bluuebunny/crossref_metadata_2025 huggingface dataset:
Revealing the neural representations underlying other-race face perception
Authors: Shoura Moaz , Liang Yong Zhong , Sama Marco , De Arijit , Nestor Adrian
Published: September 2024

The other-race effect, a disadvantage at recognizing faces of other races than one’s own, has received considerable attention, especially regarding its wide scope and underlying mechanisms. Here, we aim to elucidate its neural and representational basis by relating behavioral performance in East Asian and White individuals to neural decoding and image reconstruction relying on electroencephalography data. Our investigation uncovers a reliable neural counterpart of the other-race effect (i.e., a decoding disadvantage for other-race faces) along with its extended dynamics and prominence across individuals. Further, it retrieves, via neural-based image reconstruction, visual representations underlying other-race face perception and their intrinsic biases. Notably, our data-driven approach reveals that other-race faces are perceived not just as more typical but, also, as younger and more expressive. These findings, pointing to multiple visual biases surrounding the other-race effect, speak to the complexity of its neural mechanisms and its social implications.
Magnetic Resonance Imaging of Gastric Motility in Conscious Rats
Authors: Wang Xiaokai , Alkaabi Fatimah , Cornett Ashley , Choi Minkyu , Scheven Ulrich M. , Di Natale Madeleine R. , Furness John B. , Liu Zhongming
Published: September 2024

Introduction

Gastrointestinal (GI) magnetic resonance imaging (MRI) can simultaneously capture gastric peristalsis, emptying, and intestinal filling and transit. Performing GI MRI with animals requires anesthesia, which complicates physiology and confounds interpretation and translation from animals to humans. This study aims to enable MRI in conscious rats, and for the first time, characterize GI motor functions in awake versus anesthetized conditions.

Methods

We acclimated rats to remain awake, still, and minimally stressed during MRI. We scanned 14 Sprague-Dawley rats in both awake and anesthetized conditions after voluntarily consuming a contrast-enhanced test meal.

Results

Awake rats remained physiologically stable during MRI, showed gastric emptying of 23.7±1.4% after 48 minutes, and exhibited strong peristaltic contractions propagating through the antrum with a velocity of 0.72±0.04 mm/s, a relative amplitude of 40.7±2.3%, and a frequency of 5.1±0.1 cycles per minute. In the anesthetized condition, gastric emptying was about half of that in the awake condition, likely due to the effect of anesthesia in halving the amplitudes of peristaltic contractions rather than their frequency (not significantly changed) or velocity. In awake rats, the intestine filled more quickly and propulsive contractions were more occlusive.

Conclusion

We demonstrated the effective acquisition and analysis of GI MRI in awake rats. Awake rats show faster gastric emptying, stronger gastric contraction with a faster propagation speed, and more effective intestinal filling and transit, compared to anesthetized rats. Our protocol is expected to benefit future preclinical studies of GI physiology and pathophysiology.
Epigenetic adaptation drives monocyte differentiation into microglia-like cells upon engraftment into the retina
Authors: Liu Jie , Lei Fengyang , Yan Bin , Cui Naiwen , Sharma Jyoti , Correa Victor , Roach Lara , Nicolaou Savvas , Pitts Kristen , Chodosh James , Maidana Daniel E. , Vavvas Demetrios , Margeta Milica A , Zhang Huidan , Weitz David , Mostoslavsky Raul , Paschalis Eleftherios I.
Published: September 2024

The identification of specific markers for microglia has been a long-standing challenge. Recently, markers such as P2ry12, TMEM119, and Fcrls have been proposed as microglia-specific and widely used to explore microglial functions within various central nervous system (CNS) contexts. The specificity of these markers was based on the assumption that circulating monocytes retain their distinct signatures even after infiltrating the CNS. However, recent findings reveal that infiltrating monocytes can adopt microglia-like characteristics while maintaining a pro-inflammatory profile upon permanent engraftment in the CNS.In this study, we utilize bone marrow chimeras, single-cell RNA sequencing, ATAC-seq, flow cytometry, and immunohistochemistry to demonstrate that engrafted monocytes acquire expression of established microglia markers—P2ry12, TMEM119, Fcrls—and the pan-myeloid marker Iba1, which has been commonly mischaracterized as microglia-specific. These changes are accompanied by alterations in chromatin accessibility and shifts in chromatin binding motifs that are indicative of microglial identity. Moreover, we show that engrafted monocytes dynamically regulate the expression of CX3CR1, CCR2, Ly6C, and transcription factors PU.1, CTCF, RUNX, AP-1, CEBP, and IRF2, all of which are crucial for shaping microglial identity. This study is the first to illustrate that engrafted monocytes in the retina undergo both epigenetic and transcriptional changes, enabling them to express microglia-like signatures. These findings highlight the need for future research to account for these changes when assessing the roles of monocytes and microglia in CNS pathology.

