Biology subjects

Lu, H.

Publications and source records attributed to Lu, H..

At least 127 records · Page 7Linked to original sources

bioRxiv2024

Genome-wide mapping of native co-localized G4s and R-loops in living cells

The non-B DNA structures can act as dynamic functional genomic elements regulating gene expression. Among them, G4s and R-loops are two of the best studied. The interplay between R-loops and G4s are emerging in regulating DNA repair, replication and transcription. A comprehensive picture of native co-localized G4s and R-loops in living cells is currently lacking. Here, we describe the development of HepG4-seq and an optimized HBD-seq methods, which robustly capture native G4s and R-loops, respectively, in living cells. We successfully employed these methods to establish comprehensive maps of native co-localized G4s and R-loops in human HEK293 cells and mouse embryonic stem cells (mESCs). We discovered that co-localized G4s and R-loops are dynamically altered in a cell type-dependent manner and are largely localized at active promoters and enhancers of transcriptional active genes. We further demonstrated the helicase Dhx9 as a direct and major regulator that modulates the formation and resolution of co-localized G4s and R-loops. Depletion of Dhx9 impaired the self-renewal and differentiation capacities of mESCs by altering the transcription of co-localized G4s and R-loops - associated genes. Taken together, our work established that the endogenous co-localized G4s and R-loops are prevalently persisted in the regulatory regions of active genes and are involved in the transcriptional regulation of their linked genes, opening the door for exploring broader roles of co-localized G4s and R-loops in development and disease.

genomics↗

bioRxiv2024

Gene PointNet for Tumor Classification

The rising incidence of cancer underscores the imperative for innovative diagnostic and prognostic methodologies. This study delves into the potential of RNA-Seq gene expression data to enhance cancer classification accuracy. Introducing a pioneering approach, we model gene expression data as point clouds, capitalizing on the datas intrinsic properties to bolster classification performance. Utilizing PointNet, a typical technique for processing point cloud data, as our frameworks cornerstone, we incorporate inductive biases pertinent to gene expression and pathways. This integration markedly elevates model efficacy, culminating in developing an end-to-end deep learning classifier with an accuracy rate surpassing 99%. Our findings not only illuminate the capabilities of AI-driven models in the realm of oncology but also highlight the criticality of acknowledging biological dataset nuances in model design. This research provides insights into application of deep learning in medical science, setting the stage for further innovation in cancer classification through sophisticated biological data analysis. The source code for our study is accessible at: https://github.com/cialab/GPNet.

bioinformatics↗

bioRxiv2024

Different Emotional States Engage Distinct Descending Pathways from the Prefrontal Cortex

Effective emotional processing, crucial for adaptive behavior, is mediated by the medial prefrontal cortex (mPFC) via connections to the basolateral amygdala (BLA) and nucleus accumbens (NAc), traditionally considered functionally similar in modulating reward and aversion responses. However, the functional specialization of the mPFC[->]BLA and mPFC[->]NAc pathways in representing affective states remains unclear. We found that while overall firing patterns appeared consistent across emotional states, deeper analysis revealed distinct variabilities. Specifically, mPFC[->]BLA neurons, especially "center-ON" neurons, exhibited heightened activity during behaviors classically associated with anxiety-like states, suggesting their involvement in aversive behavioral regulation. Conversely, mPFC[->]NAc neurons were more active during exploratory and approach-related behaviors, implicating them in the processing of positively valenced behavioral states. Notably, mPFC[->]NAc neurons showed significant pattern decorrelation during social interactions, suggesting a pivotal role in processing social preference. Additionally, repeated win/loss outcomes in the tube test produced distinct hierarchy-dependent behavioral changes and elevated corticosterone levels in loser mice, supporting the biological relevance of these behaviorally defined states. Together, these findings reveal pathway-specific representations of affect-related behavioral states in mPFC circuits and provide a framework for understanding how prefrontal outputs organize adaptive behavior across environmental contexts.

neuroscience↗

bioRxiv2024

Cyclin O controls entry into the cell-cycle variant required for multiciliated cell differentiation

