Biology subjects

Duan, S.

Publications and source records attributed to Duan, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Single-Cell Genomics Elucidates Molecular Variations and Regulatory Mechanisms in Circulating Immune Cells

The human peripheral blood displays diverse molecular characteristics across populations, understanding the drivers and underlying mechanisms of which remains challenging. Here, we introduce the Chinese Immune Multi-Omics Atlas (CIMA), elucidating sex-, age-, and genetic-related molecular variations by analyzing multi-omics data from 428 adults with over 10 million immune cells. CIMA generated an enhancer-driven gene regulatory network, identifying 237 high-quality regulons and revealing cell type-specific regulatory mechanisms. Additionally, 11,521 lead cis-expression quantitative trait loci (eQTLs) and 46,339 chromatin accessibility QTLs (caQTLs) were identified at cell type level. CIMA also uncovered pleiotropic associations among immune-related disease risk loci, eQTLs, and caQTLs in a cell type-specific manner. Lastly, a novel cell language model, CIMA-CLM, was developed to predict chromatin accessibility and noncoding variant effects using chromatin sequences and gene expressions. This work represents a population-scale multi-omics resource of human immune cells, providing a valuable reference for future investigation of immune-related diseases.

immunology↗

bioRxiv2024

A novel method for in vivo assessment of soft tissue weight in bivalves

Aquaculture has been playing an increasingly important role in supplying proteins. To satisfy the rapidly growing demands for quality aquatic foods, the efficiency of aquaculture production needs to be improved. One strategy to achieve more efficient aquaculture production is to produce high-yielding seeds through breeding programs, for which in vivo assessment of target traits is indispensable to prevent candidate parents from being sacrificed for measurement and to track dynamically changing yield-related traits. Farmed mollusks, most of which are bivalves, rank the second among all aquatic animals in aquaculture production. Bivalves with heavier soft tissue, the major edible part, are preferable, target species for breeding and farming. A prerequisite for obtaining such species is to make accurate but nondestructive assessments of soft tissue weight, which cannot be accomplished using traditional dissection- or imaging-based methods. To resolve this issue, we take advantage of the complex relationships among shell dimension- and weight-related traits to construct classical, shell dimension- or wet weight-based models and novel, shell surface area-based models for in vivo assessment of soft tissue weight in Zhikong scallop (Chlamys farreri) and yesso scallop (Patinopecten yessoensis). Overall, soft tissue weight estimated by wet weight-involving models are highly correlated with observed values, indicating wet weight as a key proxy for soft tissue weight. While some models incorporating wet weight tend to systematically over- or under-estimate soft tissue weight despite the strong association between actual and estimated values, the novel, shell surface area-based model, MLR-log10Sshell-RR, generates accurate estimates free of systematic biases across populations of different ages for both species, suggesting it as a promising approach for in vivo assessment of soft tissue weight for scallops and other bivalves with bilaterally symmetrical shells.

genetics↗

bioRxiv2024

Identification of SMARCA1 as a key regulator for Colorectal Cancer

Emerging evidence indicates that aberrations in the writing, reading, or erasure of chromatin modification codes are pivotal events in various human cancers. In this study, we conducted a systematic investigation of histone modification recognition proteins in a pair of colorectal cancer cell lines, SW480 and SW620. Using chromatin fractionation combined with data-independent acquisition mass spectrometry (DIA-MS), we developed a robust method to identify changes in histone modification recognition proteins during cancer progression. Our analysis revealed 22 proteins that were significantly upregulated and 22 proteins that were significantly downregulated in SW620 cells compared to SW480 cells. Notably, SMARCA1, a member of the ISWI family belonging to ATP-dependent chromatin remodeling complexes, was downregulated in SW620 cells compared to SW480 cells. Its high expression was strongly correlated with poor patient prognosis, aligning with the proposed role of SMARCA1 in promoting colorectal cancer (CRC) metastasis. Furthermore, reduced SMARCA1 expression altered the levels of metastasis-related matrix metalloproteinases (MMPs) in these cells. In conclusion, by systematically profiling histone modification recognition proteins in a matched pair of primary and metastatic CRC cell lines, we identified SMARCA1 as a potential driver of CRC metastasis and a promising therapeutic target for CRC patients.

