bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring Temporal and Sex-Linked Dysregulation in Alzheimer’s Disease Phospho-Proteome
Authors: Yılmaz Serhan , Lopes Filipa Blasco Tavares Pereira , Schlatzer Daniela , Wang Rihua , Qi Xin , Koyutürk Mehmet , Chance Mark R. 
Published: August 2023

AbstractThis study aims to characterize dysregulation of phosphorylation for the 5XFAD mouse model of Alzheimer’s disease (AD). Employing global phosphoproteome measurements, we analyze temporal (3, 6, 9 months) and sex-dependent effects on mouse hippocampus tissue to unveil molecular signatures associated with AD initiation and progression. Our results indicate 1.9 to 4.4 times higher phosphorylation prevalence compared to protein expression across all time points, with approximately 4.5 times greater prevalence in females compared to males at 3 and 9 months. Moreover, our findings reveal consistent phosphorylation of known AD biomarkers APOE and GFAP in 5XFAD mice, alongside novel candidates BIG3, CLCN6 and STX7, suggesting their potential as biomarkers for AD pathology. In addition, we identify PDK1 as a significantly dysregulated kinase at 9 months in females, and the regulation of gap junction activity as a key pathway associated with Alzheimer’s disease across all time points. AD-Xplorer, the interactive browser of our dataset, enables exploration of AD-related changes in phosphorylation, protein expression, kinase activities, and pathways. AD-Xplorer aids in biomarker discovery and therapeutic target identification, emphasizing temporal and sex-specific nature of significant phosphoproteomic signatures. Available at:https://yilmazs.shinyapps.io/ADXplorerHighlightsPhosphorylation-level dysregulation surpasses protein expressionHigher phospho-dysregulation in females, starting as early as 3-month time pointNovel candidates BIG3, CLCN6, and STX7 exhibit consistent phospho-dysregulationDeveloped AD-Xplorer: Online tool to explore Alzheimer’s disease phospho-proteomeIn BriefThis study investigates dysregulation of phospho-proteome in an Alzheimer’s disease (AD) mouse model, identifying consistent phosphorylation of established AD biomarkers APOE and GFAP, along with novel candidate biomarkers BIG3, CLCN6, and STX7. In addition, the study observes significant PDK1 dysregulation at 9 months, particularly in females. AD-Xplorer, our interactive tool for exploring temporal and sex-linked phosphorylation changes, protein expression, kinase activities, and pathway enrichment, empowers researchers to gain deeper insights into AD mechanisms and uncover novel biomarkers and therapeutic targets.
Clock-dependent chromatin accessibility rhythms regulate circadian transcription
Authors: Yuan Ye , Chen Qianqian , Brovkina Margarita , Clowney E. Josephine , Yadlapalli Swathi 
Published: August 2023

AbstractChromatin organization plays a crucial role in gene regulation by controlling the accessibility of DNA to transcription machinery. While significant progress has been made in understanding the regulatory role of clock proteins in circadian rhythms, how chromatin organization affects circadian rhythms remains poorly understood. Here, we employed ATAC-seq (Assay for Transposase-Accessible Chromatin with Sequencing) on FAC-sorted Drosophila clock neurons to assess genome-wide chromatin accessibility over the circadian cycle. We observed significant circadian oscillations in chromatin accessibility at promoter and enhancer regions of hundreds of genes, with enhanced accessibility either at dusk or dawn, which correlated with their peak transcriptional activity. Notably, genes with enhanced accessibility at dusk were enriched with E-box motifs, while those more accessible at dawn were enriched with VRI/PDP1-box motifs, indicating that they are regulated by the core circadian feedback loops, PER/CLK and VRI/PDP1, respectively. Further, we observed a complete loss of chromatin accessibility rhythms inper01null mutants, with chromatin consistently accessible throughout the circadian cycle, underscoring the critical role of Period protein in driving chromatin compaction during the repression phase. Together, this study demonstrates the significant role of chromatin organization in circadian regulation, revealing how the interplay between clock proteins and chromatin structure orchestrates the precise timing of biological processes throughout the day. This work further implies that variations in chromatin accessibility might play a central role in the generation of diverse circadian gene expression patterns in clock neurons.Significance StatementChromatin organization plays a critical role in gene regulation in development and in disease. In this study, we discovered robust circadian oscillations in the chromatin accessibility of regulatory elements of clock-regulated genes inDrosophilaclock neurons, with enhanced accessibility either at dusk or dawn, which correlated with their peak transcriptional activity. We found enrichment of E-box motifs in genes that exhibited enhanced accessibility at dusk, and enrichment of VRI/PDP1-box motifs in genes that exhibited higher accessibility at dawn. Moreover, the complete loss of chromatin accessibility rhythms inper01mutants highlights the essential role of the Period protein in driving chromatin compaction during the repression phase. This study highlights the significance of chromatin organization in the generation of ∼24-hour circadian rhythms.
Bespoke conformation and antibody recognition distinguishes the streptococcal immune evasion factors EndoS and EndoS2
Authors: Sudol Abigail S. L. , Tews Ivo , Crispin Max 
Published: August 2023

