bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ocular biomarker profiling after complement factor I gene therapy in geographic atrophy secondary to age-related macular degeneration
Authors: Hallam Thomas M , Gardenal Emanuela , McBlane Fraser , Cho GaEun , Ferraro Lucy Lee , Pekle Eva , Lu Darlene , Carney Kate , Wenden Claire , Beadsmoore Hannah , Kaiser Sergio , Drage Lauren , Haye Thomas , Kassem Iris , Rangaswamy Nalini , Obeidat Ma’en , Grosskreutz Cyndy , Saint-Geniez Magali , Steel David H , MacLaren Robert E , Ellis Scott , Harris Claire L , Poor Stephen , Jones Amy V 
Published: June 2024

AbstractObjectiveComplement biomarker analysis in ocular fluid samples from subjects with geographic atrophy (GA) in a Phase I/II clinical trial of subretinal AAV2 complement factor I (CFI; FI) gene therapy, PPY988 (formerly GT005), to understand target pharmacokinetics/pharmacodynamics. Clinical findings were subsequently utilized to investigate the therapeutic dose in anin vitrocomplement activation assay.Design, setting and participantsBiomarker data were evaluated from 28 subjects in FOCUS, a Phase I/II clinical trial evaluating the safety and efficacy of three ascending doses of PPY988.Main outcomes and measuresVitreous humor (VH), and aqueous humor (AH) from subjects before surgery and at serial timepoints (week 5 or 12, 36, 96) were evaluated for changes in levels of intact complement factors I, B and H (FI, FB, FH) components C3, C4, and C1q and breakdown products (Ba, C3a, C3b/iC3b, C4b) using validated assays and OLINK®proteomics.A modifiedin vitroassay of complement activation modelling VH complement concentrations was used to compare PPY988 potency to the approved intravitreal C3 inhibitor pegcetacoplan (Apellis) and complement Factor H (FH).ResultsAn average 2-fold increase in VH FI was observed post-treatment at week 36 and week 96. This correlated with a marked post-treatment reduction in VH concentration of the FB breakdown product Ba and Ba:FB ratio, but minimal changes in C3a and C3b/iC3b levels. Variable concordance in complement biomarker levels in VH versus AH suggest AH is not a reliable proxy for VH for complement activation. During the experimental comparison of doses, a 2-fold increase of FI achieved in the vitreous had only a minor effect on the complement amplification loopin vitro, indicating limited impact [IC50: 1229nM]. Pegcetacoplan completely blocks C3a generation at concentrations much lower than the estimated trough level for monthly intravitreal injections [IC50: 2nM]. Supplementation with FH in the assay revealed similar potency to pegcetacoplan [IC50: 6nM].Conclusions and relevancePPY988 subretinal gene therapy may not have provided sufficient FI protein to meaningfully modulate complement activation to slow GA growth. Reviewing VH biomarkers is important for understanding target expression, pathway engagement, and determining optimal dose, thereby informing future clinical development.
Dual targeting of KDM1A and antioxidants is an effective anticancer strategy
Authors: Mudambi Shaila , Fitzgerald Megan E , Washington Deschana L , Pera Paula J , Huss Wendy J , Paragh Gyorgy 
Published: June 2024

AbstractLysine Specific Demethylase 1 (KDM1A / LSD1) regulates mitochondrial respiration and stabilizes HIF-1A (hypoxia-inducible factor 1A). HIF-1A modulates reactive oxygen species (ROS) levels by increasing cellular glucose uptake, glycolysis, and endogenous antioxidants. The role of KDM1A in cellular ROS response has not previously been described. We determined the role of KDM1A in regulating the ROS response and the utility of KDM1A inhibitors in combination with ROS-inducing cancer therapies. Our results show that KDM1A inhibition sensitized cells to oxidative stress and increased total cellular ROS, which was mitigated by treatment with the antioxidant N-acetyl cysteine. KDM1A inhibition decreased basal mitochondrial respiration and impaired induction of HIF-1A after ROS exposure. Overexpression of HIF-1A salvaged cells from KDM1A inhibition enhanced sensitivity to ROS. Thus we found that increased sensitivity of ROS after KDM1A inhibition was mediated by HIF-1A and depletion of endogenous glutathione. We also show that KDM1A-specific inhibitor bizine synergized with antioxidant-depleting therapies, buthionine sulfoximine, and auranofin in rhabdomyosarcoma cell lines (Rh28 and Rh30). In this study, we describe a novel role for KDM1A in regulating HIF- 1A functions under oxidative stress and found that dual targeting of KDM1A and antioxidant systems may serve as an effective combination anticancer strategy.
Vegetation density is the main driver of insect species richness and diversity in small private urban front gardens
Authors: Morpurgo Joeri , Huurdeman Margot , Oostermeijer J. Gerard B. , Remme Roy P. 
Published: June 2024