Multiciliated cells (MCC) ensure proper fluid circulation in various organs in metazoans. Their differentiation is marked by the massive ampliication of cilia-nucleating centrioles and is known to be controlled by various cell cycle components. Tn a companion study, we show that the differentiation of MCC is driven by a genuine cell-cycle variant characterized by sequential and wave-like expression of canonical and non-canonical cyclins such as Cyclin O (CCNO). Patients with CCNO mutations exhibit a subtype of Primary Ciliary Dyskinesia (PCD) designated as Reduced Generation of Multiple Motile Cilia (RGMC), yet the role of CCNO during MCC differentiation remains unclear. Here, using mice and human cellular models, single cell transcriptomics and functional studies, we show that Cena is activated during a strategic temporal window at the crossroads between the onset of MCC differentiation, the entry into the MCC cell cycle variant, and the activation of the centriole biogenesis program. We ind that the absence of Cena leads to a block of MCC progenitor differentiation at the G1/S-like transition, just before the beginning of centriole formation. This leads to a complete lack of centrioles and cilia in mouse brain and human airway MCC. Altogether, our study identifies CCNO as a core regulator of entry into the MCC cell cycle variant and shows that the coupling of centriole biogenesis to an S-like phase, maintained in MCC, is dependent on CCNO. One sentence summaryCyclin O is necessary for multiciliated cells to enter their differentiation cell cycle variant and allows the massive amplification of centrioles, which serve as basal bodies for cilia nucleation.

cell biology↗

bioRxiv2024

A safe insect-based Chikungunya fever vaccine affords rapid and durable protection in cynomolgus macaques

Chikungunya virus (CHIKV), which induces chikungunya fever and chronic arthralgia, is an emerging public health concern. Safe and efficient vaccination strategies are needed to prevent or mitigate virus-associated acute and chronic morbidities for preparation of future outbreaks. Eilat (EILV)/CHIKV, a chimeric alphavirus which contains the structural proteins of CHIKV and the non-structural proteins of EILV, does not replicate in vertebrate cells. The chimeric virus was previously reported to induce protective adaptive immunity in mice. Here, we assessed the capacity of the virus to induce quick and durable protection in cynomolgus macaques. EILV/CHIKV protected macaques from wild-type (WT) CHIKV infection one year after a single dose vaccination. Transcriptome and in vitro functional analyses reveal that the chimeric virus triggered toll-like receptor signaling and T cell, memory B cell and antibody responses in a dose-dependent manner. Notably, EILV/CHIKV preferentially induced more durable, robust, and broader repertoire of CHIKV-specific T cell responses, compared to a live attenuated CHIKV 181/25 vaccine strain. The insect-based chimeric virus did not cause skin hypersensitivity reactions in guinea pigs sensitized to mosquito bites. Furthermore, EILV/CHIKV induced strong neutralization antibodies and protected cynomolgus macaques from WT CHIKV infection within six days post vaccination. Transcriptome analysis also suggest that the chimeric virus induction of multiple innate immune pathways, including Toll-like receptor signaling, type I IFN and IL-12 signaling, antigen presenting cell activation, and NK receptor signaling. Our findings suggest that EILV/CHIKV is a safe, highly efficacious vaccine, and provides both rapid and long-lasting protection in cynomolgus macaques.

microbiology↗

bioRxiv2024

Unraveling the impact of host genetics and factors on the urinary microbiome in a young population

The significance of the urinary microbiome in maintaining health and contributing to disease development is increasingly recognized. However, a comprehensive understanding of this microbiome and its influencing factors remains elusive. Utilizing whole metagenomic and whole-genome sequencing, along with detailed metadata, we characterized the urinary microbiome and its influencing factors in a cohort of 1579 Chinese individuals. Our findings unveil the distinctiveness of the urinary microbiome from other four body sites, delineating five unique urotypes dominated by Gardnerella vaginalis, Sphingobium fluviale, Lactobacillus iners, Variovorax sp PDC80 and Acinetobacter junii, respectively. We identified 108 host factors significantly influencing the urinary microbiome, collectively explaining 12.92% of the variance in microbial composition. Notably, gender-related factors, including sex hormones, emerged as key determinants in defining urotype groups, microbial composition and pathways, with the urinary microbiome exhibiting strong predictive ability for gender (AUC=0.843). Furthermore, we discovered 43 genome-wide significant associations between host genetic loci and specific urinary bacteria, Acinetobacter in particular, linked to 8 host loci (p < 5x10-8). These associations were also modulated by gender and sex hormone levels. In summary, our study provides novel insights into the impact of host genetics and other factors on the urinary microbiome, shedding light on its implications for host health and disease.