Significance Statement

Monocytes can express putative microglia markers P2ry12, TMEM119, and Fcrls upon engraftment into the retina. Given their involvement in neuroinflammation, it is crucial to consider this overlap when utilizing these markers for experimental analysis.
Treatment of anti-myeloperoxidase glomerulonephritis using recombinant deoxyribonuclease I is enhanced by adeno-associated virus gene therapy
Authors: Cao Le Anne , Oudin Virginie , Dick Jonathan , Alikhan Maliha A. , Cheong Daniel Koo Yuk , Mandwie Mawj , Alexander Ian E , Kitching A. Richard , Gan Poh-Yi , Logan Grant J , O’Sullivan Kim M
Published: September 2024

Extracellular DNA (ecDNA) released from injured and dying cells powerfully induces injurious inflammation. In this study we define the role of ecDNA in systemic vasculitis affecting the kidney, using human kidney biopsies and murine models of myeloperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (MPO-ANCA GN). Twice daily administration of intravenous DNase I (ivDNase I) in two models of anti-MPO GN reduced glomerular deposition of ecDNA, histological injury, leukocyte infiltration and NETosis. Comprehensive investigation into DNase I modes of action revealed that after exposure to MPO, DNase I reduced lymph node DC numbers and their activation status, resulting in decreased frequency of MPO-specific CD4 effector T cells (IFN-γ, and IL-17A producing), and reductions in dermal anti-MPO delayed type hypersensitivity responses. To overcome the translational obstacle of the short half-life of DNase I (<5 hours), we tested an adeno-associated viral vector encoding DNase I (vec-DNase I). The method of DNase I delivery was more effective, as in addition to the histological and anti-inflammatory changes described above, a single vector treatment also reduced circulating MPO-ANCA titers and albuminuria. These results indicate ecDNA is a potent driver of anti-MPO GN and that DNase I is a potential therapeutic that can be delivered using gene technology.
Survey of gene, lncRNA and transposon transcription patterns in four mouse organs highlights shared and organ-specific sex-biased regulation
Authors: Zhuang Qinwei Kim-Wee , Bauermeister Klara , Galvez Jose Hector , Alogayil Najla , Batdorj Enkhjin , Pardo Manuel de Villena Fernando , Taketo Teruko , Bourque Guillaume , Naumova Anna K.
Published: September 2024

Background

Sex-biased gene regulation is the basis of sexual dimorphism in phenotypes and has been studied across different cell types and different developmental stages. However, sex-biased expression of transposable elements (TEs) that represent nearly half of the mammalian genome and have the potential of influencing genome integrity and regulation, remains underexplored.

Results

Here, we report a survey of gene, lncRNA and TE expression in four organs from mice with different combinations of gonadal and genetic sex. Data show remarkable variability among organs with respect to the impact of gonadal sex on transcription with the strongest effects observed in liver. In contrast, the X-chromosome dosage alone had modest influence on sex-biased transcription across different organs, albeit interaction between X-dosage and gonadal sex cannot be ruled out. The presence of the Y chromosome influenced TE, but not gene or lncRNA expression in liver. Notably, 90% of sex-biased TEs (sDETEs) reside in clusters. Moreover, 54% of these clusters overlap or reside close (<100 kb) to sex-biased genes or lncRNAs, share the same sex bias, and also have higher expression levels than sDETE clusters that do not co-localize with other types of sex-biased transcripts. We also tested the heterochromatic sink hypothesis that predicts higher expression of TEs in XX individuals and found no evidence to support it.

