bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phospholipase C-β3 is dispensable for vascular constriction but indispensable for vascular hyperplasia
Authors: Jin Seo Yeon , Ha Jung Min , Kum Hye Jin , Ma Ji Soo , Ha Hong Koo , Song Sang Heon , Yang Yong Ryoul , Lee Ho , Bae Yoon Soo , Yamamoto Masahiro , Suh Pann-Ghill , Bae Sun Sik 
Published: July 2024

AbstractAngiotensin II (AngII) induces the contraction and proliferation of vascular smooth muscle cells (VSMCs). AngII activates phospholipase C-β (PLC-β), thereby inducing Ca2+ mobilization as well as the production of reactive oxygen species (ROS). Since contraction is a unique property of contractile VSMCs, signaling cascades related to the proliferation of VSMCs may differ. However, the specific molecular mechanism that controls the contraction or proliferation of VSMCs remains unclear. AngII-induced ROS production, migration, and proliferation were suppressed by inhibiting PLC-β3, inositol trisphosphate (IP3) receptor, and NOX or by silencing PLC-β3 or NOX1 but not by NOX4. However, pharmacological inhibition or silencing of PLC-β3 or NOX did not affect AngII-induced VSMC contraction. Furthermore, the AngII-dependent constriction of mesenteric arteries isolated from PLC-β3∆SMC, NOX1−/−, NOX4−/− and normal control mice was similar. AngII-induced VSMC contraction and mesenteric artery constriction were blocked by inhibiting the L-type calcium channel Rho-associated kinase 2 (ROCK2) or myosin light chain kinase (MLCK). The activation of ROCK2 and MLCK was significantly induced in PLC-β3∆SMC mice, whereas the depletion of Ca2+ in the extracellular medium suppressed the AngII-induced activation of ROCK2, MLCK, and vasoconstriction. AngII-induced hypertension was significantly induced in NOX1−/− and PLC-β3∆SMC mice, whereas LCCA ligation-induced neointima formation was significantly suppressed in NOX1−/− and PLC-β3∆SMC mice. These results suggest that PLC-β3 is essential for vascular hyperplasia through NOX1-mediated ROS production but is nonessential for vascular constriction or blood pressure regulation.
FGFR3 drives Aβ-induced tau uptake
Authors: Kim Dong Kyu , Suh Kyujin , Park Junho , Lee Sang-Eun , Han Jihui , Chang Sunghoe , Kim Youngsoo , Mook-Jung Inhee 
Published: July 2024

AbstractThe amyloid cascade hypothesis suggests that amyloid beta (Aβ) contributes to initiating subsequent tau pathology in Alzheimer’s disease (AD). However, the underlying mechanisms through which Aβ contributes to tau uptake and propagation remain poorly understood. Here, we show that preexisting amyloid pathology accelerates the uptake of extracellular tau into neurons. Using quantitative proteomic analysis of endocytic vesicles, we reveal that Aβ induces the internalization of fibroblast growth factor receptor 3 (FGFR3). Extracellular tau binds to the extracellular domain of FGFR3 and is internalized by the FGFR3 ligand, fibroblast growth factor 2 (FGF2). Aβ accelerates FGF2 secretion from neurons, thereby inducing the internalization of tau-attached FGFR3. Knockdown of FGFR3 in the hippocampus reduces tau aggregation by decreasing tau uptake and improving memory function in AD model mice. These data suggest FGFR3 in neurons as a novel tau receptor and a key mediator of Aβ-induced tau uptake in AD.
Interaction of perceived social support and childhood maltreatment on limbic responsivity towards negative emotional stimuli in healthy individuals
Authors: Borgers Tiana , Rinck Anne , Enneking Verena , Klug Melissa , Winter Alexandra , Gruber Marius , Kraus Anna , Dohm Katharina , Leehr Elisabeth J. , Grotegerd Dominik , Förster Katharina , Goltermann Janik , Bauer Jochen , Dannlowski Udo , Redlich Ronny 
Published: July 2024