microbiology↗

bioRxiv2024

Neuromechanical Phase Lags and Gait Adaptation in the Nematode C. elegans

Undulation is a locomotor strategy in which waves of bending propagate along the body.This form of locomotion is observed in organisms that span orders of magnitude in size and represent diverse habitats and species. Despite this diversity, common neuromechanical phenomena have been observed across biologically disparate undulators, due to common mechanics. For example, Neuromechanical Phase Lags (NPL), a phenomenon where waves of muscle contraction travel at different speeds than body bends, have been observed in fish, lamprey and lizards. Existing theoretical descriptions of this phenomenon implicate the role of physical body-environment interactions. However, systematic experimental variation of body-environment interactions and measurement of the corresponding phase lags has not been performed. Using the nematode Caenorhabditis elegans we measured muscle and body curvature dynamics simultaneously, performing calcium imaging in the body wall muscles while systematically varying the environmental rheology. A mechanical model demonstrates that the measured phase lags are controlled by the relative strength of elastic torques within the body and resistive forces within the medium. We further show that the phase lags correspond with a difference in the wavenumber of the muscle activity and curvature patterns. Hence, the environmental forces that create NPL also act as a filter that shapes and modulates the gait commanded by the nervous system. Beyond nematodes, the simplicity of our model further suggests that tuning body elasticity may serve as a general means of modulating the degree of mechanical control in other undulators.

biophysics↗

bioRxiv2024

Unifying community-wide whole-brain imaging datasets enables robust automated neuron identification and reveals determinants of neuron positioning in C. elegans

We develop a data harmonization approach for C. elegans volumetric microscopy data, still or video, consisting of a standardized format, data pre-processing techniques, and a set of human-in-the-loop machine learning based analysis software tools. We unify a diverse collection of 118 whole-brain neural activity imaging datasets from 5 labs, storing these and accompanying tools in an online repository called WormID (wormid.org). We use this repository to train three existing automated cell identification algorithms to, for the first time, enable accuracy in neural identification that generalizes across labs, approaching human performance in some cases. We mine this repository to identify factors that influence the developmental positioning of neurons. To facilitate communal use of this repository, we created open-source software, code, web-based tools, and tutorials to explore and curate datasets for contribution to the scientific community. This repository provides a growing resource for experimentalists, theorists, and toolmakers to (a) study neuroanatomical organization and neural activity across diverse experimental paradigms, (b) develop and benchmark algorithms for automated neuron detection, segmentation, cell identification, tracking, and activity extraction, and (c) inform models of neurobiological development and function.

neuroscience↗

bioRxiv2024

Defective Homologous Recombination and Genomic Instability Predict Increased Responsiveness to Carbon Ion Radiotherapy in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is inherently resistant to conventional chemo-and radiation-therapy. However, clinical trials showed that carbon ion radiotherapy (CIRT) with concurrent gemcitabine can be effective for treating unresectable locally advanced PDAC. In this study, we aimed to determine features that could identify patients who would benefit most from CIRT. A panel of human PDAC cell lines with various genetic backgrounds was leveraged to determine whether a subset could be identified that preferentially responds to CIRT. The cell lines displayed a differential response to CIRT as compared to {gamma}-rays as measured by relative biological effectiveness (RBE) calculated at 10% survival, which ranged from 1.96 to 3.04. Increased radiosensitivity correlated with decreased DNA double strand break (DSB) repair as measured by {gamma}H2AX foci resolution. We determined that the cell lines most sensitive to CIRT are defective in the homologous recombination (HR) DSB repair pathway and/or have high genomic instability due to elevated replication stress. Next, this knowledge was utilized to assess whether the HR pathway could be targeted to potentiate CIRT in vitro. It was determined that pretreating a radioresistant PDAC cell line with the HR inhibitor, B02, resulted in a marked increase in sensitivity to CIRT when treated with high linear energy transfer (LET) radiation in the spread-out Bragg peak (74.1-89.3 keV/m) but not at the entry LET (13.0-16.4 keV/m) in vitro as opposed to that seen with a NHEJ inhibitor. These data suggest a greater therapeutic index with the combination therapy in the tumor over normal tissues based on LET distribution. These data support the notion that PDAC tumors with defects in HR and/or those with high inherent replication stress respond to CIRT without the concern for excessive normal tissue toxicity. With the advent of agents targeting HR, the difference in tumor cell response in the entry region vs within the SOBP based upon the respective LETs of those regions of the beam profile, will be superior to agents that target NHEJ.

