fraction of CHCHD2 and CHCHD10 oligomerize to form a high molecular weight complex of unknown function. Here, we generated a whole-bodyChchd2knockout mouse to investigate thein vivorole of CHCHD2 and its protein complex. We show that CHCHD2 is crucial for sustaining full motor capacity, normal striatal dopamine levels, and lipid homeostasis in the brain of adult male mice. We also demonstrate that in mouse tissues, CHCHD2 and CHCHD10 exist exclusively as a high molecular weight complex, whose levels are finely tuned under physiological conditions. In response to mitochondrial dysfunction, the abundance and size of the CHCHD2-CHCHD10 complex increases, a mechanism conserved across different tissues. Although the loss of CHCHD2 does not abolish CHCHD10 oligomerization, it enhances cell vulnerability to mitochondrial stress, suggesting that CHCHD2 is protective against mitochondrial damage. Our findings uncover the role of CHCHD2 in preserving tissue homeostasis and provide important insights into the involvement of the CHCHD2-CHCHD10 complex in human diseases.
Vibrotactile auricular vagus nerve stimulation alters limbic system connectivity in humans: A pilot study
Authors: Donovan Kara M. , Adams Joshua D. , Park Ki Yun , Demarest Phillip , Tan Gansheng , Willie Jon T. , Brunner Peter , Gorlewicz Jenna L. , Leuthardt Eric C. 
Published: September 2024

AbstractVibration offers a potential alternative modality for transcutaneous auricular vagus nerve stimulation (taVNS). However, mechanisms of action are not well-defined. The goal of this study was to evaluate the potential of vibrotactile stimulation as a method for activating central brain regions akin to other vagal nerve stimulation methodologies. To do so, intracranial electrophysiological signals were recorded in human subjects to perform a parametric characterization of vibrotactile taVNS and investigate changes in coherence across key brain regions. We hypothesized that vibrotactile taVNS would increase coherence between limbic brain areas, similar to areas activated by classic electrical VNS approaches. Our specific regions of interest included the orbitofrontal cortex, anterior cingulate cortex, amygdala, hippocampus, and parahippocampal gyrus. Patients with intractable epilepsy undergoing stereotactic electroencephalography (sEEG) monitoring participated in the study. Vibrotactile taVNS was administered across five vibration frequencies following a randomized stimulation on/off pattern, and sEEG signals were recorded throughout. Spectral coherence in response to stimulation was defined across four canonical frequency bands, theta, alpha, beta, and broadband gamma. At the group level, vibrotactile taVNS resulted in significantly increased global low-frequency coherence. Anatomically, multiple limbic brain regions exhibited notably increased coherence during taVNS compared to baseline. The percentage of total electrode pairs demonstrating increased coherence was also quantified at the individual level. 20 Hz vibration resulted in the highest percentage of responder pairs across low-frequency coherence measures, but notable inter-subject variability was present. Overall, vibrotactile taVNS induced significant low-frequency coherence increases involving several limbic system structures. Further, parametric characterization revealed the presence of inter-subject variability in terms of identifying the optimal vibration frequency. These findings encourage continued research into vibrotactile stimulation as an alternative modality for noninvasive vagus nerve stimulation.
Operation of spinal sensorimotor circuits controlling phase durations during tied-belt and split-belt locomotion after a lateral thoracic hemisection
Authors: Rybak Ilya A. , Shevtsova Natalia A. , Audet Johannie , Yassine Sirine , Markin Sergey N. , Prilutsky Boris I. , Frigon Alain 
Published: September 2024

AbstractLocomotion is controlled by spinal circuits that interact with supraspinal drives and sensory feedback from the limbs. These sensorimotor interactions are disrupted following spinal cord injury. The thoracic lateral hemisection represents an experimental model of an incomplete spinal cord injury, where connections between the brain and spinal cord are abolished on one side of the cord. To investigate the effects of such an injury on the operation of the spinal locomotor network, we used our computational model of cat locomotion recently published ineLife(Rybak et al., 2024) to investigate and predict changes in cycle and phase durations following a thoracic lateral hemisection during treadmill locomotion in tied-belt (equal left-right speeds) and split-belt (unequal left-right speeds) conditions. In our simulations, the “hemisection” was always applied to the right side. Based on our model, we hypothesized that following hemisection, the contralesional (“intact”, left) side of the spinal network is mostly controlled by supraspinal drives, whereas the ipsilesional (“hemisected”, right) side is mostly controlled by somatosensory feedback. We then compared the simulated results with those obtained during experiments in adult cats before and after a mid-thoracic lateral hemisection on the right side in the same locomotor conditions. Our experimental results confirmed many effects of hemisection on cat locomotion predicted by our simulations. We show that having the ipsilesional hindlimb step on the slow belt, but not the fast belt, during split-belt locomotion substantially reduces the effects of lateral hemisection. The model provides explanations for changes in temporal characteristics of hindlimb locomotion following hemisection based on altered interactions between spinal circuits, supraspinal drives, and somatosensory feedback.
No enhancement of soil carbon persistence by sheep grazing in a long-term calcareous grassland experiment
Authors: Encarnation David , Ashworth Deborah , Bardgett Richard , Edwards Mona , Hambler Clive , Kristensen Jeppe , Hector Andy 
Published: September 2024