cancer biology↗

bioRxiv2024

Multimodal single-cell analyses reveal molecular markers of neuronal senescence in human drug-resistant epilepsy

The histopathological neurons in the brain tissue of drug-resistant epilepsy exhibit aberrant cytoarchitecture and imbalanced synaptic circuit function. However, the gene expression changes of these neurons remain unknown, making it difficult for the diagnosis or to dissect the mechanism of drug-resistant epilepsy. By integrating whole-cell patch clamp recording and single-cell RNA sequencing approaches, we identified a transcriptionally distinct subset of cortical pyramidal neurons. These neurons highly expressed genes CDKN1A (P21), CCL2 and NFKBIA that associated with mTOR pathway, inflammatory response and cellular senescence. We confirmed the expression of senescent marker genes in a subpopulation of cortical pyramidal neurons with enlarged soma size in the brain tissue of drug-resistant epilepsy. We further revealed the expression of senescent cell markers P21, P53, COX2, {gamma}-H2AX, {beta}-Gal and reduction of nuclear integrity marker Lamin B1 in histopathological neurons in the brain tissue of drug-resistant epilepsy patients with different pathologies, but not in control brain tissue with no history of epilepsy. Additionally, chronic, but not acute, epileptic seizures induced senescent markers expression in cortical neurons in mouse models of drug-resistant epilepsy. These results provide important molecular markers for histopathological neurons and new insights into the pathophysiological mechanisms of drug-resistant epilepsy.

neuroscience↗

bioRxiv2024

HCN1 channels in GABAergic amygdalar neurons underpin male-biased aggressive behaviors

Aggression behaviors typically vary between sexes, but the molecular mechanisms driving these disparities in neural coding are unclear. We found that aggression selectively activates GABAergic neurons in the posterior substantia innominata (pSI), an extend amygdala region critical for aggressive behaviors in both sexes of mice, with males exhibiting higher neuronal activity during the attack. Utilizing single-nucleus RNA sequencing, we characterized the diverse molecular landscape of pSI neurons, revealing significant differences in ion channels and hormone regulator genes that may underpin sex-specific aggression. Male GABAergic pSI neurons exhibited remarkable hyperexcitability due to increased Ih currents. Strikingly, modulating HCN1 expression not only adjusted this hyperexcitability but also influenced sexual dimorphism in aggression: silencing HCN1 in the GABAergic pSI neurons reduced male aggression, while its overexpression markedly heightened aggression in females. Furthermore, testosterone was shown to intensify aggression by upregulating HCN1 and remodeling pSI circuits. These findings provide detailed sex-specific molecular mechanisms underlying social behaviors.

neuroscience↗

bioRxiv2024

Single-nucleus multiple-organ chromatin accessibility mapping in the rat

The chromatin accessibility landscape is the basis of cell-specific gene expression. We generated a multiorgan, single-nucleus chromatin accessibility landscape from the model organism Rattus norvegicus. For this single-cell atlas, we constructed 25 libraries via snATAC-seq from nine organs in the rat, with a total of over 110,000 cells. Cell classification integrating gene activity scores with known marker genes identified 77 cell types, which were strongly correlated with those in published mouse single-cell transcriptome atlases. We further investigated the enrichment of cell type- and organ-specific transcription factors (TFs), the dynamics of T-cell developmental trajectories across organs, and the conservation and specificity of gene expression patterns across species. These findings provide a foundation for further investigations of the cell composition and gene regulatory networks throughout the rat body. HighlightsO_LIGeneration of a single-cell atlas of chromatin accessibility in nine organs of the rat C_LIO_LICharacterization of cell type- and organ-specific transcription factors (TFs) C_LIO_LIDynamics of chromatin accessibility in developing T cells revealed by cross-organ analysis C_LIO_LIConservation and specificity of gene expression patterns among humans, mice, and rats revealed by cross-species analysis C_LI

genomics↗

bioRxiv2024

Deciphering gene regulatory programs in mouse embryonic skin through single-cell multiomics analysis