Conclusions

Our data show that sex-biased expression of TEs varies among organs with highest numbers of sDETEs found in liver following the trends observed for genes and lncRNAs. It is enhanced by proximity to other types of sex-biased transcripts.
Associations on the Fly, a new feature aiming to facilitate exploration of the Open Targets Platform evidence
Authors: Cruz-Castillo C , Fumis L , Mehta C , Martinez-Osorio RE , Roldan-Romero JM , Cornu H , Uniyal P , Solano-Roman A , Carmona M , Ochoa D , McDonagh E , Buniello A
Published: September 2024

Motivation

The Open Targets Platform (https://platform.opentargets.org) is a unique, comprehensive, open-source resource supporting systematic identification and prioritisation of targets for drug discovery. The Platform combines, harmonises and integrates data from >20 diverse sources to provide target-disease associations, covering evidence derived from genetic associations, somatic mutations, known drugs, differential expression, animal models, pathways and systems biology. An in-house target identification scoring framework weighs the evidence from each data source and type, contributing to an overall score for each of the 7.8M target-disease associations. However, the previous infrastructure did not allow user-led dynamic adjustments in the contribution of different evidence types for target prioritisation, a limitation frequently raised by our user community. Furthermore, the previous Platform user interface did not support navigation and exploration of the underlying target-disease evidence on the same page, occasionally making the user journey counterintuitive.

Results

Here, we describe “Associations on the Fly” (AOTF), a new Platform feature - developed as part of a wider product refactoring project - to enable formulation of more flexible and impactful therapeutic hypotheses through dynamic adjustment of the weight of contributing evidence from each source, altering the prioritisation of targets.

Availability and implementation

All Open Targets code is available as open source: [https://github.com/opentargets].

This tool was implemented using React v18 and its code is accessible here: [https://github.com/opentargets/ot-ui-apps].

The tools described in the paper are accessible through the Open Targets Platform web interface [https://platform.opentargets.org/] and GraphQL API (https://platform-docs.opentargets.org/data-access/graphql-api).

Data is available for download here: [https://platform.opentargets.org/downloads] and from the EMBL-EBI FTP: [https://ftp.ebi.ac.uk/pub/databases/opentargets/platform/].

Supplementary information

Additional information on this tool can be found on the Platform documentation pages [https://platform-docs.opentargets.org/web-interface,https://platform-docs.opentargets.org/web-interface/associations-on-the-fly,https://platform-docs.opentargets.org/target-prioritisation] and training video [https://youtu.be/2A9bksboAag].

Contact

Annalisa Buniello, EMBL-EBI,buniello@ebi.ac.uk
Optimizing the Fabrication of Shape-Defined Microparticles for Sustained Drug Delivery: the ‘Less is More’ paradigm
Authors: Murgia Denise , Estevão Bianca Martins , Portioli Corinne , Palomba Roberto , Decuzzi Paolo
Published: September 2024

Polymeric microparticles find extensive use in several pharmaceutical applications. Our group has developed poly(lactic-co-glycolic acid) (PLGA) microPLates (μPL) featuring a square base of 20×20 μm and a height of 10 μm, for the controlled and sustained delivery of a range of therapeutic payloads, including anti-inflammatory and anti-cancer drugs, small molecules for neurodevelopmental disorders, and siRNA for osteoarthritis. In this study, the morphological and pharmacological properties of PLGA-μPL were optimized by introducing new steps in the original fabrication protocol and systematically varying the polymer content. Vacuum suction was used to control solvent removal, and two different ‘cleaning’ steps were tested, resulting in six different μPL configurations with a PLGA content ranging from 2 to 10 mg. Electron and optical microscopy analyses confirmed the well-defined square shape of μPL, with a central concavity depending on the PLGA content. Fabrication yielding ranged between 10% and 70%, while encapsulation efficiencies reached approximately 15% using curcumin (CURC) as a model drug. The kinetics of CURC release was analyzed using the semi-empirical model of Korsmeyer-Peppas, suggesting either a Fickian diffusion or anomalous transport mechanisms based on the PLGA amounts. Complementary techniques were used to assess morphological alterations and mass loss, evaluating the degradation μPL over time in water and physiological solutions. Unexpectedly, μPL configurations with lower PLGA contents exhibited higher fabrication yielding, drug encapsulation, and slower drug release. The optimized fabrication approach offers greater flexibility to tailor the degradation and pharmacological properties of μPL for various therapeutic applications.
Effect of Alcohol and Cocaine Abuse on Neuronal and Non-Neuronal Cell Turnover in the Adult Human Hippocampus
Authors: Alkass Kanar , Steiner Embla , Bernard Samuel , Le Maître Tara Wardi , Dhanabalan Gopalakrishnan , Landén Mikael , Spalding Kirsty , Frisén Jonas , Mash Deborah C , Druid Henrik
Published: September 2024

