Biology subjects

Liu, Y.

Publications and source records attributed to Liu, Y..

At least 1,081 records · Page 60Linked to original sources

bioRxiv2024

SCAMPI: A scalable statistical framework for genome-wide interaction testing harnessing cross-trait correlations

Family-based heritability estimates of complex traits are often considerably larger than their single-nucleotide polymorphism (SNP) heritability estimates. This discrepancy may be due to non-additive effects of genetic variation, including variation that interacts with other genes or environmental factors to influence the trait. Variance-based procedures provide a computationally efficient strategy to screen for SNPs with potential interaction effects without requiring the specification of the interacting variable. While valuable, such variance-based tests consider only a single trait and ignore likely pleiotropy among related traits that, if present, could improve power to detect such interaction effects. To fill this gap, we propose SCAMPI (Scalable Cauchy Aggregate test using Multiple Phenotypes to test Interactions), which screens for variants with interaction effects across multiple traits. SCAMPI is motivated by the observation that SNPs with pleiotropic interaction effects induce genotypic differences in the patterns of correlation among traits. By studying such patterns across genotype categories among multiple traits, we show that SCAMPI has improved performance over traditional univariate variance-based methods. Like those traditional variance-based tests, SCAMPI permits the screening of interaction effects without requiring the specification of the interaction variable and is further computationally scalable to biobank data. We employed SCAMPI to screen for interacting SNPs associated with four lipid-related traits in the UK Biobank and identified multiple gene regions missed by existing univariate variance-based tests. SCAMPI is implemented in software for public use.

genetics↗

bioRxiv2024

BEGAN: Boltzmann-Reweighted Data Augmentation for Enhanced GAN-Based Molecule Design in Insect Pheromone Receptors

Identifying molecules that bind strongly to target proteins in rational drug design is crucial. Machine learning techniques, such as generative adversarial networks (GAN), are now essential tools for generating such molecules. In this study, we present an enhanced method for molecule generation using objective-reinforced GANs. Specifically, we introduce BEGAN (Boltzmann-Enhanced GAN), a novel approach that adjusts molecule occurrence frequencies during training based on the Boltzmann distribution exp(-{Delta}U/{tau}), where {Delta}U represents the estimated binding free energy derived from docking algorithms and{tau} is a temperature-related scaling hyperparameter. This Boltzmann reweighting process shifts the generation process towards molecules with higher binding affinities, allowing the GAN to explore molecular spaces with superior binding properties. The reweighting process can also be refined through multiple iterations without altering the overall distribution shape. To validate our approach, we apply it to the design of sex pheromone analogs targeting Spodoptera frugiperda pheromone receptor SfruOR16, illustrating that the Boltzmann reweighting significantly increases the likelihood of generating promising sex pheromone analogs with improved binding affinities to SfruOR16, further supported by atomistic molecular dynamics simulations. Furthermore, we conduct a comprehensive investigation into parameter dependencies and propose a reasonable range for the hyperparameter{tau} . Our method offers a promising approach for optimizing molecular generation for enhanced protein binding, potentially increasing the efficiency of drug discovery pipelines. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=186 SRC="FIGDIR/small/611826v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@120c4d3org.highwire.dtl.DTLVardef@5a2034org.highwire.dtl.DTLVardef@f8478aorg.highwire.dtl.DTLVardef@20db79_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

A Newborn F-box Gene Blocks Gene Flow by Selectively Degrading Phosphoglucomutase in Species Hybrids