BackgroundCell type-specific transcriptional heterogeneity in embryonic mouse skin is well-documented, but few studies have investigated the regulatory mechanisms. ResultsHere, we present high throughput single-cell chromatin accessibility and transcriptome sequencing (HT-scCAT-seq), a method that simultaneously profiles transcriptome and chromatin accessibility. We utilized HT-scCAT-seq to dissect the gene regulatory mechanism governing epidermal stratification, periderm terminal differentiation, and fibroblast specification. ConclusionsBy linking chromatin accessibility to gene expression, we identified candidate cis-regulatory elements (cCREs) and target genes crucial for dermal and epidermal development. We described cells with similar gene expression profiles that exhibit distinct chromatin accessibility statuses during periderm terminal differentiation. Finally, we characterized the underlying lineage-determining transcription factors (TFs), and demonstrated that ALX4 and RUNX2 were candidate TF regulators of the dermal papilla lineage development through in silico perturbation analysis.

developmental biology↗

bioRxiv2024

Sympathetic Nervous System Overactivation Induces Colonic Eosinophil-Associated Microinflammation and Contributes to the Pathogenesis of Irritable Bowel Syndrome

ObjectiveMucosal microinflammation is a characteristic clinical manifestation of irritable bowel syndrome (IBS), and its symptoms are often triggered by psychological stress. In the present study, we aimed to investigate the impact of early life stress-associated dysfunction of the sympathetic nervous system (SNS) on mucosal immune changes in the gastrointestinal tract (GI) and its contribution to IBS pathogenesis. DesignWe utilised a traditional animal model of IBS with maternal separation (MS) and evaluated colorectal hypersensitivity, immune alterations, and SNS activity in adult rats with MS. We conducted a series of experiments to manipulate peripheral SNS activity pharmacologically and chemogenetically to explore the interaction between SNS activity and GI events. ResultsThe MS-induced IBS model exhibited visceral hypersensitivity and eosinophilic infiltration in the colonic mucosa, along with SNS overactivation. Degeneration of the SNS using 6-OHDA neurotoxin decreased eosinophil infiltration and visceral hypersensitivity in the MS model. Notably, specific chemogenetic activation of the peripheral SNS induced eosinophil infiltration in the intestinal mucosa through the noradrenergic signalling-mediated release of eotaxin-1 from mesenchymal cells. ConclusionThis study highlights the critical role of SNS overactivation in eotaxin-1-driven eosinophil infiltration in the colon, leading to the development of visceral hypersensitivity in IBS. The results provide important insights into the mechanistic links among increased sympathetic activity, mucosal microinflammation, and visceral hypersensitivity in individuals with IBS, suggesting potential therapeutic approaches. What is already known on this topicO_LIA subgroup of patients with irritable bowel syndrome (IBS) presents with microinflammation in the gastrointestinal tract (GI). C_LIO_LIEarly life stress is recognised as a major risk factor for the development of IBS in adulthood. C_LIO_LIOveractivation of the sympathetic nervous system (SNS) is frequently associated with IBS. C_LI What this study addsO_LIMaternal separation (MS) stress induces eosinophil-associated microinflammation in the colonic mucosa of adult rats. C_LIO_LIInhibition of SNS activity suppresses eosinophil infiltration and mitigates visceral hypersensitivity in the MS model. C_LIO_LINoradrenergic signalling within the peripheral sympathetic activation stimulates mesenchymal cells to release eotaxin-1, leading to substantial eosinophil-predominant immune alterations in the colon. C_LI How this study might affect research, practice, or policyO_LITreatment with fibroblast-derived eotaxin-1 and targeting eosinophil-associated microinflammation could be a potential strategy to alleviate visceral pain in patients with IBS. C_LIO_LIThe chemogenomic method specifically manipulates peripheral SNS and provides a valuable tool for future research. C_LI

neuroscience↗

bioRxiv2024

Population genomics of the rice landrace Acuce reveals exceptional dynamics of immune receptors