AbstractThe IgG-specific endoglycosidases EndoS and EndoS2 fromStreptococcus pyogenesablate IgG function by removing the conserved N-linked glycans present on the Fc region. Their role in immune evasion, by inactivation of IgG antibodies, has led these enzymes to be investigated as therapeutics for suppressing unwanted immune activation. Their activity and precise substrate specificity has also prompted the development of these enzymes as tools for engineering IgG glycosylation. Recent structural studies have revealed how EndoS drives specificity for IgG by binding the Fc peptide surface with a domain that has homology for a carbohydrate-binding module (CBM). Here, we present the crystal structure of the EndoS2-IgG1 Fc complex at 3.0 Å resolution. Comparison with the EndoS-IgG1 Fc structure reveals a similar mode of interaction, but slightly different orientations resulting from different interfaces with glycosidase and CBM domains, leading to recognition of distinct Fc surfaces. These findings rationalise previous observations that non-catalytic domains cannot readily be substituted. The structural information presented here will guide the continued development of IgG-specific endoglycosidases in antibody glycoengineering and immunotherapy.
Spatio-temporal dynamics of microglia phenotype in human and murine cSVD: impact of acute and chronic hypertensive states
Authors: Morton Lorena , Arndt Philipp , Garza Alejandra P. , Henneicke Solveig , Mattern Hendrik , Gonzalez Marilyn , Dityatev Alexander , Yilmazer-Hanke Deniz , Schreiber Stefanie , Dunay Ildiko R. 
Published: August 2023

AbstractVascular risk factors such as chronic hypertension are well established major modifiable factors for the development of cerebral small vessel disease (cSVD). In the present study, our focus was the investigation of cSVD-related phenotypic changes in microglia in human disease and in the spontaneously hypertensive stroke-prone rat (SHRSP) model of cSVD. Our examination of cortical microglia in human post-mortem cSVD cortical tissue revealed distinct morphological microglial features specific to cSVD. We identified enlarged somata, an increase in the territory occupied by thickened microglial processes, and an expansion in the number of vascular-associated microglia. In parallel, we characterized microglia in a rodent model of hypertensive cSVD along different durations of arterial hypertension, i.e., early chronic and late chronic hypertension. Microglial somata were already enlarged in early hypertension, whereas at late-stage chronic hypertension they further exhibited elongat ed branches, thickened processes, and a reduced ramification index, mirroring the findings in human cSVD. An unbiased multidimensional flow cytometric analysis revealed phenotypic heterogeneit y among microglia cells within the hippocampus and cortex. At early-stage hypertension, hippocampal microglia exhibited upregulated CD11b/c, P2Y12R, CD200R, and CD86 surface markers. Detailed analysis of cell subpopulations revealed a unique microglial subset expressing CD11b/c, CD163, and CD86 exclusively in early hypertension. Notably, even at early-stage hypertension, microglia displayed a higher association with cerebral blood vessels. We identified several profound clusters of microglia expressing distinct marker profiles at late chronic hypertensive states. We further detected a temporal hypertension-related disturbances in blood-brain barrier integrity, accompanied by increased recruitment of leukocytes to the brain parenchyma in early hypertension. In summary, our findings demonstrate a higher vulnerability of the hippocampus, stage-specific microglial signatures based on morphological features, and cell surface protein expression in response to chronic arterial hypertension. These results indicate the diversity within microglia sub-populations and implicate the subtle involvement of microglia in cSVD pathogenesis.
Primary Human Cell-Derived Extracellular Matrix from Decellularized Fibroblast Microtissues with Tissue-Dependent Composition and Microstructure
Authors: Fonseca Vera C. , Van Vivian , Ip Blanche C. 
Published: August 2023

