Biology subjects

Yin, Z.

Publications and source records attributed to Yin, Z..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Generalizable Quantum Computing Pipeline for Real World Drug Discovery

Quantum computing, with its superior computational capabilities compared to classical approaches, holds the potential to revolutionize numerous scientific domains, including pharmaceuticals. However, the application of quantum computing for drug discovery has primarily been limited to proof-of-concept studies, which often fail to capture the intricacies of real-world drug development challenges. In this study, we diverge from conventional investigations by developing an advanced quantum computing pipeline tailored to address genuine drug design problems. Our approach underscores the pragmatic application of quantum computation and propels it towards practical industrial adoption. We specifically construct our versatile quantum computing pipeline to address two critical tasks in drug discovery: the precise determination of Gibbs free energy profiles for prodrug activation involving covalent bond cleavage, and the accurate simulation of covalent bond interactions. This work serves as a pioneering effort in benchmarking quantum computing against veritable scenarios encountered in drug design, especially the covalent bonding issue present in both of the case studies, thereby transitioning from theoretical models to tangible applications. Our results demonstrate the potential of a quantum computing pipeline for integration into real world drug design workflows.

bioinformatics↗

bioRxiv2024

Charting Single Cell Lineage Dynamics and Mutation Networks via Homing CRISPR

Single cell lineage tracing, essential for unraveling cellular dynamics in disease evolution is critical for developing targeted therapies. CRISPR-Cas9, known for inducing permanent and cumulative mutations, is a cornerstone in lineage tracing. The novel homing guide RNA (hgRNA) technology enhances this by enabling dynamic retargeting and facilitating ongoing genetic modifications. Charting these mutations, especially through successive hgRNA edits, poses a significant challenge. Our solution, LINEMAP, is a computational framework designed to trace and map these mutations with precision. LINEMAP meticulously discerns mutation alleles at single-cell resolution and maps their complex interrelationships through a mutation evolution network. By utilizing a Markov Process model, we can predict mutation transition probabilities, revealing potential mutational routes and pathways. Our reconstruction algorithm, anchored in the Markov models attributes, reconstructs cellular lineage pathways, shedding light on the cells evolutionary journey to the minutiae of single-cell division. Our findings reveal an intricate network of mutation evolution paired with a predictive Markov model, advancing our capability to reconstruct single-cell lineage via hgRNA. This has substantial implications for advancing our understanding of biological mechanisms and propelling medical research forward.

bioinformatics↗

bioRxiv2024

Inhibiting YAP1 reduced abdominal aortic aneurysm formation by suppressing adventitial fibroblast phenotype transformation and migration

BACKGROUNDThe adventitial fibroblast (AF) is the most abundant cell in the vascular adventitia, a few studies had confirmed that AF contributed to abdominal aortic aneurysm (AAA) development; YAP1 involved in several vascular diseases by promoting AF transformed to myofibroblast, the role of YAP1 in AAA is not clear yet. This study aims to determine whether YAP1 play a role in AAA process by regulating AF function. METHODSElastase-induced and Cacl2-induced mice AAA model were used in this study, we applied YAP1 inhibitor-Verteporfin in vivo to explore the role of YAP1 in AAA information; in vitro, Verteporfin and YAP1-siRNA were used to intervened TGF-{beta}1 induced fibroblasts phenotype transformation and migration model. RESULTSAt first, we use immunohistochemistry (IHC) and western blotting (WB) to compare the expression of YAP1 in aneurysm tissues of AAA patients with normal adjacent vascular tissues, we found that the expression of YAP1 in AAA tissues was significantly increased, and YAP1 mainly increased in adventitia. YAP1 also upregulated in elastase-induced and Cacl2-induced mice AAA model. Then, we diminished YAP1 function with YAP1 inhibitor-Verteporfin in above mice AAA model, AAA incident rate was remarkably declined, and the collagen deposition in the adventitia was alleviated obviously. Afterwards, we studied the effect of YAP1 on the function of AF, we found that the process of AF transforming to myofibroblast and migration were almost completely eliminated after inhibiting YAP1 expression. CONCLUSIONSThis study demonstrated that YAP1 may play a key role in AAA development, inhibiting YAP1 significantly reduced AAA formation through suppressed the process of AF transformed to myofibroblast and migration.

