bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optic nerve injury impairs intrinsic mechanisms underlying electrical activity in a resilient retinal ganglion cell
Authors: Zapadka Thomas E. , Tran Nicholas M. , Demb Jonathan B. 
Published: February 2024

AbstractRetinal ganglion cells (RGCs) are the sole output neurons of the retina and convey visual information to the brain via their axons in the optic nerve. Following an injury to the optic nerve, RGCs axons degenerate and many cells die. For example, a surgical model of compressive axon injury, the optic nerve crush (ONC), kills ∼80% of RGCs after two weeks. Surviving cells are biased towards certain ‘resilient’ types, including several types that originally produced sustained firing to light stimulation. RGC survival may depend on activity level, and there is a limited understanding of how or why activity changes following optic nerve injury. Here we quantified the electrophysiological properties of a highly resilient RGC type, the sustained ON-Alpha RGC, seven days post-ONC with extracellular and whole-cell patch clamp recording. Both light- and current-driven firing were reduced after ONC, but synaptic inputs were largely intact. Resting membrane potential and input resistance were relatively unchanged, while voltage-gated currents were impaired, including a reduction in voltage-gated sodium channel density in the axon initial segment and function. Hyperpolarization or chelation of intracellular calcium partially rescued firing rates. These data suggest that an injured resilient RGC reduces its activity by a combination of reduced voltage-gated channel expression and function and downregulation of intrinsic excitability via a Ca2+-dependent mechanism without substantial changes in synaptic input. Reduced excitability may be due to degradation of the axon but could also be energetically beneficial for injured RGCs, preserving cellular energy for survival and regeneration.Graphical AbstractSchematic view of the effects of axon injury (optic nerve crush) on the physiology of an sustained ON-Alpha (AlphaONS) retinal ganglion cell. These cells are highly resilient to axon injury and survive for several weeks while other retinal ganglion cell types perish. At one week after injury, the AlphaONS RGC has diminished spontaneous and light-evoked action potential firing. Reduced firing depends not on changes in synaptic inputs but rather on reductions in intrinsic excitability. Reduced excitability is explained by a Ca2+-dependent mechanism and by a reduction in sodium channel density and function.Key Points Summary1)Retinal ganglion cell (RGC) types show diverse rates of survival after axon injury.2)A resilient RGC type maintains its synaptic inputs one week post-injury.3)The resilient RGC type shows diminished firing and reduced expression of axon initial segment (AIS) genes following injury4)Activity deficits arise from intrinsic dysfunction (Na+channels, intracellular Ca2+), not from loss of excitation or enhanced inhibition.
Rejuvenating silicon probes for acute electrophysiology
Authors: Shoup Alden M. , Porwal Natasha , Fakharian Mohammad Amin , Hage Paul , Orozco Simon P. , Shadmehr Reza 
Published: February 2024

AbstractElectrophysiological recording with a new probe often yields better signal quality than with a used probe. Why does the signal quality degrade after only a few experiments? Here, we considered silicon probes in which the contacts are densely packed, and each is coated with a conductive polymer that increases its surface area. We tested 12 Cambridge Neurotech silicon probes during 61 recording sessions from the brain of 3 marmosets. Out of the box, each probe arrived with an electrodeposited polymer coating on 64 gold contacts, and an impedance of around 50k Ohms. With repeated use, the impedance increased and there was a corresponding decrease in the number of well-isolated neurons. Imaging of the probes suggested that the reduction in signal quality was due to a gradual loss of the polymer coating. To rejuvenate the probes, we first stripped the contacts, completely removing their polymer coating, and then recoated them in a solution of 10 mM EDOT monomer with 32 uM PSS using a current density of about 3mA/cm2for 30 seconds. This recoating process not only returned probe impedance to around 50k Ohms, it also yielded significantly improved signal quality during neurophysiological recordings. Thus, insertion into the brain promoted loss of the polymer that coated the contacts of the silicon probes. This led to degradation of signal quality, but recoating rejuvenated the probes.
Empowering high-throughput high-content analysis of 3D tumor models: Open-source software for automated non-confocal image analysis
Authors: Wiggin Noah , Cook Carson , Black Mitchell , Cadena Ines , Rahal-Arabi Salam , Fogg Kaitlin 
Published: February 2024