AbstractHuman extracellular matrix (ECM) exhibits complex protein composition and architecture depending on tissue and disease state, which remains challenging to reverse engineer. One promising approach is based on cell-secreted ECM from human fibroblasts, which can then be decellularized into an acellular biomaterial. However, fibroblasts initially seeded on rigid tissue culture plastic or biomaterial scaffolds experience aberrant mechanical cues that influence ECM deposition. Here, we show that engineered microtissues of primary human fibroblasts seeded in low-adhesion microwells can be decellularized to produce human, tissue-specific ECM. We investigate: 1) cardiac fibroblasts, as well as 2) lung fibroblasts from healthy, idiopathic fibrosis and chronic obstructive pulmonary disease donors. We demonstrate optimized culture and decellularization conditions, then characterize gene expression and protein composition. We further characterize ECM microstructure and mechanical properties. We envision that this method could be utilized for biomanufacturing of patient and tissue-specific ECM for organoid drug screening as well as implantable scaffolds.ImpactIn this study, we demonstrate a method for preparing decellularized matrix using primary human fibroblasts with tissue and disease-specific features. We aggregate single cell dispersions into engineered tissues using low adhesion microwells and show culture conditions that promote ECM deposition. We demonstrate this approach for cardiac fibroblasts as well as lung fibroblasts (both normal and diseased). We systematically investigate tissue morphology, matrix architecture, and mechanical properties, along with transcriptomic and proteomic analysis. This approach should be widely applicable for generating personalized ECM with features of patient tissues and disease state, relevant for culturing patient cells ex vivo as well as implantation for therapeutic treatments.
Laminar Dynamics of Target Selection in the Posterior Parietal Cortex of the Common Marmoset
Authors: Selvanayagam Janahan , Johnston Kevin D. , Everling Stefan 
Published: August 2023

AbstractThe lateral intraparietal area (LIP) plays a crucial role in target selection and attention in primates, but the laminar microcircuitry of this region is largely unknown. To address this, we used ultra-high density laminar electrophysiology with Neuropixels probes to record neural activity in the posterior parietal cortex (PPC) of two adult marmosets while they performed a simple visual target selection task. Our results reveal neural correlates of visual target selection in the marmoset, similar to those observed in macaques and humans, with distinct timing and profiles of activity across cell types and cortical layers. Notably, a greater proportion of neurons exhibited stimulus related activity in superficial layers whereas a greater proportion of infragranular neurons exhibited significant post-saccadic activity. Stimulus-related activity was first observed in granular layer putative interneurons, whereas target discrimination activity emerged first in supragranular layers putative pyramidal neurons, supporting a canonical laminar circuit underlying visual target selection in marmoset PPC. These findings provide novel insights into the neural basis of visual attention and target selection in primates.
Analyzing microbial evolution through gene and genome phylogenies
Authors: Teichman Sarah , Lee Michael D. , Willis Amy D. 
Published: August 2023