pathology↗

bioRxiv2023

RLKdb: A comprehensive curated receptor-like kinase family database

Dear Editor, Since the first plant receptor-like kinase (RLK) gene ZmPK1 was cloned from Zea mays in 1990 (Walker & Zhang, 1990), this large gene family has been extensively studied and shown to play crucial roles in growth, development, and immunity (Tang et al., 2017). RLKs are widespread in the plant kingdom, while the biological functions of most RLKs remain largely elusive (Dievart et al., 2020). Given RLKs share a conserved monophyletic RLK/Pelle kinase domain, RLKs in several model plants are classified into distinct families by extracellular domains (ECDs) (Shiu & Bleecker, 2001). However, independent domain shuffling in specific lineages drives the origin of novel families, which raises a question: how about the landscape of RLKs in the whole plant kingdom? Previously, sequence homology-based methods have been widely used for RLK identification and classification, which probably will miss the distantly related proteins but with similar structures and potential novel families unmentioned in the literature. The academic community urgently requires a dedicated database for a systematic overview of the RLK gene family, providing data support for in-depth research on RLK genes. Here, we used a topology-based method to accurately isolate the RLKomes from proteomes. The obtained RLKomes were further classified into (sub)families based on ECD domains. We constructed a comprehensively curated plant RLK database (https://biotec.njau.edu.cn/rlkdb/), which contains valuable resources for investigating the origin and evolution of the RLK family and multiple online tools for personalized analysis.

plant biology↗

bioRxiv2023

Structural basis of a regulatory switch in mammalian complex I

Respiratory complex I powers oxidative phosphorylation in mammalian mitochondria by using the reducing potential of NADH to reduce ubiquinone-10 and drive protons across the inner mitochondrial membrane. High-resolution cryoEM structures have provided a molecular framework for complex I catalysis, but controversies about how to assign functional properties to the states identified in single-particle analyses are preventing progress on its energy-converting mechanism. Here, we combine precise biochemical definition with high-resolution cryoEM structures in the phospholipid bilayer of coupled vesicles and show that the closed and open states observed in mammalian complex I preparations are components of the deactive transition that occurs during ischaemia. Populations of the cryoEM open state and biochemical deactive state match exactly. Deactivation switches the enzyme off, converting the closed state that is capable of rapid, reversible catalysis into an open, dormant state that is unable to start up in reverse. The deactive state is switched back on by slow priming reactions with NADH and ubiquinone-10. Thus, by developing a versatile membrane system to unite structure and function, we define the role of large-scale conformational transitions in complex I and establish a new gold standard for structure-based investigations of catalysis by energy-coupled proteins.

biochemistry↗

bioRxiv2023

Cross-Dataset Identification of Human Disease-Specific Cell Subtypes Enabled by the Gene Print-based Algorithm--gPRINT

Despite extensive efforts in developing cell annotation algorithms for single cell RNA sequencing results, most algorithms fail to achieve cross-dataset mapping of cell subtypes due to factors such as batch effects between datasets. This limitation is particularly evident when rapidly annotating disease-specific cell subtypes across multiple datasets. In this study, we present gPRINT, a machine learning tool that utilizes the unique one-dimensional "gene print" expression patterns of individual cells. gPRINT is capable of automatically predicting cell types and annotating disease-specific cell subtypes. The development of gPRINT involved curation and harmonization of public datasets, algorithm validation within and across datasets, and the annotation of disease-specific fibroblast subtypes across various disease subgroups and datasets. Additionally, we created a preliminary single-cell atlas of human tendinopathy fibroblasts and successfully achieved automatic prediction of disease-specific cell subtypes in tendon disease. Furthermore, we conducted an exploration of key targets and related drugs specific to this subtype in tendon disease. The proposed approach offers an automated and unified method for identifying disease-specific cell subtypes across datasets, serving as a valuable reference for annotating fibroblast-specific subtypes in different disease states and facilitating the exploration of therapeutic targets in tendon disease.