In cultivated plants such as Oryza sativa, landraces harbour high levels of diversity, in sharp contrast with genetically uniform modern varieties. The Yuanyang terraces (China) are renowned for traditional farming involving landraces and low disease incidence. To understand the molecular basis of these resistance levels, we explored the genomic diversity of Acuce, one of the oldest landraces in the region. Based on whole-genome resequencing of over 200 Acuce plants, we evaluated the diversity of immunity and agronomical genes with respect to the rest of the genome. In parallel, we analysed the genetic basis of pathogen resistance and agronomical traits. Acuce exhibits high levels of diversity, reaching 38% of the worldwide levels. We uncovered an excess of diversity and signatures of directional selection associated with immunity genes, in contrast with agricultural traits. Furthermore, cultures of mixed genotypes exhibited superior performances for both pathogen resistance and agricultural traits. We showed that, within one single landrace, traditional farmer practices selected optimal agricultural traits while maintaining diversity enabling pathogen resistance. This study elucidates the complex interplay between genetic diversity, natural selection related to pathogens, and selection for agricultural traits within traditional landraces, providing insights into sustainable agricultural practices in diverse cropping systems.

genomics↗

bioRxiv2024

Huntingtin is an RNA-binding protein and participates in NEAT1-mediated paraspeckles

AbstractHuntingtin protein, mutated in Huntington disease, is implicated in nucleic acid- mediated processes, yet evidence for direct huntingtin-nucleic acid interaction is limited. Here we show wildtype and mutant huntingtin co-purify with nucleic acids, primarily RNA, and interact directly with G-rich RNAs in in vitro assays. Huntingtin RNA immunoprecipitation sequencing from patient-derived fibroblasts and neuronal progenitor cells expressing wildtype and mutant huntingtin revealed NEAT1 as a significantly enriched transcript. Altered NEAT1 levels were evident in Huntingtons disease cells and postmortem brain tissues, and huntingtin knockdown decreased NEAT1 levels. Huntingtin co-localized with NEAT1 in paraspeckles, and we identified a high-affinity RNA motif preferred by huntingtin. This study highlights NEAT1 as a novel huntingtin interactor, demonstrating huntingtins involvement in RNA-mediated functions and paraspeckle regulation. One-Sentence SummaryHTT is an RNA-binding protein that interacts with G-rich sequences, including those in the paraspeckle lncRNA NEAT1.

cell biology↗

bioRxiv2024

Turnover of RNA-binding Proteins and MicroRNAs by intrinsically disordered region-directed ZSWIM8 ubiquitin ligase during brain development

Widely present in mammalian proteomes, intrinsically disordered regions (IDRs) in proteins play important biological functions by conferring structural flexibility and mediating biomolecular interactions. IDR-containing proteins, including many RNA-binding proteins (RBPs), are prone to misfolding and aggregation and must be constantly monitored. Here we show that the conserved ZSWIM8-type Cullin-RING ubiquitin ligase (CRLZSWIM8) is a master regulator of such proteins during brain development. ZSWIM8 selects its substrates via an IDR-dependent mechanism, and deletion of ZSWIM8 causes aberrant accumulation of numerous RBPs including AGO2 and ELAV1 in neonatal brains. Furthermore, AGO2 ubiquitination by ZSWIM8 is triggered by microRNA binding, leading to target-directed microRNA degradation (TDMD) of MiR7. Dysregulation of MiR7 in the absence of ZSWIM8 results in defects in oligodendrocyte maturation and functions. Together, our findings have demonstrated that, by utilizing variable target-recognition strategies, ZSWIM8 controls the abundance of conformationally flexible RBPs and miRNA metabolism that are essential for brain development. TeaserA conserved ubiquitin ligase controls the quality of disordered proteins to ensure brain development.

developmental biology↗

bioRxiv2023

Aberrant connective tissue sheath contraction drives premature hair follicle regression by inducing progenitor cell depletion in androgenetic alopecia

