bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship between alcohol consumption and dementia with Mendelian randomization approaches among older adults in the United States
Authors: Campbell Kyle A. , Fu Mingzhou , MacDonald Elizabeth , Zawistowski Matthew , Bakulski Kelly M. , Ware Erin B. 
Published: December 2023

AbstractBackgroundIn observational studies, the association between alcohol consumption and dementia is mixed.MethodsWe performed two-sample Mendelian randomization (MR) using summary statistics from genome-wide association studies of weekly alcohol consumption and late-onset Alzheimer’s disease and one-sample MR in the Health and Retirement Study (HRS), wave 2012. Inverse variance weighted two-stage regression provided odds ratios of association between alcohol exposure and dementia or cognitively impaired, non-dementia relative to cognitively normal.ResultsAlcohol consumption was not associated with late-onset Alzheimer’s disease using two-sample MR (OR=1.15, 95% confidence interval (CI):[0.78, 1.72]). In HRS, doubling weekly alcohol consumption was not associated with dementia (African ancestries, n=1,322, OR=1.00, 95% CI [0.45, 2.25]; European ancestries, n=7,160, OR=1.37, 95% CI [0.53, 3.51]) or cognitively impaired, non-dementia (African ancestries, n=1,322, OR=1.17, 95% CI [0.69, 1.98]; European ancestries, n=7,160, OR=0.75, 95% CI [0.47, 1.22]).ConclusionAlcohol consumption was not associated with cognitively impaired, non-dementia or dementia status.
Artemisinin resistance mutations inPfcoroninimpede hemoglobin uptake
Authors: Ullah Imran , Farringer Madeline A. , Burkhard Anna Y. , Hathaway Erica , Khushu Malhar , Willett Bailey C. , Shin Sara H. , Sharma Aabha I. , Martin Morgan C. , Shao Kairon L. , Dvorin Jeffrey D. , Hartl Daniel L. , Volkman Sarah K. , Bopp Selina , Absalon Sabrina , Wirth Dyann F. 
Published: December 2023

AbstractArtemisinin (ART) combination therapies have been critical in reducing malaria morbidity and mortality, but these important drugs are threatened by growing resistance associated with mutations inPfcoroninandPfkelch13. Here, we describe the mechanism ofPfcoronin-mediated ART resistance.PfCoronin interacts withPfActin and localizes to the parasite plasma membrane (PPM), the digestive vacuole (DV) membrane, and membrane of a newly identified preDV compartment—all structures involved in the trafficking of hemoglobin from the RBC for degradation in the DV.Pfcoroninmutations alterPfActin homeostasis and impair the development and morphology of the preDV. Ultimately, these changes are associated with decreased uptake of red blood cell cytosolic contents by ring-stagePlasmodium falciparum. Previous work has identified decreased hemoglobin uptake as the mechanism ofPfkelch13-mediated ART resistance. This work demonstrates thatPfCoronin appears to act via a parallel pathway. For bothPfkelch13-mediated andPfcoronin-mediated ART resistance, we hypothesize that the decreased hemoglobin uptake in ring stage parasites results in less heme-based activation of the artemisinin endoperoxide ring and reduced cytocidal activity. This study deepens our understanding of ART resistance, as well as hemoglobin uptake and development of the DV in early-stage parasites.
Development and patterning of a highly versatile visual system in spiders
Authors: Gonzalez Luis Baudouin , Schönauer Anna , Harper Amber , Arif Saad , Leite Daniel J. , Steinhoff Philip O. M. , Pechmann Matthias , Telizhenko Valeriia , Pande Atal , Kosiol Carolin , McGregor Alistair P. , Sumner-Rooney Lauren 
Published: December 2023