AbstractPurposeThe primary aim of this study was to develop an open-source Python-based software for the automated analysis of dynamic cell behaviors in three-dimensional tumor models using non-confocal microscopy. This research seeks to address the existing gap in accessible tools for high-throughput analysis of cancer and endothelial cell dynamicsin vitro, facilitating the rapid assessment of drug sensitivity.MethodsOur approach involved annotating over 1000 2 mm Z-stacks of cancer and endothelial cell co-culture model and training machine learning models to automatically calculate cell coverage, cancer invasion depth, and microvessel dynamics. Specifically, cell coverage area was computed using focus stacking and Gaussian mixture models to generate thresholded Z-projections. Cancer invasion depth was determined using a deep neural network binary classification model, measuring the distance between Z-planes with invaded cells. Lastly, microvessel dynamics were assessed through a U-Net Xception-style deep learning model for segmentation, a disperse algorithm for network graph representation, then persistent homology to quantify microvessel length and connectivity. Finally, we reanalyzed an image set from a high-throughput drug screen involving a chemotherapy agent on a 3D cervical and endothelial co-culture model.ResultsThe software accurately measured cell coverage, cancer invasion, and microvessel length, yielding drug sensitivity IC50values with a 95% confidence level compared to manual calculations. Additionally, it significantly reduced the image processing time from weeks down to hours.ConclusionsOur free and open source software offers an automated solution for quantifying 3D cell behavior in tumor models using non-confocal microscopy, providing the broader Cellular and Molecular Bioengineering community with an alternative to standard confocal microscopy paired with proprietary software.
Normative and individual, non-normative intrinsic networks and the transition to impaired cognition
Authors: Zhang Qirui , Hudgins Stacy , Struck Aaron F , Ankeeta Ankeeta , Javidi Sam S. , Sperling Michael R , Hermann Bruce P , Tracy Joseph I. 
Published: February 2024

AbstractDespite their temporal lobe pathology, a significant subgroup of temporal lobe epilepsy (TLE) patients are able to maintain normative cognitive functioning. Here, we identify TLE patients with intact versus impaired cognitive profiles, and interrogate for the presence of both normative and highly individual intrinsic connectivity networks(ICN) – all towards understanding the transition from impaired to intact neurocognitive status. We retrospectively investigated data from 88 TLE patients and matched 91 healthy controls with resting-state functional MRI. Functional MRI data were decomposed using independent component analysis to obtain individualized ICNs. Here, we calculated the degree of match between individualized ICNs and canonical ICNs (e.g., Yeo et.al 17 resting-state network) and divided each participant’s ICNs into normative or non-normative status based on the degree of match. We found that the individualized networks matched the canonical networks less well in the cognitively impaired compared to the cognitively intact TLE patients. The cognitively impaired patients showed significant abnormalities in the profiles of both normative and non-normative networks, whereas the intact patients showed abnormalities only in non-normative networks. At the same time, we found normative networks held a strong, positive association with the neuropsychological measures, with this association negative in non-normative networks. We were able to provide the initial data demonstrating that significant cognitive deficits are associated with the status of highly-individual ICNs, making clear that the transition from intact to impaired cognitive status is not simply the result of disruption to normative brain networks.
Integrating short-read and long-read single-cell RNA sequencing for comprehensive transcriptome profiling in mouse retina
Authors: Wang Meng , Li Yumei , Wang Jun , Oh Soo Hwan , Chen Rui 
Published: February 2024

