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Weng, Y.

Publications and source records attributed to Weng, Y..

At least 37 records · Page 2Linked to original sources

Graph pangenome reveals structural variation dynamics during cucumber breeding

Structural variants (SVs) represent a significant yet underexplored component of plant genome diversity. Analyzing SV dynamics is important for understanding their contributions to phenotypic variation and their influence on genome evolution. Here, we present a graph-based pangenome for cucumber, constructed from 39 reference-level genome assemblies. The pangenome captures 171,892 high-confidence SVs and enables genotyping of these SVs across 443 cucumber accessions, representing diverse geographic origins and spanning wild progenitors, landraces, and modern cultivars. Our analyses reveal that during cucumber domestication, a substantial portion of mildly deleterious SNPs are retained, whereas SVs are consistently purged, highlighting their potentially highly deleterious nature. During the geographic expansion of cucumber, a reduction in SV burden and a younger age of SVs than SNPs were observed, suggesting stronger purifying selection acting on SVs. Additionally, notable gene flow from wild population to African and European populations was detected, resulting in an increased SV burden, potentially due to hitchhiking effects. Importantly, incorporating SV burden into genomic prediction models improved the prediction accuracy for several agronomically important traits. This study illuminates the dynamics of SVs during cucumber domestication and improvement, highlights the complex interplay between SVs and selection pressures, and underscores the extensive implications of SVs for future cucumber breeding.

plant biology↗

The role of mating systems in postzygotic reproductive isolation between two recently divergent Aquilegia Species

Mating systems play a crucial role in plant speciation. In particular, hybrid seed inviability is prevalent among species with different mating systems due to parental conflict for resource allocation to offspring. However, whether such a postzygotic barrier can be rapidly established in recently diverged species remains poorly understood. In this study, we integrate population genomic and ecological approaches to address this question using recently diverged species pairs Aquilegia kansuensis and A. ecalcarata, which diverged approximately 0.256 Ma, in a sympatric population from Qinghai, China. Population structure and demographic history results reveal clear genetic differentiation between the two species, corroborating their recent divergence. The results of outcrossing rate estimation based on microsatellite markers indicated that A. kansuensis and A. ecalcarata exhibit high selfing and mixed mating systems, respectively. We performed reciprocal crosses between A. kansuensis and A. ecalcarata and found that A. ecalcarata yielded a very small number of small-sized seeds when selfed A. kansuensis was used as pollen donors, resulting in strong asymmetric reproductive isolation. An approximate Bayesian computation framework identified that approximately 4.6% of genomic loci are associated with reproductive isolation, and gene ontology analyses of these loci highlighted key pathways involved in seed maturation and post-embryonic development. Therefore, our findings provide evidence that A. ecalcarata and A. kansuensis represent a novel case of parental conflict and postzygotic isolation driven by divergent mating systems, suggesting mating systems can play a critical role in rapid plant speciation.

evolutionary biology↗

Kidney cortex macrophages prevent the formation of mineral stones by reabsorbing phosphate from the urine

Resident macrophages are important in maintaining tissue homeostasis by meeting specialized physiological demands and mitigating the unique stresses each tissue endures. In the kidney, urine is formed in a process of glomerular filtration and tubular reabsorption. Supersaturation of mineral solutes such as calcium phosphate poses a persistent challenge to the kidney; if left unchecked, kidneys stones form, which will cause tubular obstruction and even kidney failure. However, cellular mechanisms of preventing kidney stone formation remain incompletely understood. In this study, we found that resident macrophages in kidney cortex distinguishably expressed phosphate transporter SLC34A1. These cells extend transtubular protrusions and were capable of reabsorbing phosphate from the urine through the SLC34A1, a function previously only attributed to tubular epithelial cells. Depletion of Slc34a1 from kidney cortex macrophages led to increased urinary phosphate excretion, disrupting body phosphorus balance. More importantly, loss of macrophage-mediated phosphate reabsorption from the urine resulted in a drastic over-deposition of calcium phosphate microcrystals in kidney tubules, particularly in the late proximal tubules of inner cortex where intratubular calcium concentration is high. This also accelerated mineral stone formation. Exposure to mineral crystals stimulated cortex macrophages to upregulate SLC34A1 expression, a response mechanistically driven by lysosomal disruption. As such, cortex macrophages employed phosphate reabsorption as a proactive strategy to prevent mineral stone formation.