cancer biology↗

bioRxiv2024

Electromagnetic Modeling within a Microscopically Realistic Brain - Implications for Brain Stimulation

Modeling brain stimulation at the microscopic scale may reveal new paradigms for various stimulation modalities. We present the largest map to date of extracellular electric field distributions within a layer L2/L3 mouse primary visual cortex brain sample. This was enabled by the automated analysis of serial section electron microscopy images with improved handling of image defects, covering a volume of 250 x 140 x 90 m3. The map was obtained by applying a uniform brain stimulation electric field at three different polarizations and accurately computing microscopic field perturbations using the boundary element fast multipole method. We used the map to identify the effect of microscopic field perturbations on the activation thresholds of individual neurons. Previous relevant studies modeled a macroscopically homogeneous cortical volume. Our result shows that the microscopic field perturbations - an electric field spatial noise with a mean value of zero - only modestly influence the macroscopically predicted stimulation field strengths necessary for neuronal activation. The thresholds do not change by more than 10% on average. Under the stated limitations and assumptions of our method, this result justifies the conventional theory of "invisible" neurons embedded in a macroscopic brain model for transcranial magnetic and transcranial electrical stimulation. However, our result is solely sample-specific and largely neglects the effect of the microcapillary network. Furthermore, we only considered the uniform impressed field and a single- pulse stimulation time course. Significance statementThis study is arguably the first attempt to model brain stimulation at the microscopic scale, enabled by automated analysis of modern scanning electron microscopy images of the brain. It concentrates on modeling microscopic perturbations of the extracellular electric field caused by the physical cell structure and is applicable to any type of brain stimulation. Data availability statementPost-processed cell CAD models (383, stl format), microcapillary CAD models (34, stl format), post-processed neuron morphologies (267, swc format), extracellular electric field and potential distributions at different polarizations (267x3, MATLAB format), *.ses projects files for biophysical modeling with Neuron software (267x2, Neuron format), and computed neuron activating thresholds at different conditions (267x8, Excel tables, without the sample polarization correction from Section 2.8) are made available online through BossDB, a volumetric open-source database for 3D and 4D neuroscience data.

neuroscience↗

bioRxiv2024

Senolytic therapy preserves blood-brain barrier integrity and promotes microglia homeostasis in a tauopathy model

Cellular senescence, characterized by expressing the cell cycle inhibitory proteins, is evident in driving age-related diseases. Senescent cells play a crucial role in the initiation and progression of tau-mediated pathology, suggesting that targeting cell senescence offers a therapeutic potential for treating tauopathy associated diseases. This study focuses on identifying non-invasive biomarkers and validating their responses to a well-characterized senolytic therapy combining dasatinib and quercetin (D+Q), in a widely used tauopathy mouse model, PS19. We employed human-translatable MRI measures, including water extraction with phase-contrast arterial spin tagging (WEPCAST) MRI, T2 relaxation under spin tagging (TRUST), longitudinally assessed brain physiology and high-resolution structural MRI evaluated the brain regional volumes in PS19 mice. Our data reveal increased BBB permeability, decreased oxygen extraction fraction, and brain atrophy in 9-month-old PS19 mice compared to their littermate controls. (D+Q) treatment effectively preserves BBB integrity, rescues cerebral oxygen hypometabolism, attenuates brain atrophy, and alleviates tau hyperphosphorylation in PS19 mice. Mechanistically, D+Q treatment induces a shift of microglia from a disease-associated to a homeostatic state, reducing a senescence-like microglial phenotype marked by increased p16/INK4a. D+Q-treated PS19 mice exhibit enhanced cue-associated cognitive performance in the tracing fear conditioning test compared to the vehicle-treated littermates, implying improved cognitive function by D+Q treatment. Our results pave the way for application of senolytic treatment as well as these noninvasive MRI biomarkers in clinical trials in tauopathy associated neurological disorders.

