Biology subjects

Li, S.

Publications and source records attributed to Li, S..

At least 937 records · Page 52Linked to original sources

bioRxiv2021

Concerted cellular responses to type I interferon propel memory impairment associated with amyloid β plaques

Despite well-documented maladaptive neuroinflammation in Alzheimers disease (AD), the principal signal that drives memory and cognitive impairment remains elusive. Here, we reveal robust, age-dependent cellular reactions to type I interferon (IFN), an innate immune cytokine aberrantly elicited by {beta} amyloid plaques, and examine their role in cognition and neuropathology relevant to AD in a murine amyloidosis model. Long-term blockade of IFN receptor rescued both memory and synaptic deficits, and also resulted in reduced microgliosis, inflammation, and neuritic pathology. Interestingly, microglia-specific IFN receptor ablation attenuated the loss of post-synaptic terminals, whereas IFN signaling in neural cells contributed to pre-synaptic alteration and plaque accumulation. Intriguingly, IFN pathway activation displayed a strong inverse correlation with cognitive performance, promoting selective synapse engulfment by microglia rather than amyloid plaques. Overall, IFN signaling represents a critical module within the neuroinflammatory network of AD and prompts a concerted cellular state that is detrimental to memory and cognition.

neuroscience↗

bioRxiv2021

Emergence of an adaptive epigenetic cell state in human bladder urothelial carcinoma evolution

Intratumor heterogeneity (ITH) of bladder cancer (BLCA) facilitates therapy resistance and immune evasion to affect clinical prognosis directly. However, the molecular and cellular mechanism generating ITH in BLCA remains elusive. Here we show that a TM4SF1-positive cancer subpopulation (TPCS) drives ITH diversification in BLCA. By extensive profiling of the epigenome and transcriptome of BLCA from 79 donors across all stages, we elucidated the evolution trajectories of luminal and basal BLCA. TPCS emerges from the basal trajectory and shows extensive transcriptional plasticity with a distinct epigenomic landscape. Clinically, TPCS were enriched in advanced stage patients and associated with poor prognosis. Our results showed how cancer adapts to its environment by adopting a stem cell-like epigenomic landscape.

cancer biology↗

bioRxiv2021

PHB3 Regulates Lateral Root Primordia Formation via NO-mediated Degradation of AUX/IAAs

We previously showed that PHB3 regulates auxin-stimulated lateral root (LR) formation; however, the underlying molecular mechanism is unknown. Here, we demonstrate that PHB3 regulates LR development mainly through influencing lateral root primordia (LRP) initiation via affecting nitric oxide (NO) accumulation. The reduced LRP in phb3 was largely rescued by exogenous NO donor SNAP treatment. The decreased NO accumulation in phb3 caused a lower expression of GATA23 and LBD16 through inhibiting the degradation of IAA14/28. Overexpression of either GATA23 or LBD16 in phb3 mutant background recovered the reduced LRP number phenotype. These results indicate that PHB3 regulates LRP initiation via NO-mediated auxin signaling through regulating the degradation of IAA14/28. HighlightPHB3 regulates IAA28 and IAA14 degradation by controlling NO accumulation, and thereby regulating LR founder cell identification and the transition to asymmetric division.

developmental biology↗

bioRxiv2021

Two type II phosphatidylinositol 4-kinases function sequentially in tubule-mediated cargo delivery from early endosomes to melanosomes

Melanosomes are pigment cell-specific lysosome-related organelles in which melanin pigments are synthesized and stored. Melanosome maturation requires delivery of melanogenic cargoes via tubular transport carriers that emanate from early endosomes and that require BLOC-1 for their formation. Here we show that phosphatidylinositol-4-phosphate (PtdIns4P) and the type II PtdIns-4-kinases (PI4KII and PI4KII{beta}) support BLOC-1-dependent tubule formation to regulate melanosome biogenesis. Depletion of either PI4KII or PI4KII{beta} with shRNAs in melanocytes reduced melanin content and misrouted BLOC-1-dependent cargoes to late endosomes/lysosomes. Genetic epistasis, cell fractionation, and quantitative live-cell imaging analyses show that PI4KII and PI4KII{beta} function sequentially and non-redundantly downstream of BLOC-1 during tubule elongation towards melanosomes by generating local pools of PtdIns4P. The data show that both type II PtdIns-4-kinases are necessary for efficient BLOC-1-dependent tubule elongation and subsequent melanosome contact and content delivery during melanosome biogenesis. The independent functions of PtdIns-4-kinases in tubule extension are downstream of likely redundant functions in BLOC-1-dependent tubule initiation. SUMMARYContents are delivered to maturing melanosomes from early endosomal intermediates through tubular transport carriers. Zhu et al show that two type II phosphatidylinositol kinases, PI4KII and PI4KII{beta}, sequentially generate phosphatidylinositol-4-phosphate during tubule initiation and elongation for ultimate melanosome content delivery.