AbstractThe vast majority of protein-coding genes in the human genome produce multiple mRNA isoforms through alternative splicing, significantly enhancing the complexity of the transcriptome and proteome. To establish an efficient method for characterizing transcript isoforms within tissue samples, we conducted a systematic comparison between single-cell long-read and conventional short-read RNA sequencing techniques. The transcriptome of approximately 30,000 mouse retina cells was profiled using 1.54 billion Illumina short reads and 1.40 billion Oxford Nanopore long reads. Consequently, we identified 44,325 transcript isoforms, with a notable 38% previously uncharacterized and 17% expressed exclusively in distinct cellular subclasses. We observed that long-read sequencing not only matched the gene expression and cell-type annotation performance of short-read sequencing but also excelled in the precise identification of transcript isoforms. While transcript isoforms are often shared across various cell types, their relative abundance shows considerable cell-type-specific variation. The data generated from our study significantly enhance the existing repertoire of transcript isoforms, thereby establishing a foundational resource for future research into the mechanisms and implications of alternative splicing within retinal biology and its links to related diseases.
Antimicrobial resistance, virulence genes profiles and molecular epidemiology of carbapenem-resistantKlebsiella pneumoniaestrains from captive giant pandas (Ailuropoda melanoleuca)
Authors: Yan Xia , Yang Mei , Ayala James Edward , Li Lin , Zhou Yang , Hou Rong , Liu Songrui , Li Yunli , Yue Chanjuan , Zhang Dongsheng , Su Xiaoyan 
Published: February 2024

AbstractThis study aimed to investigate the antibiotic susceptibility, antibiotic resistance genes (ARGs), mobile genetic elements (MGEs), virulence genes, and molecular epidemiology of carbapenem-resistantKlebsiella pneumoniae(CRKP) strains isolated from giant pandas. The screening of 178 nonduplicatedKlebsiella pneumoniaestrains identified eight CRKP strains, with the most abundant ARGs observed in ampC/blaDHA, blaSHV-01, blaSHV-02, tetB-01, tetB-02, tetC-01, and tetC-02. MGE analysis revealed the presence of intI1 in all strains, while other MGEs exhibited varying detection rates. Strain 24 exhibited the highest diversity in terms of MGE species. Seven virulence genes including wabG, uge, ycf, entB, kpn, alls, and wcaG, showed positive results with different proportions across the strains. Molecular epidemiology analysis using pulsed-field gel electrophoresis (PFGE) patterns indicated a high level of genetic diversity among the CRKP strains. Multi-locus sequence typing (MLST) analysis classified the strains into different sequence types (STs). In conclusion, this study highlighted the diverse nature of CRKP strains found in giant pandas, which exhibited varying levels of antibiotic resistance along with multiple ARGs and virulence genes present. These findings emphasized the importance of monitoring and researching antibiotic resistance within wildlife populations to safeguard the health status of these endangered animals.
The 2023 wildfire season in Québec: an overview of extreme conditions, impacts, lessons learned and considerations for the future
Authors: Boulanger Yan , Arseneault Dominique , Bélisle Annie Claude , Bergeron Yves , Boucher Jonathan , Boucher Yan , Danneyrolles Victor , Erni Sandy , Gachon Philippe , Girardin Martin P. , Grant Eliane , Grondin Pierre , Jetté Jean-Pierre , Labadie Guillemette , Leblond Mathieu , Leduc Alain , Puigdevall Jesus Pascual , St-Laurent Martin-Hugues , Tremblay Junior A. , Waldron Kaysandra 
Published: February 2024