AbstractSoils hold a globally important carbon pool that is generally more persistent than the carbon stored in plant biomass. However, this carbon is becoming increasingly vulnerable to disturbances such as soil warming, fire, and erosion. Managing land to increase soil carbon sequestration and persistence may therefore improve long-term soil carbon storage and contribute to climate change mitigation. It has been hypothesized that grazing by large herbivores may enhance the persistence of soil carbon by increasing the amount of soil organic matter forming more stable associations with mineral particles (mineral-associated organic matter). We compared sheep-grazed and ungrazed plots within the Gibson Grazing and Successional Experiment located in the Upper Seeds calcareous grassland in Wytham Woods, Oxfordshire, using organic matter fractionation to estimate the surface (0-5 cm) carbon stocks in the mineral-associated and particulate organic matter fractions. Counter to predictions, after 35 years sheep grazing had not increased mineral-associated organic matter carbon stocks relative to ungrazed plots. We hypothesize that this indicates the saturation of mineral surfaces in both grazed and ungrazed treatments and the inability of grazing to increase soil nitrogen stocks and decrease pH to levels conducive for mineral-associated carbon sequestration. Only one of twelve soil properties examined showed statistically detectable responses to grazing: spring-grazing increased the C:N ratio in the mineral-associated organic matter. While the number of tests performed (24) means this may be a false-positive result, if genuine it would be consistent with a more direct pathway from plant exudates to mineral-associated organic matter formation due to compensatory growth in response to spring-grazing. Overall, the results of this long-term experiment do not support the hypothesis that grazing can improve the persistence of the soil carbon pool.
Haplotype-resolved assemblies provide insights into genomic makeup of the oldest grapevine cultivar (Munage) in Xinjiang
Authors: Zhong Haixia , Shi Xiaoya , Zhang Fuchun , Wang Xu , Yadav Vivek , Zhou Xiaoming , Cao Shuo , Zhang Songlin , Zhang Chuan , Qiao Jiangxia , Liu Zhongjie , Zhang Yingchun , Liu Yuting , Wang Hao , Xue Hui , Zhang Mengyan , Zhang Tianhao , Zhou Yongfeng , Wu Xinyu , Xiao Hua 
Published: September 2024

AbstractsMunage, an ancient grape variety that has been cultivated for thousands of years in Xinjiang, China, is recognized for its exceptional fruit traits. There are two main types of Munage: white fruit (WM) and red fruit (RM). However, the lack of a high-quality genomic resources has impeded effective breeding and restricted the potential for expanding these varieties to other growing regions. In this study, we assembled haplotype-resolved genome assemblies for WM and RM, alongside integrated whole genome resequencing (WGS) data and transcriptome data to illuminate specific mutations and associated genes in Munake and the genes associated with fruit color traits. Selective analysis between Munage clones and Eurasian grapes suggested that adaptive selection exists in Munage grapes, with genes enriched in processes including cell maturation, plant epidermal cell differentiation, and root epidermal cell differentiation. The study examined the mutations within Munage grapes and found that the genesPMAT2on chromosome 12 andMYB123on chromosome 13 are likely responsible for color variation in RM. These findings provide crucial genetic resources for investigating the genetics of the ancient Chinese grape variety, Munage, and will facilitate the genetic improvement in grapevine.
SMN deficiency induces an early non-atrophic myopathy with alterations in the contractile and excitatory coupling machinery of skeletal myofibers in the SMNΔ7 mouse model of spinal muscular atrophy
Authors: Berciano María T. , Gatius Alaó , Puente-Bedia Alba , Rufino-Gómez Alexis , Tarabal Olga , Rodríguez-Rey José C. , Calderó Jordi , Lafarga Miguel , Tapia Olga 
Published: September 2024

ABSTRACTSpinal muscular atrophy (SMA) is caused by a deficiency of the ubiquitously expressed survival motor neuron (SMN) protein. The main pathological hallmark of SMA is the degeneration of lower motor neurons (MNs) with subsequent denervation and atrophy of skeletal muscle. However, increasing evidence indicates that low SMN levels not only are detrimental to the central nervous system but also directly affect other peripheral tissues and organs, including skeletal muscle. To better understand the potential primary impact of SMN deficiency in muscle, we explored the cellular, ultrastructural, and molecular basis of SMA myopathy in the SMNΔ7 mouse model of severe SMA at an early postnatal period (P0-7) prior to muscle denervation and MN loss (preneurodegenerative [PND] stage). This period contrasts with the neurodegenerative (ND) stage (P8-14), in which MN loss and muscle atrophy occur. At the PND stage, we found that SMNΔ7 mice displayed early signs of motor dysfunction with overt myofiber alterations in the absence of atrophy. Focal and segmental lesions in the myofibrillar contractile apparatus were noticed in myofibers. These lesions were observed in association with specific myonuclear domains and included abnormal accumulations of actin-thin myofilaments, sarcomere disruption, and the formation of minisarcomeres. The sarcoplasmic reticulum and triads also exhibited ultrastructural alterations, suggesting decoupling during the excitation-contraction process. Finally, changes in intermyofibrillar mitochondrial organization and dynamics, indicative of mitochondrial biogenesis overactivation, were also found. Overall, our results demonstrated that SMN deficiency induces early and MN loss-independent alterations in myofibers that essentially contribute to SMA myopathy. This strongly supports the view of an intrinsic alteration of skeletal muscle in SMA, suggesting that this peripheral tissue is a key therapeutic target for the disease.Graphical summarySchematic representation of the main cellular and ultrastructural changes occurring intibialis anterior(TA) myofibers of the SMNΔ7 mouse model of severe SMA during the pre-neurodegenerative stage (PND, P0-P7). See that the PND stage is characterized by the absence of MN loss and muscular atrophy but, SMN deficient myofibers display multiple alterations. Observe the early impact of low SMN levels on sarcoplasmic reticulum and triads, myofibril contractile cytoskeleton, and intermyofibrillar mitochondria. Notice that all alterations are associated with a specific myonuclear domain. Changes in mRNA levels of different genes involved in myogenesis and mitochondrial biogenesis are also shown compared to age-matched WT animals. Figure created withBioRender.com.