bluuebunny/crossref_metadata_2025_split huggingface dataset:
Positive Allosteric Modulation of the α5-GABAA receptors prevents neuronal atrophy and cognitive decline independently of tau tangle accumulation in the PS19 mouse model
Authors: Dharavath Ravinder N. , Bernardo Ashley M. , Marceau-Linhares Cassandra , Marcotte Michael , Wong Kayla , Pina-Leblanc Celeste , Bouchet Adrien , Sharmin Dishary , Pandey Kamal P. , Cook James M. , Prevot Thomas D. , Sibille Etienne L. 
Published: September 2024

ABSTRACTBackgroundDysregulated tau phosphorylation is one of the hallmarks of Alzheimer’s disease (AD), and it results in cognitive impairments, neuronal atrophy, and neurofibrillary tangle accumulation. Evidence shows that impaired somatostatin (SST) expression, particularly in SST-expressing GABAergic neurons, significantly contributes to AD-related pathophysiology and may increase cognitive burden. Additionally, SST+ interneurons in cortical layers and the hippocampus inhibit the dendrites of excitatory neurons, primarily through α5-GABAA receptors involved in cognitive regulation. Leveraging the potential of a newly developed small molecule that targets the α5-GABAA receptors via positive allosteric modulation (α5-PAM), we aim to assess its effects on tau phosphorylation-related neuronal morphology, cognitive deficits and protein expression.MethodsIn the PS19 transgenic mouse mode, we administered the α5-PAM, GL-II-73, either acutely or chronically at 3 and 6 months. We assessed spatial working memory using the Y-maze. Golgi staining analyzed dendritic morphology in chronically exposed mice to α5-PAM. Western blotting was used to quantify p-Tau and Tau expression.Resultsα5-PAM effectively reverses spatial working memory deficits induced by tau phosphorylation both acutely and chronically. Chronic treatment at 3and 6 months mitigates tau-induced loss of spine density. However, α5-PAM does not directly influence p-Tau levels, suggesting cognitive and neurotrophic benefits of GL-II-73s are independent of Tau burden.ConclusionsThese results demonstrate the potential for both symptomatic and disease-modifying effects, highlighting the promise of α5-GABAA receptor positive allosteric modulation as a novel therapeutic strategy for addressing cognitive deficits associated with tau phosphorylation in AD pathology.
Binocular integration of prey stimuli in the zebrafish visual system
Authors: Tian Guangnan , Chung Lam Thomas Ka , Yan Gewei , He Yingzhu , Khan Biswadeep , Qu Jianan Y. , Semmelhack Julie L. 
Published: September 2024

AbstractMost animals with two eyes combine the inputs to achieve binocular vision, which can serve numerous functions, and is particularly useful in hunting prey. However, the mechanisms by which visual information from the two eyes are combined remain largely unknown. Here, we designed a device to reversibly occlude the eyes of a head-fixed zebrafish larva, and used large-scale volumetric two-photon imaging to identify binocular neurons that respond to prey stimuli. We found these binocular prey-responsive neurons (bino-PRNs) were primarily located in three areas, the pretectum, thalamus, and nucleus isthmi. We then characterized the bino-PRNs’ functional properties, and found that their left and right eye receptive fields are offset to varying degrees, which would correspond to objects at naturalistic hunting distances for a larva with converged eyes. We also found that bino-PRNs have a significantly greater response in hunting trials, which could be the result of an eye convergence-related corollary discharge. We then optogenetically induced prey capture eye and tail movements, and found that this hunting command activates prey responsive neurons in the pretectum, thalamus, and nucleus isthmi. These findings indicate that bino-PRNs receive visual and motor input that would allow them to encode prey position in three dimensions.
IL-1β-mediated Immunometabolic Adaptation in Corneal Epithelial Cells
Authors: Sanches Jose Marcos , Ramachandra Rajalakshmy Ayilam , Mussi Natalia , Baniasadi Hamid , Robertson Danielle M. 
Published: September 2024