Clinical studies on humans with a history of chronic abuse of alcohol or cocaine show cognitive impairments associated with hippocampal atrophy. Adult hippocampal neurogenesis is a process important for memory formation and has been shown to be impaired by alcohol and cocaine in rodent models. It has thus been suggested that a reduction in adult neurogenesis may contribute to cognitive dysfunctions seen in patients with abuse. In addition, reduced adult neurogenesis has been suggested to play a role in the pathology of addiction vulnerability. We have previously demonstrated persistent adult hippocampal neurogenesis throughout life by measuring14C concentrations in genomic DNA, incorporated during cell division, in a mixed cohort of subjects. In this study, we use the same strategy to assess the extent of cell turnover of neuronal and non-neuronal cells in the hippocampus of humans with known history of alcohol and cocaine abuse and compare these with healthy controls. We find that there is significant neuronal and non-neuronal turnover in healthy controls, as well as in individuals with long term alcohol use orcocaine use. Using mathematical modelling, we compare the extent of cell turnover of neurons and non-neuronal cells and did not find any significant difference between healthy controls and the two addiction groups. While we cannot exclude scenarios of altered adult neurogenesis over shorter periods of time, our data does not support the theory of low neurogenesis as a mechanism of addiction vulnerability.
Task-relevant representational spaces in human memory traces
Authors: Heinen Rebekka , Rau Elias M.B. , Herweg Nora A. , Axmacher Nikolai
Published: September 2024

During encoding, stimuli are embedded into memory traces that allow for their later retrieval. However, we cannot remember every aspect of our experiences. Here, we show that memory traces consist of multidimensional representational spaces whose formats are flexibly strengthened or weakened during encoding and consolidation. In a series of behavioral experiments, participants compared pairs of natural images on either two conceptual or two perceptual dimensions, leading them to incorporate the images into representational “spaces”. We found that distances in task-relevant but not irrelevant spaces affected memory strengths. Interestingly, conceptual encoding did not impair subsequent rejection of similar lures, suggesting that task-irrelevant perceptual information remained in the memory trace. However, targeted memory reactivation following conceptual encoding deteriorated perceptual discrimination, indicating that it weakened the accessibility of perceptual formats. Our results demonstrate that representational formats are flexibly incorporated into memory, and more generally show how the organization of information in cognitive representational spaces shapes behavior.
Identifying, Prioritizing, and Visualizing Functional Promoter SNVs with the Recurrence-agnostic REMIND-Cancer Pipeline and pSNV Hunter
Authors: Abad Nicholas Allen Baclig , Glas Irina , Hong Chen , Pageaud Yoann , Hutter Barbara , Brors Benedikt , Korner Cindy , Feuerbach Lars
Published: September 2024

Cancer is a heterogeneous disease that arises due to mutations that drive cancer progression. However, the identification of these functional mutations has typically focused only on protein-coding DNA. Among non-coding mutations, only a few have been clearly associated with cancer. We hypothesize that this gap in discovery is partly due to the limitations of current methods requiring high recurrence of mutations. To support candidate selection for experimental validation of lowly recurrent and singleton promoter mutations, new computational approaches for the integrated analysis of multi-omics data are required. To address this challenge, the REMIND-Cancer Pipeline leverages whole-genome sequencing and RNA-Seq data to extract and prioritize functional promoter mutations, regardless of their recurrence status. Subsequently, pSNV Hunter aggregates and visualizes comprehensive information for each candidate. We demonstrate the functionality of both tools by applying it to the PCAWG dataset. This workflow successfully identified and prioritized known highly-recurrent mutations, as well as, novel singletons and lowly recurrent candidates. Hence, the output of our workflow directly supports hypothesis generation for subsequent experimental validation to overcome limitations of recurrence-based approaches.
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

Astrocytes 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.

Highlights

Single-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

Protein 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

Control 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

Platelets 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.

Significance

We 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

Background

Diabetic 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.

Methods

We 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).

Results

We 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.