AbstractUrbanisation changes the natural ecosystems and vegetation to urban green spaces, and causes insect communities to experience novel challenges for survival. New evidence suggests that urban green spaces, no matter how small, can provide meaningful habitats for insects. Information on design and management of small gardens (<10m2) in dense urban areas is still scarce. In particular, it is hardly known which garden designs provide most benefits to insects. We surveyed 65 small private urban front gardens (μ=1.7m2) in Amsterdam and The Hague in The Netherlands and measured a series of garden attributes thought to be relevant for general, flower-visiting and herbivorous insect species richness and diversity. Plant coverage and richness were the strongest predictors for insect biodiversity and species richness. We found no support for associations with native vs. exotic plants or garden size.Synthesis and applicationsTo strengthen insect biodiversity in the urban environment, we recommend future design of urban green spaces to focus on maximising coverage and richness of vegetation, potentially even using exotic species to fill in the gaps where native plant species cannot survive.HighlightsSmall urban gardens hold large potential for supporting urban insect communitiesTotal vegetation cover was the strongest predictor for insect diversity and richnessPlant richness was the second strongest predictor, but not for herbivorous insectsGarden size had no effect on insect diversity or richnessNative vegetation did not impact insect diversity or richnessAbstract FigureGraphical abstract. Shown are either plus or minus signs indicating a positive or negative trends from the models that predict species richness and Shannon biodiversity of insects, pollinators or herbivores by the design of small urban gardens.*indicates a statistically significant trend at p-value < 0.05. A plus or minus sign without*means a visible statistically non-significant trend. A greyed out square indicates exclusion of the term in the model. A white square indicates non-significant and non-visible trend.
Effective anti-tumor immune responses are orchestrated by immune cell partnership network that functions through tissue homeostatic pathways, not direct cytotoxicity
Authors: Koelsch Nicholas , Mirshahi Faridoddin , Aqbi Hussein F. , Seneshaw Mulugeta , Idowu Michael O. , Olex Amy L. , Sanyal Arun J. , Manjili Masoud H. 
Published: June 2024

AbstractThe liver hosts a diverse array of immune cells that play pivotal roles in both maintaining tissue homeostasis and responding to disease. However, the precise contributions of these immune cells in the progression of nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) remain unclear. Utilizing a systems immunology approach, we reveal that liver immune responses are governed by a dominant-subdominant hierarchy of ligand-receptor-mediated homeostatic pathways. In healthy individuals, inflammatory immune responses operate within these pathways, challenging the notion of the liver as a purely tolerogenic organ. Chronic consumption of a Western diet (WD) disrupts hepatocyte function and reconfigures immune interactions, resulting in hepatic stellate cells (HSCs), cancer cells, and NKT cells driving 80% of the immune activity during NAFLD. In HCC, 80% of immune response involves NKT cells and monocytes collaborating with hepatocytes and myofibroblasts to restore disrupted homeostasis. Interestingly, dietary correction during NAFLD yields nonlinear outcomes: tumor progression coincides with the failure of mounting homeostatic immune responses, whereas tumor prevention is associated with sustained immune responses, predominantly orchestrated by monocytes. These monocytes actively target fibroblasts and myofibroblasts, creating a tumor-suppressive microenvironment. Notably, only 5% of T cells displayed apoptosis-inducing activity, selectively contributing to the turnover of hepatic stromal cells, particularly myofibroblasts and fibroblasts. Our findings suggest that effective anti-tumor immune responses in the liver are primarily mediated by immune cells sustaining tissue homeostasis, rather than relying on direct cytotoxic mechanisms.
Evaluating the Roles of Drift and Selection in Trait Loss along an Elevational Gradient
Authors: Buysse Sophia F. , Pérez Samuel G. , Puzey Joshua R. , Garrison Ava , Bradburd Gideon S. , Oakley Christopher G. , Tonsor Stephen J. , Picó F. Xavier , Josephs Emily B. , Conner Jeffrey K 
Published: June 2024