AbstractVisual systems provide a key interface between organisms and their surroundings, and have evolved in many forms to perform diverse functions across the animal kingdom. Spiders exhibit a range of visual abilities and ecologies, the diversity of which is underpinned by a highly versatile, modular visual system architecture. This typically includes eight eyes of two developmentally distinct types, but the number, size, location, and function of the eyes can vary dramatically between lineages. Previous studies of visual system development in spiders have confirmed that many components of the retinal determination gene (RDG) network are conserved with other arthropods, but so far, comparative studies among spiders are lacking. We characterised visual system development in eight species of spiders representing a range of morphologies, visual ecologies, and phylogenetic positions, to determine how these diverse configurations are formed, and how they might evolve. Combining synchrotron radiation tomography, transcriptomics, in situ hybridisation, and selection analyses, we characterise the repertoires and expression of key RDGs in relation to adult morphology. We identify key molecular players, timepoints, and developmental events that may contribute to adult diversity, in particular the molecular and developmental underpinnings of eye size, number, position, and identity across spiders.
The RNA-binding protein RbpB is a central regulator of polysaccharide utilization in gutBacteroides
Authors: Rüttiger Ann-Sophie , Ryan Daniel , Spiga Luisella , Lamm-Schmidt Vanessa , Prezza Gianluca , Reichardt Sarah , Barquist Lars , Faber Franziska , Zhu Wenhan , Westermann Alexander J. 
Published: December 2023

ABSTRACTParamount to human health, symbiotic bacteria in the gastrointestinal tract rely on the breakdown of complex polysaccharides to thrive in this sugar-deprived environment. GutBacteroidesare metabolic generalists and deploy dozens of polysaccharide utilization loci (PULs) to forage diverse dietary and host-derived glycans. The expression of the multi-protein PUL complexes is tightly regulated at the transcriptional level. However, how PULs are orchestrated at translational level in response to the fluctuating levels of their cognate substrates is unknown. Here, we identify the RNA-binding protein RbpB and a family of noncoding RNAs as key players in post-transcriptional PUL regulation. Ablation of RbpB inBacteroides thetaiotaomicrondisplays compromised colonization in the mouse gut in a host diet-dependent manner. Current dogma holds that individual PULs are regulated by dedicated transcriptional regulators. We demonstrate that RbpB acts as a global RNA binder that directly interacts with several hundred cellular transcripts. This includes a paralogous noncoding RNA family comprised of 14 members, the FopS (familyofparalogoussRNAs) cluster. Through a series ofin-vitroandin-vivoassays, we reveal that FopS sRNAs repress the translation of a SusC-like glycan transporter when substrates are limited—an effect antagonized by RbpB. Together, this study implicates RNA-coordinated metabolic control as an important, yet previously overlooked, factor contributing to thein-vivofitness of predominant microbiota species in dynamic nutrient landscapes.
FGF8-mediated gene regulation affects regional identity in human cerebral organoids
Authors: Bertacchi Michele , Maharaux Gwendoline , Loubat Agnès , Jung Mathieu , Studer Michèle 
Published: December 2023

SUMMARYThe morphogen FGF8 establishes graded positional cues imparting regional cellular responsesviamodulation of early target genes. The roles of FGF signaling and its effector genes remain poorly characterized in human experimental models mimicking early fetal telencephalic development. We used hiPSC-derived cerebral organoids as an in vitro platform to challenge the effect of FGF8 signaling on neural identity and differentiation. We found that FGF8 treatment increases cellular heterogeneity leading to distinct telencephalic and mesencephalic-like domains that co-develop in multi-regional organoids. Within telencephalic domains, FGF8 affects the anteroposterior and dorsoventral identity of neural progenitors, the balance between GABAergic and glutamatergic neurons, thus impacting spontaneous neuronal network activity. Moreover, FGF8 efficiently modulates key regulators responsible for several human neurodevelopmental disorders. Overall, our results show that FGF8 signaling is directly involved in both regional patterning and cellular diversity in human cerebral organoids and in modulating genes associated with normal and pathological neural development.
Mefloquine-induced conformational shift in Cx36 N-terminal helix leading to channel closure mediated by lipid bilayer
Authors: Cho Hwa-Jin , Lee Hyung Ho 
Published: December 2023

AbstractConnexin 36 (Cx36) forms interneuronal gap junctions, establishing electrical synapses for rapid synaptic transmission. In disease conditions, inhibiting Cx36 gap junction channels (GJCs) is beneficial, as it prevents abnormal synchronous neuronal firing and apoptotic signal propagation, mitigating seizures and progressive cell death. Here, we present cryo-electron microscopy structures of human Cx36 GJC in complex with known channel inhibitors, such as mefloquine, arachidonic acid, and 1-hexanol. Notably, these inhibitors competitively bind to the binding pocket of the N-terminal helices (NTH), inducing a conformational shift from the pore-lining NTH (PLN) state to the flexible NTH (FN) state. This leads to the obstruction of the channel pore by flat double-layer densities of lipids. These studies elucidate the molecular mechanisms of how Cx36 GJC can be modulated by inhibitors, providing valuable insights into potential therapeutic applications.
Mutations in Fibronectin Dysregulate Chondrogenesis in Skeletal Dysplasia
Authors: Dinesh Neha E. H. , Rousseau Justine , Mosher Deane F. , Strauss Mike , Mui Jeannie , Campeau Philippe M. , Reinhardt Dieter P. 
Published: December 2023