The establishment of reproductive barriers such as postzygotic hybrid incompatibility (HI) remains the key to speciation. Gene duplication followed by differential functionalization has long been proposed as a major model underlying HI, but few supporting evidence exists. Here, we demonstrate that a new-born F-box gene, Cni-neib-1, of the nematode Caenorhabditis nigoni specifically inactivates an essential phosphoglucomutase encoded by Cbr-shls-1 in its sister species C. briggsae and their hybrids. Zygotic expression of Cni-neib-1 specifically depletes Cbr-SHLS-1, but not Cni-SHLS-1, in approximately 40 minutes starting from gastrulation, causing embryonic death. Cni-neib-1 is one of thirty-three paralogues emerging from a recent surge in F-box gene duplication events within C. nigoni, all of which are evolving under positive selection. Cni-neib-1 undergoes turnover even among C. nigoni populations. Differential expansion of F-box genes between the two species could reflect their distinctive innate immune responses. Collectively, we demonstrate how recent duplication of genes involved in protein degradation can cause unintended destruction of targets in hybrids that leads to HI, providing an invaluable insight into mechanisms of speciation. Significance statementUnderstanding how reproductive isolation forms and triggers speciation remains a central topic in evolutionary biology. In this study, the authors reveal a novel molecular mechanism that obstructs gene flow between the nematodes Caenorhabditis briggsae and C. nigoni. A recently evolved, species-specific F-box gene in C. nigoni selectively depletes an essential phosphoglucomutase enzyme in C. briggsae, leading to embryonic lethality in hybrids. This mechanism effectively prevents gene flow from C. nigoni to C. briggsae. This discovery underscores how a newborn gene, arising from recent gene duplication, can contribute to reproductive isolation by inadvertently disrupting a functionally important protein in hybrid offspring.

evolutionary biology↗

bioRxiv2024

Caves as species pumps: key innovations, isolation, and periodic introgression drive the world's largest cavefish radiation in a dynamic karstic landscape

Species diversification is shaped by intricate interactions among biotic drivers, including gene flow, hybridization, and key innovations, and abiotic drivers, such as historical climate change, geological events, and ecological opportunity. However, the relative contributions of these drivers in large radiations remain poorly understood. We investigate the interplay among these factors in the diversification of Sinocyclocheilus, a cavefish radiation comprising 79 species. Sinocyclocheilus include typical surface-dwelling forms, with well-developed eyes and pigmentation, to cave-dwelling forms with regressed eyes, reduced pigmentation, and the presence of a horn and a hump. Using reduced representation genomic data (RADseq), we show extensive gene flow events across different species, with introgression playing a key role compared to incomplete lineage sorting in creating phylogenetic discordance and contributing genetic variation for cave adaptation and diversification in this group. Key traits such as eye degeneration, reduced pigmentation, and horn evolved independently multiple times, as adaptations for effectively exploiting cave environments. Furthermore, the uplift of the Tibetan plateau and the late Miocene cooling also significantly impacted speciation rates. Demographic analyses suggest population expansions during the Gonghe Movement and stability during the Last Glacial Maximum, possibly due to cave refugia. Periodic events of introgression promoted by isolation and reconnections due to the changing climate and geological activity, combined with the repeated evolution of key cave-adapted traits, are the primary drivers of this radiation. Our findings underscore the complex interplay of biotic and abiotic factors in the evolution of Sinocyclocheilus fish, offering new insights into the mechanisms of cave adaptation and diversification.

evolutionary biology↗

bioRxiv2024

Genetic regulation of microRNAs in the older adult brain and their contribution to neuropsychiatric conditions

MicroRNAs are essential post-transcriptional regulators of gene expression and involved in many biological processes; however, our understanding of their genetic regulation and role in brain illnesses is limited. Here, we mapped brain microRNA expression quantitative trait loci (miR-QTLs) using genome-wide small RNA sequencing profiles from dorsolateral prefrontal cortex (dlPFC) samples of 604 older adult donors of European ancestry. miR-QTLs were identified for 224 miRNAs (48% of 470 tested miRNAs) at false discovery rate < 1%. We found that miR-QTLs were enriched in brain promoters and enhancers, and that intragenic miRNAs often did not share QTLs with their host gene. Additionally, we integrated the brain miR- QTLs with results from 16 GWAS of psychiatric and neurodegenerative diseases using multiple independent integration approaches and identified four miRNAs that contribute to the pathogenesis of bipolar disorder, major depression, post-traumatic stress disorder, schizophrenia, and Parkinsons disease. This study provides novel insights into the contribution of miRNAs to the complex biological networks that link genetic variation to disease.