immunology↗

Community assembly modeling of microbial evolution within Barrett's esophagus and esophageal adenocarcinoma

Mathematical modeling of somatic evolution, a process impacting both host cells and microbial communities in the human body, can capture important dynamics driving carcinogenesis. Here we considered models for esophageal adenocarcinoma (EAC), a cancer that has dramatically increased in incidence over the past few decades in Western populations, with high case fatality rates due to late-stage diagnoses. Despite advancements in genomic analyses of the precursor Barretts esophagus (BE), prevention of late-stage EAC remains a significant clinical challenge. Previous microbiome studies in BE and EAC have focused on quantifying static microbial abundance differences rather than evolutionary dynamics. Using whole genome sequencing data from esophageal tissues, we first applied a robust bioinformatics pipeline to extract non-host DNA reads, mapped these putative reads to microbial taxa, and retained those taxa with high genomic coverage. When applying mathematical models of microbial evolution to sequential stages of progression to EAC, we observed evidence of neutral dynamics in community assembly within normal esophageal tissue and BE, but not EAC. In a case-control study of BE patients who progressed to EAC cancer outcomes (CO) versus those who had non-cancer outcomes (NCO) during follow-up (mean=10.5 years), we found that Helicobacter pylori deviated significantly from the neutral expectation in BE NCO, suggesting that factors related to H. pylori or H. pylori infection itself may influence EAC risk. Additionally, simulations incorporating selection recapitulated non-neutral behaviors observed in the datasets. Formally modeling dynamics during progression holds promise in clinical applications by offering a deeper understanding of microbial involvement in cancer development.

cancer biology↗

Humidity-driven ABA depletion determines plant-pathogen competition for leaf water

Bacterial phytopathogens, such as Pseudomonas syringae pv. tomato (Pst) DC3000, induce water-soaked lesions in the leaf apoplast under high humidity, facilitating infection. However, it remains largely unclear how plants regulate their resistance to restrict bacterial infection in response to humidity. Here, we demonstrate that abscisic acid (ABA)-catabolizing ABA 8-hydroxylase, encoded by CYP707A3, plays a critical role in this resistance in Arabidopsis thaliana. Elevated humidity induces CYP707A3 expression, which is essential for reducing ABA levels and promoting stomatal opening, thereby limiting bacterial water-soaking and infection following leaf invasion. High humidity also increases cytosolic Ca2+ levels via the Ca2+ channels CNGC2 and CNGC4, with partial involvement from CNGC9, activating the calmodulin-binding transcription activator CAMTA3 to drive CYP707A3 induction. However, Pst DC3000 counteracts this defense response using type III secretion effectors, particularly AvrPtoB, facilitating water-soaking. These findings provide insights into the mechanisms underlying the competition between plants and bacteria for leaf water under elevated humidity.

plant biology↗

Single-Nucleus Neuronal Transcriptional Profiling of Male C. elegans Uncovers Regulators of Sex-Specific and Sex-Shared Behaviors

Sexual differentiation of the nervous system drives profound neurobiological and behavioral differences between the sexes across various organisms, including Caenorhabditis elegans. Using single-nucleus RNA sequencing, we profiled and compared adult male and hermaphrodite C. elegans neurons, generating an atlas of adult male-specific and sex-shared neurons. We expanded the molecular map of male-specific neurons, and identified highly dimorphic expression of GPCRs, neuropeptides, and ion channels. Our data demonstrate sex-shared neurons exhibit substantial heterogeneity between the sexes, while sex-specific neurons repurpose conserved molecular pathways to regulate dimorphic behaviors. We show that the PHD neurons display remarkable similarity to sex-shared AWA neurons, suggesting partial repurposing of conserved pathways, and that they and the GPCR SRT-18 may play a role in pheromone sensing. We further demonstrate that the ubiquitously expressed MAPK phosphatase vhp-1 regulates both sex-specific and sex-shared behaviors. Our data provide a rich resource for discovering sex-specific transcriptomic differences and the molecular basis of sex-specific behaviors.