neuroscience↗

bioRxiv2024

Functional characterization of fatty acid synthase in Hermetia illucens

Fatty acid synthase (FAS) is a key role in de novo lipogenesis (DNL) in most lives. In insects, type I FAS functions in homodimer, activated by a phosphopantetheine transferase (PPT), to de novo produce essential saturated fatty acid for cellular processes. In a nova insect species Hermetia illucens (Diptera: Stratiomyidae), different from most animals and insects, lauric acid (LA) accumulates to a noticeable level, near content of that in coconut oil or palm kernel oil. However, the origin of LA, from de novo biosynthesis or as degraded products from long chain fatty acid, was still ambiguous. Here, in this study, we mined a FAS genes (HiOGS16234) from H. illucens genome and initially characterized its abilities of LA production in a free-fatty-acid producible yeast. After clear the yeast metabolites background of fatty acid by deletion of ScFAS1 and ScELO1 sequentially, which responsible for fatty acid genesis and elongation respectively, functions of HiOGS16234 from H. illucens was in vitro elucidated by analyzing its product portfolio. Through protein domain swap in HiOGS16234, we found the ketoacyl synthase domain and thioesterases domain were responsible for the different product portfolio of HiOGS16234, compared with DmFASN1. Through in vitro assay in yeast, the origin of LA in BSF was firstly elucidated at molecular level, which support DNL origin hypothesis in BSF.

synthetic biology↗

bioRxiv2024

Preeclamptic phenotype in transgenic mice with fetuses carrying APOL1 risk variants

African-American women have a maternal mortality rate approximately three times higher than European-American women. This is partially due to hypertensive disorders of pregnancy, including preeclampsia. Fetal APOL1 high-risk genotype increases preeclampsia risk, although mechanisms remain elusive. We characterized two mouse models to investigate whether fetal-origin APOL1 induces preeclampsia and which cell types contribute. We in vitro fertilized mice with sperm from two transgenic mouse lines: APOL1 transgenic mice carrying human genomic locus constructs from bacterial artificial chromosomes (BAC) containing the APOL1 gene, mimicking expression and function of human APOL1 (BAC/APOL1 mice) and albumin promoter APOL1 transgenic mice expressing APOL1 in liver and plasma (Alb/APOL1 mice). Dams carrying either BAC/APOL1-G1 or Alb/APOL1-G1 fetuses had elevated systolic blood pressure, while dams carrying BAC/APOL1-G0 or Alb/APOL1-G0 fetuses did not. BAC/APOL1-G1 and Alb/APOL1-G1 fetuses weighed less than littermates, indicating intrauterine growth restriction. Single-nucleus RNA-seq of APOL1-G1 placentas showed increased expression of osteopontin/Spp1, most prominently in vascular endothelial cells with robust APOL1 expression. Cell-cell interaction analysis indicated pro-inflammatory signaling between placental cells and maternal monocytes. These models show that fetal origin APOL1-G1 causes preeclampsia, inducing pro-inflammatory response in placenta and maternal monocytes. The APOL1-G1 variant poses a multi-generational problem, causing effects in mothers and offspring.

molecular biology↗

bioRxiv2024

Directed biomechanical compressive forces enhance fusion efficiency in model placental trophoblast cultures

