bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamics of cell states and alternative splicing following kidney ischemia-reperfusion injury
Authors: Markiewitz Dana , Goldberger Jacob , Kalisky Tomer 
Published: October 2024

ABSTRACTThe progression of kidney damage in chronic kidney disease (CKD) involves multiple post-injury stages and complex cellular and molecular mechanisms that are not yet fully understood. In our study we set to characterize the dynamics of mRNA splicing following kidney injury. To this end, we analyzed publicly available bulk RNA-seq data covering nine time points following a kidney ischemia-reperfusion injury (IRI) mouse experiment. Using topic modeling we discerned five distinct temporal phases corresponding to the following cell states: “early injury response”, “injury”, “repairing”, “failed recovery”, and “healthy proximal tubule”. Additionally, we discovered a set of genes that are alternatively spliced between selected time points associated with these cell states, some of which are related to injury, stress, EMT, and apoptosis. Finally, we found several putative splicing regulators that are differentially expressed between the different time points and whose binding motifs are enriched in the vicinity of alternatively spliced exons, indicating that they may play critical roles in mRNA splicing dynamics following kidney injury and repair. These findings enhance our understanding of the molecular mechanisms involved in kidney injury and repair, offering potential avenues for developing targeted therapeutic strategies for acute kidney injury (AKI) and its progression to CKD.
NLGN3 contributes to angiogenesis in myocardial infarction via activation of the Gαi1/3-Akt Pathway
Authors: Qiao Shunsong , Tang Chao , Zhu Jingjing , Cao Cong , Feng Yu , Gu Xiaosong 
Published: October 2024

BACKGROUNDAngiogenesis is an important repair mechanism for myocardial infarction. Neuroligin-3 (NLGN3) can promote angiogenesis by activating Gαi1/3-Akt signaling following ischemic brain injury. This study investigated the role of NLGN3 in myocardial infarction (MI).METHODS AND RESULTSOn the 7thday after MI, the plasma level of NLGN3 in patients was significantly higher than in the control group. A mouse model of MI also showed significantly increased expression of NLGN3 in heart tissue. Single-nucleus transcriptome analysis revealed that NLGN3 was located predominantly in cardiac fibroblasts and endothelial cells (ECs). Endothelial-specific knockdown of NLGN3, or inhibition of NLGN3 using ADAM10i, significantly increased the ischemic area, reduced angiogenesis, and worsened cardiac function. Co-immunoprecipitation (Co-IP) experiments showed that NLGN3 interacted with Gαi1/3. The Gαi1/3 knockout (Gαi1/3-KO) mouse model of MI showed an increased ischemic area, decreased angiogenesis, and impaired cardiac function. Mechanistic studies showed that the NLGN3-Gαi1/3 signaling pathway exerts cardioprotective effects by promoting EC proliferation and tube formation through the PI3K-Akt-mTOR pathway. Silencing of Gαi1/3 largely eliminated the ability of NLGN3-promoting cardiac ECs to proliferate and form tubes.CONCLUSIONOur findings suggest the endothelial NLGN3-Gαi1/3 signaling pathway promotes angiogenesis and reduces the ischemic area following MI, which is critical for maintaining cardiac function and repairing tissues. Targeting of the NLGN3-Gαi1/3 signaling pathway may have clinical therapeutic potential in protecting the heart from ischemic injury.What Is Known?Myocardial infarction (MI) leads to a significantly increased risk of recurrent events in individually vascularized regions, which then stimulates adverse systemic vascular effects.Gαi proteins play a key role in receptor tyrosine kinase (RTK) and other non-GPCR receptor-mediated signaling.Neuroligin 3 (NLGN3) is a major member of the NLGN family of proteins that help to form synapses between neurons. It is known be cleaved and secreted in an activity-dependent manner, but its function in heart disease is still poorly understood.What New Information Does This Article Contribute?NLGN3 expression was found to be markedly increased in the heart after MI, especially in cardiac ECs.Knockdown of Gαi1/3 significantly reduced angiogenesis and impaired cardiac function, while knockdown of NLGN3 increased the ischemic area and reduced angiogenesis through Gαi1/3.NLGN3-Gαi1/3 signaling promotes vascular EC proliferation and tube formation through the PI3K-Akt-mTOR pathway, thereby protecting the ischemic heart.
Complex Properties of Training Stimuli Affect Brain Alignment in a Deep Network Model of Mouse Visual Cortex
Authors: Torabian Parsa , Chen Yinghan , Ng Candace , Mihalas Stefan , Buice Michael , Bakhtiari Shahab , Tripp Bryan 
Published: October 2024

