Biology subjects

Yao, X.

Publications and source records attributed to Yao, X..

At least 109 records · Page 6Linked to original sources

bioRxiv2021

Diterpenoid Vinigrol activates ATF4/DDIT3-mediated PERK/eIF2 arm of unfolded protein response to drive breast cancer cell death

Vinigrol is a natural diterpenoid with unprecedented chemical structure, driving great efforts into its total synthesis and the chemical analogs in the past decades. Despite its pharmacological efficacies reported on anti-hypertension and anti-clot, comprehensive functional investigations on Vinigrol and the underlying molecular mechanisms are entirely missing. In this study, we carried out a complete functional prediction of Vinigrol using a transcriptome-based strategy, Connectivity Map, and identified "anti-cancer" as the most prominent biofunction ahead of anti-hypertension and anti-depression/psychosis. A broad cytotoxicity was subsequently confirmed on multiple cancer types. Further mechanistic investigation on MCF7 cells revealed that its anti-cancer effect is mainly through activating PERK/eIF2 arm of unfolded protein response (UPR) and subsequent upregulation of p53/p21 to halt the cell cycle. The other two branches of UPR, IRE1 and ATF6, are functionally irrelevant to Vinigrol-induced cell death. CRISPR/Cas9-based gene activation, repression, and knockout systems identified essential contribution of ATF4/DDIT3 not ATF6 to the death process. This study unraveled a broad anti-cancer function of Vinigrol and its underlying targets and regulatory mechanisms, and also paved the way for further inspection on the structure-efficacy relationship of the whole compound family, making them a novel cluster of chemical hits for cancer therapy.

pharmacology and toxicology↗

bioRxiv2021

Genetic Influence underlying Brain Connectivity Phenotype: A Study on Two Age-Specific Cohorts

BackgroundHuman brain structural connectivity is an important imaging quantitative trait for brain development and aging. Mapping the network connectivity to the phenotypic variation provides fundamental insights in understanding the relationship between detailed brain topological architecture, function, and dysfunction. However, the underlying neurobiological mechanism from gene to brain connectome, and to phenotypic outcomes, and whether this mechanism changes over time, remain unclear. MethodsThis study analyzes diffusion weighted imaging data from two age-specific neuroimaging cohorts, extracts structural connectome topological network measures, performs genome-wide association studies (GWAS) of the measures, and examines the causality of genetic influences on phenotypic outcomes mediated via connectivity measures. ResultsOur empirical study has yielded several significant findings: 1) It identified genetic makeup underlying structural connectivity changes in the human brain connectome for both age groups. Specifically, it revealed a novel association between the minor allele (G) of rs7937515 and the decreased network segregation measures of the left middle temporal gyrus across young and elderly adults, indicating a consistent genetic effect on brain connectivity across the lifespan. 2) It revealed rs7937515 as a genetic marker for body mass index (BMI) in young adults but not in elderly adults. 3) It discovered brain network segregation alterations as a potential neuroimaging biomarker for obesity. 4) It demonstrated the hemispheric asymmetry of structural network organization in genetic association analyses and outcome-relevant studies. DiscussionThese imaging genetic findings underlying brain connectome warrant further investigation for exploring their potential influences on brain-related diseases, given the significant involvement of altered connectivity in neurological, psychiatric and physical disorders. Impact StatementThe genetic architecture underlying brain connectivity, and whether this mechanism changes over time, remain largely unknown. To understand the inter-individual variability at different life stages, this study performed genome-wide association studies of brain network connectivity measures from two age-specific neuroimaging cohorts, and identified a common association between the minor allele (G) of rs7937515 and decreased network segregation measures of the left middle temporal gyrus. The mediation analysis further elucidated neurobiological pathway of brain connectivity mediators linking the genes FAM86C1/FOLR3 with body mass index. This study provided new insights into the genetic mechanism of inter-regional connectivity alteration in the brain.

genetics↗

bioRxiv2021

Gastric cancer derived exosomes induce peritoneal mesothelial cell EMT through TGF-β1/Smads pathway to promote peritoneal metastasis

Epithelial-mesenchymal transition (EMT) plays an important role in peritoneal metastasis of Gastric cancer (GC). Tumor exosomes can mediate tumor directed metastasis, and TGF-{beta}1 is an important factor in inducing tumor Epithelial mesenchymal transition. However, it is not clear whether GC derived exosomes can induce peritoneal mesothelial cells through the TGF-{beta}1/ Smads pathway and the effect of injured peritoneal mesothelial cells on the biological characteristics of GC cells. In this study, we demonstrated that GC-derived exosomes can activate the TGF-{beta}1/Smads pathway in peritoneal mesothelial cells and induce the corresponding EMT process, and that the injured peritoneal mesothelial cells can improve the migration and adhesion of GC cells. Taken together, these data further support the critical role of exosomes in the remodeling of the pre-metastatic microenvironment.