AbstractThe 2023 wildfire season in Québec set records due to extreme warm and dry conditions, burning 4.5 million hectares and indicating persistent and escalating impacts associated with climate change. The study reviews the unusual weather conditions that led to the fires, discussing their extensive impacts on the forest sector, fire management, boreal caribou habitats, and particularly the profound effects on First Nation communities. The wildfires led to significant declines in forest productivity and timber supply, overwhelming fire management resources, and necessitating widespread evacuations. First Nation territories were dramatically altered, facing severe air quality issues and disruptions. While caribou impacts were modest across the province, the broader ecological, economical, and social repercussions were considerable. To mitigate future extreme wildfire seasons, the study suggests changes in forest management practices to increase forest resilience and resistance, adapting industrial structures to new timber supplies, and enhancing fire suppression and risk management strategies. It calls for a comprehensive, unified approach to risk management that incorporates the lessons from the 2023 fire season and accounts for ongoing climate change. The study underscores the urgent need for detailed planning and proactive measures to reduce the growing risks and impacts of wildfires in a changing climate.
Antidiabetic effect of 1-deazapurines derivatives with alpha-glucosidase Enzyme: A molecular tools approach
Authors: Hacene Faiza Boukli , Cherrak Sabri Ahmed , Soufi Wassila , Ghalem Said 
Published: February 2024

AbstractAlpha-glucosidase inhibition has been shown by several 1-deazapurine derivatives that have already been synthesized and evaluated in vitro, providing a potential treatment target for type 2 diabetes. Six of them were shown to have higher percentages of inhibition against the alpha-glucosidase enzyme and lower IC50 values. The binding mechanism and stability of the generated complexes are investigated in the current work using various molecular modeling methodologies. The ligands L17, L11, and L4 present the best binding energy with the establishment of interaction toward the site active, based on the results of the molecular docking simulation. The stability of the chosen complexes was then validated using molecular dynamics simulation. However, ADME-T prediction and Drug-likeness results show that these compounds have promising pharmacokinetic properties and oral bioavailability. Finally, these results imply that compounds L4 and L11 are very promising as a target for creating a lead molecule for type 2 diabetes.
Genomic localization bias of secondary metabolite gene clusters and association with histone modifications inAspergillus
Authors: Zhang Xin , Leahy Iseult , Collemare Jérȏme , Seidl Michael F. 
Published: February 2024

AbstractFungi are well-known producers of bioactive secondary metabolites (SMs), which have been exploited for decades by humankind for various medical applications like therapeutics and antibiotics. SMs are synthesized by biosynthetic gene clusters (BGCs) – physically co-localized and co-regulated genes. Because BGCs are often regulated by histone post-translational modifications (PTMs), it was suggested that their chromosomal location is important for their expression. Studies in a few fungal species indicated an enrichment of BGCs in sub-telomeric regions; however, there is no evidence that BGCs with distinct genomic localization are regulated by different histone PTMs. Here, we used 174Aspergillusspecies covering 22 sections to determine the correlation between BGC genomic localization, gene expression and histone PTMs. We found a high abundance and diversity of SM backbone genes across theAspergillusgenus, with notable unique genes within sections. Being unique or conserved in many species, BGCs showed a strong bias for being localized in low-synteny regions, regardless of their position in chromosomes. Using chromosome-level assemblies, we also confirmed a significantly biased localization in sub-telomeric regions. Notably, SM backbone genes in sub-telomeric regions and about half of those in low-synteny regions exhibit higher gene expression variability, likely due to the similar higher variability in H3K4me3 and H3K36me3 histone PTMs; while variations in histone H3 acetylation and H3K9me3 are not correlated to genomic localization and expression variation, as analyzed in twoAspergillusspecies. Expression variability across fourAspergillusspecies further supports that BGCs tend to be located in low-synteny regions and that regulation of expression in those regions likely involves different histone PTMs than the most commonly studied modifications.SignificanceFungi are known for producing an array of bioactive compounds with medical benefits, yet our understanding of how the production of these compounds is regulated remains limited. Here, we focused on the fungal genusAspergillus, containing many species known to be prolific producers of bioactive compounds, to systematically uncover the diversity and genomic localization of biosynthetic pathways. By expanding our knowledge beyond the few commonly studied fungal species, this research offers novel insights into how the genomic localization of biosynthetic pathways matters for the regulation of their expression. Thanks to a new view on BGC localization and expression in relation to histone modifications, our results are expected to stimulate functional research on neglected histone modifications that will support the discovery and harnessing of new fungal metabolites for medical and industrial applications.
Imaging and quantification of prostate cancer-associated bone by polarization-sensitive optical coherence tomography
Authors: Zhou Chris , Jung Naomi , Xu Samuel , Eltit-Guersetti Felipe , Lu Xin , Wang Qiong , Liang Doris , Morrissey Colm , Corey Eva , True Lawrence D. , Wang Rizhi , Tang Shuo , Cox Michael E. 
Published: February 2024