AbstractTraits that have lost function sometimes persist through evolutionary time. These traits may persist if there is not enough standing genetic variation for the trait to allow a response to selection, if selection against the trait is weak relative to drift, or if the trait has a residual function. To determine the evolutionary processes shaping whether nonfunctional traits are retained or lost, we investigated short stamens in 16 populations ofArabidopsis thalianaalong an elevational cline in northeast Spain. We found a cline in short stamen number from retention of short stamens in high elevation populations to incomplete loss in low elevation populations. We did not find evidence that limited genetic variation constrains the loss of short stamens at high elevations, nor evidence for divergent selection on short stamens between high and low elevations. Finally, we identified loci associated with short stamens in northeast Spain that are different from loci associated with variation in short stamen number across latitudes from a previous study. Overall, we did not identify the evolutionary mechanisms contributing to an elevational cline in short stamen number but did identify different genetic loci underlying variation in short stamen along similar phenotypic clines.Teaser textThe evolutionary mechanisms underlying loss or retention of traits that have lost function are poorly understood. Short stamens inArabidopsis thalianaprovide a compelling system to investigate the roles of genetic drift and selection in trait loss across latitudinal and elevational clines. This study investigates how drift and selection shape short stamen loss in 16 populations ofA. thalianaalong an elevational gradient in Northeast Spain. An investigation of the loci underlying variation in short stamen number suggests variants in different genes may cause trait loss in similar phenotypic clines within a species.
Xenometabolome of Early-Life Stage Salmonids Exposed to 6PPD-Quinone
Authors: Ankley Phillip J. , da Silva Francisco C. , Hunnie Blake , Roberts Catherine , Eriksson Andreas N. M. , Kohlman Evan , Corker Jennifer , Westcott Jodi , Germain Bradlee , Martin Michael J. , Dubiel Justin , Anderson-Bain Katherine , Urrutia Rayen M. , Hogan Natacha , Giesy John P. , Wiseman Steve , Krol Ed , Hecker Markus , Brinkmann Markus 
Published: June 2024

AbstractN-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone (6PPD-Q) is a ubiquitous transformation product (TP) derived from the rubber tire antioxidantN-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) and is acutely toxic to certain species ofSalmonidae. Not all salmonids are sensitive to acute lethality caused by 6PPD-Q, with 6PPD-Q potency varying by several orders of magnitude among teleosts. The main driver(s) of species sensitivity differences is (are) a pressing question, with one area of interest examining whether differences in teleosts ability to biotransform and detoxify 6PPD-Q could be a key factor. This study utilized liquid-chromatography high-resolution mass spectrometry (LC-HRMS) to assess biotransformation and metabolome-wide effects of 6PPD-Q on early-life stage salmonids, including two sensitive species, rainbow trout (Oncorhynchus mykiss) and lake trout (Salvelinus namaycush), and one tolerant species, brown trout (Salmo trutta). Three phase I TPs and seven phase II TPs were detected, with differences in peak areas revealing that brown trout had the greatest ability to detoxify 6PPD-Q. Monohydroxylated TPs were verified using co-developed analytical standards that will be of use for future biomonitoring and exposure assessment. Several endogenous metabolites were found to be dysregulated in rainbow and lake trout, indicative of mitochondrial dysfunction, altered metabolism, and disrupted membrane permeability. Results of this study indicate a difference in the biotransformation capability of 6PPD-Q amongSalmonidaefish species and subsequent unique metabolome responses.Graphical AbstractSynopsisInter-species salmonid differences in the biotransformation capability of 6PPD-Q leads to sensitivity variability and subsequent unique metabolome responses.
Inferring single-cell spatial gene expression with tissue morphology via explainable deep learning
Authors: Zhao Yue , Alizadeh Elaheh , Liu Yang , Xu Ming , Mahoney J Matthew , Li Sheng 
Published: June 2024