AbstractDeep convolutional neural networks are important models of the visual cortex that ac-count relatively well for brain activity and are able to perform ethologically relevant functions. However, it is unknown which combination of factors, such as network ar-chitecture, training objectives, and data best align this family of models with the brain. Here we investigate the statistics of training data. We hypothesized that stimuli that are naturalistic for mice would lead to higher similarity between deep network models and activity in mouse visual cortex. We used a video-game engine to create training datasets in which we varied the naturalism of the environment, the movement statis-tics, and the optics of the modelled eye. The naturalistic environment substantially and consistently led to greater brain similarity, while the other factors had more subtle and area-specific effects. We then hypothesized that differences in brain similarity between the two environments arose due to differences in spatial frequency spectra, distribu-tions of color and orientation, and/or temporal autocorrelations. To test this, we created abstract environments, composed of cubes and spheres, that resembled the naturalis-tic and non-naturalistic environments in these respects. Contrary to our expectations, these factors accounted poorly for differences in brain similarity due to the naturalis-tic and non-naturalistic environments. This suggests that the higher brain similarities we observed after training with the naturalistic environment were due to more complex factors.
A Comparative Study on Deep Convolutional Neural Networks and Histogram Equalization Techniques for Glaucoma Detection From Fundus Images
Authors: Kulkarni Ashish , Ahmed H Shafeeq 
Published: October 2024

ABSTRACTAimsTo evaluate the performance of eight different convolutional neural network (CNN) models and histogram equalization techniques for glaucoma detection from fundus images.Material and MethodsThe study utilized the ACRIMA database, comprising 705 fundus images (396 glaucomatous and 309 normal). The CNN architectures evaluated include VGG-16, VGG-19, ResNet-50, ResNet-152, Inception v3, Xception, DenseNet-121, and EfficientNetB7. Two histogram-based preprocessing methods were applied: histogram equalization (HE) and contrast limited adaptive histogram equalization (CLAHE). The models were trained using supervised learning, with image augmentation techniques applied. Performance metrics such as accuracy, sensitivity, specificity, precision, negative predictive value, Dice Similarity Coefficient, and Area Under the Receiver Operating Characteristics Curve (AUC ROC) were used for evaluation.ResultsVGG-19 achieved the highest accuracy (97.9%) in the raw data setting, followed closely by VGG-16 (97.2%). ResNet-50 and ResNet-152 showed the highest specificity scores (98.4%). The sensitivity of the models ranged from 91.3% to 98.8%, with VGG-16 and VGG-19 demonstrating the highest values. CLAHE preprocessing resulted in improved performance, particularly for ResNet-152, which achieved an accuracy of 97.5% and sensitivity of 97.9%. The AUC ROC values varied from 0.937 to 0.996, with VGG-16 having the highest value (0.998).ConclusionThe study highlights the importance of selecting suitable CNN architectures and preprocessing techniques in developing effective glaucoma detection systems. While VGG-19 exhibited the highest accuracy with raw data, VGG-16 and ResNet-50 offered consistent performance across different preprocessing techniques, making them reliable options for clinical applications.
Aberrant iron deposition in the multiple sclerosis spinal cord relates to neurodegeneration
Authors: Pisa Marco , Lockhart Andrew , Angell Thomas , Avery Aimee , Waldman Alex , Rodriguez Carla , Duarte Tiago , Pansieri Jonathan , Dhari Zaenab , Bailey Mary , Hametner Simon , Drakesmith Hal , Hofer Monika , Limbaeck Clara , DeLuca Gabriele C 
Published: October 2024

