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Chen, S.

Publications and source records attributed to Chen, S..

At least 289 records · Page 16Linked to original sources

Proteome analysis of daily urine samples of pregnant rats unveils developmental processes of fetus as well as physiological changes of mother rats

Significant physiological changes occur in both fetus and mother during pregnancy. Urine proteins have been shown to reflect a wide range of physiological and pathological changes in the body. To comprehensively explore the daily changes in urine proteins during pregnancy, this study employed low-abundance protein-enriched magnetic nanobeads to conduct an in-depth analysis of the daily changes in urine proteins throughout the entire pregnancy of rats. Based on the 3,455 identified urine proteins, fetal and maternal dynamic changes were observed in the pregnancy group compared to the control group, including blastocyst formation and cell division in the early stage of pregnancy, embryonic development and organ morphogenesis in the intermediate and mid-to-late stages of pregnancy, and maternal-specific change such as lactation in the late stage of pregnancy. These results indicate that urine protein can reflect the fetal and maternal dynamic physiological alterations during pregnancy, which suggests the potential value of urine protein analysis in pregnancy health monitoring. It is emphasized that the analysis focuses on the daily variations in the urine proteins, as these daily changes are expected to reveal more dynamic and detailed information about the physiological processes during pregnancy.

developmental biology↗

Both composition and configuration of forests and urban development shape bat activity and diversity in North American temperate forests

Temperate forest ecosystems are important habitats for many bat species. However, these habitats are increasingly affected by anthropogenic disturbances, particularly urban development, leading to landscapes with varying land cover composition and configuration. Limited research has examined how forest and urban landscape composition and configuration influence bat activity and diversity. Using a multi-year statewide bat acoustic monitoring dataset from North Carolina, United States, we investigated the effects of forest and urban composition and configuration at multiple spatial scales on bat activity and diversity. First, we constructed single-variable landscape index regression models and found that both composition and configuration of forests and urban developments influenced bat activity and diversity in a species-specific manner. Next, we applied a hierarchical partitioning approach to compare the relative contributions of composition and configuration indices in explaining variance in bat activity. For big brown bats and hoary bats, evergreen forest and urban development composition indices contributed the most to explaining activity variance. In contrast, for eastern red bats, evening bats, and tricolored bats, deciduous forest fragmentation indices describing landscape configuration were the most influential factors. Silver-haired bat activity variance was primarily explained by an evergreen forest fragmentation index. Lastly, urban development configuration indices were the strongest predictors of Mexican free-tailed bat activity and total bat activity. These results suggest that forest and urban landscape configuration should be considered in conservation and management planning for North American temperate forest ecosystems, particularly in regions that have not experienced drastic deforestation in recent decades.

ecology↗

AMPK- and cGAS-Mediated Dual Sensing of Glucose and dsDNA Synergizes to Enhance Antitumor Immunity

Intratumoral glucose availability is linked considerably to tumor growth, immune evasion, and metastasis. However, the precise molecular mechanisms by which glucose levels govern cellular and immune responses against tumors remain incompletely understood. Here, we explored the context of tumors of intersections between AMP-activated protein kinase (AMPK) and cGAS-STING signaling, a key pathway initiating antitumor immunity. We unexpectedly found that AMPK activation robustly enhances cGAS-STING signaling within cancer and immune cells, which potently impacts melanoma and colorectal cell senescence, organoid apoptosis, and the infiltration of CD4+ and CD8+ T lymphocytes. Using classic or newly developed AMPK agonist Aldometanib, TBK1S511E/S511E knock-in (KI) mice, glucose metabolic modulator, as well as AMPK1/2 dKO melanoma, we demonstrated that dual sensing of intratumoral glucose and dsDNA integrated by the AMPK-TBK1 cascade is essential for initiating antitumor immunity and suppressing cancer progressions. Notably, novel AMPK agonists or intervening in glucose glycolysis by Lonidamine synergized effectively with STING agonists, substantially inhibiting melanoma growth. Therefore, these findings unravel a concise mechanism integrating glucose metabolism and innate DNA sensing into cancer cell fate and propose an effective therapeutic strategy to enhance antitumor immunity. HIGHLIGHTSO_LIDual and synergistic sensing of glucose and dsDNA facilitates antitumor immunity in melanoma and colorectal cancer; C_LIO_LIAMPK substitutes intratumoral cGAS-STING-IRF3 signaling through TBK1 phosphorylation at S511; C_LIO_LIGlucose deficiency induces cancer cell senescence, apoptosis, and T lymphocyte infiltration via the AMPK-TBK1 cascade; C_LIO_LINewly developed AMPK agonists synergize with STING agonists to retrieve striking tumor suppression. C_LI

cancer biology↗

Streptococcus mutans LiaS gene regulates its cross-kingdom interactions with Candida albicans to promote oral candidiasis