Androgenetic alopecia (AGA) is characterized by progressive miniaturization of hair, forming a distinctive patterned baldness in the scalp; yet, the mechanisms for hair miniaturization in this disease remain largely unknown. Here by single-cell transcriptome analysis, we describe a concise single-cell atlas, and identify the early changes in cell subpopulations, hair follicle (HF) stem cell fate determination and cell-cell communications in AGA anagen HF units. Thereinto, apoptotic loss of HF progenitor cells is significantly increased, correlated with HF miniaturization in AGA. Mechanistically, enhanced contraction of connective tissue sheath (CTS) activates the mechanosensitive channel PIEZO1, which triggers ectopic apoptosis of progenitor cells in human anagen HFs. Continuous CTS contraction during AGA causes long-term loss of progenitor cells via inducing persistent ectopic apoptosis through PIEZO1, eventually leading to premature hair regression. Most importantly, we show that targeting CTS contraction by ML-7, a selective myosin light chain kinase (MLCK) inhibitor, can obviously improve the growth of HFs from balding scalps of AGA patients. Our study reveals the cellular hierarchies and identifies CTS with increased muscle contraction activity as a driver of premature hair regression in AGA, highlighting CTS surrounding human HF as the therapeutic target for treating this disorder.

pathology↗

bioRxiv2023

The dual coding of a single sex pheromone receptor in regulating the mating behavior of Asian Honeybee Apis cerana

In honeybee society, a virgin queen usually mates only once with several drones before founding a colony. For the rest of her prolific life, she will not engage in subsequent mating events. In the Asian honeybee Apis cerana, the mechanisms controlling this reproductive strategy involves the queen-released mandibular pheromone (QMP). This pheromone blend regulates the physiology and reproductive behavior of workers and drones. Its main component, 9-oxo-(E)-2-decenoic acid (9-ODA), acts as a sex pheromone and attracts drones. However, how the QMP prevents additional mating later in the queens life remains elusive. Using behavioral and chemical analysis, we show that the QMP component methyl p-hydroxybenzoate (HOB) released by mated queens inhibits male attraction to 9-ODA. Furthermore, in vivo electroantennogram and single sensillum recording data indicated that HOB alone significantly reduces the spontaneous spike activity of 9-ODA-sensitive olfactory receptor neurons (ORNs). To explore the molecular mechanism underlying this inverse effect, we conducted qPCR and in situ hybridization assays. The results indicated that AcerOr11 is specifically expressed in sensilla placodea from the drones antennae, which are the sensilla that narrowly respond to both 9-ODA and HOB. We then cloned and expressed AcerOr11 in a Xenopus oocyte expression system, where AcerOr11 induced robust inward (regular) currents in response to 9-ODA. Intriguingly, HOB induced inverse currents in a dose-dependent manner. This suggests that HOB may act as an inverse agonist against AcerOr11, providing additional odor-coding information. Based on these findings, we propose a model in which AcerOr11 function as a dual modulators in regulating the mating behavior of A. cerana. The inverse agonist, HOB, can help manage the population dynamics of honeybees in apiculture.

molecular biology↗

bioRxiv2023

Paternal genomic resources from the YanHuang cohort suggested a Weakly-Differentiated Multi-source Admixture model for the formation of Hans founding ancestral lineages