cell biology↗

bioRxiv2021

Lactate Increases Stemness of CD8+ T Cells to Augment Anti-Tumor Immunity

Nutrients and metabolites play important roles in immune functions. Recent studies show lactate instead of glucose can serve as a primary carbon fuel source for most tissues. The role of lactate in tumor immunity is not well understood with immune suppressive functions reported for lactic acid, the conjugate acid form of lactate. In this study, we report lactate increases the stemness of CD8+ T cells and augments anti-tumor immunity. Subcutaneous administration of lactate but not glucose shows CD8+ T cell-dependent tumor growth inhibition. Single cell transcriptomics analysis revealed lactate treatment increased a subpopulation of stem-like TCF-1-expressing CD8+ T cells, which is further validated by ex vivo culture of CD8+ T cells from mouse splenocytes and human peripheral blood mononuclear cells. The inhibition of histone deacetylase activity by lactate increased acetylation in the histone H3K27 site at the Tcf7 super enhancer locus and increased the gene expression of Tcf7. Adoptive transfer of CD8+ T cells pretreated with lactate in vitro showed potent tumor growth inhibition in vivo. Our results elucidate the immune protective role of lactate in anti-tumor immunity without the masking effect of acid. These results may have broad implications for T cell therapy and the understanding of lactate in immune metabolism.

immunology↗

bioRxiv2021

PDXNet Portal: Patient-Derived Xenograft model, data, workflow, and tool discovery

We created the PDX Network (PDXNet) Portal (https://portal.pdxnetwork.org/) to centralize access to the National Cancer Institute-funded PDXNet consortium resources (i.e., PDX models, sequencing data, treatment response data, and bioinformatics workflows), to facilitate collaboration among researchers, and to make resources easily available for research. The portal includes sections for resources, analysis results, metrics for PDXNet activities, data processing protocols, and training materials for processing PDX data. The initial portal release highlights PDXNet model and data resources, including 334 new models across 33 cancer types. Tissue samples of these models were deposited in the NCIs Patient-Derived Model Repository (PDMR) for public access. These models have 2,822 associated sequencing files from 873 samples across 307 patients, which are hosted on the Cancer Genomics Cloud powered by Seven Bridges and the NCI Cancer Data Service for long-term storage and access with dbGaP permissions. The portal also includes results from standardized analysis workflows on PDXNet sequencing files and PDMR data (2,594 samples from 463 patients across 78 disease types). These 15 analysis workflows for whole-exome and RNA-Seq data are freely available, robust, validated, and standardized. The model and data lists will grow substantially over the next two years and will be continuously updated as new data are available. PDXNet models support multi-agent treatment studies, determination of sensitivity and resistance mechanisms, and preclinical trials. The PDXNet portal is a centralized location for these data and resources, which we expect to be of significant utility for the cancer research community.

cancer biology↗

bioRxiv2021

iHypoxia: an integrative database of the expression dynamics of proteins in response to hypoxia in animals