AbstractChildhood maltreatment (CM) is associated with increased limbic activity, while social support is linked to decreased limbic activity towards negative stimuli. Our study aimed to explore the interaction of perceived social support with CM, and their combined impact on limbic activity in negative emotion processing. A total of 130 healthy individuals (HC) underwent a negative emotional face processing paradigm. They were divided into two groups based on the Childhood Trauma Questionnaire: n = 65 HC without CM matched with n = 65 HC with CM. In a region-of-interest approach of the bilateral amygdala-hippocampus-complex (AHC), regression analyses investigating the association of CM and perceived social support with limbic activity and a social support x CM ANCOVA were conducted. CM was associated with increased AHC activity, while perceived social support tended to be associated with decreased AHC activity during negative emotion processing. The ANCOVA showed a significant interaction in bilateral AHC activity (pFWE ≤ 0.024) driven by a negative association between perceived social support and bilateral AHC activity in HC without CM. No significant association was observed in HC with CM. Exploratory analyses using continuous CM scores support this finding. Our results suggest that CM moderates the link between perceived social support and limbic activity, with a protective effect of perceived social support only in HC without CM. The lack of this effect in HC with CM suggests that CM may alter the buffering effect of perceived social support on limbic functioning, highlighting the potential need for preventive interventions targeting social perception of HC with CM.
Shared functional specialization in transformer-based language models and the human brain
Authors: Kumar Sreejan , Sumers Theodore R. , Yamakoshi Takateru , Goldstein Ariel , Hasson Uri , Norman Kenneth A. , Griffiths Thomas L. , Hawkins Robert D. , Nastase Samuel A. 
Published: July 2024

AbstractWhen processing language, the brain is thought to deploy specialized computations to construct meaning from complex linguistic structures. Recently, artificial neural networks based on the Transformer architecture have revolutionized the field of natural language processing. Transformers integrate contextual information across words via structured circuit computations. Prior work has focused on the internal representations (“embeddings”) generated by these circuits. In this paper, we instead analyze the circuit computations directly: we deconstruct these computations into the functionally-specialized “transformations” that integrate contextual information across words. Using functional MRI data acquired while participants listened to naturalistic stories, we first verify that the transformations account for considerable variance in brain activity across the cortical language network. We then demonstrate that the emergent computations performed by individual, functionally-specialized “attention heads” differentially predict brain activity in specific cortical regions. These heads fall along gradients corresponding to different layers and context lengths in a low-dimensional cortical space.
Impacts of ocean warming on fish size reductions on the world’s hottest coral reefs
Authors: Johansen Jacob L. , Mitchell Matthew D. , Vaughan Grace O. , Ripley Daniel M. , Shiels Holly A. , Burt John A. 
Published: July 2024

AbstractThe impact of ocean warming on fish and fisheries is vigorously debated. Leading theories project limited adaptive capacity of tropical fishes and 14-39% size reductions by 2050 due to mass-scaling limitations of oxygen supply in larger individuals. Using the world’s hottest coral reefs in the Persian/Arabian Gulf as a natural laboratory for ocean warming - where species have survived >35.0 °C summer temperatures for over 6000 years and are 14-40% smaller at maximum size compared to cooler locations - we identified two adaptive pathways that enhance survival at elevated temperatures across 10 metabolic and swimming performance metrics. Comparing Lutjanus ehrenbergii and Scolopsis ghanam from reefs both inside and outside the Persian/Arabian Gulf across temperatures of 27.0 °C, 31.5 °C and 35.5 °C, we reveal that these species show a lower-than-expected rise in basal metabolic demands and a right-shifted thermal window, which aids in maintaining oxygen supply and aerobic performance to 35.5 °C. Importantly, our findings challenge traditional oxygen-limitation theories, suggesting a mismatch in energy acquisition and demand as the primary driver of size reductions. Our data support a modified resource-acquisition theory to explain how ocean warming leads to species-specific size reductions and why smaller individuals are evolutionarily favored under elevated temperatures.
HIV-1 Vpr combats the PU.1-driven antiviral response in primary human macrophages
Authors: Virgilio Maria C. , Ramnani Barkha , Chen Thomas , Disbennett W. Miguel , Lubow Jay , Welch Joshua D. , Collins Kathleen L. 
Published: July 2024