Conclusion

We 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

The 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

Vibration 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

Locomotion 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.
Lack of cortistatin worsens neurological outcome and exacerbates aging-related glial and vascular dysfunction in stroke
Authors: Castillo Gonzalez Julia , Vargas Rodriguez Pablo , Serrano Martinez Ignacio , Forte-Lago Irene , Price Melanie , Buscemi Lara , Hirt Lorenz , Gonzalez-Rey Elena
Published: September 2024

Ischemic stroke is the second leading cause of death globally. Neuroinflammation, blood-brain barrier (BBB) disruption, and immune dysregulation are key features of the pathogenesis and clinical outcomes of brain ischemia. A comprehensive understanding of the interconnected mechanisms and endogenous mediators that regulate these processes is essential for the development of effective therapeutic strategies. In this context, the present study investigates the role of cortistatin, a neuropeptide broadly distributed within the central nervous and immune systems. Given its anti-inflammatory, immunomodulatory, and neuroprotective properties, cortistatin positions as a promising endogenous factor in the pathogenesis of ischemic stroke. To evaluate its potential effects, we employed the widely recognized preclinical model of stroke, middle cerebral artery occlusion (MCAO), in young (3 months) and middle-aged (6 months) cortistatin-deficient mice and compared them with wild-type mice, assessing both short-term (48 hours) and long-term (7 days) outcomes. Our findings indicate that cortistatin deficiency in both young and middle-aged mice results in increased susceptibility to stroke and a significantly worsened prognosis, characterized by severe neurological deficits, altered microglial activity, impaired astrocytic scar formation, BBB disruption, dysregulated angiogenesis, and exacerbated immune infiltration and peripheral immune responses. Notably, the administration of cortistatin reversed these adverse outcomes, underscoring the critical role of cortistatin in regulating the complex interactions between the nervous and immune systems. Furthermore, cortistatin treatment for one week markedly improved key processes involved in stroke recovery, including neuronal repopulation, myelin repair, and the restoration of BBB integrity. The multifaceted therapeutic effects of cortistatin across various pathological stages and phenotypes suggest that multimodal therapies could represent a novel and more effective approach for treating ischemic stroke, offering advantages over current interventions that typically target only a single aspect of stroke pathology. In conclusion, our findings emphasize the significance of identifying the endogenous and therapeutic roles of neuro-immune mediators such as cortistatin in ischemic stroke
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

Soils 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

Abstracts

Munage, 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

Spinal 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 summary

Schematic 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.
Tomato cystatin SlCYS8 as a trigger of drought tolerance and tuber yield in potato
Authors: Dorval Maude , Langlois Andréane , Tremblay Jonathan , Veillet Gabrielle , Chiasson Marc-Antoine , Goulet Marie-Claire , Gumiere Thiago , Pepin Steeve , Goulet Charles , Michaud Dominique
Published: September 2024

Current climate change scenarios predict an increased incidence of drought episodes likely to affect potato crops worldwide. Potato exhibits a low-density, shallow root system that makes it particularly vulnerable to water shortage and any successful attempt to implement drought tolerance in cultivated potato varieties is potentially relevant from an agronomic standpoint. In this study, we assessed the potential of tomato cystatin SlCYS8 to promote drought tolerance in SlCYS8-expressing potato lines by induction of stress-related pleiotropy. Up to now, protease inhibitors of the cystatin protein superfamily have been mostly considered as biotechnological tools to engineer pest or pathogen resistance in crops, but several recent studies have also revealed a possible link between abiotic stress tolerance and these regulatory proteins in leaf tissue. SlCYS8-expressing plantlets grown on culture medium containing the drought mimic polyethylene glycol (PEG) exhibited an elevated root-to-shoot ratio, an indicator of drought tolerance in potato. A similar conclusion could be drawn with greenhouse-grown acclimated plants, confirming a relative root growth-promoting effect for the recombinant inhibitor upon water deficit. SlCYS8-potato lines also showed a high tuber yield compared to the control line under both limiting and non-limiting water regimes, suggesting an improved efficiency of the primary metabolism and the avoidance of a growth– stress response tradeoff in the modified lines. Accordingly, SlCYS8 expression was associated with a stress response-oriented proteome in leaves likely explained by pleiotropic effects of the recombinant cystatin driving the constitutive expression of stress-related proteins and the upregulation of primary metabolism-associated proteins. Overall, these data suggest the potential of cystatins as molecular triggers of tuber biomass production and drought resilience in potato. Complementary studies will be warranted to assess tuber yield of the SlCYS8-lines under different water regimes in field conditions.