AbstractBackgroundIron accumulates in microglia-macrophages at the edge of multiple sclerosis (MS) lesions in the brain. Iron-rimmed brain lesions strongly predict disability accumulation, supporting iron metabolism is crucial in MS pathology. Little is known about iron distribution in the spinal cord.MethodsAutopsy cervical, thoracic and lumbar spinal cord samples from 9 controls and 46 MS donors of whom a subset (n=36) had mesiofrontal motor cortical tissue available for study, were labelled and systematically assessed for iron (DAB-enhanced Turnbull), myelin (PLP), axons (Palmgren silver), microglia-macrophages (TMEM119, Iba1, CD68), astroglia (GFAP), oligodendroglia (OLIG2), acute axonal injury (B-APP, SMI-32, NPY-1R) and oxidative stress (E06). MS lesional and non-lesional areas were considered. Total non-haem iron was quantified by inductively coupled plasma optical emission spectroscopy (ICP-OES).ResultsIn controls, iron predominantly localised to oligodendrocytes with total non-haem iron relating to total myelin fraction, which markedly differed in MS where iron accumulated in microglia-macrophages, subpial astrocytes, and axons in non-lesional areas. Iron laden microglia-macrophages were over-represented relative to total microglial-macrophages and displayed dysmorphic features. Iron-positive axons showed a disto-proximal gradient (highest at lumbar level) with a predilection for the corticospinal tracts. The extent of iron axon positivity related to smaller spinal cord area, lower total axonal counts, and greater oxidative stress. Iron positivity in each cellular compartment (i.e. subpial astrocytes, microglia-macrophage and axons) related to one-another and total non-haem iron correlated with axonal counts in MS. No iron-rimmed lesions were detected in the spinal cord unlike in cortical grey and subcortical white matter of the same cases where 22% and 80% of iron-rimmed lesions, respectively, were seen.ConclusionsDespite the conspicuous absence of iron-rimmed lesions in the MS spinal cord, we demonstrate widespread aberrant iron distribution in the MS spinal cord that relates to oxidative stress and neurodegeneration independent of demyelination. The distal cord predominant and corticospinal tract specific accumulation of iron in axons mirrors the pattern of length-dependent motoric disability commonly encountered in progressive MS. These findings implicate aberrant iron accumulation as a novel, clinically relevant, feature of MS spinal cord pathology.
CD90 identifies distinct fractions of muscle stem cells with different modalities of activation and quiescence maintenance
Authors: Kheir Eyemen , Libergoli Michela , Metti Samuele , Jensen Jonas Brorson , Wang Jakob , Jessen Niels , Florio Francesca , Murganti Francesca , Di Savino Serena , Belicchi Marzia , Villa Chiara , Vissing Kristian , Verma Mayank , Giordani Lorenzo , Bonaldo Paolo , Torrente Yvan , Farup Jean , Biressi Stefano 
Published: October 2024

SUMMARYStem cell transition from quiescence to activation is crucial to guarantee productive tissue regeneration. Here we show that CD90 diversifies quiescent muscle stem cells (MuSCs) in murine and human muscle into two subpopulations differing in the kinetics of activation, CD90+veMuSCs exhibiting a faster exit quiescence and predominating the initial phases of regeneration compared to CD90-veMuSCs. In the absence of injury, the CD90+vefraction is primed toward activation through an active CD90-AMPK axis but is maintained in quiescence through signals from the extracellular matrix. Our studies show that Collagen VI, which is preferentially expressed by CD90+veMuSCs, binds to the Calcitonin receptor and plays a role in this context. Moreover, while the number of CD90+veand CD90-vesubpopulations is similar in healthy muscles, the CD90-vefraction predominates in the muscles of murine models of Duchenne and Ullrich congenital muscular dystrophies. These findings provide novel insights into the mechanistic determinants of MuSCs functional heterogeneity and have implications for understanding the stimulation of repair in dystrophic muscle.
Mechanical regulation of tissue flatness inMarchantia
Authors: Ferria Jordan , Fournié Carla J.A. , Jankowska Magdalena H. , Grossman Doron , Roeder Adrienne H.K. , Drevensek Stéphanie , Boudaoud Arezki 
Published: October 2024

AbstractThe production of flat organs involves a tight regulation of tissue expansion. During growth, the cell wall is under mechanical tension and continuous remodelling, requiring mechanisms to sense and maintain cell wall integrity (CWI). Here we studied the link between CWI sensing and flatness ofMarchantia polymorphathalli. We consideredFERONIA(FER), a CWI sensor, and assessed its role in the maintenance of thallus shape. We developed a pipeline to quantify flatness at multiple scales. We found that both abolishing and increasingFERexpression leads to loss of flatness. Based on experiments that reduce cell wall tension and partially restore wild-type cell size and thallus morphology, we ascribe loss of flatness to under- or to over-reaction of plants to mechanical stress. Altogether, our results support the concept that responses to mechanical stress contribute to the robustness of morphogenesis
Biotic interactions shape infection outcomes inArabidopsis
Authors: Mahmoudi Maryam , Almario Juliana , Hu Yiheng , Tenzer Lynn-Marie , Nieselt Kay , Kemen Eric 
Published: October 2024