Decreased oxygen concentrations (hypoxia) outside of the physiological range may severely subvert cell, tissue, and organism survival. Mammals have evolved mechanisms to sense hypoxia and induce a series of hypoxic responses. In recent years, high-throughput techniques have greatly promoted global perturbation studies of protein expression during hypoxia, and these studies have contributed to the understanding of the complex regulatory networks of hypoxia. In this study, we developed an integrated resource for the expression dynamics of proteins in response to hypoxia (iHypoxia), which contains 1,629 expression events of 1,215 proteins identified by low-throughput experiments (LTEs) and 154,953 quantitative expression events of 36,194 proteins identified by high-throughput experiments (HTEs) from five mammals that exhibit a response to hypoxia. Various experimental details such as the hypoxic experimental conditions, expression patterns, and samples were carefully collected and integrated. In addition, we conducted an orthologous search and identified 581,763 proteins that may respond to hypoxia among 50 animals. An enrichment analysis of human proteins identified from LTEs showed that these proteins were enriched in certain drug targets and cancer genes. The annotation of known posttranslational modification (PTM) sites to proteins identified by LTEs revealed that these proteins underwent extensive PTMs, particularly phosphorylation, ubiquitination and acetylation. Based on the results, iHypoxia provides a convenient and user-friendly method for users to obtain hypoxia-related information of interest. We anticipate that iHypoxia, which is freely accessible at http://ihypoxia.omicsbio.info, will advance the understanding of hypoxia and serve as a valuable data resource.

bioinformatics↗

bioRxiv2021

Multi-omics analysis of multiple glucose-sensing receptor systems in yeast

The yeast Saccharomyces cerevisiae has long been used to produce alcohol from glucose and other sugars. While much is known about glucose metabolism, relatively little is known about the receptors and signaling pathways that indicate glucose availability. Here we compare the two glucose receptor systems in S. cerevisiae. The first is a heterodimer of transporter-like proteins (transceptors), while the second is a seven-transmembrane receptor coupled to a large G protein (Gpa2) and two small G proteins (Ras1 and Ras2). Through comprehensive measurements of glucose-dependent transcription and metabolism, we demonstrate that the two receptor systems have distinct roles in glucose signaling: the G protein-coupled receptor directs carbohydrate and energy metabolism, while the transceptors regulate ancillary processes such as ribosome, amino acids, cofactor and vitamin metabolism. The large G protein transmits the signal from its cognate receptor, while the small G protein Ras2 (but not Ras1) integrates responses from both receptor pathways. Collectively, our analysis reveals the molecular basis for glucose detection and the earliest events of glucose-dependent signal transduction in yeast.

genomics↗

bioRxiv2021

Deactivation of SARS-CoV-2 surrogate porcine epidemic diarrhea virus with electron beam irradiation under the cold chain transportation condition

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has prevailed all over the world and emerged as a significant public health emergency. The rapid outbreak of SARS-CoV-2 is largely due to its high transmission capacity. Studies implied that the cold chain logistics would be a potential route for the spread of SARS-CoV-2. The low temperature condition of the cold chain is conducive to survival and transmission of virus. Thus, the virus disinfection in cold chain should not be neglected for controlling COVID-19. However, due to the low temperature feature of the cold-chain, the virus disinfecting methods suitable in cold chain are limited. Here the high-energy electron beam irradiation is proposed to disinfect the SARS-CoV-2 in cold chain logistics. We evaluated the impact of high-energy electron beam irradiation on porcine epidemic diarrhea virus (PEDV), an enveloped virus surrogate for SARS-CoV-2, and explored the possible mechanism of the action of high-energy electron beam irradiation on PEDV. The irradiation dose of 10 kGy inactivated 98.1 % PEDV on the both top and bottom surfaces of various packaging materials under cold chain frozen condition. High-energy electron beam inactivated PEDV by inducing damages on viral genome or even capsid.

microbiology↗

bioRxiv2021

Narcolepsy with cataplexy is caused by epigenetic silencing of hypocretin neurons

Narcolepsy with cataplexy is a chronic sleep disorder characterized by hypocretin deficiency. The condition is believed to result from autoimmune destruction of hypocretin (HCRT) neurons, although direct evidence is lacking and mere Hcrt gene inactivation causes full-blown narcolepsy in mice. Here we show that the expression of another hypothalamic neuropeptide, QRFP, is lost in mouse models with HCRT cell-ablation, but tends to be even increased in Hcrt gene knockout mice, suggesting that QRFP expression can be used as a proxy for the presence or absence of HCRT neurons. Similar to Hcrt knockout mice, narcolepsy patients show intact hypothalamic QRFP expression, and cerebrospinal fluid levels of QRFP peptide are increased, suggesting their HCRT neurons are intact. We show that the human HCRT gene promoter is methylation-sensitive in vitro, and is hypermethylated in the hypothalamus of patients selectively at a putative PAX5:ETS1 binding site within the proximal HCRT promoter. Ets1-KO mice display downregulated Hcrt expression, while pax5-ets1 knockdown in zebrafish causes decreased hcrt expression, decreased activity and sleep fragmentation, similar to narcolepsy patients. Our results suggest that HCRT neurons are alive, but epigenetically silenced, in the hypothalamus of narcolepsy patients, opening the possibility to reverse or cure narcolepsy.