Candida albicans and Streptococcus mutans are commonly associated with oral candidiasis and dental caries, respectively. C. albicans is frequently detected in the dental plaque of early childhood caries. The synergistic interaction between C. albicans and S. mutans in dental caries suggests that fungi enhance the production of acidic metabolites and contributes to the development of caries. However, the cross-kingdom interaction of S. mutans in oral candidiasis and the pathways regulating hyphal formation remain unclear. The liaS gene of S. mutans 593 plays a crucial role in maintaining membrane homeostasis. In comparison to the S. mutans 593 and liaS- complementary strains, the liaS- strain significantly diminished the proliferation, biofilm formation, extracellular polysaccharide production, and C. albicans hyphal transformation of co-cultured microorganisms. The deletion of liaS gene in the dual-species downregulated the expression of yeast-hyphal transformation related genes hwp1, ece1, als1, and als3 in C. albicans, while also impacted the expression of phr1 and phr2. Additionally, liaS- inhibited glycolysis and pyruvate kinase activity in S. mutans, leading to a decreased in water-soluble and water-insoluble glucans production in biofilm. The significant downregulation of glucosyltransferase transcription relates genes expression in liaS- resulted in inhibition of the cross-kingdom interaction in the dual-species. In the murine oropharyngeal candidiasis model, dual-species infection with liaS- results in a reduction of fungal and hyphal invasion compared to the combinations of C. albicans and S. mutans 593. In conclusion, S. mutans/liaS play a crucial role in the development of oral candidiasis suggests that it could be a targeted strategy for managing this condition. ImportanceCandidiasis involves the transition of C. albicans into hyphae and the fungi invasion of the oropharyngeal mucosa. The transformation of hyphal is influenced by a variety of internal and external environmental factors. Our research findings suggest that the deletion of the liaS gene leads to a reduction in gtfs gene expression, impacting glycolysis efficiency and effectively decreasing EPS production in the dual-species biofilm. Also, downregulation of the expression levels of yeast-hyphal transformation related genes to inhibiting the virulence function of C. albicans. Our study demonstrates that S. mutans 593/liaS promotes epithelial invasion of C. albicans in mouse oropharyngeal candidiasis, offering a potential therapeutic approach for addressing cross-kingdom infections.

microbiology↗

Neuropixels Opto: Combining high-resolution electrophysiology and optogenetics

High-resolution extracellular electrophysiology is the gold standard for recording spikes from distributed neural populations, and is especially powerful when combined with optogenetics for manipulation of specific cell types with high temporal resolution. We integrated these approaches into prototype Neuropixels Opto probes, which combine electronic and photonic circuits. These devices pack 960 electrical recording sites and two sets of 14 light emitters onto a 70 m wide, 1 cm long shank, allowing spatially addressable optogenetic stimulation with blue and red light. In mouse cortex, Neuropixels Opto probes delivered high-quality recordings together with spatially addressable optogenetics, differentially activating or silencing neurons at distinct cortical depths. In mouse striatum and other deep structures, Neuropixels Opto probes delivered efficient optotagging, facilitating the identification of two cell types in parallel. Neuropixels Opto probes represent an unprecedented tool for recording, identifying, and manipulating neuronal populations.

neuroscience↗

DNA repair functions are essential for bacterial stress defense but render antibiotic tolerant sub-populations susceptible to ciprofloxacin and gentamicin upon prolonged treatment