genetics↗

bioRxiv2024

High-coverage, massively parallel sequencing of single-cell genomes with CAP-seq

Microbial communities are extraordinarily diverse and play crucial roles in health and disease, yet current methods lack the resolution and scalability needed to dissect their genomic and ecological complexity at the single-cell level. Here, we present CAP-seq, a high-throughput single-microbe genomics platform that combines hydrogel-based semi-permeable encapsulation with minimal microfluidics to recover thousands of single-amplified genomes (SAGs) with long reads and high completeness at low sequencing depth. We benchmarked CAP-seq using defined microbial communities, demonstrating strain-level resolution, accurate detection of rare taxa, and genome recovery exceeding 50% at [~]10x coverage. Applying CAP-seq to pediatric Clostridioides difficile infection microbiomes, we generated a high-resolution single-cell atlas comprising tens of thousands of SAGs across hundreds of species. Host-resolved profiling of the cryptic plasmid pBI143 revealed previously hidden low-abundance host associations, six new plasmid versions, and their coexistence within individuals, indicating complex plasmid evolution in situ. Longitudinal analysis during fecal microbiota transplantation and vancomycin treatment uncovered dynamic remodeling of microbial hosts, antimicrobial resistance genes, and plasmids at single-cell resolution. CAP-seq enables scalable, high-performance single-cell genomics and provides a practical, widely accessible platform for microbiome analysis, paving the way for large-scale exploration of microbial dark matter and host-microbe interactions across diverse ecosystems.

genomics↗

bioRxiv2024

The African Swine Fever Virus gene MGF_360-4L inhibits interferon signaling by recruiting mitochondrial selective autophagy receptor SQSTM1 degrading MDA5 antagonizing innate immune responses

Multigene family (MGF) 360 genes, which are African swine fever virus (ASFV) virulence genes, primarily target key host immune molecules to suppress host interferon (IFN) production and interferon-stimulated gene (ISG) transcription, impairing host innate immune responses for efficient viral replication. However, the interactions between MGF 360 virulence genes and host molecules, as well as the mechanisms through which MGF 360 genes regulate host immune responses and interferon signaling, require further elucidation. In this study, we discovered that ASFV MGF_360-4L interacts with MDA5 and recruits the mitochondrial selective autophagy receptor SQSTM1 to degrade MDA5, thus impairing interferon signaling and compromising host innate immune responses. Furthermore, MGF_360-4L inhibits the interaction between MDA5 and MAVS, blocking ISG15-mediated ISGylation of MDA5. MGF_360-4L deficiency significantly attenuated virus-induced mitochondrial autophagy in vitro. Additionally, OAS1 ubiquitinates MGF_360-4L at residues K290, K295 and K327. Finally, a recombinant ASFV lacking the MGF_360-4L gene (ASFV-{Delta}MGF_360-4L) was generated using ASFV-CN/SC/2019 as the backbone, which demonstrated that the replication kinetics of ASFV-{Delta}MGF_360-4L in PAM cells were like those of the highly virulent parental ASFV-WT in vitro. Domestic pigs infected with ASFV-{Delta}MGF_360-4L exhibited milder symptoms than those infected with parental ASFV-WT, and ASFV-{Delta}MGF_360-4L-infected pigs presented with enhanced host innate antiviral immune response, confirming that the deletion of the MGF_360-4L gene from the ASFV genome highly attenuated virulence in pigs and provided effective protection against parental ASFV challenge. In conclusion, we identified a novel ASFV virulence gene, MGF_360-4L, further elucidating ASFV infection mechanisms and providing a new candidate for vaccine development. IMPORTANCEAfrican swine fever virus (ASFV) infection causes acute death in pigs, and there is currently no effective vaccine available for prevention. Multigene family (MGF) virulence genes have been shown to be crucial for ASFV ability to evade host innate immune responses. However, the functions of most MGF genes remain unknown, which poses significant challenges for the development of ASFV vaccines and antiviral drugs. In this study, we identified a virulence gene of ASFV, MGF_360-4L, that targets and recruits the selective autophagy receptor p62 to mediate the degradation of the dsRNA sensor MDA5, thereby blocking interferon signaling. Additionally, it inhibits the ISG15-mediated ISGylation activation of MDA5. ASFV lacking MGF_360-4L showed reduced virulence and provided protection in pigs. Our data identify a novel virulence gene and provide new insights for ASFV vaccine development.