bioinformatics↗

bioRxiv2023

Dopamine and neuromodulation shorten the latency from motor intention to execution in Parkinson's disease

The ability to initiate volitional action is fundamental to human behaviour. Loss of dopaminergic neurons in Parkinsons disease is associated with impaired action initiation, also termed akinesia. Both dopamine and subthalamic deep brain stimulation (DBS) can alleviate akinesia, but the underlying mechanisms are unknown. An important question is whether dopamine and DBS facilitate de novo build-up of neural dynamics for motor execution or accelerate existing cortical movement initiation signals through shared modulatory circuit effects. Answering these questions can provide the foundation for new closed-loop neurotherapies with adaptive DBS, but the objectification of neural processing delays prior to performance of volitional action remains a significant challenge. To overcome this challenge, we studied readiness potentials and trained brain signal decoders on invasive neurophysiology signals in 25 DBS patients (12 female) with Parkinsons disease during performance of self-initiated movements. Combined sensorimotor cortex electrocorticography (ECoG) and subthalamic local field potential (LFP) recordings were performed OFF therapy (N=22), ON dopaminergic medication (N=18) and ON subthalamic deep brain stimulation (N=8). This allowed us to compare their therapeutic effects on neural latencies between the earliest cortical representation of movement intention as decoded by linear discriminant analysis classifiers and onset of muscle activation recorded with electromyography (EMG). In the hypodopaminergic OFF state, we observed long latencies between motor intention and motor execution for readiness potentials and machine learning classifications. Both, dopamine and DBS significantly shortened these latencies, hinting towards a shared therapeutic mechanism for alleviation of akinesia. To investigate this further, we analysed directional cortico-subthalamic oscillatory communication with multivariate granger causality. Strikingly, we found that both therapies independently shifted cortico-subthalamic oscillatory information flow from antikinetic beta (13-35 Hz) to prokinetic theta (4-10 Hz) rhythms, which was correlated with latencies in motor execution. Our study reveals a shared brain network modulation pattern of dopamine and DBS that may underlie the acceleration of neural dynamics for augmentation of movement initiation in Parkinsons disease. Instead of producing or increasing preparatory brain signals, both therapies modulate oscillatory communication. These insights provide a link between the pathophysiology of akinesia and its therapeutic alleviation with oscillatory network changes in other non-motor and motor domains, e.g. related to hyperkinesia or effort and reward perception. In the future, our study may inspire the development of clinical brain computer interfaces based on brain signal decoders to provide temporally precise support for action initiation in patients with brain disorders.

neuroscience↗

bioRxiv2023

A bioactive peptide from the pearl has dual roles in resisting SARS-CoV-2 infection and its complications

Angiotensin-converting enzyme 2 (ACE2) is a critical receptor for the entry of the SARS-CoV-2 virus into cells. Moreover, a decrease in ACE2 level and its activity due to SARS-CoV-2 infection is considered a crucial reason for the development of Covid-19-associated complications. Here, we report a bioactive peptide derived from the seawater pearl oyster Pinctada fucata, named SCOL polypeptide, which binds strongly to ACE2 and effectively inhibits 65% of the binding of the SARS-CoV-2 S protein to ACE2; thus, this peptide can be used as a blocker to enable cells to resist SARS-CoV-2 infection. The SCOL polypeptide also increases ACE2 enzyme activity by 3.76 times. Previous studies have shown that ACE2 deficiency is associated with inflammation, pain, cardiovascular diseases, insulin resistance, and nervous system injury. Therefore, the SCOL polypeptide can be used to treat or alleviate complications such as lung inflammation, pain, diabetes, cardiovascular diseases, and loss of taste or smell caused by SARS-CoV-2 infection. Thus, the SCOL polypeptide can play a dual role in resisting SARS-CoV-2 infection.