AbstractFibronectin (FN) is an extracellular matrix glycoprotein essential for the development and function of major vertebrate organ systems. Mutations in FN result in an autosomal dominant skeletal dysplasia termed corner fracture-type spondylometaphyseal dysplasia (SMDCF). The precise pathomechanisms through which mutant FN induces impaired skeletal development remain elusive. Here, we have generated patient-derived induced pluripotent stem cells as a cell culture model for SMDCF to investigate the consequences of FN mutations on mesenchymal stem cells (MSCs) and their differentiation into cartilage-producing chondrocytes. In line with our previous data, FN mutations disrupted protein secretion from MSCs, causing a notable increase in intracellular FN and a significant decrease in extracellular FN levels. Analyses of plasma samples from SMDCF patients also showed reduced FN in circulation. FN and endoplasmic reticulum (ER) protein folding chaperones (BIP, HSP47) accumulated in MSCs within ribosome-covered cytosolic vesicles that emerged from the ER and transitioned into lysosomes. Massive amounts of these vesicles were not cleared from the cytosol. The accumulation of intracellular FN and ER proteins elevated cellular stress markers and altered mitochondrial structure. Bulk RNA sequencing revealed a specific transcriptomic dysregulation of the patient-derived cells relative to controls. Analysis of MSC differentiation into chondrocytes showed impaired mesenchymal condensation, reduced chondrogenic markers, and compromised cell proliferation in mutant cells. FN mutant cells also displayed altered FN splice variants under chondrogenic stimuli. Moreover, FN mutant cells exhibited significantly lower transforming growth factor beta-1 (TGFβ1) expression, crucial for mesenchymal condensation. Exogenous FN or TGFβ1 supplementation effectively improved the MSC condensation and promoted chondrogenesis in FN mutant cells. These findings demonstrate the cellular consequences of FN mutations in SMDCF and explain the molecular pathways involved in the associated altered chondrogenesis.Significance /Highlights• SMDCF-causing mutations in fibronectin impair protein secretion in iPSC-derived mesenchymal stem cells.• Mutant fibronectin and ER protein folding chaperones are directly exported from the rough endoplasmic reticulum into vesicles covered with ribosomes, which transition into lysosomes.• The cells cannot clear the massive accumulation of cytosolic vesicles.• Mutations in fibronectin impair stem cell proliferation, mesenchymal condensation, and the differentiation of MSCs into chondrocytes.• Exogenous addition of purified fibronectin or TGFβ-1 improves mesenchymal condensation and chondrogenesis of the FN mutant stem cells.
Host-Pathogen Interactions in thePlasmodium-Infected Mouse Liver at Spatial and Single-Cell Resolution
Authors: Hildebrandt Franziska , Urrutia-Iturritza Miren , Zwicker Christian , Vanneste Bavo , Hul Noémi Van , Semle Elisa , Pascini Tales , Saarenpää Sami , He Mengxiao , Andersson Emma R. , Scott Charlotte L. , Vega-Rodriguez Joel , Lundeberg Joakim , Ankarklev Johan 
Published: December 2023

ABSTRACTUpon infecting its vertebrate host, the malaria parasite initially invades the liver where it undergoes massive replication, whilst remaining clinically silent. The spatial coordination of factors regulating immune responses and metabolic zonation during malaria infection, in the true tissue context, remains unexplored. Here, we perform spatial transcriptomics in combination with single-nuclei RNA-sequencing (snRNA-seq) over multiple time points during liver infection to delineate transcriptional programs of host-pathogen interactions acrossP. berghei-infected liver tissues. Our data suggest changes in gene expression related to lipid metabolism in response toPlasmodiuminfection in the proximity of infected hepatocytes, such as the modulation of the expression of genes involved in peroxisome proliferator-activated receptor pathway signaling. The data further indicate the presence of inflammatory hotspots with distinct cell type compositions and differential liver inflammation programs along the lobular axis in the malaria-infected tissues. Furthermore, a significant upregulation of genes involved in inflammation is observed in liver tissues of control mice injected with mosquito salivary gland components, which is considerably delayed compared toP. bergheiinfected mice. Our study establishes a benchmark for investigating transcriptome changes during host-parasite interactions in tissues, it provides informative insights regardingin vivostudy design linked to infection, and provides a useful tool for the discovery and validation ofde novointervention strategies aimed at malaria liver stage infection.
Fully automated workflow for integrated sample digestion and Evotip loading enabling high-throughput clinical proteomics
Authors: Kverneland Anders H. , Harking Florian , Vej-Nielsen Joel Mario , Huusfeldt Magnus , Bekker-Jensen Dorte B. , Svane Inge Marie , Bache Nicolai , Olsen Jesper V. 
Published: December 2023