neuroscience↗

Proteome allocation of the microbiome reveals how diet and metabolic dysbiosis impact disease

The gut microbiome plays a critical role in human health, spurring extensive research into host-microbe interactions using multi-omic technologies. Although these tools offer valuable insights, they often fall short in capturing the complexity of microbial interactions and assigning causality to disease onset, progression, and treatment. Proteome allocation is intertwined with microbial interactions, yet there is little mechanistic knowledge. Here, we deploy models of metabolism and gene expression (ME-models) that predict proteome allocation. Despite their potential, their deployment has been limited by the laborious reconstruction process. To address this, we reconstructed 495 ME-models for human gut microbes using an automated pipeline. By integrating ME-models with multi-omics data from patients with inflammatory bowel disease (IBD), we identified taxa responsible for variations in amino acids, short-chain fatty acids, and pH in the gut of IBD patients. Thus, this approach provides a mechanistic understanding and paves the way for new intervention strategies.

systems biology↗

Cell-type-specific striatal modulation of amygdalar acetylcholine in salience assignment

The salience assignment is pivotal for both natural and artificial intelligence. Pioneering studies established that basal forebrain cholinergic neurons process behaviorally relevant salient information. However, the neural circuit mechanism underlying salience assignment remains poorly understood. Here we show that the acetylcholine (ACh) level in the basolateral amygdala (BLA) dynamically represented behavioral salience. Distinct neuronal subpopulations in the nucleus accumbens (NAc), D1- and D2-expressing medium spiny neurons (MSNs), antagonistically and specifically promote and suppress ACh release in the BLA, but not the cortex and hippocampus. These striatal D1 and D2 MSNs regulate BLA ACh by disinhibiting and inhibiting cholinergic neurons in the basal forebrain subregion substantia innominata (SI), respectively. Optogenetic manipulations of the pathway from striatal D1 and D2 MSNs to the SI opposingly affect associative learning. Our findings uncover an unconventional role of striatal MSNs in salience assignment via regulating the salience-representing amygdalar ACh activity.

neuroscience↗

A synthetic skin microbial community (SkinCom) enables reproducible investigations of the human skin microbiome

Existing models of the human skin have aided our understanding of skin health and disease. However, they currently lack a microbial component, despite microbes demonstrated connections to various skin diseases. Here we present a robust, standardized model of the skin bacterial community (SkinCom) to support complex in vitro and in vivo investigations. Our methods lead to an accurate, reproducible, and diverse community formation of aerobic and anaerobic bacteria. Subsequent testing of SkinCom on the dorsal skin of mice allowed for DNA and RNA recovery from both the applied SkinCom and from dorsal skin, highlighting its practicality for in vivo studies and -omics analyses. Furthermore, our results indicate that 65.6% of the responses to common cosmetic chemicals in vitro were recapitulated in a human trial. Therefore, SkinCom represents a valuable, standardized tool for investigating microbe-metabolite interactions and facilitates the experimental design of in vivo studies targeting host-microbe relationships.

microbiology↗

Filamin A mediates embryonical palatal fusion by linking mechanotransduction with β-Catenin/Smad2

To decipher potential mechanisms underlying cleft palate (CP), we used advanced bioinformatic integrated with literature mining and genome-wide association study (GWAS). Re-analysis of RNA-seq data (GSE45568, GSE185279) combined with literature mining highlighted the roles of Filamin A (Flna) and Epithelial-Mesenchymal Transition (EMT) in palatal development. Immunofluorescence of in vivo palatal shelves showed increased Flna in medial edge epithelial (MEE) cells and EMT cells located in an epithelial triangle. Inhibition of TGF-{beta} or RhoA and mechanical stimuli impacted Flna expression in ex vivo cultured palatal shelves. Re-analysis of scRNA-seq data (GSE155928) highlighted a correlation between Flna and Ctnnb1 in EMT cells. Flna knockdown affected {beta}-catenin/Smad2 expression in cultured palatal shelves and HaCaT cells. Epithelium-specific knockout of Flna delayed palatal fusion in female mice but not males. Mendelian randomization analysis suggested that parental habitual physical activity (HPA) was causally associated with lower risk of CP in their offspring. Together, these findings suggested that parental HPA could benefit their offsprings palatal development through Flna by linking mechanotransduction with the Wnt/TGF-{beta}/Smad signaling pathways during palatal fusion.