microbiology↗

bioRxiv2024

Neural Circuit Underlying Individual differences in Visual Escape Habituation

Emotions, like fear, are internal states enabling organisms to effectively confront environmental threats. When repeatedly exposed to predators, individuals show divergent adaptive responses. However, the neural circuit mechanisms underlying individual differences in to repeated threats remain largely unknown. Here, we identify two distinct types of visual escape--consistent escape (T1) and rapid habituation (T2) -- with unambiguous arousal states to repetitive threat stimuli. We systematically investigate distinct pathways originating from the superior colliculus (SC) and insula that project to the basolateral amygdala (BLA), with relay stations in the mediodorsal thalamus (MD) and ventral tegmental area (VTA), mediating T1 and T2 behavioral types. Additionally, we identify the MD as a critical hub integrating SC and insula inputs, projecting to the BLA and contributing to reduced arousal and attenuated defensive behaviors against looming stimuli. Our findings offer significant insights into the mechanisms of internal states, arousal modulation, and behavioral adaptability. O_FIG O_LINKSMALLFIG WIDTH=178 HEIGHT=200 SRC="FIGDIR/small/611366v1_ufig1.gif" ALT="Figure 1"> View larger version (77K): org.highwire.dtl.DTLVardef@164df34org.highwire.dtl.DTLVardef@17a01e6org.highwire.dtl.DTLVardef@112de44org.highwire.dtl.DTLVardef@1be6aea_HPS_FORMAT_FIGEXP M_FIG Graph Abstract C_FIG In briefWe identify two distinct visual escape behaviors--consistent escape (T1) and rapid habituation (T2)--linked to unique SC and insula pathways projecting to the BLA via MD and VTA. The MD acts as a hub integrating sensory inputs to modulate arousal and defensive responses. These findings advance our understanding of the neural mechanisms driving internal states, arousal modulation, and behavioral adaptability. Highlights[bullet] We identify two distinct visual escape behaviors with unambiguous arousal states--consistent escape (T1) and rapid habituation (T2) --to repeated looming stimuli. [bullet]The SC-VTA-BLA pathway mediated T1 behavioral type, while the SC-MD-BLA pathway mediated T2 type. [bullet]MD as a central hub integrating SC and insula inputs to modulate arousal and defensive behavioral adaptation.

neuroscience↗

bioRxiv2024

Photochemical processes drive thermal responses of dissolved organic matter in the dark ocean

How dissolved organic matter (DOM) responds to climate warming is critical for understanding its role in future ocean carbon cycling. Here, we use a highly resolved dataset of over 800 DOM samples covering the surface waters to the deep Atlantic, Southern, and Pacific oceans to examine the changes in DOM molecular composition in response to warming water temperatures, referred to as DOM thermal responses. Towards the deep waters, the strength (i.e., overall magnitude) and diversity (i.e., variation among molecules) of these thermal responses both decline. However, these responses show opposite trends with the concentration of more recalcitrant molecules, decreasing and increasing, respectively. These contrasting trends concur with the observation that, compared to the strength of thermal responses, their diversity is more strongly explained by photochemical processes of DOM. By projecting global ocean thermal responses from 1950 to 2020 using environmental temperature, salinity and radiation, we predict that increases in the diversity of thermal responses are unexpectedly largest at deeper depths (> 1,000 m). Such increases could elevate the recalcitrant deep-ocean carbon sink by approximately 10 Tg C yr-1, which accounts for > 5% of the carbon flux reaching and persisting in the deep ocean. Our findings highlight the role of photochemical processes in imprinting DOM thermal responses, offering new insights into the future capacity of the oceanic carbon sink under global climate change.

ecology↗

bioRxiv2024

Characterization of tumor heterogeneity through segmentation-free representation learning

The interaction between tumors and their microenvironment is complex and heterogeneous. Recent developments in high-dimensional multiplexed imaging have revealed the spatial organization of tumor tissues at the molecular level. However, the discovery and thorough characterization of the tumor microenvironment (TME) remains challenging due to the scale and complexity of the images. Here, we propose a self-supervised representation learning framework, CANVAS, that enables discovery of novel types of TMEs. CANVAS is a vision transformer that directly takes high-dimensional multiplexed images and is trained using self-supervised masked image modeling. In contrast to traditional spatial analysis approaches which rely on cell segmentations, CANVAS is segmentation-free, utilizes pixel-level information, and retains local morphology and biomarker distribution information. This approach allows the model to distinguish subtle morphological differences, leading to precise separation and characterization of distinct TME signatures. We applied CANVAS to a lung tumor dataset and identified and validated a monocytic signature that is associated with poor prognosis.

cancer biology↗

bioRxiv2024

Neutralization and Stability of JN.1-derived LB.1, KP.2.3, KP.3 and KP.3.1.1 Subvariants