AbstractProtein identification and quantification is an important tool for biomarker discovery. With the increased sensitivity and speed of modern mass spectrometers, sample-preparation remains a bottleneck for studying large cohorts. To address this issue, we prepared and evaluated a simple and efficient workflow on the Opentrons OT-2 (OT-2) robot that combines sample digestion, cleanup and Evotip loading in a fully automated manner, allowing the processing of up to 192 samples in 6 hours. Our results demonstrate a highly sensitive workflow yielding both reproducibility and stability even at low sample inputs. The workflow is optimized for minimal sample starting amount to reduce the costs for reagents needed for sample preparation, which is critical when analyzing large biological cohorts. Building on the digesting workflow, we incorporated an automated phosphopeptide enrichment step using magnetic Ti-IMAC beads. This allows for a fully automated proteome and phosphoproteome sample preparation in a single step with high sensitivity. Using the integrated workflow, we evaluated the effects of cancer immune therapy on the plasma proteome in metastatic melanoma patients.
Metabolomics profiling reveals distinct, sex-specific signatures in the serum and brain metabolomes in the mouse models of Alzheimer’s disease
Authors: Pandey Ravi S. , Arnold Mattias , Batra Richa , Krumsiek Jan , Kotredes Kevin P. , Garceau Dylan , Williams Harriet , Sasner Michael , Howell Gareth R. , Kaddurah-Daouk Rima , Carter Gregory W. 
Published: December 2023

Structured AbstractINTRODUCTIONIncreasing evidence suggests that metabolic impairments contribute to early Alzheimer’s disease (AD) mechanisms and subsequent dementia. Signals in metabolic pathways conserved across species provides a promising entry point for translation.METHODSWe investigated differences of serum and brain metabolites between the early-onset 5XFAD and late-onset LOAD1 (APOE4.Trem2*R47H) mouse models of AD to C57BL/6J controls at six months of age.RESULTSWe identified sex differences for several classes of metabolites, such as glycerophospholipids, sphingolipids, and amino acids. Metabolic signatures were notably different between brain and serum in both mouse models. The 5XFAD mice exhibited stronger differences in brain metabolites, whereas LOAD1 mice showed more pronounced differences in serum.DISCUSSIONSeveral of our findings were consistent with results in humans, showing glycerophospholipids reduction in serum of APOE4 carriers and replicating the serum metabolic imprint of the APOE4 genotype. Our work thus represents a significant step towards translating metabolic dysregulation from model organisms to human AD.
3D genome organization during TGFB-induced transcription requires nuclear microRNA and G-quadruplexes
Authors: Cordero Julio , Swaminathan Guruprasadh , Rogel-Ayala Diana G , Rubio Karla , Elsherbiny Adel , Günther Stefan , Braun Thomas , Dobreva Gergana , Barreto Guillermo 
Published: December 2023