developmental biology↗

Adult Single-nucleus Neuronal Transcriptomes of Insulin Signaling Mutants Reveal Regulators of Behavior and Learning

The insulin/insulin-like signaling (IIS) pathway regulates many of C. elegans adult functions, including learning and memory1. While whole-worm and tissue-specific transcriptomic analyses have identified IIS targets2,3, a higher-resolution single-cell approach is required to identify changes that confer neuron-specific improvements in the long-lived insulin receptor mutant, daf-2. To understand how behaviors that are controlled by a small number of neurons change in daf-2 mutants, we used the deep resolution of single-nucleus RNA sequencing to define each neuron types transcriptome in adult wild-type and daf-2 mutants. First, we found surprising differences between wild-type L4 larval neurons and young adult neurons in chemoreceptor expression, synaptic genes, and learning and memory genes. These Day 1 adult neuron transcriptomes allowed us to identify adult AWC-specific regulators of chemosensory function and to predict neuron-to-neuron peptide/receptor pairs. We then identified gene expression changes that correlate with daf-2s improved cognitive functions, particularly in the AWC sensory neuron that controls learning and associative memory4, and used behavioral assays to test their roles in cognitive function. Combining deep single-neuron transcriptomics, genetic manipulation, and behavioral analyses enabled us to identify genes that may function in a single adult neuron to control behavior, including conserved genes that function in learning and memory. One-Sentence SummarySingle-nucleus sequencing of adult wild-type and daf-2 C. elegans neurons reveals functionally relevant transcriptional changes, including regulators of chemosensation, learning, and memory.

neuroscience↗

Featural and spatial interference with functionally active and passive items in working memory

Functionally active and passive states in working memory have been related to different neural mechanisms. Memoranda in active states might be maintained by persistent neural firing, whereas memoranda in passive states might be maintained through short-term synaptic plasticity. We reasoned that this might make these items differentially susceptible to interference during maintenance, in particular that passively maintained items might be more robust. To test this hypothesis, we gave our participants a working memory task in which one item was prioritised (active) by always probing it first, while the other item was deprioritised (passive) by always probing it second. In two experiments, on half the trials, we presented an interfering task during memory maintenance, in which the stimuli matched either the feature dimension of the memory items (colour or orientation), or their spatial location. Whether the interfering task appeared on a given trial was unpredictable. In a third experiment where participants were given prior knowledge of the interference condition, and finally in a fourth experiment we used a reward-based prioritisation cue. Across experiments, we found that both active and passive memory items were affected by interference to a similar extent, with overall performance being closely matched in all experiments. We further investigated precision and probability of target response parameters from the standard mixture model, which also showed no differences between states. We conclude that active and passive items, although potentially stored in different neuronal states, do not show differential susceptibility to interference. Public significance statementThe ability to briefly remember information is critical to human cognition. Our so-called working memory is nevertheless rather limited, able to hold only a few items at any one time, and prone to forgetting when we are briefly distracted. Yet, there is reason to believe that not all information in working memory is equally vulnerable. Items that are more passively stored, because they will only be required after some time, might be more resilient to interference. Items that are stored actively, for more immediate recall, might be more easily disrupted. Here, we investigated the effect of an interference task on the retention of both active and passive items in working memory. Our results showed that active and passive items are equally affected by interference, suggesting that resilience in working memory does not depend on the functional state of the items therein.