During the summer of 2024, COVID-19 cases surged globally, driven by variants derived from JN.1 subvariants of SARS-CoV-2 that feature new mutations, particularly in the N-terminal domain (NTD) of the spike protein. In this study, we report on the neutralizing antibody (nAb) escape, infectivity, fusion, and stability of these subvariants--LB.1, KP.2.3, KP.3, and KP.3.1.1. Our findings demonstrate that all of these subvariants are highly evasive of nAbs elicited by the bivalent mRNA vaccine, the XBB.1.5 monovalent mumps virus-based vaccine, or from infections during the BA.2.86/JN.1 wave. This reduction in nAb titers is primarily driven by a single serine deletion (DelS31) in the NTD of the spike, leading to a distinct antigenic profile compared to the parental JN.1 and other variants. We also found that the DelS31 mutation decreases pseudovirus infectivity in CaLu-3 cells, which correlates with impaired cell-cell fusion. Additionally, the spike protein of DelS31 variants appears more conformationally stable, as indicated by reduced S1 shedding both with and without stimulation by soluble ACE2, and increased resistance to elevated temperatures. Molecular modeling suggests that the DelS31 mutation induces a conformational change that stabilizes the NTD and strengthens the NTD-Receptor-Binding Domain (RBD) interaction, thus favoring the down conformation of RBD and reducing accessibility to both the ACE2 receptor and certain nAbs. Additionally, the DelS31 mutation introduces an N-linked glycan modification at N30, which shields the underlying NTD region from antibody recognition. Our data highlight the critical role of NTD mutations in the spike protein for nAb evasion, stability, and viral infectivity, and suggest consideration of updating COVID-19 vaccines with antigens containing DelS31.

molecular biology↗

bioRxiv2024

Genome-wide CRISPRi-seq identified ferredoxin-NADP reductase FprB as a synergistic target for gallium therapy in Pseudomonas aeruginosa

With the rise of antibiotic-resistant bacteria, non-antibiotic therapies like gallium are increasingly gaining attention. Gallium ions exhibit potent activity against multidrug-resistant bacteria and intravenous gallium nitrite is under phase 2 clinical trials to treat chronic Pseudomonas aeruginosa infections in cystic fibrosis patients. However, its clinical efficacy is constrained by the achievable peak concentration in human tissue. To address this limitation, we applied a genome-wide CRISPR interference approach (CRISPRi-seq), to identify potential synergistic targets with gallium. Through the systemic screening, we classified the essential genes by response time and growth reduction, pinpointing the most vulnerable therapeutic targets in this species. In addition, we identified a highly conserved gene fprB, encoding a ferredoxin-NADP+ reductase, the downregulation of which dramatically sensitized the cells to gallium. Using a null mutant, we confirmed the loss of fprB lowers the minimum inhibitory concentration of gallium from 320 {micro}M to 10 {micro}M and shifted galliums mode of action from bacteriostatic to bactericidal. Further investigation revealed that FprB plays a critical role in modulating oxidative stress induced by gallium, via control of the iron homeostasis and reactive oxygen species accumulation. Deleting fprB also enhanced galliums efficacy against biofilms formation and improved outcomes in murine lung infection model of P. aeruginosa, suggesting FprB as a promising drug target in combination with gallium. Overall, our data showed CRISPRi-seq as a powerful tool for systematic genetic analysis of P. aeruginosa, advancing identification of novel therapeutic targets.

microbiology↗

bioRxiv2024

Diversity and ecological roles of RNA viral communities in the cryosphere of the Tibetan Plateau

RNA viruses play crucial roles in modulating host communities, but their diversity and ecological roles in the cryosphere are poorly understood. We investigated the RNA virome from the cryosphere of the Tibetan Plateau (TPC), the largest area of the cryosphere in the mid-low latitude regions, which includes 79 metatranscriptomes from ecosystems including glaciers, proglacial lake sediments, permafrost wetland and upland soils. We obtained 8,799 RNA-dependent RNA polymerase encoding contigs, which clustered into 5,333 viral species, adding more than 4,900 new RNA viral species to the global RNA virome database. The recovered RNA viruses primarily infect prokaryotes, distinctively different from the dominance of eukaryotic RNA viruses in oceanic ecosystems. In addition to the known taxa such as Leviviricetes, we identified novel clades of putative prokaryotic RNA viruses, which greatly extended our understanding of their diversity. We further expanded the host of RNA virus by 20 additional prokaryotic phylum- or class-level taxonomic groups. Moreover, the TPC RNA viruses encoded dozens of auxiliary metabolic genes that could reprogram the metabolisms of diverse hosts, including photosynthesis in glacier eukaryotic algae and cyanobacteria, which may exert great impacts on glacier dynamics through modulating host adaptation. Furthermore, we identified potential pathogenic RNA viruses in various cryosphere environments, though their overall risks are low. This study provides the first comprehensive view of cryosphere RNA virome, highlighting their high diversity, vital ecological functions, and potential health impacts.