AbstractProstate cancer frequently metastasizes to bone, leading to a spectrum of osteosclerotic and osteolytic lesions that cause debilitating symptoms. Accurate differentiation of bone tissue or lesion types can provide opportunity for local pathologic investigation, which is critical for understanding the bone metastasis and remains challenging. Current imaging methods lack the ability to directly differentiate tissues based on collagen organization and may induce invasive effect on bone tissues. We introduce Polarization-Sensitive Optical Coherence Tomography (PS-OCT) to investigate normal, osteosclerotic, and osteolytic bone tissues. High-resolution PS-OCT imaging reveals collagen fiber arrangement, enabling nuanced distinction of degree of collagen alignment among different bone tissue types or regions. We present a novel feature named degree of ordered organization (DOO), derived from the multiple contrasts of PS-OCT that can quantitatively evaluate bone samples from different pathologic groups, including control,osteoblastic and osteolytic tissues. The capacity of PS-OCT to differentiate trabecular/lamellar and irregular (woven bone) regions within the same specimen is tested and validated on ex-vivo samples extracted from 13 subjects. Our study is the first time that PS-OCT is applied to metastatic bone disease with the aim of enhancing the understanding of bone-related pathologies, and potentially impacting clinical practice. This work demonstrates that PS-OCT can provide useful insight into bone microstructures, and thus it has potential applications across diverse bone disorders.
Arginine Di-methylation of RIPK3 Safeguards Necroptosis for Intestinal Homeostasis
Authors: Zhao Pan , Dan Hanjun , Wang Yazhou , Chen Xin , Jiang Xiangling , Shen Yao , Wang Jiajia , Yang Zhiwei , Zhao Jiasheng , Zhang Yingying , Zheng Jianyong , Liu Wen , Zhang Jian 
Published: February 2024

AbstractThe necroptosis mediated by RIPK3 is stringently regulated for intestinal homeostasis. Here we found that mice lackingPrmt5(Protein arginase methyltransferase 5) in intestinal epithelial cells (IECs) caused premature death with IECs necroptosis, villus atrophy and loss of Paneth cells. This pathology can be partially rescued by antibiotic treatment, germ-free breeding condition and pharmaceutical inhibition of RIPK1 and RIPK3, but aggravated for embryonic lethality byCaspase-8 deficiency, which demonstrating the importance of commensal bacteria and necroptosis for thePrmt5-IEC deficiency. Intriguingly, tumor-necrosis factor (TNF) receptor 1(Tnfr1) deficiency could not completely rescue the pathology, and mice deficit in Z- DNA binding protein 1(ZBP1) exhibited shorter lifespan compared withPrmt5null mice, suggestingPrmt5loss might trigger TNFR-RIPK1-depenfent and ZBP1- dependent necroptosis. Mechanically, we identified the 479-arginine residue of RIPK3 di-methylated by PRMT5 was an endogenous checkpoint for necroptosis. Furthermore, RIPK3-R479K mutation had higher affinity with both RIPK1 and ZBP1 by immunoprecipitation and STORM (Stochastic Optical Reconstruction Microscopy) analysis, which might explain the endogenous necroptosis triggered by mutated RIPK3 even without upstream stimuli. Moreover, the peptide of RIPK3-SDMA (Symmetric dimethylarginine of 479) could rescue lethality ofPrmt5 lacking mice through necrosome formation inhibition, which demonstrating the great potential for necroptosis-related disease treatment through RIPK3 dimethylation targeting.