The syncytiotrophoblast is a multinucleated structure that arises from fusion of mononucleated cytotrophoblasts, to sheath the placental villi and regulate transport across the maternal-fetal interface. Here, we ask whether the dynamic mechanical forces that must arise during villous development might influence fusion, and explore this question using in vitro choriocarcinoma trophoblast models. We demonstrate that mechanical stress patterns arise around sites of localized fusion in cell monolayers, in patterns that match computational predictions of villous morphogenesis. We then externally apply these mechanical stress patterns to cell monolayers and demonstrate that equibiaxial compressive stresses (but not uniaxial or equibiaxial tensile stresses) enhance expression of the syndecan-1 marker of fusion. These findings suggest that the mechanical stresses that contribute towards sculpting the placental villi may also impact fusion in the developing tissue. We then extend this concept towards 3D cultures and demonstrate that fusion can be enhanced by applying low isometric compressive stresses to spheroid models, even in the absence of an inducing agent. These results indicate that mechanical stimulation is a potent activator of cellular fusion, suggesting novel avenues to improve experimental reproductive modelling, placental tissue engineering, and understanding disorders of pregnancy development.

biophysics↗

bioRxiv2024

Mechanistic dissection of the CHD4 enhancers reveals cooperative functions among the homotypic ZNF410 clustered motifs

Transcription factors often regulate numerous target genes. However, ZNF410 controls only a single gene, CHD4, in human erythroid cells by its highly restricted chromatin occupancy to the CHD4 locus via two clusters of ZNF410 binding motifs. Here, we uncover that ZNF410 controls chromatin accessibility and activity of the two CHD4 enhancer regions. Combining CRISPR/Cas9 genomic deletion with CRISPRi approaches, we demonstrate that both enhancer regions additively contribute to CHD4 gene expression. Mutations of the di-adenine nucleotides within the ZNF410 binding motif fully disrupt ZNF410-DNA interaction. Luciferase assays, ChIP-seq, and ATAC-seq studies reveal that the homotypic clustered motifs within the CHD4 enhancers are recognized by ZNF410 in a collaborative fashion. Especially, the three ZNF410 motifs located in the 3 end of the distal enhancer act as "switch motifs" to control the chromatin accessibility and activity of the whole distal enhancer region. Together, our findings expose a complex functional hierarchy of motifs, where clustered motifs bound by the same transcription factor cooperate to fine-tune the expression of target gene. HighlightsO_LIZNF410 maintains the accessibility of the CHD4 enhancer regions C_LIO_LIThe two enhancer elements additively modulate CHD4 gene expression C_LIO_LIThe dinucleotide "AA" is the key bases within ZNF410 binding motif C_LIO_LIZNF410 binds to homotypic clustered motifs in a cooperative manner C_LI

molecular biology↗

bioRxiv2024

Androgens modulate the immune profile in a mouse model of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is associated with a low-grade inflammation, but it is unknown how hyperandrogenism, the hallmark of PCOS, affects the immune system. Using a well-established PCOS-like mouse model, we demonstrate that androgen exposure affects immune cell populations in reproductive, metabolic, and immunological tissues differently in a site-specific manner. Co-treatment with flutamide, an androgen receptor antagonist, prevents most of these alterations, demonstrating that these effects are mediated through androgen receptor activation. Dihydrotestosterone (DHT)-exposed mice display a drastically reduced eosinophil population in uterus compared to controls, coupled with lower levels of eotaxin (CCL11), suggesting a reduced recruitment from blood. Decreased frequencies of eosinophils were also seen in visceral adipose tissue (VAT). A higher expression level of CD69, a marker of activation or tissue residency, was consistently found on natural killer (NK) cells in all analyzed tissues. However, a higher frequency of NK cells and elevated levels of IFN-{gamma} and TNF- were only seen in uteri of androgen-exposed mice, while NK cell frequencies were unaffected in all other analyzed compartments. Distinct alterations of macrophages in ovaries, uterus and VAT were also found in DHT-exposed mice and could potentially be linked to PCOS-like traits of the model. Indeed, androgen-exposed mice were insulin resistant and displayed an aberrant immune profile in VAT, albeit unaltered fat mass. Collectively, we demonstrate that hyperandrogenism causes tissue-specific alterations of immune cells in reproductive organs and VAT, which could have considerable implications on tissue function and contribute to the reduced fertility and metabolic comorbidities associated with PCOS.