neuroscience↗

Male-specific features of C. elegans neuronal aging

Aging is a complex biological process, with sexually dimorphic aspects. For example, men and women differ in their vulnerabilities in cognitive decline, suggesting biological sex may contribute to the heterogeneous nature of aging. Although we know a great deal about the cognitive aging of hermaphrodites of the model system C. elegans, less is known about cognitive decline in males. Through behavioral analyses, we found that the cognitive aging process has both sex-shared and sex-dimorphic characteristics. Through neuron-specific sequencing, we identified neuronal age-associated sex-differential targets. In addition to sex-shared neuronal aging genes, males differentially downregulate mitochondrial metabolic genes and upregulate GPCR genes with age. In addition, the X chromosome exhibits increased gene expression in hermaphrodites and altered dosage compensation complex expression with age, indicating possible X-chromosomal dysregulation that contributes to sexual dimorphism in cognitive aging. Finally, we found that the sex-differentially expressed gene hrg-7, which encodes an aspartic-type endopeptidase, regulates male behavior during cognitive aging but does not affect hermaphrodites behaviors. Overall, these results suggest that males and hermaphrodites exhibit different age-related neuronal changes. This study will strengthen our understanding of sex-specific vulnerability and resilience and help identify new pathways to target with novel treatments that could benefit both sexes.

neuroscience↗

Glucosylceramide depletion disrupts endolysosomal function in GBA-linked Parkinsons fibroblasts?

In Gaucher and Niemann-Pick C diseases, the glucosylceramide (GlcCer) depletion hypothesis states that depletion of non-lysosomal sphingolipid pools can lead to dysfunction in the secretory and lysosomal system. The hypothesis suggests: 1) lysosomal dysfunction can be separated from lysosomal storage, 2) Lysosomal/secretory dysfunction/vATPase activity is corrected by increasing non-lysosomal GlcCer pools, and 3) Changes in higher glycosphingolipid synthesis due to changes in Golgi pH and/or GlcCer non-vesicular transport. Evidence for this mechanism includes 1) Successful treatment of cells and animals by imino sugar inhibition of the non-lysosomal neutral pH GlcCer hydrolase GBA2, 2) Increasing ER/cytosol GlcCer increases in vATPase regulatory V0a1 subunit expression. Heterozygous mutations in GBA1, a lysosomal glucocerebrosidase (GCase), cause GCase misfolding and mislocalisation in the ER/cytoplasm which is linked to Parkinsons disease (GBA-PD). Unexpectedly, similar to previous results in storing fibroblasts, N370S and L444P fibroblasts revealed increased endolysosomal pH and size despite the absence of glucolipid storage. Induction of storage by reducing residual lysosomal GCase activity in the N370S/L444P fibroblasts by the addition conduritol B-epoxide had no further effect on lysosomal function. In contrast, the addition of a soluble GlcCer analogue (adaGlcCer) reverses increased endolysosomal pH and volume in N370S mutant fibroblasts. The results are consistent with ER/cytosolic glucolipid depletion in GBA-PD fibroblasts. We discuss the potential for toxic/ectopic GBA1 hydrolysis and disrupted vATPase activity may lead to defective dopamine packaging and synaptic vesicle endocytosis as a new hypothesis in GBA-PD.

cell biology↗

Analysis of the Neuron-specific IIS/FOXO Transcriptome in Aged Animals Reveals Regulators of Neuronal and Cognitive Aging

Cognitive decline is a significant health concern in our aging society. Here, we used the model organism C. elegans to investigate the impact of the IIS/FOXO pathway on age-related cognitive decline. The daf-2 Insulin/IGF-1 receptor mutant exhibits a significant extension of learning and memory span with age compared to wild-type worms, an effect that is dependent on the DAF-16 transcription factor. To identify possible mechanisms by which aging daf-2 mutants maintain learning and memory with age while wild-type worms lose neuronal function, we carried out neuron-specific transcriptomic analysis in aged animals. We observed downregulation of neuronal genes and upregulation of transcriptional regulation genes in aging wild-type neurons. By contrast, IIS/FOXO pathway mutants exhibit distinct neuronal transcriptomic alterations in response to cognitive aging, including upregulation of stress response genes and downregulation of specific insulin signaling genes. We tested the roles of significantly transcriptionally-changed genes in regulating cognitive functions, identifying novel regulators of learning and memory. In addition to other mechanistic insights, comparison of the aged vs young daf-2 neuronal transcriptome revealed that a new set of potentially neuroprotective genes is upregulated; instead of simply mimicking a young state, daf-2 may enhance neuronal resilience to accumulation of harm and take a more active approach to combat aging. These findings suggest a potential mechanism for regulating cognitive function with age and offer insights into novel therapeutic targets for age-related cognitive decline.