AbstractMicrobiome scientists critically need modern tools to explore and analyze microbial evolution. Often this involves studying the evolution of microbial genomes as a whole. However, different genes in a single genome can be subject to different evolutionary pressures, which can result in distinct gene-level evolutionary histories. To address this challenge, we propose to treat estimated gene-level phylogenies as data objects, and present an interactive method for the analysis of a collection of gene phylogenies. We use a local linear approximation of phylogenetic tree space to visualize estimated gene trees as points in low-dimensional Euclidean space, and address important practical limitations of existing related approaches, allowing an intuitive visualization of complex data objects. We demonstrate the utility of our proposed approach through microbial data analyses, including by identifying outlying gene histories in strains ofPrevotella, and by contrastingStreptococcusphylogenies estimated using different gene sets. Our method is available as an open-source R package, and assists with estimating, visualizing and interacting with a collection of bacterial gene phylogenies. dimension reduction, microbiome, non-Euclidean, statistical genetics, visualization
New insights into functional divergence and adaptive evolution of uncultured bacteria in anammox community by complete genome-centric analysis
Authors: Wang Yi-Cheng , Mao Yanping , Fu Hui-Min , Wang Jin , Weng Xun , Liu Zi-Hao , Xu Xiao-Wei , Yan Peng , Fang Fang , Guo Jin-Song , Shen Yu , Chen You-Peng 
Published: August 2023

AbstractAnaerobic ammonium-oxidation (anammox) bacteria play a crucial role in global nitrogen cycling and wastewater nitrogen removal, but they share symbiotic relationships with various other microorganisms. No pure culture is available for anammox bacteria so far. Although shotgun metagenomics based on short reads has been widely used in anammox research, metagenome-assembled genomes (MAGs) are often discontinuous and highly contaminated, which limits in-depth analyses of anammox communities. Here, for the first time, we performed Pacific Biosciences high-fidelity (HiFi) long-read sequencing on the anammox granule sludge sample from a lab-scale bioreactor, and obtained 30 accurate and complete metagenome-assembled genomes (cMAGs). These cMAGs were obtained by selecting high-quality circular contigs from initial assemblies of long reads generated by HiFi sequencing, eliminating the need for Illumina short reads, binning, and reassembly. One new anammox species and species from three novel families were found in this anammox community. cMAG-centric analysis revealed divergences in general and nitrogen metabolism among members of the anammox community. Furthermore, we identified mobile genetic elements (MGEs) and putative horizontal gene transfer (HGT) events within these cMAGs to explore the adaptive evolution of the community. The results suggest that MGEs and HGT events, particularly transposons containingtnpAin anammox bacteria, might play important roles in the adaptive evolution of this anammox community. The cMAGs generated in the present study could be used to establish of a comprehensive database for anammox bacteria and associated microorganisms. Our findings highlight the advantages of HiFi sequencing for the studies of complex mixed cultures such as anammox communities and advance our understanding of anammox communities.
Coronaviruses Spike glycoprotein endodomains: the sequence and structure-based comprehensive study
Authors: Kumar Prateek , Bhardwaj Aparna , Mukherjee Bodhidipra , Joshi Richa , Giri Rajanish 
Published: August 2023

AbstractThe flexibility of proteins makes them available to interact with many biomolecules in the cell. Specifically, such interactions in viruses help them to perform more functions despite having a smaller genome. Therefore, these flexible regions can be exciting and essential targets to be explored for their role in pathogenicity and therapeutic developments as they achieve essential interactions. In the continuation with our previous study on disordered analysis of SARS-CoV-2 spike cytoplasmic tail (CTR), or endodomain, here we have explored the disordered potential endodomains of six other coronaviruses using multiple bioinformatics approaches and molecular dynamics simulations. Based on the comprehensive analysis of its sequence and structural composition, we report the varying disorder propensity in endodomains of spike proteins of coronaviruses. The observations of this study may help to understand the importance of spike glycoprotein endodomain and creating therapeutic interventions against them.
Differences in personality within and between five species of ants in open field tests
Authors: Pedraza Alexandra Rodriguez 
Published: August 2023