neuroscience↗

bioRxiv2021

Intergenerational effects of a paternal Western diet during adolescence on offspring gut microbiota, stress reactivity and social behavior

The global consumption of highly processed, calorie-dense foods has contributed to an epidemic of overweight and obesity, along with negative consequences for metabolic dysfunction and disease susceptibility. As it becomes apparent that overweight and obesity have ripple effects through generations, understanding of the processes involved is required, in both maternal and paternal epigenetic inheritance. We focused on the patrilineal effects of a Western-style high-fat (21%) and high-sugar (34%) diet (WD) compared to control diet (CD) during adolescence and investigated F0 and F1 mice for physiological and behavioral changes. F0 males (fathers) showed increased body weight, impaired glycemic control, and decreased attractiveness to females. Paternal WD caused significant phenotypic changes in F1 offspring, including higher body weights of pups, increased Actinobacteria abundance in the gut microbiota (ascertained using 16S microbiome profiling), a food preference for WD pellets, increased male dominance and attractiveness to females, as well as decreased behavioral despair. These results collectively demonstrate the long-term intergenerational effects of a Western-style diet during paternal adolescence. The behavioral and physiological alterations in F1 offspring provide evidence of adaptive paternal programming via epigenetic inheritance. These findings have important implications for understanding paternally mediated intergenerational inheritance, and its relevance to offspring health and disease susceptibility.

neuroscience↗

bioRxiv2021

Delayed implantation induced by letrozole in mice

Implantation timing is key for a successful pregnancy. Short delay in embryo implantation caused by targeted gene ablation produced a cascading problem in the later stages of the pregnancy. Although several delayed implantation models have been established in wild mice, almost none of them is suitable for investigating the delay on the late events of pregnancy. Here, we report a new delayed implantation model established by the intraperitoneally administration of letrozole at 5 mg/kg body weight on the day 3 of pregnancy. In these mice, initiation of implantation was induced at will by the injection of estradiol (E2). When the estradiol (3 ng) was injected on day 4 of pregnancy (i.e., without delay), the embryo implantation restarted, and the pregnancy continued normally. However, high dose of estrogen (25 ng) caused compromised implantation. We also found that only 67% of the female mice could be pregnant normally and finally gave birth when the injection of estradiol (3 ng) was on day 5 of pregnancy (i.e., one day delay). Most of the failed pregnancies had impaired decidualization, decreased plasma progesterone levels and compromised angiogenesis. Progesterone supplementation could rescue decidualization failure in the mice. Collectively, we established a new model of delayed implantation by letrozole, which can be easily used to study the effect and mechanisms of delay of embryo implantation on the progression of late pregnancy events.

developmental biology↗

bioRxiv2021

Angiocrine IGFBP3 Spatially Coordinates IGF Signaling During Neonatal Cardiac Regeneration

To identify non-cell-autonomous effectors of cardiomyocyte mitosis, we analyzed a transcriptomic screen of regenerating and non-regenerating neonatal hearts for differentially-expressed secreted proteins - which we hypothesized could include candidate mitogens. We identified and validated IGFBP3, which has a Janus-like stabilizing and sequestering effect on IGF growth factors, as a neonatal injury-associated secreted protein. IGFBP3 is expressed by and secreted from vascular cells in the neonatal heart after cardiac injury, notably in the infarct border zone. We found that global deletion of IGFBP3 blunted neonatal regeneration, while gain-of-function experiments using recombinant IGFBP3 and a transgenic mouse model uncovered a pro-mitotic effect of IGFBP3 on cardiomyocytes in vitro and in the adult heart. We show that site-specific expression of an IGFBP3 protease (PAPP-A2) and its inhibitor (STC2) coordinate the spatial release of IGF2 in the infarct zone to regio-selectively activate the INSR-ERK-AKT cell growth pathways in cardiomyocytes. Collectively, our work highlights the spatiotemporal orchestration of endothelial-cardiomyocyte interactions that are required for neonatal cardiac regeneration.