ecology↗

bioRxiv2024

Inhibition of Soluble Epoxide Hydrolase Ameliorates Cerebral Blood Flow Autoregulation and Cognition in Alzheimer's Disease and Diabetes-Related Dementia Rat Models

Alzheimers Disease and Alzheimers Disease-related dementias (AD/ADRD) pose major global healthcare challenges, with diabetes mellitus (DM) being a key risk factor. Both AD and DM-related ADRD are characterized by reduced cerebral blood flow, although the exact mechanisms remain unclear. We previously identified compromised cerebral hemodynamics as early signs in TgF344-AD and type 2 DM-ADRD (T2DN) rat models. Genome-wide studies have linked AD/ADRD to SNPs in soluble epoxide hydrolase (sEH). This study explored the effects of sEH inhibition with TPPU on cerebral vascular function and cognition in AD and DM-ADRD models. Chronic TPPU treatment improved cognition in both AD and DM-ADRD rats without affecting body weight. In DM-ADRD rats, TPPU reduced plasma glucose and HbA1C levels. Transcriptomic analysis of primary cerebral vascular smooth muscle cells from AD rats treated with TPPU revealed enhanced pathways related to cell contraction, alongside decreased oxidative stress and inflammation. Both AD and DM-ADRD rats exhibited impaired myogenic responses and autoregulation in the cerebral circulation, which were normalized with chronic sEH inhibition. Additionally, TPPU improved acetylcholine-induced vasodilation in the middle cerebral arteries (MCA) of DM-ADRD rats. Acute TPPU administration unexpectedly caused vasoconstriction in the MCA of DM-ADRD rats at lower doses. In contrast, higher doses or longer durations were required to induce effective vasodilation at physiological perfusion pressure in both control and ADRD rats. Additionally, TPPU decreased reactive oxygen species production in cerebral vessels of AD and DM-ADRD rats. These findings provide novel evidence that chronic sEH inhibition can reverse cerebrovascular dysfunction and cognitive impairments in AD/ADRD, offering a promising avenue for therapeutic development.

molecular biology↗

bioRxiv2024

Role of AMPK in Atrial Metabolic Homeostasis and Substrate Preference

Atrial fibrillation is the most common clinical arrhythmia and may be due in part to metabolic stress. Atrial specific deletion of the master metabolic sensor, AMP-activated protein kinase (AMPK), induces atrial remodeling culminating in atrial fibrillation in mice, implicating AMPK signaling in the maintenance of atrial electrical and structural homeostasis. However, atrial substrate preference for mitochondrial oxidation and the role of AMPK in regulating atrial metabolism are unknown. Here, using LC-MS/MS methodology combined with infusions of [13C6]glucose and [13C4]{beta}-hydroxybutyrate in conscious mice, we demonstrate that conditional deletion of atrial AMPK catalytic subunits shifts mitochondrial atrial metabolism away from fatty acid oxidation and towards pyruvate oxidation. LC-MS/MS-based quantification of acyl-CoAs demonstrated decreased atrial tissue content of long-chain fatty acyl-CoAs. Proteomic analysis revealed a broad downregulation of proteins responsible for fatty acid uptake (LPL, CD36, FABP3), acylation and oxidation. Atrial AMPK deletion reduced expression of atrial PGC1- and downstream PGC1-/PPAR/RXR regulated gene transcripts. In contrast, atrial [14C]2-deoxyglucose uptake and GLUT1 expression increased with fasting in mice with AMPK deletion, while the expression of glycolytic enzymes exhibited heterogenous changes. Thus, these results highlight the crucial homeostatic role of AMPK in the atrium, with loss of atrial AMPK leading to downregulation of the PGC1-/PPAR pathway and broad metabolic reprogramming with a loss of fatty acid oxidation, which may contribute to atrial remodeling and arrhythmia.