The unresponsiveness of bacterial tolerant subpopulations to antibiotics has been attributed to physiological dormancy triggered by environmental stresses. In this work, we showed that protein and DNA synthesis activities in tolerant subpopulations that formed during nutrient starvation remained at a high level and only dropped gradually during the course of six days-starvation. Interestingly, upon decline of these activities, the tolerant subpopulations became susceptible to antibiotics that target protein and DNA synthesis, which was found to be required to support DNA repair functions essential for prolonged survival of the tolerant subpopulation. The increasing susceptibility of the bacterial tolerant subpopulation to antibiotics was also due to diminishing energy production, antioxidant defense and efflux functions, which resulted in weakening defense and further inhibition of synthesis and functions of DNA repair and other defense proteins. These findings confirm that bacterial tolerant subpopulations remain physiological active, and open new opportunities for combating bacterial tolerance with existing antibiotics.

microbiology↗

Active DNA demethylation is upstream of rod-photoreceptor fate determination and required for retinal development

Retinal cell fate specification from multipotent retinal progenitors is governed by dynamic changes in chromatin structure and gene expression. Methylation at cytosines in DNA (5mC) is actively regulated for proper control of gene expression and chromatin architecture. Numerous genes display active DNA demethylation across retinal development; a process that requires oxidation of 5mC to 5-hydroxymethylcytosine (5hmC) and is controlled by the ten-eleven translocation methylcytosine dioxygenase (TET) enzymes. Using an allelic series of conditional TET enzyme mutants, we determine that DNA demethylation is required upstream of NRL and NR2E3 expression for the establishment of rod-photoreceptor fate. Using histological, behavioral, transcriptomic, and base-pair resolution DNA methylation analyses, we establish that inhibition of active DNA demethylation results in global changes in gene expression and methylation patterns that prevent photoreceptor precursors from adopting a rod-photoreceptor fate, instead producing a retina in which all photoreceptors specify as cones. Our results establish the TET enzymes and DNA demethylation as critical regulators of retinal development and cell fate specification, elucidating a novel mechanism required for the specification of rod-photoreceptors.

developmental biology↗

Cellular mechanisms of early brain overgrowth in autistic children: elevated levels of GPX4 and resistance to ferroptosis

Autistic individuals with disproportionate megalencephaly (ASD-DM), characterized by enlarged brains relative to body height, have higher rates of intellectual disability and face more severe cognitive challenges than autistic children with average brain sizes. The cellular and molecular mechanisms underlying this neurophenotype remain poorly understood. To investigate these mechanisms, we generated human induced pluripotent stem cells from non-autistic typically developing children and autistic children with and without disproportionate megalencephaly. We assessed these children longitudinally from ages two to twelve years using magnetic resonance imaging and comprehensive cognitive and medical evaluations. We show that neural progenitor cells (NPCs) derived from ASD-DM children exhibit increased rates of cell survival and suppressed cell death, accompanied by heightened oxidative stress and ferrous iron accumulation. Despite these stressors, ASD-DM NPCs actively suppress apoptosis and ferroptosis by regulating proteins such as caspase-3 (CASP3), poly(ADP-ribose) polymerase 1 (PARP1), and glutathione peroxidase 4 (GPX4). Cellular ferroptotic signatures are further supported by elevated expression of selenocysteine genes, including GPX4, in the blood of ASD-DM children and their mothers, suggesting potential hereditary or environmental influences. Furthermore, we show that peripheral expression of GPX4 and other selenocysteine genes correlate with cognitive outcomes (IQ). These findings underscore the role of ferroptosis in autism, pointing to potential diagnostic biomarkers and targets for intervention.

neuroscience↗

Dicer loss in Muller glia leads to a defined sequence of pathological events beginning with cone dysfunction

PurposeThe loss of Dicer in Muller glia (MG) results in severe photoreceptor degeneration as it occurs in retinitis pigmentosa or AMD. However, the sequence of events leading to this severe degenerative state is unknown. The aim of this study was to conduct a chronological functional and structural characterization of the pathological events in MG-specific Dicer-cKO mice in vivo and histologically. MethodsTo delete Dicer and mature microRNAs (miRNAs) in MG, two conditional Dicer1 knock-out mouse strains namely RlbpCre:Dicer-cKOMG and GlastCre:Dicer-cKOMG, were created. Optical coherence tomography (OCT), electroretinograms (ERGs) as well as histological analyses were conducted to investigate structural and functional changes up to six months after Dicer deletion. ResultsDicer/miRNA loss in MG leads to 1) impairments of the external limiting membrane (ELM) - retinal pigment epithelium (RPE), 2) cone photoreceptor dysfunction and 3) retinal remodeling and functional loss of the inner retina, 1, 3 and 6 months after Dicer loss, respectively, in both strains. Furthermore, in the Rlbp:Dicer-cKOMG strain, rod photoreceptor impairment was found 4 months after Dicer depletion (4) accompanied by alteration of RPE integrity (5). ConclusionsMG Dicer loss in the adult mouse retina impacts cone function prior to any measurable changes in rod function, suggesting a pivotal role for MG Dicer and miRNAs in supporting cone health. A partially impaired RPE however seems to accelerate rod degeneration and overall degenerative events.