cell biology↗

bioRxiv2021

Regional Cell Atlas of Human Intestine Shapes Distinct Immune Surveillance

Regional intestinal immune surveillance remains obscure. In this study, we integrated single-cell RNA sequencing and spatial transcriptomics to create a regional atlas of fetal and adult intestines, consisting of 59 cell subsets, of which eight new subsets and ILCs transition states were identified. Results revealed that microenvironment determines in-situ cell differentiation and shapes the regional molecular characteristics, allowing different intestinal segments with diverse functions. We characterized the regional expression of mucins, immunoglobulins, and antimicrobial peptides (AMPs) and their shift during development and in inflammatory bowel disease. Notably, -defensins expressed most abundantly in small intestinal LGR5+ stem cells, rather than in Paneth cells, and down-regulated as cell maturing. Common upstream transcription factors controlled the AMPs expression, illuminating the concurrent change of AMPs during epithelial differentiation, and the spatial co-expression patterns. We demonstrated the correspondence of cell focus of risk genes to diseases location susceptibility and identified distinct cell-cell crosstalk and spatial heterogeneity of immune cell homing in different gut segments. Overall, a cross-spatiotemporal approach to transcriptomes at single-cell resolution revealed that the regional milieu of the human intestine determined cellular and molecular cues of immune surveillance, dictating gut homeostasis and disease.

cell biology↗

bioRxiv2021

Exosomal MFGE8 from high glucose induced endothelial cells is involved in calcification/senescence of vascular smooth muscle cells

Vascular calcification/aging is a crucial feature of diabetic macro vasculopathy, resulting in serious cardiovascular diseases. The calcification/senescence of vascular smooth muscle cells (VSMCs) induced by hyperglycemia can cause diabetic vascular calcification/aging. However, the mechanism of VSMCs calcification/senescence involved in diabetic vascular calcification/aging remains unknown. The purpose of this study was to determine how the high glucose (HG) information in circulating blood is transmitted from vascular endothelial cells (ECs) to VSMCs, which are not contacted with blood directly. Exosomes have attracted much attention for their vital roles in regulating cell-to-cell communication. In this study, we found that milk fat globule epidermal growth factor 8 (MFGE8) was enriched in high glucose induced human umbilical vein endothelial cell exosomes (HG-HUVEC-Exo) and regulate VSMCs calcification/senescence, characterized by up-regulated expressions of alkaline phosphatase (ALP) and Runt-related transcription factor 2 (Runx2), as well as the increased mineralized nodules and senescence-associated {beta}-galactosidase (SA-{beta}-gal) positive cells. Upstream mechanism studies showed that sirtuin1 (SIRT1) was involved in VSMCs calcification/senescence by affecting the expression of MFGE8. We also found that inflammatory response mediated by IL-1{beta}, IL-6, and IL-8 was closely associated with MFGE8 and played a key role in regulating HG-HUVEC-Exo-induced VSMCs calcification/senescence. These findings provide a new insight into the mechanism of exosomal MFGE8 as a potential preventive and therapeutic target for the intervention of diabetic vascular calcification/aging.

molecular biology↗

bioRxiv2021

The histone deacetylase activity of HDAC1/2 is required to safeguard zygotic genome activation in mice and cattle