biochemistry↗

bioRxiv2023

Efficacy of the first bioactive peptide from the pearl

Pearls have high medicinal value. In the present study, we discovered the first bioactive peptide in pearls. The bioactive peptide, KKCHFWPFPW, was a novel angiotensin I-converting enzyme (ACE)-inhibitory peptide derived from the pearl matrix of Pinctada fucata. It was screened and identified using quadrupole time-of-flight mass spectrometry. The molecular weight of the peptide was 1417.5 Da, and its theoretical isoelectric point was 9.31. The half-maximal inhibitory concentration of the peptide was 4.17M, as determined by high-performance liquid chromatography. The Lineweaver-Burk plot showed that this peptide competitively inhibited ACE activity. As the peptide concentration increased, the ACE inhibition rate also increased. The molecular docking was simulated using Maestro 2022-1 Glide software to understand the potential mechanisms underlying the ACE-inhibitory activity of KKCHFWPFPW. These results indicated that the peptide from the P. martensii pearl matrix might be a potential source of antihypertensive peptides.

biochemistry↗

bioRxiv2023

Bio-inspired mineralization collagen induce fibrocartilage regeneration after tendon-bone injury by activating Gli1+Dkk3+ progenitor cells

A fibrocartilaginous connection between the tendon and bone, plays a critical role in transferring force from muscle to bone to enable joint movement. However, due to the high mechanical stress it experiences, the enthesis is vulnerable to injury and incapable of regenerating. The spatial relationship and functional basis of the principal components of the fibrocartilage - mineral and collagen - have not been clearly elucidated, which is a significant remaining gap in reconstructing complex architectures for promoting interface tissue regeneration. Here, using three-dimensional electron tomography imaging and high-resolution two-dimensional electron microscopy, we discover that mineral particles form a continuous cross-fibrillar phase within the fibrocartilage region. By developing a "floating mineralization" system, we fabricate a three-layer hydrogel that mimics the hierarchical nano- to micro-scale structure of tendon-bone interface (TBI). The middle layer is noteworthy for its resemblance to the nanostructure of fibrocartilage and its superior ability to induce mineralized fibrochondrogenesis in vitro. Based on motor function analysis, imaging diagnosis, histological staining, immunofluorescence staining, and biomechanics performance, we demonstrate that in situ transplantation of the gradient hydrogel achieved tendon-fibrocartilage-bone synchronous regeneration and result in 68% maximum mechanical recovery at 8-week postoperation. Single-cell RNA sequencing analysis reveals that a unique atlas of in situ stem/progenitor cells is generated during the TBI healing in vivo. Notably, the bio-inspired hydrogel microenvironment drived endogenous Gli1+Dkk3+ progenitor cells, playing a key role in TBI regeneration. Therefore, we have successfully decoded and reconstructed the nanostructure of fibrocartilage, which has great potential in TBI regeneration.

bioengineering↗

bioRxiv2023

Multi-omics analysis reveals signatures of selection and loci associated with complex traits in pigs

Selection signatures that contribute to phenotypic diversity, especially morphogenesis in pigs, remain to be further elucidated. To reveal the regulatory role of genetic variations in phenotypic differences between Eastern and Western pig breeds, we performed a systematic analysis based on seven high-quality de novo assembled genomes, 1,081 resequencing data representing 78 domestic breeds, 162 methylomes, and 162 transcriptomes of skeletal muscle from Tongcheng (Eastern) and Landrace (Western) pigs at 27 developmental stages. Selective sweep uncovers different genetic architectures behind divergent selection directions for the Eastern and Western breeds. Notably, two loci showed functional alterations by almost fixed missense mutations. By integrating time-course transcriptome and methylome, we revealed differences in developmental timing during myogenesis between Eastern and Western breeds. Genetic variants under artificial selection have critical regulatory effects on progression patterns of heterochronic genes like GHSR and BDH1, by the interaction of local DNA methylation status, particularly during embryonic development. Altogether, our work not only provides valuable resources for understanding pig complex traits, but also contributes to human biomedical research.