neuroscience↗

Single-AAV CRISPR editing of skeletal muscle in non-human primates with NanoCas, an ultracompact nuclease

CRISPR gene editing is a transformative technology for addressing genetic diseases, but delivery constraints have largely limited its therapeutic applications to liver-targeted and ex vivo therapies. Here, we present the discovery and engineering of NanoCas, an ultracompact CRISPR nuclease capable of extending CRISPRs reach in vivo beyond liver targets. We experimentally screened 176 ultracompact CRISPR systems found in metagenomic data and applied protein engineering approaches to enhance the editing efficiency of NanoCas. The optimized NanoCas exhibits potent editing capabilities across various cell systems and tissues in vivo when administered via adeno-associated viral (AAV) vectors. This is accomplished despite NanoCas being approximately one-third the size of conventional CRISPR nucleases. In proof-of-concept experiments, we observed robust editing with our optimized NanoCas in mouse models targeting Pcsk9, a gene involved in cholesterol regulation, and targeting exon splice sites in dystrophin to address Duchenne muscular dystrophy (DMD) mutations. We further tested the efficacy of our NanoCas system in vivo in non-human primates (NHPs) resulting in editing levels above 30% in muscle tissues. The compact size of NanoCas, in combination with robust nuclease editing, opens the door for single-AAV editing of non-liver tissues in vivo, including the use of newer editing modalities such as reverse transcriptase (RT) editing, base editing, and epigenetic editing.

bioengineering↗

Toti: an integrated multi-omics database to decipher the epigenetic regulation of gene expression in totipotent stem cells

Totipotent cells (TSCs), the origin of mammalian life and foundation to early mammalian embryogenesis, are characterized by the highest differentiation capacity and extensive developmental potential. However, none of the existing embryonic databases have provided epigenetic and transcriptomic resources on totipotency, greatly limiting our understanding of the mechanisms governing the establishment and exit of totipotency. Here, we present Toti, a pioneering multi-omics database exclusively developed for totipotency, covering in vivo, in vitro and genome-edited human and mouse embryonic TSCs, TSC-like cells, pluripotent cells (PSCs), and embryos spanning preimplantation stages, with a total of 8,265 samples. Toti facilitates an in-depth exploration of the molecular mechanisms underlying totipotency by offering Search, Browse and Analysis modules available at http://toti.zju.edu.cn/.

developmental biology↗

Lower spatial turnover of rare fungal taxa dominantly shaped by stochastic processes in grassland soils

The spatial pattern and community assembly of soil microbial taxa have notable meanings for biodiversity shaping and maintaining mechanisms. Rare fungal taxa may exhibit distinct patterns and assembly mechanisms compared to abundant taxa, but such information is limited, especially at large scales. Here, we investigated distance-decay patterns and underlying assembly mechanisms for abundant and rare fungal taxa in 129 soil samples collected across 4,000 km in Chinese Northern grasslands, based on high-throughput sequencing data. A total of 208 abundant OTUs (relative abundance > 0.1%, 2.73% of entire OTUs) and 5,779 rare OTUs (relative abundance < 0.01%, 75.85% of entire OTUs) were identified. Both abundant and rare fungal taxa showed significant distance-decay relationships (P < 0.001), but the turnover rate for rare taxa (0.0024 per 100 km) was nearly half that of abundant taxa (0.0054 per 100 km) based on the binary Bray-Curtis distance. The lower turnover of rare fungal taxa was likely due to their community assembly mechanism dominated by stochastic processes, which were less influenced by environmental gradients. In contrast, abundant taxa assembly was dominated by deterministic factors like soil variables and plant traits, which varied significantly along the geographic distance. Consistently, rare fungal taxa were also less sensitive to environmental changes, with a lower turnover rate by environmental distance (0.0027 vs. 0.0099) than abundant taxa. In summary, our findings revealed that rare fungal taxa, shaped mainly by stochastic processes, had lower spatial turnover compared to abundant taxa, dominated by deterministic processes, enhancing our understanding of rare microbial biogeography.