AbstractPurposeAs an external mucosal surface, the corneal epithelium is subject to a barrage of stressors that are known to trigger inflammation. IL-1β, a master regulator of inflammation, is secreted into the preocular tear film by ocular surface epithelial cells and infiltrating immune cells. While increased levels of IL-1β have been associated with corneal disease, the effects of IL-1β on mitochondrial function in corneal epithelial cells (CECs) is unknown.MethodsTo investigate the effects of IL-1β on mitochondrial function, telomerase immortalized human CECs were cultured in either 50 ng/mL or 100 ng/mL IL-1β for short term (24 hours) or prolonged (72 hours) time periods. Cells were assessed for ROS, inflammatory cytokine production, mitochondrial polarization and ultrastructure, mitophagy, and changes in the metabolite composition. Lipid drops were examined using light and fluorescent microscopy.ResultsShort term exposure to IL-1β triggered an increase in IL-8 and ROS levels that corresponded to a reduction in mitochondrial membrane potential. Long term exposure also showed increased levels of IL-8 and IL-6 and further increased ROS. After long term exposure however, there was a paradoxical increase in mitochondrial membrane potential that was associated an increase in spare respiratory capacity and mitochondrial hyperfusion. Metabolomics confirmed an upregulation of the pentose phosphate pathway and the TCA cycle. Fumarate was also increased, suggesting an increase in flux through complex II. Changes in lipid metabolism included an upregulation in cardiolipin andde novotriacylglyceride biosynthesis, along with increasing numbers of lipid droplets.ConclusionProlonged exposure to IL-1β induces metabolic rewiring in CECs that results in an increase in spare respiratory capacity. These findings suggest that the corneal epithelium is able to adapt to certain levels of chronic inflammation and may have important implications in our understanding of immune tone and cellular stress responses in ocular surface epithelia.
G3BP1 Maintains Vascular Endothelial Barrier Integrity by Negatively Regulating the MYD88-ARNO-ARF6 Signaling Pathway
Authors: Sun Weiyue , Wu Haoran , He Yuxi , Chen Huiqiao , Meng Yuanhui , Tang Guofang , Zhu Jinshun , Wen Zhengwang , Wu Rongzhou , Wu Guowei , Zhang Chunxiang , Chu Maoping , Wen Bin 
Published: September 2024

ABSTRACTEndothelial permeability is essential for vascular function. This process is regulated by intercellular junctions, including adherens junctions (AJs) and tight junctions (TJs), which form the endothelial barrier and dynamically connect adjacent cells. However, the mechanisms that control endothelial permeability are not fully understood.We investigated the role of the RNA-binding protein G3BP1 in regulating endothelial permeability. We examined the effects of Loss of g3bp1 in conditional knockout mice and primary human HUVEC cells. We analyzed endothelial barrier integrity and permeability, focusing on AJ and TJ expression, under both normal and LPS-induced inflammatory conditions.Loss of g3bp1 in vascular endothelial cells decreased AJ and TJ expression, compromised barrier integrity, and increased permeability. These effects were exacerbated under LPS-induced inflammatory conditions. Loss of g3bp1 also increased the expression of MYD88, ARNO, and ARF6, and enhanced ARF6 activity. Mechanistically, G3BP1 bound to and stabilized MYD88 mRNA, negatively regulating the MYD88-ARNO-ARF6 signaling pathway. Inhibiting this pathway by reducing MYD88 or ARF6 expression, or inhibiting ARNO activity, restored AJ/TJ expression and barrier function in G3BP1-deficient models.Our findings identify G3BP1 as a novel regulator of vascular endothelial permeability. G3BP1 acts by negatively regulating the MYD88-ARNO-ARF6 signaling pathway. Targeting G3BP1 may be a potential therapeutic strategy for diseases associated with endothelial barrier dysfunction.
A genome-wide association screen for genes affecting leaf trichome development and epidermal metal accumulation in Arabidopsis
Authors: Bezvoda Radek , Landeo-Ríos Yazmín Mónica , Kubátová Zdeňka , Kollárová Eva , Kulich Ivan , Busch Wolfgang , Žárský Viktor , Cvrčková Fatima 
Published: September 2024