AbstractThe plant microbiome protects plants from stresses, including pathogen attacks. However, identifying microbes that provide plant protection remains challenging in complex microbial communities. In this study, we analysed samples from naturalA. thalianapopulations, including both plants infected with the pathogenic oomyceteAlbugo laibachiiand uninfected plants, over six years. Using machine learning classification models, we achieved high accuracy in distinguishing infected and uninfected plants based on microbiome abundance. We identified 80 key taxa associated with health and disease. Among the health-associated microbes (HCom), we selected bacteria, fungi, and cercozoa that effectively reduced pathogen presence in co-inoculation assays. In comparison, disease-associated microbes (DCom) were less effective in conferring protection. Our findings highlight the complexity of plant-microbe interactions and advance our understanding of microbial roles in plant disease ecology. By integrating ecological insights with machine learning, we take a significant step towards designing robust microbial consortia that enhance plant resilience against pathogens.
Thymidine kinase-expressing yellow fever 17D reporter virus facilitates prodrug activation and bioorthogonal labelling of infected cells
Authors: Yakass Michael B. , Jansen Sander , Lemmens Viktor , Sanchez-Felipe Lorena , Neyts Johan , Luedtke Nathan W. , Quaye Osbourne , Dallmeier Kai 
Published: October 2024

SUMMARYTracking of viral replication and tissue tropism byin vivoimaging can help to unveil how live-attenuated vaccines such as the yellow fever 17D (17D) work, and likewise, to understand how adverse effects develop. Here we validate 17D-TK, a reporter virus derived from 17D that expresses herpes virus thymidine kinase (TK) that specifically converts nucleoside analogues such as Ganciclovir (GCV) to induce cell death, or difluoro-EdU (dF-EdU) for bioorthogonal labelling of infected cells by Click chemistry. 17D-TK induces a cytopathic effect in infected cell cultures, as well as mortality in intracranially inoculated mouse pups in a GCV dependent manner. Preferential phosphorylation of difluoro-EdU (dF-EdU) in 17D-TK infected cells allows to selectively stain cells that support 17D replication. Prospectively, 17D-TK can be used in combination with radiolabeled tracers for real-time detection and localization of sites of active viral replication in living animals using positron emission tomography (PET).
Dysregulation of FicD AMPylation causes diabetes by disrupting pancreatic endocrine homeostasis
Authors: Casey Amanda K. , Stewart Nathan M. , Zaidi Naqi , Gray Hillery F. , Fields Hazel A. , Sakurai Masahiro , Pinzon-Arteaga Carlos A. , Evers Bret M. , Wu Jun , Orth Kim 
Published: October 2024

AbstractBi-functional enzyme FicD regulates the endoplasmic reticulum chaperone BiP using AMPylation and deAMPylation during ER homeostasis and stress, respectively. Human FicD with an arginine-to-serine mutation disrupts FicD deAMPylation activity resulting in severe neonatal diabetes. We generated theFicDR371Smutation in mice to create a pre-clinical murine model for neonatal diabetes. We observed elevated BiP AMPylation levels across multiple tissues and signature markers for diabetes including glucose intolerance and reduced serum insulin levels. While the pancreas ofFicDR371Smice appeared normal at birth, adultFicDR371Smice displayed disturbed pancreatic islet organization that progressed with age.FicDR371Smice provide a preclinical mouse model for the study of UPR associated diabetes and demonstrate the essentiality of FicD for tissue resilience.
Mitochondrial cardiolipin metabolism controlled by tafazzin enables ferroptosis
Authors: Wohlfarter Yvonne , Hagenbuchner Judith , Horzum Utku , Oemer Gregor , Winter Andreas , Seifert Markus , Schwärzler Julian , Kokot Janik , Hernansanz Agustín Pablo , Juric Viktorija , Garcia Suoza Luiz Felipe , Talasz Heribert , Enríquez Domínguez José Antonio , Farhan Hesso , Adolph Timon E. , Weiss Günter , Zschocke Johannes , Keller Markus A. 
Published: October 2024

AbstractMitochondria are important producers of reactive oxygen species, which are involved in triggering ferroptosis, a lipid peroxidation driven form of cell death. Paradoxically, in the rare inherited metabolic disease Barth Syndrome, we discovered a protection from erastin-induced ferroptosis, despite intrinsically elevated mitochondrial ROS levels. The affected transacylase tafazzin, which is mutated in Barth Syndrome, is pivotal for remodeling of the dimeric phospholipid cardiolipin. They unique to mitochondria and essential for shaping their membrane functionalities. We investigated which downstream effects of the pathogenic membrane alterations are responsible for the protective effect against ferroptosis. We found that while iron metabolism, the unsaturation of membrane lipids, and the metabolic activity of the cells were modifying factors, they were not causal. However, we observed that cardiolipin abnormalities are not limited to impair only inner, but also outer mitochondrial membrane protein complexes. Specifically, they impact abundance and oligomerization of voltage-dependent anion channels (VDAC) in response to oxidative stress. We found that tafazzin deficiency via alteration of cardiolipins affects VDAC functionality, thereby modulating small molecule transport and signaling between mitochondria and the remaining cell. This is in line with a reduction of mitochondria-associated membranes (MAM) sites that are formed through VDACs and trapping ROS in mitochondria where they are unable to contribute to ferroptosis. These findings demonstrate that the mitochondrial membrane architecture impacting on subcellular small molecule distribution crucially impact on the manifestation of cell fate decisions, including ferroptosis.
Structure of human MUTYH and functional profiling of cancer-associated variants reveal an allosteric network between its [4Fe-4S] cluster cofactor and active site required for DNA repair
Authors: Trasviña-Arenas Carlos H. , Dissanayake Upeksha C. , Tamayo Nikole , Hashemian Mohammad , Lin Wen-Jen , Demir Merve , Hoyos-Gonzalez Nallely , Fisher Andrew J. , Cisneros G. Andrés , Horvath Martin P. , David Sheila S. 
Published: October 2024