genomics↗

bioRxiv2023

Losartan rewires ovarian cancer tumor-immune microenvironment and suppresses IGF-1 to amplify chemo-immunotherapy sensitivity

Ovarian cancer (OvCa) is the most lethal of the gynecologic malignancies. Immune checkpoint inhibitors, which have revolutionized the treatment of multiple malignancies, have had limited efficacy in OvCa patients. Here, using syngeneic OvCa models and genetic and pharmacologic perturbations, we discovered that losartan - a widely prescribed anti-hypertensive drug - exhibits dual effects on both the tumor microenvironment and cancer cells to sensitize OvCa to chemo-immunotherapy. Specifically, losartan treatment i) reprograms the tumor microenvironment leading to increased vascular perfusion, and thus enhances drug delivery and immune effector cell intratumoral infiltration and function; and ii) rewires the OvCa cells by suppressing the IGF-1 signaling, resulting in enhanced chemosensitivity. As a result of the combined tumor and stromal effects, losartan treatment enhances the efficacy of chemo-immunotherapy in OvCa models. The safety and low cost (less than $1-2/day) of losartan warrant rapid translation of our findings to patients with OvCa.

cancer biology↗

bioRxiv2023

Plant immunity activated and suppressed by a conserved effector protein family in mirid bug Riptortus pedestris

Riptortus pedestris (Fabricius) a major soybean pest migrates into soybean fields during pod filling stage resulting in a leaf and stem staygreen while pods without beans syndrome. Given the agricultural importance of this species and the lack of characterized HAMP from piercing-sucking insects we performed a large scale of screening by expression of 87 R. pedestris salivary proteins with signal peptides in Nicotiana benthamiana obtaining a candidate HAMP RPH1. RPH1 activated a series of PTI responses including ROS burst upregulation of defense marker genes such as PR1 WRKY7 WRKY8 Acre31 and CYP71D20 MAPK activation and biosynthesis of phytohormones in plants. RPH1 significantly enhances soybean resistance against R. pedestris feeding. PRR coreceptors BAK1 and SOBIR1 were required for RPH1-induced PTI responses. Remarkably RPH1 homologs were widely distributed in herbivorous insects and majority of homologs from selected species induced cell death or ROS. Thus our results demonstrated that RPH1 is a conserved HAMP within chewing and piercing-sucking insects. We also discovered that R. pedestris evolved four paralogs to overcome the plant immunity triggered by RPH1. This study filled a major gap of HAMP identification from piercing-sucking insect and also deciphered a novel evasion strategy of plant immunity exploited by herbivorous insects. One sentence summaryRiptortus pedestris RPH1, a conserved HAMP in herbivores, activates a variety of PTI responses in plants. To couterdefense, R. pedestris evolved four paralogs to suppress RPH1-induced PTI responses. The author(s) responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the Instructions for Authors (https://academic.oup.com/plcell/pages/General-Instructions) is: Ai Xia (xia@njau.edu.edu).

plant biology↗

bioRxiv2023

Long noncoding RNAs and mRNAs profiling in ovary during laying and broodiness in Taihe Black-Bone Silky Fowls (Gallus gallus domesticus Brisson)