AbstractHIV-1 Vpr promotes efficient spread of HIV-1 from macrophages to T cells by transcriptionally downmodulating restriction factors that target HIV-1 Envelope protein (Env). Here we find that Vpr induces broad transcriptomic changes by targeting PU.1, a transcription factor necessary for expression of host innate immune response genes, including those that target Env. Consistent with this, we find silencing PU.1 in infected macrophages lacking Vpr rescues Env. Vpr downmodulates PU.1 through a proteasomal degradation pathway that depends on physical interactions with PU.1 and DCAF1, a component of the Cul4A E3 ubiquitin ligase. The capacity for Vpr to target PU.1 is highly conserved across primate lentiviruses. In addition to impacting infected cells, we find that Vpr suppresses expression of innate immune response genes in uninfected bystander cells, and that virion-associated Vpr can degrade PU.1. Together, we demonstrate Vpr counteracts PU.1 in macrophages to blunt antiviral immune responses and promote viral spread.
Time-calibrated phylogenetic and chromosomal mobilome analyses of Staphylococcus aureus CC398 reveal geographical and host-related evolution
Authors: Fernandez Javier Eduardo , Egli Adrian , Overesch Gudrun , Perreten Vincent 
Published: July 2024

AbstractAn international collection of Staphylococcus aureus of clonal complex (CC) 398 from diverse hosts spanning all continents and a 30 year-period is studied based on whole-genome sequencing (WGS) data. The collection consists of publicly available genomic data from 2994 strains and 134 recently sequenced Swiss methicillin-resistant S. aureus (MRSA) CC398 strains. A time-calibrated phylogeny reveals the presence of distinct phylogroups present in Asia, North and South America and Europe. European MRSA diverged from methicillin-susceptible S. aureus (MSSA) at the beginning of the 1950s. Two major European phylogroups (EP4 and EP5), which diverged approximately 1974, are the main drivers of MRSA CC398 spread in Europe. Within EP5, an emergent MRSA lineage spreading among the European horse population (EP5-Leq) diverged approximately 1996 from the pig lineage (EP5-Lpg), and also contains human-related strains. EP5-Leq is characterized by staphylococcal cassette chromosome mec (SCCmec) IVa and spa type t011 (CC398-IVa-t011), and EP5-Lpg by CC398-SCCmecVc-t011. The lineage-specific antibiotic resistance and virulence gene patterns are mostly mediated by the acquisition of mobile genetic elements like SCCmec, S. aureus Genomic Islands (SaGIs), prophages and transposons. Different combinations of virulence factors are present on S. aureus pathogenicity islands (SaPIs), and novel antimicrobial resistance gene containing elements are associated with certain lineages expanding in Europe. This WGS-based analysis reveals the actual evolutionary trajectory and epidemiological trend of the international MRSA CC398 population considering host, temporal, geographical and molecular factors. It provides a baseline for global WGS-based One-Health studies of adaptive evolution of MRSA CC398 as well as for local outbreak investigations.
De novo atomic protein structure modeling for cryoEM density maps using 3D transformer and HMM
Authors: Giri Nabin , Cheng Jianlin 
Published: July 2024

AbstractAccurately building 3D atomic structures from cryo-EM density maps is a crucial step in cryo-EM-based protein structure determination. Converting density maps into 3D atomic structures for proteins lacking accurate homologous or predicted structures as templates remains a significant challenge. Here, we introduce Cryo2Struct, a fully automated de novo cryo-EM structure modeling method. Cryo2Struct utilizes a 3D transformer to identify atoms and amino acid types in cryo-EM density maps, followed by an innovative Hidden Markov Model (HMM) to connect predicted atoms and build protein backbone structures. Cryo2Struct produces substantially more accurate and complete protein structural models than the widely used ab initio method Phenix. Additionally, its performance in building atomic structural models is robust against changes in the resolution of density maps and the size of protein structures.
CTCF mutation at R567 causes developmental disorders via 3D genome rearrangement and abnormal neurodevelopment
Authors: Zhang Jie , Hu Gongcheng , Lu Yuli , Ren Huawei , Huang Yin , Wen Yulin , Ji Binrui , Wang Diyang , Wang Haidong , Liu Huisheng , Ma Ning , Zhang Lingling , Pan Guangjin , Qu Yibo , Wang Hua , Zhang Wei , Miao Zhichao , Yao Hongjie 
Published: July 2024