AbstractTo identify novel genes engaged in plant epidermal development, we characterized the phenotypic variability of rosette leaf epidermis of 310 sequencedArabidopsis thalianaaccessions, focusing on trichome shape and distribution, compositional characteristics of the trichome cell wall, and histologically detectable metal ion distribution. Some of these traits correlated with climate parameters of ourq accession’s locations of origin, suggesting environmental selection. A novel metal deposition pattern in stomatal guard cells was observed in some accessions. Subsequent GWAS analysis identified 1546 loci with protein sequence-altering SNPs associated with one or more traits, including 5 genes with previously reported relevant mutant phenotypes and 80 additional genes with known or predicted roles in relevant developmental and cellular processes. Some candidates, including GFS9/TT9, exhibited environmentally correlated allele distribution. Several large gene families, namely DUF674, DUF784, DUF1262, DUF1985, DUF3741, cytochrome P450, receptor-like kinases, Cys/His-rich C1 domain proteins and formins were overrepresented among the candidates for various traits, suggesting epidermal development-related functions. A possible participation of formins in guard cell metal deposition was supported by observations in available loss of function mutants. Screening of candidate gene lists against the STRING interactome database uncovered several predominantly nuclear protein interaction networks with possible novel roles in epidermal development.
LM11a-31 Inhibits p75 Neurotrophin Receptor (p75NTR) Cleavage and is Neuroprotective in a Cell Culture Model of Parkinson’s Disease
Authors: Pokharel Poshan V. , Newchurch Aaron M. , Overby Sunny C. , Spease Cassidy A. , Darzi Lorelei G. , Kraemer Bradley R. 
Published: September 2024

AbstractThe p75 Neurotrophin Receptor (p75NTR) is a multifunctional transmembrane protein that mediates neuronal responses to pathological conditions in specific regions of the nervous system. In many biological contexts, p75NTRsignaling is initiated through sequential cleavage of the receptor by α- and γ-secretases, which releases receptor fragments for downstream signaling. Our previous work demonstrated that proteolytic processing of p75NTRin this manner is stimulated by oxidative stress in Lund Human Mesencephalic (LUHMES) cells, a dopaminergic neuronal cell line derived from human mesencephalic tissue. Considering the vulnerability of dopaminergic neurons in the ventral mesencephalon to oxidative stress and neurodegeneration associated with Parkinson’s disease (PD), we investigated the role of this signaling cascade in neurodegeneration and explored cellular processes that govern oxidative stress-induced p75NTRsignaling. In the present study, we provide evidence that oxidative stress induces cleavage of p75NTRby promoting c-Jun N-terminal Kinase (JNK)-dependent internalization of p75NTRfrom the cell surface. This activation of p75NTRsignaling is counteracted by tropomyosin-related kinase (Trk) receptor signaling; however, oxidative stress leads to Trk receptor downregulation, thereby enhancing p75NTRprocessing. Importantly, we demonstrate that this pathway can be inhibited by LM11a-31, a small molecule modulator of p75NTR, thereby conferring protection against neurodegeneration. Treatment with LM11a-31 significantly reduced p75NTRcleavage and neuronal death associated with oxidative stress. These findings reveal novel mechanisms underlying activation of p75NTRin response to oxidative stress, underscore a key role for p75NTRin dopaminergic neurodegeneration, and highlight p75NTRas a potential therapeutic target for reducing neurodegeneration in PD.
Whole genome sequencing of hepatitis B virus (HBV) using tiled amplicon (HEP-TILE) and probe-based enrichment on Illumina and Nanopore platforms
Authors: Lumley Sheila F , Kent Chris , Jennings Daisy , Chai Haiting , Airey George , Waddilove Elizabeth , Delphin Marion , Trebes Amy , McNaughton Anna L , Mohammed Khadija Said , Wilkinson Sam , Wu Yanxia , MacIntyre-Cockett George , Kimono Beatrice , Kwizera Moses , Ojambo Kevin , Maponga Tongai G , de Lara Catherine , Martin Jacqueline , Campbell James , Van Schalkwyk Marije , Goedhals Dominique , Newton Robert , Barnes Eleanor , Loman Nicholas J , Piazza Paolo , Quick Joshua , Ansari M Azim , Matthews Philippa C 
Published: September 2024