The large-scale human genome revolution and rapidly advanced statistical innovation have updated our understanding of the fine-scale and complex genetic structure, the entire landscape of genetic diversity and the evolutionary trajectories of spatiotemporally different ancients and ethnolinguistically diverse modern populations. Recent ancient DNA research provided a detailed and complex admixture picture of ancient Europeans but limited insights into East Asians as the few available genomes. Y-chromosome variations in the male-specific regions, served as molecular archaeological tool, have unique evolutionary features that can be utilized to reconstruct the origin and subsequent interaction of ancient East Asian paternal lineages. We launched the YanHuang cohort using our designed highest-resolution capture sequencing panel to explore the detailed evolutionary trajectory of the Han Chinese, one of the largest ethnic groups in the world. We reported one of the largest uniparental genomic resources and observed multiple founding paternal lineages dominant in ancient western Eurasian, Siberian and East Asian participating in the formation of the gene pool of the Han Chinese. We identified fine-scale paternal genetic structure correlated with different patterns of ancient population interaction and geographical mountain barriers (Qinling-Huaihe line and Nanling Mountains), suggesting isolation-enhanced and admixture-introduced genetic differentiation enhanced the complexity of the Han Chinese genomic diversity. We observed a strong direct correlation between the frequency of multiple founding lineages of the Han Chinese and the proportion of subsistence-related ancestry sources related to western pastoralists, Holocene Mongolian Plateau people and ancient East Asians, reflecting the ancient migration events contributed to our identified patterns of Chinese paternal genomic diversity. We finally provided one novel and the most plausible admixture-by-admixture model, the Weakly-Differentiated Multi-Source Admixture model, as the major genetic mechanism to illuminate our observed pattern of complex interactions of multiple ancestral sources and landscape of the Han Chinese paternal genetic diversity. Generally, we presented one large-scale uniparental genomic resource from the YanHuang cohort, portrayed one novel admixture formation model and presented the entire genomic landscape with multiple ancestral sources related to ancient herders, hunter-gatherers and farmers who participated in the ancestral formation of the Han Chinese.

evolutionary biology↗

bioRxiv2023

Recruitment of FBXO22 for Targeted Degradation of NSD2

Targeted protein degradation (TPD) is an emerging therapeutic strategy that would benefit from new chemical entities with which to recruit a wider variety of ubiquitin E3 ligases to target proteins for proteasomal degradation. Here, we describe a TPD strategy involving the recruitment of FBXO22 to induce degradation of the histone methyltransferase and oncogene NSD2. UNC8732 facilitates FBXO22-mediated degradation of NSD2 in acute lymphoblastic leukemia cells harboring the NSD2 gain of function mutation p.E1099K, resulting in growth suppression, apoptosis, and reversal of drug resistance. The primary amine of UNC8732 is metabolized to an aldehyde species, which engages C326 of FBXO22 in a covalent and reversible manner to recruit the SCFFBXO22 Cullin complex. We further demonstrate that a previously reported alkyl amine-containing degrader targeting XIAP is similarly dependent on SCFFBXO22. Overall, we present a highly potent NSD2 degrader for the exploration of NSD2 disease phenotypes and a novel FBXO22-dependent TPD strategy.

biochemistry↗

bioRxiv2023

Ancient farmer and steppe pastoralist-related founding lineages contributed to the complex landscape of episodes in the diversification of Chinese paternal lineages

Ancient DNA advances have reported the complex genetic history of Eurasians, but how the knowledge of ancient subsistence strategy shifts and population movements influenced the fine-scale paternal genetic structure in East Asia has not been assessed. Here, we reported one integrated Y-chromosome genomic database of 15,530 people, including 1753 ancient people and newly-reported 919 individuals genotyped using our recently-developed targeted sequencing YHSeqY3000 panel, to explore Chinese genomic diversity, population evolutionary tracts and their genetic formation mechanism. We identified four major ancient technological innovations and population movements that shaped the landscape of Chinese paternal lineages. First, the expansion of millet farmers and early East Asians from the Yellow River Basin carrying the major O2/D subclades promoted the formation of the Sino-Tibetan peoples major composition and accelerated the Tibetan Plateaus permanent occupation. Second, rice farmers dispersal from the Yangtze River Valley carrying O1 and some sublineages of O2 contributed significantly to Tai-Kadai, Austronesian, Hmong-Mien, Austroasiatic people and southern Han Chinese. Third, Siberian-related paternal lineages of Q and C originated and boomed from Neolithic hunter-gatherers from the Mongolian Plateau and the Amur River Basin and significantly influenced the gene pools of northern Chinese. Fourth, western Eurasian-derived J, G and R lineages initially spread with Yamnaya steppe pastoralists and other proto-Indo-European people and further widely dispersed via the trans-Eurasian cultural communication along the Eurasian Steppe and the ancient Silk Road, remaining genetic trajectories in northwestern Chinese. Our work provided comprehensive modern and ancient genetic evidence to illuminate the impact of population interaction from the ancient farmer or herder-based societies on the genetic diversity patterns of modern people, revised our understandings of ancestral sources of Chinese paternal lineages, underscored the scientific imperative of the large-scale genomic resources of dense spatiotemporal underrepresented sampling populations to understand human evolutionary history.