Broodiness is one of the important factors affecting poultry egg production, with the black-bone Silky (Gallus gallus domesticus Brisson) exhibiting strong broodiness behavior. Changes in ovarian signaling can offer insights into the mechanisms influencing broodiness. However, research comparing the characteristics of long non- coding RNAs (lncRNAs) in the ovaries during the broody chickens (BC) and high egg- laying chickens (GC) groups of poultry is still limited. In this study, we employed RNA-seq to analyze the ovarian transcriptomes (lncRNAs and mRNAs) of eight brooding and high egg-laying Taihe Black-Bone Silky Fowls (TBsf). We identified a total of 16,444 mRNAs and 18,756 lncRNAs, among which 349 mRNAs and 651 lncRNAs (P < 0.05) showed significantly different expression (DE) between the BC and GC groups. Additionally, we identified the cis-regulated and trans-regulated target genes of differentially abundant lncRNA transcripts and constructed an lncRNA- mRNA trans-regulated interaction network associated with ovarian follicle development. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation analyses revealed that DE mRNAs and target genes of DE lncRNAs were associated with neuroactive ligand-receptor interaction, CCR6 chemokine receptor binding, G-protein coupled receptor binding, Cytokine-cytokine receptor interaction, and ECM-receptor interaction pathways. Our study provides a catalogue of lncRNAs and mRNAs related to ovarian development and constructs a predicted interaction network of differentially abundant lncRNAs and Differentially Expressed Genes (DEGs) in TBsf, thus enhancing our understanding of the interactions between lncRNAs and genes regulating brooding behavior. Author summaryIn this study, we performed transcriptome sequencing analysis of the ovaries from BC and GC groups in TBsf. A total of 349 significantly differentially expressed mRNAs and 651 significantly differentially expressed lncRNAs were detected. Furthermore, we identified 10 key genes that may affect reproductive performance in chickens: STC1, MMP13, IL8, AT2, FSHB, RARB, THOC7, FGF12, EPHA1, and NPY5R. Based on GO and KEGG enrichment analyses, we preliminarily explored five pathways that may influence egg production performance: neuroactive ligand-receptor interaction, CCR6 chemokine receptor binding, G-protein coupled receptor binding, cytokine-cytokine receptor interaction and ECM-receptor interaction. These genes and pathways may play crucial roles in improving broodiness behavior. This study establishes a foundation for subsequent screening of candidate functional genes and functional validation of important production traits in TBsf, providing a theoretical basis for further molecular breeding and enhancing egg-laying performance in TBsf.

bioinformatics↗

bioRxiv2023

CD4+ T cell senescence is associated with reduced reactogenicity in severe/critical COVID-19

BackgroundAging is a critical risk factor for unfavorable clinical outcomes among COVID-19 patients and may affect vaccine efficacy. However, whether the senescence of T cells impact the progression to severe COVID-19 in the elderly individuals remains unclear. MethodsBy using flow cytometry, we analyzed the frequency of senescent T cells (Tsens) in the peripheral blood from 100 elderly patients hospitalized for COVID-19 and compared the difference between mild/moderate and severe/critical illness. We also assessed correlations between the percentage of Tsens and the quantity and quality of spike-specific antibodies by ELISA, neutralizing antibody test kit and Elispot assay respectively, cytokine production profile of COVID-19 reactive T cells as well as plasma soluble factors by cytometric bead array (CBA). ResultsWe found a significant elevated level of CD4+ Tsens in severe/critical disease compared to mild/moderate illness and patients with a higher level of CD4+ Tsens (>19.78%) showed a decreased survival rate as compared to those with a lower level (<19.78%), especially in the breakthrough infection. The percentage of CD4+ Tsens was negatively correlated with spike-specific antibody titers, neutralization ability and COVID-19 reactive IL-2+ CD4+ T cells. Additionally, IL-2 producing T cells and plasma levels of IL-2 were positively correlated with antibody levels. ConclusionOur data illustrated that the percentage of CD4+ Tsens in the peripheral blood could act as an efficient biomarker for the capacity of spike-specific antibody production and the prognosis of severe COVID-19, especially in the breakthrough infection. Therefore, restoration of the immune response of CD4+ Tsens is one of the key factors to prevent severe illness and improve vaccine efficacy in older adults.