AbstractHepatitis B virus (HBV) whole genome sequencing (WGS) is currently limited as the DNA viral loads (VL) of many clinical samples are below the threshold required to generate full genomes using current sequencing methods. We developed two pan-genotypic viral enrichment methods, using probe-based capture and tiled amplicon PCR (HEP-TILE) for HBV WGS. We demonstrate using mock samples that both enrichment methods are pan-genotypic (genotypes A-J). Using clinical samples, we demonstrate that HEP-TILE amplification successfully amplifies full genomes at the lowest HBV VL tested (30 IU/ml), and the PCR products can be sequenced using both Nanopore and Illumina platforms. Probe-based capture with Illumina sequencing required VL >300,000 IU/ml to generate full length HBV genomes. The capture-Illumina and HEP-TILE-Nanopore pipelines had consensus sequencing accuracy of 100% in mock samples with known DNA sequences. Together, these protocols will facilitate the generation of HBV sequence data, enabling a more accurate and representative picture of HBV molecular epidemiology, cast light on persistence and pathogenesis, and enhance understanding of the outcomes of infection and its treatment.
Rising prevalence ofPlasmodium falciparumartemisinin resistance mutations in Ethiopia
Authors: Brhane Bokretsion G. , Fola Abebe A. , Nigussie Helen , Leonetti Alec , Kassa Moges , Hailgiorgis Henok , Wuletaw Yonas , Abera Adugna , Mohammed Hussein , Sime Heven , G/Tsadik Abeba , Assefa Gudissa , Solomon Hiwot , Tasew Geremew , Tollera Getachew , Hailu Mesay , Juliano Jonathan J. , Assefa Ashenafi , Parr Jonathan B. , Bailey Jeffrey A. 
Published: September 2024

AbstractEthiopia is striving to eliminate local malaria transmission by 2030, despite a recent resurgence of malaria cases due to multiple factors. A significant contributor to this resurgence could be drug resistance, particularly the emergence of partial resistance to artemisinin (ArtR) in Ethiopia and other regions of Eastern Africa. This situation highlights the necessity for genomic surveillance to monitor relevant drug resistance markers. This study reports sentinel site-based genomic surveillance results forP. falciparumantimalarial drug resistance mutations. From 2019 to 2022, dried blood spots (DBS) were collected from febrile outpatients ≥1 year of age with microscopically confirmed falciparum malaria at 12 sentinel sites across 5 regions. Molecular inversion probe (MIP) sequencing targeted mutations associated with artemisinin and partner drug resistance, includingk13,mdr1, crt, dhfr,anddhpsgenes, along with genome-wide markers to assess the complexity of infection (COI) and parasite relatedness. A total of 1,199 falciparum-positive patients were assessed, with a median age of 20 years (IQR: 14-30) and including 463 (38.6%) females. The WHO-validated K13 R622I mutation had a high but regionally variable prevalence (15.7%, range 0-58.8%). The validated K13 A675V mutation was detected for the first time in Ethiopia in the Gambella Region (4.5%), as well as P441L and P574L mutations were detected at low frequencies in Southern and Oromia Regions, respectively. Several partner drug resistance markers were identified, with mutations in MDR1(184F), DHPS, DHFR, and CRT nearly fixed across the country. Most samples (87.2%) were monogenic infections (COI=1) and showed high genetic relatedness, particularly within the health facilities. Principal component analysis revealed regional clustering of parasites, particularly in Gambella. The prevalence of K13 R622I across the country and the presence of multiple additional ArtR markers emphasizes the urgent need for rigorous monitoring of artemisinin combination therapy (ACT) efficacy to detect partner drug resistance and ACT failure early and its impact on malaria resurgence in Ethiopia.
How does date-rounding affect phylodynamic inference for public health?
Authors: Featherstone Leo A. , Ingle Danielle J. , Wirth Wytamma , Duchene Sebastian 
Published: September 2024

AbstractPhylodynamic analyses enable the inference of epidemiological parameters from pathogen genome sequences for enhanced genomic surveillance in public health. Pathogen genome sequences and their associated sampling times are the essential data in every analysis. However, sampling times are usually associated with hospitalisation or testing dates and can sometimes be used to identify individual patients, posing a threat to patient confidentiality. To lower this risk, sampling times are often given with reduced date-resolution to the month or year, which can potentially bias inference of epidemiological parameters. Here, we characterise the extent to which reduced date-resolution biases phylodynamic analyses across a diverse range of empirical and simulated datasets. We develop a practical guideline on when date-rounding biases phylodynamic inference and we show that this bias is both unpredictable in its direction and compounds with decreasing date-resolution, higher substitution rates, and shorter sampling intervals. We conclude by discussing future solutions that prioritise patient confidentiality and propose a method for safer sharing of sampling dates by translating them uniformly by a random number.
Protein identification using cryo-EM and artificial intelligence guides improved sample purification
Authors: Carr Kenneth D. , Zambrano Dane Evan D. , Weidle Connor , Goodson Alex , Eisenach Helen E. , Pyles Harley , Courbet Alexis , King Neil P. , Borst Andrew J. 
Published: September 2024