physiology↗

bioRxiv2024

Liprin-α/RIM complex regulates the dynamic assembly of presynaptic active zones via liquid-liquid phase separation

Presynaptic scaffold proteins, including liprin-, RIM, and ELKS, are pivotal to the assembly of the active zone and regulating the coupling of calcium signals and neurotransmitter release, yet the underlying mechanism remains poorly understood. Here, we determined the crystal structure of the liprin-2/RIM1 complex, revealing a multifaceted intermolecular interaction that drives the liprin-/RIM assembly. Neurodevelopmental disease-associated mutations block the formation of the complex. Disrupting this interaction in neurons impairs synaptic transmission and reduces the readily releasable pool of synaptic vesicles. Super-resolution imaging analysis supports a role for liprin- in recruiting RIM1 to the active zone, presumably by promoting the liquid-liquid phase separation (LLPS) of RIM1. Strikingly, the liprin-/RIM interaction modulates the competitive distribution of ELKS1 and voltage-gated calcium channels (VGCCs) in RIM1 condensates. Disrupting the liprin-/RIM interaction significantly decreased VGCC accumulation in the condensed phase and rendered release more sensitive to the slow calcium buffer EGTA, suggesting an increased physical distance between VGCC and vesicular calcium sensors. Together, our findings provide a plausible mechanism of the liprin-/RIM complex in regulating the coupling of calcium channels and primed synaptic vesicles via LLPS for efficient synaptic transmission and uncover the pathological implication of liprin- mutations in neurodevelopmental disorders.

neuroscience↗

bioRxiv2024

Ecosystem stability relies on diversity difference between trophic levels

The stability of ecological communities has a profound impact on humans, ranging from individual health influenced by the microbiome to ecosystem services provided by fisheries. A long-standing goal of ecology is the elucidation of the interplay between biodiversity and ecosystem stability, with some ecologists warning of instability due to loss of species diversity while others arguing that greater diversity will instead lead to instability. Here, by considering a minimal two-level ecosystem with multiple predator and prey species, we show that stability does not depend on absolute diversity but rather on diversity differences between levels. We discovered that increasing diversity in either level first destabilizes but then stabilizes the community (i.e., a re-entrant stability transition). We therefore find that it is the diversity difference between levels that is the key to stability, with the least stable communities having similar diversities in different levels. An analytical stability criterion is derived, demonstrating quantitatively that the critical diversity difference is determined by the correlation between how one level affects another and how it is affected in turn. Our stability criterion also applies to consumer-resource models with other forms of interaction such as cross-feeding. Finally, we show that stability depends on diversity differences in ecosystems with three trophic levels. Our finding of a non-monotonic dependence of stability on diversity provides a natural explanation for the variety of diversity-stability relationships reported in the literature, and emphasizes the significance of level structure in predicting complex community behaviors.

ecology↗

bioRxiv2024

ARHGAP12 suppresses F-actin assembly to control epithelial tight junction mechanics and paracellular leak pathway permeability

Tight junctions (TJ) separate body compartments and control the paracellular transport of ions, solutes, and macromolecules across epithelial barriers. There is evidence that claudin-based ion transport (the pore pathway) and the paracellular transport of macromolecules (the leak pathway) are independently regulated processes. However, how leak pathway permeability is controlled is not well understood. Here we have identified the Cdc42/Rac GTPase activating protein ARHGAP12 as a novel and specific regulator of the leak pathway. ARHGAP12 is recruited to TJ via an interaction between its SH3 domain and the TJ protein ZO-2. Using a combination of biochemical and biophysical approaches, in vitro actin polymerisation assays, and permeability assays in MDCK-II cells, we show that ARHGAP12 suppresses N-WASP-mediated F-actin assembly at TJ to dampen junctional tension. This promotes paracellular leak pathway permeability without affecting ion flux. Mechanistically, we demonstrate that the ARHGAP12 tandem WW domain interacts directly and in a multivalent manner with an array of PPxR motifs in the proline-rich domain of N-WASP. This interaction is sufficient to suppress SH3 domain-mediated N-WASP oligomerisation and Arp2/3-driven F-actin assembly in vitro. Collectively our data demonstrate a critical role for ARHGAP12 in suppressing junctional F-actin assembly and tension to promote the flux of small macromolecules across the TJ.

cell biology↗