AbstractThe three-dimensional genome structure organized by CTCF is required for development. Clinically identified mutations in CTCF have been linked to adverse developmental outcomes. Nevertheless, the underlying mechanism remains elusive. In this investigation, we explore the regulatory roles of a clinically relevant R567W point mutation, located within the 11th zinc finger of CTCF, by introducing this mutation into both murine models and human embryonic stem cell-derived cortical organoid models. Mice with homozygous CTCFR567W mutation exhibit growth impediments, resulting in postnatal mortality, and deviations in brain, heart, and lung development at the pathological and single-cell transcriptome levels. This mutation induces premature stem-like cell exhaustion, accelerates the maturation of GABAergic neurons, and disrupts neurodevelopmental and synaptic pathways. Additionally, it specifically hinders CTCF binding to peripheral motifs upstream to the core consensus site, causing alterations in local chromatin structure and gene expression, particularly at the clustered protocadherin locus. Comparative analysis using human cortical organoids mirrors the consequences induced by this mutation. In summary, this study elucidates the influence of the CTCFR567W mutation on human neurodevelopmental disorders, paving the way for potential therapeutic interventions.
Prefrontal cortex neurons encode ambient light intensity differentially across regions and layers
Authors: Zangen Elyashiv , Hadar Shira , Lawrence Christopher , Obeid Mustafa , Rasras Hala , Hanzin Ella , Aslan Ori , Zur Eyal , Schulcz Nadav , Cohen-Hatab Daniel , Samama Yona , Nir Sarah , Li Yi , Dobrotvorskia Irina , Sabbah Shai 
Published: July 2024

AbstractWhile light can affect emotional and cognitive processes of the medial prefrontal cortex (mPFC), no light-encoding was hitherto identified in this region. Here, extracellular recordings in awake mice revealed that over half of studied mPFC neurons showed photosensitivity, that was diminished by inhibition of intrinsically photosensitive retinal ganglion cells (ipRGCs), or of the upstream thalamic perihabenular nucleus (PHb). In 15% of mPFC photosensitive neurons, firing rate changed monotonically along light-intensity steps and gradients. These light-intensity-encoding neurons comprised four types, two enhancing and two suppressing their firing rate with increased light intensity. Similar types were identified in the PHb, where they exhibited shorter latency and increased sensitivity. Light suppressed prelimbic activity but boosted infralimbic activity, mirroring the regions’ contrasting roles in fear-conditioning, drug-seeking, and anxiety. We posit that prefrontal photosensitivity represents a substrate of light-susceptible, mPFC-mediated functions, which could be ultimately studied as a therapeutical target in psychiatric and addiction disorders.
Central amygdala CRF+ neurons promote heightened threat reactivity following early life adversity in mice
Authors: Demaestri Camila , Pisciotta Margaux , Altunkeser Naira , Berry Georgia , Hyland Hannah , Breton Jocelyn , Darling Anna , Williams Brenna , Bath Kevin G. 
Published: July 2024

AbstractFailure to appropriately predict and titrate reactivity to threat is a core feature of fear and anxiety-related disorders and is common following early life adversity (ELA). A population of neurons in the lateral central amygdala (CeAL) expressing corticotropin releasing factor (CRF) have been proposed to be key in processing threat of different intensities to mediate active fear expression. Here, we use in vivo fiber photometry to show that ELA results in sex-specific changes in the activity of CeAL CRF+ neurons, yielding divergent mechanisms underlying the augmented startle in ELA mice, a translationally relevant behavior indicative of heightened threat reactivity and hypervigilance. Further, chemogenic inhibition of CeAL CRF+ neurons selectively diminishes startle and produces a long-lasting suppression of threat reactivity. These findings identify a mechanism for sex-differences in susceptibility for anxiety following ELA and have broad implications for understanding the neural circuitry that encodes and gates the behavioral expression of fear.
Co-immobilization of whole cells and enzymes by covalent organic framework for biocatalysis process intensification
Authors: Zheng Dong , Zheng Yunlong , Tan Junjie , Zhang Zhenjie , Huang He , Chen Yao 
Published: July 2024