AbstractWhen confronted to new situations individuals may express different kinds of behaviors. They can be atracted, explore, get immobile, attack, hide or increase their motor activity in order to confront or avoid this situation. Several studies have been conducted on vertebrate species and different patterns have been observed depending on factors as genetic or environmental ones as well as cases of rigidity or flexibility in behaviorl reaction. Less studies have been conducted on insects personalities but the current research is improving in this aspect. Here I present the case of five ant species that I tested in open field tests in order to detect if they present different response profiles when confronted to a novel environment and how these profiles can vary depending on factors as species, ambient conditions or ecological realities of the studied populations. In this article I expose hypothesis to explain you how they react in these circumstancies and how the observed differences can subtend some of their living realities.
The eIF4A2 negative regulator of mRNA translation promotes extracellular matrix deposition to accelerate hepatocellular carcinoma initiation
Authors: Moore Madeleine , Pardo-Fernandez Luis , Mitchell Louise , Schmidt Tobias , Waldron Joseph A , May Stephanie , Muller Miryam , Smith Rachael C. L. , Strathdee Douglas , Bryson Sheila , Hodge Kelly , Lilla Sergio , Wilczynska Ania , McGarry Lynn , Gillen Sarah , Peter-Durairaj Ruban , Kanellos Georgios , Nixon Colin , Zanivan Sara , Sansom Owen J. , Bird Thomas G. , Bushell Martin , Norman Jim C. 
Published: August 2023

AbstractIncreased protein synthesis supports growth of established tumours. However, how mRNA translation contributes to early tumorigenesis remains unclear. Here we show that following oncogene activation, hepatocytes enter a non-proliferative/senescent-like phase characterized by α5β1 integrin-dependent deposition of fibronectin-rich extracellular matrix (ECM) niches. These niches then promote exit from oncogene-induced senescence to permit progression to proliferating hepatocellular carcinoma (HCC). Removal of eIF4A2, a negative regulator of mRNA translation, boosts the synthesis of membrane/secretory proteins which drives a compensatory increase in the turnover/degradation of membrane proteins including α5β1 integrin. This increased membrane protein degradation, in turn, compromises generation of ECM-rich tumour initiation niches, senescence-exit and progression to proliferating HCC. Consistently, pharmacological inhibition of mRNA translation following eIF4A2 loss restores ECM deposition and reinstates HCC progression. Thus, although inhibition of protein synthesis may be an effective way to reduce tumour biomass and the growth of established tumours, our results highlight how agents which reduce mRNA translation, if administered during early tumorigenesis, may awaken senescent cells and promote tumour progression.
TroR is the primary regulator of the iron homeostasis transcription network in the halophilic archaeonHaloferax volcanii
Authors: Pastor Mar Martinez , Sakrikar Saaz , Hwang Sungmin , Hackley Rylee , Soborowski Andrew , Maupin-Furlow Julie A. , Schmid Amy 
Published: August 2023

ABSTRACTMaintaining intracellular iron concentration within the homeostatic range is vital to meet cellular metabolic needs and reduce oxidative stress. Previous research revealed that the haloarchaeonHalobacterium salinarumencodes four diphtheria toxin repressor (DtxR) family transcription factors (TFs) that together regulate the iron response through an interconnected transcriptional regulatory network (TRN). However, the metal specificity of DtxR TFs and the conservation of the TRN remained poorly understood. Here we identified and characterized the TRN ofHaloferax volcaniifor comparison. Genetic analysis demonstrated thatHfx. volcaniirelies on three DtxR transcriptional regulators (Idr, SirR, and TroR), with TroR as the primary regulator of iron homeostasis. Bioinformatics and molecular approaches revealed that TroR binds a conservedcis-regulatory motif located ∼100 nt upstream of the start codon of iron-related target genes. Transcriptomics analysis demonstrated that, under conditions of iron sufficiency, TroR repressed iron uptake and induced iron storage mechanisms. TroR repressed the expression of one other DtxR TF, Idr. This reduced DtxR TRN complexity relative to that ofHbt. salinarumappeared correlated with natural variations in iron availability. Based on these data, we hypothesize that increasing TRN complexity appears selected for under variable environmental conditions such as iron availability.