AbstractThe spatial arrangement of cells is vital in developmental processes and organogenesis in multicellular life forms. Deep learning models trained with spatial omics data uncover complex patterns and relationships among cells, genes, and proteins in a high-dimensional space, providing new insights into biological processes and diseases. State-of-the-artin silicospatialmulti-cellgene expression methods using histological images of tissue stained with hematoxylin and eosin (H&E) to characterize cellular heterogeneity. These computational techniques offer the advantage of analyzing vast amounts of spatial data in a scalable and automated manner, thereby accelerating scientific discovery and enabling more precise medical diagnostics and treatments.In this work, we developed a vision transformer (ViT) framework to map histological signatures to spatialsingle-celltranscriptomic signatures, named SPiRiT (Spatial OmicsPrediction andReproducibility integratedTransformer). Our framework was enhanced by integrating cross validation with model interpretation during hyper-parameter tuning. SPiRiT predicts single-cell spatial gene expression using the matched histopathological image tiles of human breast cancer and whole mouse pup, evaluated by Xenium (10x Genomics) datasets. Furthermore, ViT model interpretation reveals the high-resolution, high attention area (HAR) that the ViT model uses to predict the gene expression, including marker genes for invasive cancer cells (FASN), stromal cells (POSTN), and lymphocytes (IL7R). In an apple-to-apple comparison with the ST-Net Convolutional Neural Network algorithm, SPiRiT improved predictive accuracy by 40% using human breast cancer Visium (10x Genomics) dataset. Cancer biomarker gene prediction and expression level are highly consistent with the tumor region annotation. In summary, our work highlights the feasibility to infer spatial single-cell gene expression using tissue morphology in multiple-species, i.e., human and mouse, and multi-organs, i.e., mouse whole body morphology. Importantly, incorporating model interpretation and vision transformer is expected to serve as a general-purpose framework for spatial transcriptomics.
Estrogen-induced chromatin looping changes identify a subset of functional regulatory elements
Authors: Abewe Hosiana , Richey Alexandra , Vahrenkamp Jeffery M , Ginley-Hidinger Matthew , Rush Craig M , Kitchen Noel , Zhang Xiaoyang , Gertz Jason 
Published: June 2024

AbstractTranscriptional enhancers can regulate individual or multiple genes through long-range three-dimensional (3D) genome interactions, and these interactions are commonly altered in cancer. Yet, the functional relationship between changes in 3D genome interactions associated with regulatory regions and differential gene expression appears context-dependent. In this study, we used HiChIP to capture changes in 3D genome interactions between active regulatory regions of endometrial cancer cells in response to estrogen treatment and uncovered significant differential long-range interactions strongly enriched for estrogen receptorα(ER) bound sites (ERBS). The ERBS anchoring differential chromatin loops with either a gene’s promoter or distal regions were correlated with larger transcriptional responses to estrogen compared to ERBS not involved in differential 3D genome interactions. To functionally test this observation, CRISPR- based Enhancer-i was used to deactivate specific ERBS, which revealed a wide range of effects on the transcriptional response to estrogen. However, these effects are only subtly and not significantly stronger for ERBS in differential chromatin loops. In addition, we observed an enrichment of 3D genome interactions between the promoters of estrogen upregulated genes and found that looped promoters can work together cooperatively. Overall, our work reveals that estrogen treatment causes large changes in 3D genome structure in endometrial cancer cells; however, these changes are not required for a regulatory region to contribute to an estrogen transcriptional response.
ParallelEvolCCM: Quantifying co-evolutionary patterns among genomic features
Authors: Beiko Robert G. , Liu Chaoyue , Cavalcante João Vitor , Fink Ryan C. 
Published: June 2024

AbstractConcerted gains and losses of genomic features such as genes and mobile genetic elements can provide key clues into related functional roles and shared evolutionary trajectories. By capturing phylogenetic signals, a co-evolutionary model can outperform comparative methods based on shared presence and absence of features.We previously developed the Community Coevolution Model, which represents the gain/loss probability of each feature as a combination of its own intrinsic rate, combined the joint probabilities of gain and loss with all other features. Originally implemented as an R library, we have now developed a R wrapper that adds parallelization and several options to pre-filter the features to increase the efficiency of comparisons. Here we describe the functionality of EvolCCM and apply it to a dataset of 1000 genomes of the genus Bifidobacterium. ParallelEvolCCM is released under the MIT license and available athttps://github.com/beiko-lab/arete/blob/master/bin/ParallelEvolCCM.R.Significance StatementPatchy phylogenetic distributions of genes, mobile genetic elements, and other genomic features can constitute evidence for lateral gene transfer. Comparing the presence/absence patterns of multiple features can reveal important associations among them, but the phylogenetic relationships must be taken into consideration in order to avoid spurious correlations. Our new ParallelEvolCCM software embeds these comparisons in a coevolutionary framework, offers a range of options to optimize the speed and comparisons, and offers helper scripts to visualize relationships among features.
Wolbachiastrain wMelM disrupts egg retention byAedes aegyptifemales prevented from ovipositing
Authors: Ross Perran A. , Yeatman Ella , Gu Xinyue , Hoffmann Ary A. , van Heerwaarden Belinda 
Published: June 2024