ABSTRACTStudying the dynamics of three-dimensional (3D) chromatin structure is essential to understand biological processes in the cell nucleus. Recent publications based on integrative analysis of multi-omics studies have provided comprehensive and multilevel insights into 3D genome organization emphasizing its role during transcriptional regulation. While enhancers are regulatory elements that play a central role in the spatiotemporal control of gene expression, chromatin looping has been broadly accepted as a means for enhancer-promoter interactions allowing them to stablish cell-type-specific gene expression signatures. On the other hand, G-quadruplexes (G4s) are non-canonical DNA secondary structures that are both, enriched at promoters and related to increased gene expression. However, the role of G4s in promoter-distal regulatory elements, such as super-enhancers (SE), as well as in 3D genome organization and chromatin looping mediating long-range enhancer-promoter interactions has remained elusive. Here we show that mature microRNA 9 (miR-9) is enriched at promoters and SE of genes that are inducible by tissue growth factor beta 1 (TGFB1) signaling. Further, we found that nuclearmiR-9is required for chromatin features related to increased transcriptional activity, such as broad domains of the euchromatin histone mark H3K4me3 (histone 3 tri-methylated lysine 4) and G4s. Moreover, we show that nuclearmiR-9is required for promoter-super-enhancer looping. Our study places a nuclear microRNA in the same structural and functional context with G4s and promoter-enhancer interactions during 3D genome organization and transcriptional activation induced by TGFB1 signaling, a critical regulator of proliferation programs in cancer and fibrosis.
MCFBM: a behavioral analysis system enabling objective inference of songbirds’ attention during social interactions
Authors: Fujibayashi Mizuki , Abe Kentaro 
Published: December 2023

AbstractUnderstanding animal behavior is crucial in behavioral neuroscience, which aims to unravel the mechanism driving these behaviors. A milestone in this field is the analysis of behavioral reactions among animals engaging in social interactions. Although many studies have revealed the fundamental roles of social interaction in social learning, the behavioral aspects of these interactions remain poorly understood, largely due to the lack of tools for analyzing complex behaviors and the attention of subjects in naturalistic, free-moving conditions. Here, we introduce a high-precision system for behavior analysis in songbirds using a marker-based motion capture technique. This system accurately tracks the body location and head direction of freely moving finches and is applicable to multiple subjects during social interaction. With this system, we have quantitatively analyzed behaviors of zebra finches (Taeniopygia guttata) related to visual attention. Our analysis revealed variations in the use of right and left eyes, as well as the duration of sight, among the individuals presented. Further analysis and comparison of their behaviors during both virtual and live presentation identified the similarities and differences in their behavioral reactions. Additionally, we observed changes in their behavioral reactions during a conditioned learning paradigm. This system provides an efficient and easy-to-use tool for advanced behavioral analysis in songbirds, providing an objective method to infer their focus of attention.
Quantitative spatial analysis of bacterial transcriptome and chromosome structural data with GRATIOSA: application to twin-supercoiled domain distribution
Authors: Pineau Maïwenn , Forquet Raphaël , Reverchon Sylvie , Nasser William , Hommais Florence , Meyer Sam 
Published: December 2023

AbstractWhile classical models of transcriptional regulation focus on transcription factors binding at promoters, gene expression is also influenced by chromosome organization. Understanding this spatial regulation strongly benefits from integrated and quantitative spatial analyses of genome-scale data such as RNA-Seq and ChIP-Seq. We introduce Genome Regulation Analysis Tool Incorporating Organization and Spatial Architecture (GRATIOSA), a Python package making such combined analyses more automatic, systematic and reproducible. While current software focuses on initial analysis steps (read mapping and counting), GRAsTIOSA proposes an integrated framework for subsequent analyses, providing a broad range of spatially-resolved quantitative data comparisons and representations. As an example, we quantitatively assess the validity and extension of the twin-supercoiled domain model inEscherichia coligenome-wide transcription, using recent topoisomerase ChIP-Seq data. We show that topoisomerases are locally recruited by the 40% most highly expressed transcription units, with a magnitude correlating with the expression level. The recruitment of topoisomerase I extends to around 10 kb upstream, whereas DNA gyrase is recruited at least 30 kb downstream of transcription units. This organization is the primary determinant of topoisomerase I recruitment, whereas gyrase binding is additionally modulated at larger 100-200 kb length-scale. Further analyses of spatial regulation will be facilitated by GRATIOSA.
KAGE 2: Fast and accurate genotyping of structural variation using pangenomes
Authors: Grytten Ivar , Rand Knut Dagestad , Sandve Geir Kjetil 
Published: December 2023

AbstractStructural variation is known to play an important and often overlooked role in regulating disease and traits, but accurately detecting structural variants from sequencing data has traditionally been difficult. However, recent improvements in high-quality genome assembly along with methodological advancements in pangenome creation have opened up the landscape for methods that use such pangenomes for structural variant calling and genotyping. We here present KAGE2, which accurately and efficiently genotypes structural variation by exploiting the availability of pangenomes that represent known variation in a population. Through comprehensive benchmarking, we highlight limitations of existing methodology and show that KAGE2 is more accurate and considerably faster than existing methods.