immunology↗

bioRxiv2024

Chronic alcohol exposure induces cerebral microbleeds by TGF-β1/Smad signaling pathway mediated remodeling of cerebral small vessels

BackgroundLong-term heavy drinking is a major risk factor for cerebral microbleeds(CMBs), which are increasingly gaining attention as a pathological phenotype of cerebral small vessel diseases(CSVD). Under pathological conditions, remodeling of the extracellular matrix(ECM) on the walls of small vessels causes disarray in the structure and function of these vessels, leading to cerebral small vessel sclerosis and consequent rupture and bleeding. This can result in cognitive and emotional disorders, abnormal gait and increased risk of falling. However, the mechanisms underlying how long-term alcohol consumption leads to CMBs and decline in motor function remain unknown. MethodsWe constructed a chronic alcohol exposure mouse model and measured the deposition of ECMs on the small vessels in motor-related brain regions. The presence of microbleeds was confirmed through Prussian blue staining and Magnetic Resonance Imaging. We also extracted primary cerebral microvascular smooth muscle cells (CMVSMCs) from the newborn mice and explored the effects of alcohol on the phenotypic transformation and substance synthesis function. Additionally, we conducted interventional experiments on the cell and animal models with an anti-fibrotic drugs Pirfenidone(PFD). ResultsWe found that mice with long-term alcohol exposure showed decreased motor function. In their motor-related brain regions, such as the motor cortex(MC), thalamus/basal ganglia(Tha/BG), and cerebellum(CB), we observed microbleeds. On the small vessels in these areas, we detected excessive deposited ECM proteins. In vitro experiments with primary CMVSMCs revealed that after alcohol treatment, the cells underwent a transformation into fibroblast-like phenotypes, and excessive production of the aforementioned ECM proteins, which is regulated by upstream TGF{beta}1/Smad signaling pathway. Additionally, PFD applied on cell and animal models could reverse the above processes to some extent. ConclusionsOur study found that the remodeling of ECM accompanied by activation of TGF-{beta}1/Smad signaling pathway may be involved in alcohol-induced CMBs. It could be a potential therapeutic target for CMBs or CSVD.

molecular biology↗

bioRxiv2024

Beyond over- or under-sampling: autistic children's inflexibility in sampling costly information

BackgroundEfficient information sampling is crucial for human inference and decision-making, even for young children. Information sampling is also closely associated with the core symptoms of autism spectrum disorder (ASD), since both the social interaction difficulties and repetitive behaviors suggest that autistic people may sample information from the environment distinctively. Previous research on information sampling in ASD focused mainly on adolescents and adults, and on whether they over- or under-sample. The specific ways in which autistic children sample information, especially when facing explicit costs and adapting to environmental changes, remain unclear. MethodsWe employed an adapted bead task to investigate the sampling behavior of 24 autistic and 41 neurotypical children, matched for age and IQ. In each trial of our experiment, children gathered information about an unknown target isle by drawing samples from it and then guessed the target between two isles based on their samples. In conditions where sampling was costly, children needed to weigh the benefits of information against the costs of acquiring additional samples. Through computational modeling and intricate behavioral measures, we revealed how the two groups of children differed in sampling decisions and underlying cognitive mechanisms. ResultsUnder conditions involving costs, autistic children showed less efficient sampling than their neurotypical peers. This inefficiency was due to their increased variability in the number of samples taken across trials rather than a systematic bias. Computational models indicated that while both groups shared a similar decision process, autistic childrens sampling decisions were less influenced by dynamic changes and more driven by recent evidence, thus leading to their increased sampling variation and reduced efficiency. LimitationsTo refine ASD subtyping and correlate symptom severity with behavioral characteristics and computational findings, future research may need larger participant groups and more comprehensive clinical assessments. ConclusionsThis study reveals an inefficiency of autistic children in information sampling and tracks down this inefficiency to their increased sampling variability, primarily due to their cognitive preference for more local and static information. These findings are consistent with several influential behavioral theories of ASD and highlight the needs of a multi-level understanding of cognitive flexibility in ASD.

neuroscience↗