AbstractProtein purification is essential in protein biochemistry, structural biology, and protein design. It enables the determination of protein structures, the study of biological mechanisms, and the biochemical and biophysical characterization of both natural and de novo designed proteins. Despite the broad application of various protein purification protocols, standard strategies can still encounter challenges, such as the unintended co-purification of unknown contaminants alongside the target protein. In particular, co-purification issues pose significant challenges for designed self-assembling protein nanomaterials, as it is difficult to determine whether unexpected observed geometries represent novel assembly states of the designed system, cross-contamination from other assemblies, or native proteins originating from the expression host. In this study, we assessed the ability of an automated structure-to-sequence pipeline to unambiguously identify an unknown co-purifying protein found across several purified designed protein samples. Using cryo-electron microscopy (Cryo-EM), ModelAngelo’s sequence-agnostic automated model-building feature, and the Basic Local Alignment Search Tool (BLAST), we identified the unknown protein as dihydrolipoamide succinyltransferase (DLST). This identification was further confirmed by comparing the cryo-EM data with available DLST structures in the Protein Data Bank (PDB) and AlphaFold 3 predictions from the top BLAST hits. The clear identification of DLST informed our subsequent literature search and led to the rational modification of our protein purification protocol, ultimately enabling the exclusion of the contaminant from preparations of our target nanoparticle. This study demonstrates the successful application of a structure-to-sequence workflow, integrating Cryo-EM, ModelAngelo, protein BLAST, PDB structures, and AlphaFold 3 predictions, to identify and remove an unknown protein from a purified sample. It also highlights the broader potential of integrating Cryo-EM with AI-driven tools for accurate protein identification across various samples and contexts within protein science.HighlightsAn unknown protein was consistently found in multiple de novo designed protein samples.The protein was identified as dihydrolipoamide succinyltransferase (DLST) using Cryo-EM, ModelAngelo and BLAST, and further verified using AlphaFold 3 and the PDB.Identification enabled rational modification of the purification protocol to exclude the contaminant.This method enables accurate protein identification without requiring near-atomic resolution or prior sequence and structural data, making it broadly applicable to various areas of protein science.Graphical Abstract
The Impacts of Neighborhood Disparities on US Population Health During the COVID-19 Pandemic: A Literature Review and Policy Analysis for Future Response
Authors: White Brianna M. , Brakefield Whitney S. , Olusanya Olufunto A. , Prasad Rameshwari , Kumsa Fekede , Hashtarkhani Soheil , Shaban-Nejad Arash 
Published: September 2024

AbstractIntroduction/BackgroundThe COVID-19 pandemic has disrupted major aspects of daily life since its emergence in late 2019, impacting health and well-being worldwide. Aside from genetic predisposition, numerous external factors play key roles in determining levels of disease susceptibility and overall health status.Aim/ObjectivesThis review and policy analysis sought to examine literature focused on the impact of neighborhood environments on population health and well-being during the COVID-19 pandemic period. Examined studies explore the impacts of various aspects of the neighborhood environment (i.e., walkability, transportation, access to healthcare/vaccination, etc.) during the COVID-19 era on population health and well-being.MethodsDatabases were searched for studies published from March 2020 to August 2022. Selected studies examine the impacts of various aspects of the neighborhood environment (i.e., walkability, transportation, access to healthcare/vaccination, climate, crime rates, persistent poverty, the social spread of misinformation, etc.) during the COVID-19 era on population health and well-being.ResultsFindings from our review suggest that those living in less-than-favorable environments were faced with significant challenges, making vulnerable populations more prone to the severity of COVID-19 infection.ConclusionWe argue these results establish cause for the consideration of the effects of neighborhood environments in developing intelligent intervention strategies for both pandemic recovery and preparation for future public health emergencies, especially among vulnerable populations.