immunology↗

bioRxiv2023

CryoEM insights into RNA primer synthesis by the human primosome

Eukaryotic DNA replication depends on the primosome - a complex of DNA polymerase alpha (Pol ) and primase - to initiate DNA synthesis by polymerisation of an RNA - DNA primer. Primer synthesis requires the tight coordination of primase and polymerase activities. Recent cryo-electron microscopy (cryoEM) analyses have elucidated the extensive conformational transitions required for RNA primer handover between primase and Pol and primer elongation by Pol . Because of the intrinsic flexibility of the primosome however, structural information about the initiation of RNA primer synthesis is still lacking. Here, we capture cryoEM snapshots of the priming reaction to reveal the conformational trajectory of the human primosome that brings the PRIM1 and PRIM2 subunits of primase together, poised for RNA synthesis. Furthermore, we provide experimental evidence for the continuous association of primase subunit PRIM2 with the RNA primer during primer synthesis and for how both initiation and termination of RNA primer polymerisation are licensed by specific rearrangements of POLA1, the polymerase subunit of Pol . Our findings fill a critical gap in our understanding of the conformational changes that underpin the synthesis of the RNA primer by the primosome. Together with existing evidence, they provide a complete description of the structural dynamics of the human primosome during DNA replication initiation.

molecular biology↗

bioRxiv2023

Structural insights into complex I deficiency and assembly from the disease-related ndufs4-/- mouse

Respiratory complex I (NADH:ubiquinone oxidoreductase) is essential for cellular energy production and NAD+ homeostasis. Complex I mutations cause neuromuscular, mitochondrial diseases, such as Leigh Syndrome, but their molecular-level consequences remain poorly understood. Here, we use a popular complex I-linked mitochondrial disease model, the ndufs4-/- mouse, to define the structural, biochemical and functional consequences of the absence of subunit NDUFS4. Cryo-EM analyses of mouse-heart ndufs4-/- complex I revealed a loose association of the NADH-dehydrogenase module, and discrete classes containing either assembly factor NDUFAF2 or subunit NDUFS6. Subunit NDUFA12 (that replaces its paralogue NDUFAF2 in mature complex I) is absent from all classes, compounding the deletion of NDUFS4 and preventing maturation of an NDUFS4-free but otherwise complete enzyme. We propose NDUFAF2 as the recruiter of the NADH dehydrogenase module during assembly of the complex. Our results provide new molecular level understanding of the ndufs4-/- mouse model and complex I-linked mitochondrial disease.

biochemistry↗

bioRxiv2023

A Gpr35 tuned gut-brain metabolic axis regulates depressive-like behavior

Gene-environment interactions shape animal behavior and the susceptibility to neurobehavioral symptoms such as depression. However, little is known about the signaling pathway that integrates genetic and environmental inputs with neurobehavioral outcomes, preventing the development of targeted therapies. Here we report that Gpr35 engages a gut microbe-to-brain metabolic pathway to modulate neuronal plasticity and depressive behavior in mice. Chronic stress decreases gut epithelial Gpr35, the genetic deletion of which induces despair and social impairment in a microbiome-dependent manner. We identify a dominant role for the imbalance of microbe-derived indole-3-carboxaldehyde (IAld) and indole-3-lactate (ILA) in the behavioral symptoms with Gpr35 deficiency. Mechanistically, these bacterial metabolites counteractively modulate dendritic spine density and synaptic transmission in the nucleus accumbens. Supplementation of IAld, which is similarly decreased in depressive patients, produce anti-depressant effects in mice with stress or gut epithelial Gpr35 deficiency. Together, these findings identify a genetics-shaped gut-brain connection underlying the susceptibility to depression and suggest a microbial metabolite-based therapeutic strategy to genetic predisposition.

animal behavior and cognition↗