ABSTRACTMUTYH is a clinically important DNA glycosylase that thwarts mutations by initiating base-excision repair at 8-oxoguanine (OG):A lesions. The roles for its [4Fe-4S] cofactor in DNA repair remain enigmatic. Functional profiling of cancer-associated variants near the [4Fe-4S] cofactor revealed that most variations abrogate both retention of the cofactor and enzyme activity. Surprisingly, R241Q and N238S retained the metal center and bound substrate DNA tightly but were completely inactive. We solved the crystal structure of human MUTYH bound to a transition state mimic and this revealed that Arg241 and Asn238 build an H-bond network connecting the [4Fe-4S] cluster to the catalytic Asp236 that mediates base excision. The structure of the bacterial MutY variant R149Q, along with molecular dynamics simulations of the human enzyme, show the cofactor functions to position and activate the catalytic Asp. These results suggest that allosteric cross-talk between the DNA binding [4Fe-4S] cofactor and the base excision site regulate DNA repair.
LSD1 inhibition attenuates targeted therapy-induced lineage plasticity inBRAFV600Ecolorectal cancer
Authors: Ladaika Christopher A. , Chakraborty Averi , Masood Ashiq , Hostetter Galen , Yi Joo Mi , O’Hagan Heather M. 
Published: October 2024

AbstractBRAFactivating mutations occur in approximately 10% of metastatic colorectal cancer (CRCs) and are associated with worse prognosis due to an inferior response to standard chemotherapy. Standard of care for patients with refractory metastaticBRAFV600ECRC is treatment with BRAF and EGFR inhibitors. However, responses are not durable. Lineage plasticity to neuroendocrine cancer is an emerging mechanism of targeted therapy resistance in several cancer types.Enteroendocrine cells (EECs), the neuroendocrine cell of the intestine, are uniquely present inBRAFV600ECRC as compared toBRAFwildtype CRC. Here, we demonstrated that combined BRAF and EGFR inhibition enriches for EECs in several models ofBRAFV600ECRC. Additionally, EECs and other secretory cell types were enriched in a subset ofBRAFV600ECRC patient samples following targeted therapy. Importantly, inhibition of the lysine demethylase LSD1 with a clinically relevant inhibitor attenuated targeted therapy-induced EEC enrichment through blocking the interaction of LSD1, CoREST2 and STAT3.Statement of SignificanceOur findings that BRAF plus EGFR inhibition induces lineage plasticity inBRAFV600ECRC represents a new paradigm for how resistance to BRAF plus EGFR inhibition occurs and our finding that LSD1 inhibition blocks lineage plasticity has the potential to improve responses to BRAF plus EGFR inhibitor therapy in patients.
Shifts in embryonic oxygen levels cue heterochrony in limb initiation
Authors: Zhu Meng , Catta-Preta Rinaldo , Lee ChangHee , Tabin Clifford 
Published: October 2024

AbstractHeterochrony, or the alteration of developmental timing, is an important mechanism of evolutionary change. Avian species display synchronized growth of the forelimbs and hindlimbs, while mammalian species show delayed hindlimb development. We find that mammalian limb heterochrony is evident from the start of limb bud formation, and is associated with heterochronic expression of T-box transcription factors. This heterochronic shift is not due to changes in cis-regulatory sequences controlling T-box gene expression, but unexpectedly, is dependent upon differential oxygen levels to which avian and mammalian embryos are exposed prior to limb initiation, mediated, at least partially, by an NFKB transcription factor, cRel. Together, these results provide mechanistic understanding of an important example of developmental heterochrony and exemplify how the maternal environment regulates timing during embryonic development.