AbstractAedes aegyptimosquitoes are well adapted to dry climates and can retain their eggs for extended periods in the absence of suitable habitat.Wolbachiastrains transferred from other insects to mosquitoes can be released to combat dengue transmission by blocking virus replication and spreading through populations, but host fitness costs imposed byWolbachia, particularly under some environments, can impede spread. We therefore assessed the impact of twoWolbachiastrains being released for dengue control (wAlbB andwMelM) on fecundity and egg viability following extended egg retention (12 or 18 d) under laboratory conditions. Egg viability decreased to a greater extent in females carryingwMelM compared to uninfected orwAlbB females. Fertility fully recovered in uninfected females following a second blood meal after laying retained eggs, whilewMelM females experienced only partial recovery. Effects ofwMelM on egg retention were similar regardless of whether females were crossed to uninfected orwMelM males, suggesting that fitness costs were triggered byWolbachiapresence in females. The fecundity and hatch proportions of eggs ofwMelM females declined with age, regardless of whether females used stored sperm or were recently inseminated. Costs of someWolbachiastrains during egg retention may affect the invasion and persistence ofWolbachiain release sites where larval habitats are scarce and/or intermittent.
Latrophilin-2 mediates fluid shear stress mechanotransduction at endothelial junctions
Authors: Tanaka Keiichiro , Chen Minghao , Prendergast Andrew , Zhuang Zhenwu , Nasiri Ali , Joshi Divyesh , Hintzen Jared , Chung Minhwan , Kumar Abhishek , Mani Arya , Koleske Anthony , Crawford Jason , Nicoli Stefania , Schwartz Martin A. 
Published: June 2024

AbstractEndothelial cell responses to fluid shear stress from blood flow are crucial for vascular development, function and disease. A complex of PECAM-1, VE-cadherin, VEGF receptors (VEGFRs) and PlexinD1 located at cell-cell junctions mediates many of these events. But available evidence suggests that another mechanosensor upstream of PECAM-1 initiates signaling. Hypothesizing that GPCR and Gα proteins may serve this role, we performed siRNA screening of Gα subunits and found that Gαi2 and Gαq/11 are required for activation of the junctional complex. We then developed a new activation assay, which showed that these G proteins are activated by flow. We next mapped the Gα residues required for activation and developed an affinity purification method that used this information to identify latrophilin-2 (Lphn-2/ADGRL2) as the upstream GPCR. Latrophilin-2 is required for all PECAM-1 downstream events tested. In both mice and zebrafish, latrophilin-2 is required for flow-dependent angiogenesis and artery remodeling. Furthermore, endothelial specific knockout demonstrates that latrophilin plays a role in flow-dependent artery remodeling. Human genetic data reveal a correlation between the latrophilin-2-encodingAdgrl2gene and cardiovascular disease. Together, these results define a pathway that connects latrophilin-dependent G protein activation to subsequent endothelial signaling, vascular physiology and disease.
Deep brain stimulation induces white matter remodeling and functional changes to brain-wide networks
Authors: Fujimoto Satoka H. , Fujimoto Atsushi , Elorette Catherine , Seltzer Adela , Andraka Emma , Verma Gaurav , Janssen William GM , Fleysher Lazar , Folloni Davide , Choi Ki Sueng , Russ Brian E. , Mayberg Helen S. , Rudebeck Peter H. 
Published: June 2024

AbstractDeep brain stimulation (DBS) is an emerging therapeutic option for treatment resistant neurological and psychiatric disorders, most notably depression. Despite this, little is known about the anatomical and functional mechanisms that underlie this therapy. Here we targeted stimulation to the white matter adjacent to the subcallosal anterior cingulate cortex (SCC-DBS) in macaques, modeling the location in the brain proven effective for depression. We demonstrate that SCC-DBS has a selective effect on white matter macro- and micro-structure in the cingulum bundle distant to where stimulation was delivered. SCC-DBS also decreased functional connectivity between subcallosal and posterior cingulate cortex, two areas linked by the cingulum bundle and implicated in depression. Our data reveal that white matter remodeling as well as functional effects contribute to DBS’s therapeutic efficacy.