neuroscience↗

Structural insights into dual-antagonize mechanism of AB928 on adenosine A2 receptors

The adenosine subfamily G protein-coupled receptors A2AR and A2BR were identified as promising candidates for cancer immunotherapy within recent years. One of the A2AR/A2BR dual antagonist, AB928, has progressed to phase II clinic trial for the treatment of rectal cancer. However, the precise mechanism underlying its dual-antagonistic properties remains elusive. Herein, we report crystal structures of A2AR in complex with AB928 and a selective A2AR antagonist, 2-118. The structures reveal a common binding mode on A2AR, wherein the ligands establish extensive interactions with residues from both the orthosteric pocket and the secondary pocket. Conversely, the cAMP assay together with molecular dynamics simulations conducted on both A2AR and A2BR indicate that the ligands adopt distinct binding modes on A2BR. Detailed analysis of their chemical structures suggests that AB928 can readily adapt to the A2BR pocket, while 2-118 cannot due to its intrinsic differences. This disparity potentially accounts for their divergent inhibitory efficacies between A2BR and A2AR. The findings from this study can serve as valuable structural templates for future development of selective or dual inhibitors targeting A2AR/A2BR in the context of cancer therapy.

cell biology↗

Neuronal Activation of the Gαq Protein EGL-30/GNAQ Late in Life Rejuvenates Cognition Across Species

Cognitive decline is perhaps the most devastating aging loss. EGL-30/GNAQ and Gq signaling pathways are highly conserved between C. elegans and mammals. We find that activation of EGL-30 in aged worms at least triples memory span, and we wondered if this highly conserved pathway could also improve memory in very old mice. Murine Gnaq is enriched in hippocampal excitatory neurons and declines with age. Furthermore, GNAQ gain-of-function significantly improved memory in aged mice: GNAQ(gf) in hippocampal neurons of 24-month-old mice rescued age-related impairments in health metrics and long-term memory. Single-nucleus RNAseq revealed gene expression changes related to synaptic function, axon guidance, and learning and memory pathways. Several worm orthologs of mouse genes upregulated by GNAQ(gf) overexpression are required for EGL-30(gf)-dependent memory improvement. These results demonstrate that the molecular and genetic pathways between C. elegans and mammals are highly conserved, as activation of EGL-30/GNAQ, a pathway first identified in worms, rejuvenates cognitive function in two-year old mice (the equivalent of 70-80 yo humans). To our knowledge, this is the oldest age an intervention has successfully improved age-related cognitive decline. One-Sentence SummaryNeuronal activation of the Gq protein EGL-30/GNAQ restores long-term memory at old age in worms and mice.

neuroscience↗

Atypical connectome topography and signal flow in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is one of the most common pharmaco-resistant epilepsies in adults. While hippocampal pathology is the hallmark of this condition, emerging evidence indicates that brain alterations extend beyond the mesiotemporal epicenter and affect macroscale brain function and cognition. We studied macroscale functional reorganization in TLE, explored structural substrates, and examined cognitive associations. We investigated a multisite cohort of 95 patients with pharmaco-resistant TLE and 95 healthy controls using state-of-the-art multimodal 3T magnetic resonance imaging (MRI). We quantified macroscale functional topographic organization using connectome dimensionality reduction techniques and estimated directional functional flow using generative models of effective connectivity. We observed atypical functional topographies in patients with TLE relative to controls, manifesting as reduced functional differentiation between sensory/motor networks and transmodal systems such as the default mode network, with peak alterations in bilateral temporal and ventromedial prefrontal cortices. TLE-related topographic changes were consistent in all three included sites and reflected reductions in hierarchical flow patterns between cortical systems. Integration of parallel multimodal MRI data indicated that these findings were independent of TLE-related cortical grey matter atrophy, but mediated by microstructural alterations in the superficial white matter immediately beneath the cortex. The magnitude of functional perturbations was robustly associated with behavioral markers of memory function. Overall, this work provides converging evidence for macroscale functional imbalances, contributing microstructural alterations, and their associations with cognitive dysfunction in TLE.

neuroscience↗