AbstractCo-immobilization of cells and enzymes is often essential for the cascade biocatalytic processes of industrial-scale feasibility but remains a vast challenge. Herein, we create a facile co-immobilization platform integrating enzymes and cells in covalent organic frameworks (COFs) to realize the highly efficient cascade of inulinase and E. coli for bioconversion of natural products. Enzymes can be uniformly immobilized in the COF armor, which coats on the cell surface to produce cascade biocatalysts with high efficiency, stability and recyclability. Furthermore, this one-pot in situ synthesis process facilitates a gram-scale fabrication of enzyme-cell biocatalysts, which can generate a continuous-flow device conversing inulin to D-allulose, achieving space-time yield of 161.28 g L−1 d−1 and high stability (remaining >90% initial catalytic efficiency after 7 days of continuous reaction). The created platform is applied for various cells (e.g., E. coli, Yeast) and enzymes, demonstrating excellent universality. This study paves a pathway to break the bottleneck of extra- and intracellular catalysis, creates a high-performance and customizable platform for enzyme-cell cascade biomanufacturing, and expands the scope of biocatalysis process intensification.
Detection of helical water flows in sub-nanometer channels
Authors: Zelenovskii Pavel , Soares Márcio , Bornes Carlos , Marin-Montesinos Ildefonso , Sardo Mariana , Kopyl Svitlana , Kholkin Andrei , Mafra Luís , Figueiredo Filipe 
Published: July 2024

AbstractNanoscale flows of liquids can be revealed in various biological processes and underlie a wide range of nanofluidic applications. Though the integral characteristics of these systems, such as permeability and effective diffusion coefficient, can be measured in experiments, the behaviour of the flows within nanochannels is still a matter of speculation. Herein, we used a combination of quadrupolar solid-state NMR spectroscopy, computer simulation, and dynamic vapour sorption measurements to analyse water diffusion inside peptide nanochannels. We detected a helical water flow coexisting with a conventional axial flow that are independent of each other, immiscible, and associated with diffusion coefficients that may differ up to 3 orders of magnitude. The trajectory of the helical flow is dictated by the screw-like distribution of ionic groups within the channel walls, while its flux is governed by external water vapour pressure. Similar flows may occur in other types of nanochannels containing helicoidally distributed ionic groups and be exploited in various nanofluidic lab-on-a-chip devices.
A dual-center analysis of conservative versus liberal glycoprotein IIb–IIIa antagonist strategies in the treatment of ST-elevation myocardial infarction
Authors: Callichurn Kashi , Simard Philippe , De Marco Corrado , Jamali Payman , Saada Yacine , Matteau Alexis , Schampaert Érick , Mansour Samer , Hatem Raja , Potter Brian J. 
Published: July 2024

AbstractWhile the efficacy of GpIIb–IIIa-inhibitors during primary PCI (pPCI) for ST-elevated myocardial infarction (STEMI) has previously been demonstrated, its ongoing role and safety in combination with newer P2Y12-inhibitors is unclear. We therefore sought to compare outcomes between two centers with divergent approaches to the use of GpIIbIIIa antagonists in pPCI. We performed a retrospective chart review of all-comer STEMI patients treated with pPCI at two high-volume Montreal academic tertiary care centers. One center tended to use GpIIb–IIIa-inhibitors up-front in a large proportion of patients (liberal strategy) and the other preferring a bail-out approach (conservative strategy). Baseline patient characteristics and procedural data were compared between the two groups. The main efficacy outcome was rate of no-reflow/slow-reflow and the main safety outcome was BARC ≥ 2 bleeding events. A total of 459 patients were included, of whom 167 (36.5%) were exposed to a GpIIb–IIIa-antagonist. There was a significant overall difference in use of GpIIb–IIIa-antagonist between the two centers (60.5% vs. 16.1%, p < 0.01). Rate of no-reflow/slow-reflow was similar between groups (2.6% vs. 1.4%, p = 0.22). In-hospital rates of unplanned revascularization, stroke and death were also not different between groups. Use of a liberal GpIIb-–IIIa-antagonist strategy was however associated with a higher risk of bleeding (OR 3.16, 95% CI 1.57–6.37, p < 0.01), which persisted after adjustment for covariables (adjusted OR 2.85, 95% CI 1.40–5.81, p < 0.01). In this contemporary retrospective cohort, a conservative, bail-out only GpIIb-–IIIa-antagonist strategy was associated with a lower incidence of clinically relevant bleeding without any signal for an increase in no-reflow/slow-reflow or ischemic clinical events.