ecology↗

The liver clock tunes transcriptional rhythms in skeletal muscle to regulate mitochondrial function

Circadian clocks present throughout the brain and body coordinate diverse physiological processes to support daily homeostasis and respond to changing environmental conditions. The local dependencies within the mammalian clock network are not well defined. We previously demonstrated that the skeletal muscle clock controls transcript oscillations of genes involved in fatty acid metabolism in the liver, yet whether the liver clock also regulates the muscle was unknown. Here, we use hepatocyte-specific Bmal1 KO mice (Bmal1hep-/-) and reveal that approximately one third of transcriptional rhythms in skeletal muscle are regulated by the liver clock vivo. Treatment of myotubes with serum harvested from Bmal1hep-/- mice inhibited expression of genes involved in metabolic pathways, including oxidative phosphorylation. Overall, the transcriptional changes induced by liver clock-driven endocrine-communication revealed from our in vitro system were small in magnitude, leading us to surmise that the liver clock acts to fine-tune metabolic gene expression in muscle. Strikingly, treatment of myotubes with serum from Bmal1hep-/- mice inhibited mitochondrial ATP production compared to WT and this effect was only observed with serum harvested during the active phase. Overall, our results reveal communication between the liver clock and skeletal muscle-uncovering a bidirectional endocrine communication pathway dependent on clocks in these two key metabolic tissues. Targeting liver and muscle circadian clocks may represent a potential avenue for exploration for diseases associated with dysregulation of metabolism in these tissues.

cell biology↗

Triple-effect correction for Cell Painting data with contrastive and domain-adversarial learning

Cell Painting (CP), as a high-throughput imaging technology, generates extensive cell-stained imaging data, providing unique morphological insights for biological research. However, CP data contains three types of technical effects, referred to as triple effects, including batch effects, gradient-influenced row and column effects (well position effects). The interaction of various technical effects can obscure true biological signals and complicate the characterization of CP data, making correction essential for reliable analysis. Here, we propose cpDistiller, a triple-effect correction method specially designed for CP data, which leverages a pre-trained segmentation model coupled with a semi-supervised Gaussian mixture variational autoencoder utilizing contrastive and domain-adversarial learning. Through extensive qualitative and quantitative experiments across various CP profiles, we demonstrate that cpDistiller effectively corrects triple effects, especially well position effects, a challenge that no current methods address, while preserving cellular heterogeneity. Moreover, cpDistiller effectively captures system-level phenotypic responses to genetic perturbations and reliably infers gene functions and interactions both when combined with scRNA-seq data and independently. cpDistiller also excels at identifying gene and compound targets, which is a critical step in drug discovery and broader biological research.

bioinformatics↗

Reappraisal of the Dilution and Amplification Effect Framework: A Case Study in Lyme Disease

The role of biodiversity in regulating zoonotic disease in ecological communities has been broadly referred to as the biodiversity-disease relationship in disease ecology. Whether biodiversity decreases or increases disease risk, known as a dilution or amplification effect respectively, remains unclear. The literature has focused on the strength, generality, nature, and context dependencies that could explain contradictory evidence. We suggest that a continued focus on this approach to resolving the biodiversity-disease debate detracts from a more foundational problem with testing these dilution and amplification hypotheses, in that these hypotheses are not falsifiable as proposed. When tested and interpreted as net effects in a system, these hypotheses do not possess a true null outcome and they are vulnerable to ad hoc explanations. To remedy this problem, we propose that biodiversity and disease risk can be modelled as latent variables in multivariate causal models to test specific mechanistic pathways. We present a case study on Lyme disease through a systematic review and meta-analysis, concluding that there is little evidence for a net dilution or amplification effect. We demonstrate how testing these net effect hypotheses falls short of providing robust evidence for its underlying mechanisms. While these hypotheses have previously been helpful in conceptualizing this idea of biodiversity as a potentially protective factor for human health, they need further specificity and clarity to move forwards with greater unity.