genetics↗

bioRxiv2023

Malaria resistance-related biological adaptation and complex evolutionary footprints of Tai-Kadai people inferred from 796 genomes

Pathogen-host adaptative interaction and complex population demographical processes, including admixture, drift and Darwen selection, have considerably shaped the Neolithic-to-Modern Western Eurasian population structure and genetic susceptibility to modern human diseases. However, the genetic footprints of evolutionary events in East Asia keep unknown as the underrepresentation of genomic diversity and the design of large-scale population studies. We reported one aggregated database of genome-wide-SNP variations from 796 Tai-Kadai (TK) genomes, including Bouyei first reported here, to explore the genetic history, population structure and biological adaptative features of TK-speaking people from Southern China and Southeast Asia. We found geography-related population substructure among TK-speaking people using the state-of-the-art population genetic structure reconstruction techniques based on the allele frequency spectrum and haplotype-resolved phased fragments. We found that the Northern TK-speaking people from Guizhou harboured one TK-dominant ancestry maximised in Bouyei people, and the Southern one from Thailand obtained more influences from Southeast Asians and indigenous people. We reconstructed the fitted admixture models and demographic graphs, which showed that TK-speaking people received gene flow from ancient rice farmer-related lineages related to the Hmong-Mien and Austroasiatic people and Northern millet farmers associated with the Sino-Tibetan people. Biological adaptation focused on our identified unique TK lineages related to Bouyei showed many adaptive signatures conferring Malaria resistance and low-rate lipid metabolism. Further gene enrichment, the allele frequency distribution of derived alleles, and their correlation with the incidence of Malaria further confirmed that CR1 played an essential role in the resistance of Malaria in the ancient "Baiyue" tribes.

genetics↗

bioRxiv2023

Spatial profiling of neuro-immune interactions in gastroenteropancreatic NETs

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous malignancies that arise from complex cellular interactions within the tissue microenvironment. Here, we sought to decipher tumor-derived signals from the surrounding microenvironment by applying Nanostring Digital Spatial Profiling (DSP) to hormone-secreting and non-functional GEP-NETs. DSP was used to evaluate the expression of 40 neural and immune-related proteins in surgically resected duodenal and pancreatic NETs (n=20) primarily comprised of gastrinomas (18/20). A total of 279 regions of interest were examined between tumors, adjacent normal and abnormal-appearing epithelium, and the surrounding stroma. The results were stratified by tissue type and Multiple Endocrine Neoplasia I (MEN1) status and protein expression was validated by immunohistochemical (IHC) staining. A tumor immune cell autonomous inflammatory signature was further evaluated by IHC and RNAscope, while functional pro-inflammatory signaling was confirmed using patient-derived duodenal organoids. Gastrin-secreting and non-functional pancreatic NETs showed a higher abundance of immune cell markers and immune infiltrate compared to duodenal gastrinomas. Tumors displayed strong intra-tissue variation in the expression of neural- and immune-related proteins. Compared to non-MEN1 tumors, MEN1 gastrinomas showed reduced expression of immune cell markers and upregulated expression of neuropathological proteins. Duodenal gastrinomas showed strong expression of the pro- inflammatory and pro-neural factor IL-17B. Treatment of human duodenal organoids with IL- 17B activated NF-kB and STAT3 signaling and induced the expression of neuroendocrine markers. In conclusion, multiplexed spatial protein analysis identified tissue-specific neuro- immune signatures in GEP-NETs. Moreover, duodenal gastrinomas cell autonomously express immune and pro-inflammatory factors, including tumor-derived IL-17B, that stimulate the neuroendocrine phenotype.

cancer biology↗