The genome is transcriptionally inert at fertilization and must be activated through a remarkable developmental process called zygotic genome activation (ZGA). The gene expression pattern formed over the course of ZGA is required for establishing totipotency in early embryos and subsequent development. Substantial epigenetic reprogramming contributes significantly to the pronounced change in gene expression during ZGA, however the mechanism has yet to be resolved. Here, we find histone deacetylase 1 and 2 (HDAC1/2) are critical histone modifiers that regulate ZGA through the histone deacetylase activity. Notably, we show that H3K27ac level declines dramatically during ZGA with a dynamic change in its genome-wide distribution. In mouse embryos, ectopic expression of HDAC1/2 dominant negative mutant leads to a failure of H3K27ac removal and a developmental arrest at 2-cell stage. RNA-seq results reveal a remarkable transcriptomic change with 6565 differentially expressed genes identified. Further analysis shows 64% of down-regulated genes are ZGA genes and 49% of up-regulated genes are developmental genes. Low input ChIP-seq analysis exhibits an increase and decrease of H3K27ac enrichment at the promoter region of up- and down-regulated genes, respectively. Moreover, HDAC1 mutants prohibited removal of broad H3K4me3 domain via impeding the expression of Kdm5s during ZGA. Importantly, the developmental block can be greatly overcome through injection of Kdm5b mRNA and expression of the majority of dysregulated genes partially corrected. Similar functional significance of HDAC1/2 in ZGA is conserved in bovine embryos. Together, we propose that HDAC1/2 is indispensable for mouse and bovine ZGA via creating correct transcriptional repressive and active states.

developmental biology↗

bioRxiv2021

Hierarchical Timescales in the Neocortex: Mathematical Mechanism and Biological Insights

A cardinal feature of the neocortex is the progressive increase of the spatial receptive fields along the cortical hierarchy. Recently, theoretical and experimental findings have shown that the temporal response windows also gradually enlarge, so that early sensory neural circuits operate on short-time scales whereas higher association areas are capable of integrating information over a long period of time. While an increased receptive field is accounted for by spatial summation of inputs from neurons in an upstream area, the emergence of timescale hierarchy cannot be readily explained, especially given the dense inter-areal cortical connectivity known in modern connectome. To uncover the required neurobiological properties, we carried out a rigorous analysis of an anatomically-based large-scale cortex model of macaque monkeys. Using a perturbation method, we show that the segregation of disparate timescales is defined in terms of the localization of eigenvectors of the connectivity matrix, which depends on three circuit properties: (1) a macroscopic gradient of synaptic excitation, (2) distinct electrophysiological properties between excitatory and inhibitory neuronal populations, and (3) a detailed balance between long-range excitatory inputs and local inhibitory inputs for each area-to-area pathway. Our work thus provides a quantitative understanding of the mechanism underlying the emergence of timescale hierarchy in large-scale primate cortical networks. Significance StatementIn the neocortex, while early sensory areas encode and process external inputs rapidly, higher association areas are endowed with slow dynamics suitable for accumulating information over time. Such a hierarchy of temporal response windows along the cortical hierarchy naturally emerges in a model of multi-areal primate cortex. This finding raises the question of why diverse temporal modes are not mixed in roughly the same way across the whole cortex, despite high connection density and an abundance of feedback loops. We investigate this question by mathematically analyzing the anatomically-based network model of macaque cortex, and show that three general principles of synaptic excitation and inhibition are crucial for timescale segregation in a hierarchy, a functionally important characteristic of the cortex.

neuroscience↗

bioRxiv2021

Global anti-tumor immunity after localized, bioengineered Treg depletion

Over 90% of deaths from cancer occur due to solid tumors, occurring at a rate of [~]1,500 deaths per day in the US, highlighting a profound and unmet need for new therapies. Solid tumors evade clearance by T cells due to a variety of immunosuppressive properties of the tumor microenvironment. However, this immunosuppression cannot be easily blocked on a global level because systemic activation of the immune system elicits a host of complications. An ideal therapy for solid tumors would act locally to activate the immune response without evoking global adverse effects. Here we present a biodegradable, macroporous scaffold that is implanted adjacent to the tumor and suppresses the main obstacle to cancer immunosurveillance: intratumoral regulatory T cells. The scaffold also promotes the recruitment and activation of T cell effectors into the tumor, resulting in clearance of otherwise aggressive and fatal tumors in mice. Unexpectedly, the local depletion of Tregs results in an "immunological abscopal effect" acting on distant tumors. We demonstrate that this versatile platform can also deliver tumor-antigen-specific T cells directly to the peri-tumoral environment, bypassing difficulties in intravenous delivery including the environmental barriers imposed by the tumors vasculature. By orchestrating multiple local immunomodulatory treatments, this scaffold offers a general approach to engineer T-cell responses to solid tumors without systemic toxicities.

immunology↗