ecology↗

CellUntangler: separating distinct biological signals in single-cell data with deep generative models

Single-cell RNA-seq data have provided new insights into intracellular and intercellular processes. Because multiple processes are active in each cell simultaneously, such as its cell type program, differentiation, the cell cycle, and environmental responses, their respective signals can confound one another, requiring methods that can separate and filter different complex biological signals. Each such signal is based on different gene activities and can define different relationships between cells. However, existing methods often focus on a single process or rely on overly restrictive assumptions, thus removing, rather than disentangling biological signals. Here, we develop CellUntangler, a deep generative model that embeds cells into a flexible latent space composed of multiple subspaces, each designed with an appropriate geometry to capture a distinct signal. We apply CellUntangler to datasets containing only cycling cells and both cycling and non-cycling cells, generating embeddings in which the cell cycle signal is disentangled from non-cell cycle specific signals, such as cell type or differentiation trajectory. We demonstrate CellUntanglers extensibility by using it to capture and separate spatial from non-spatial signals. With CellUntangler, we can obtain latent embeddings that capture various biological signals and perform enhancement or filtering at the gene expression level for downstream analyses.

bioinformatics↗

AI-Driven Toolset for IPF and Aging Research Associates Lung Fibrosis with Accelerated Aging

Idiopathic pulmonary fibrosis (IPF) is a condition predominantly affecting the elderly and leading to a decline in lung function. Our study investigates the aging-related mechanisms in IPF using artificial intelligence (AI) approaches. We developed a pathway-aware proteomic aging clock using UK Biobank data and applied it alongside a specialized version of Precious3GPT (ipf-P3GPT) to demonstrate an AI-driven mode of IPF research. The aging clock shows great performance in cross-validation (R2=0.84) and its utility is validated in an independent dataset to show that severe cases of COVID-19 are associated with an increased aging rate. Computational analysis using ipf-P3GPT revealed distinct but overlapping molecular signatures between aging and IPF, suggesting that IPF represents a dysregulation rather than mere acceleration of normal aging processes. Our findings establish novel connections between aging biology and IPF pathogenesis while demonstrating the potential of AI-guided approaches in therapeutic development for age-related diseases.

bioinformatics↗

Micromorphology and ammonium transmembrane transport characteristics in roots of rice seedlings

During the seedling stage, rice root exhibit rapid growth and absorb significant quantities of nutrients. This study involved cultivating rice seedlings in two different seedling-raising mediums characterized by high ammonium concentration (HN, NH4+ 1.2 mg g-1) and low ammonium concentration (LN, NH4+ 0.006 mg g-1). The morphology of distinct root zones (root cap, meristematic zone, elongation zone, and maturation zone) was observed under a microscope throughout root development, and variations in transmembrane flux rates of NH4+ in different root zones were assessed using Non-invasive micro-test technology (NMT). Results showed that the root caps of both seminal and adventitious roots became separated from the root tip between 9 and 12 days after root emergence. During this time, the root tip transformed from a sharp to a round shape, and the distance from the maturation zone to the root tip progressively decreased from over 900 m on 6 days after sowing (DAS) to under 500 m on DAS12. The meristematic zone was the primary site for NH4+ absorption in new root and proved to be particularly sensitive to environmental NH4+ concentration. At DAS 6, the net NH4+ flux rate was highest in the meristematic zone under both HN and LN treatments. Additionally, the external NH4+ concentration influenced the direction of NH4+ flux in the meristematic zone at DAS9, with HN being a net NH4+ influx and LN being an NH4+ efflux, and the net NH4+ influx in the meristematic zone persisted for 3 days longer in the HN treatment compared to the LN treatment. In mature roots, the root hair zone emerged as the primary site of NH4+ uptake, exhibiting an infNH4+ influx rate of 40-140 pmol cm-1 s-1, and this low rate of uptake could be sustained for up to 12 days after root emergence. By DAS15, a net NH4+ efflux was observed in the entire seminal root, signaling the loss of NH4+ absorption function 15 days post-emergence. A similar trend was noted in adventitious roots, where NH4+ uptake remained functional for 12-15 days after root emergence. As rice seedlings continued to grow, new adventitious roots replaced old ones, facilitating ongoing NH4+ uptake.

plant biology↗