cancer biology↗

bioRxiv2021

Willingness to Pay in the Human Brain: A fMRI Activation Likelihood Estimation Meta-analysis

The neural substrate of willingness to pay (WTP) ultimately supports human economic exchange activities and plays a crucial role in daily life. This paper aimed to identify the neural basis of WTP for food and nonfood, as well as the brain regions related to real and hypothetical WTP choices. We found the human brain centers of WTP by performing an activation likelihood estimation (ALE) meta-analysis (27 experiments, 796 subjects) on the existing neuroimaging studies. The conjunction analysis revealed that WTP for food and nonfood engaged a common cluster in the paracingulate and cingulate gyrus, revealing a common reward circuit in the brain. The frontal medial cortex and paracingulate gyrus were particularly activated by WTP for nonfood. Furthermore, the left caudate, left thalamus, angular gyrus and supramarginal gyrus (subregions of inferior parietal lobule) were more convergently activated by hypothetical WTP choice. Our findings support the idea that a common currency representation in the brain and reward-specific neural basis. Results also provide evidence of neural representations of the hypothetical bias.

neuroscience↗

bioRxiv2021

Loose ends in cancer genome structure

Recent pan-cancer studies have delineated patterns of structural genomic variation across thousands of tumor whole genome sequences. It is not known to what extent the shortcomings of short read ([≤] 150 bp) whole genome sequencing (WGS) used for structural variant analysis has limited our understanding of cancer genome structure. To formally address this, we introduce the concept of "loose ends" - copy number alterations that cannot be mapped to a rearrangement by WGS but can be indirectly detected through the analysis of junction-balanced genome graphs. Analyzing 2,319 pan-cancer WGS cases across 31 tumor types, we found loose ends were enriched in reference repeats and fusions of the mappable genome to repetitive or foreign sequences. Among these we found genomic footprints of neotelomeres, which were surprisingly enriched in cancers with low telomerase expression and alternate lengthening of telomeres phenotype. Our results also provide a rigorous upper bound on the role of non-allelic homologous recombination (NAHR) in large-scale cancer structural variation, while nominating INO80, FANCA, and ARID1A as positive modulators of somatic NAHR. Taken together, we estimate that short read WGS maps >97% of all large-scale (>10 kbp) cancer structural variation; the rest represent loose ends that require long molecule profiling to unambiguously resolve. Our results have broad relevance for future research and clinical applications of short read WGS and delineate precise directions where long molecule studies might provide transformative insight into cancer genome structure.

genomics↗

bioRxiv2021

Disrupted microglial iron homeostasis in progressive multiple sclerosis

Multiple Sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system (CNS). Despite therapies that reduce relapses, many patients eventually develop secondary progressive MS (SPMS), characterized by ongoing and irreversible neurodegeneration and worsening clinical symptoms. Microglia are the resident innate immune cells of the CNS. While the cellular and molecular determinants of disability progression in MS remain incompletely understood, they are thought to include non-resolving microglial activation and chronic oxidative injury. In this study, our aim was to better characterize microglia in SPMS tissues to identify disease-related changes at the single cell level. We performed single nucleus RNA-seq (snRNA-seq) on cryopreserved post-mortem brain cortex and identified disease associated changes in multiple cell types and in particular distinct SPMS-enriched microglia subsets. When compared to the cluster most enriched in healthy controls (i.e. homeostatic microglia), we found a number of SPMS-enriched clusters with transcriptional profiles reflecting increased oxidative stress and perturbed iron homeostasis. Using histology and RNA-scope, we confirmed the presence of iron accumulating, ferritin-light chain (FTL)-expressing microglia in situ. Among disease-enriched clusters, we found evidence for divergent responses to iron accumulation and identified the antioxidant enzyme GPX4 as a key fate determinant. These data help elucidate processes that occur in progressive MS brains, and highlight novel nodes for therapeutic intervention.

neuroscience↗

bioRxiv2021

Integrative Omics Reveals Subtle Molecular Perturbations Following Ischemic Conditioning in a Porcine Kidney Transplant Model

BackgroundRemote Ischemic Conditioning (RIC) has been proposed as a therapeutic intervention to circumvent the ischemia/reperfusion injury (IRI) that is inherent to organ transplantation. Using a porcine kidney transplant model, we aimed to decipher the subclinical molecular effects of a RIC regime, compared to non-RIC controls. MethodsKidney pairs (n = 8+8) were extracted from brain dead donor pigs and transplanted in juvenile recipient pigs following a period of cold ischemia. One of the two kidney recipients in each pair was subjected to RIC prior to kidney graft reperfusion, while the other served as non-RIC control. We designed a modern integrative Omics strategy combining transcriptomics, proteomics, and phosphoproteomics to deduce molecular signatures in kidney tissue that could be attributed to RIC. ResultsIn kidney grafts taken out 10 h after transplantation we detected minimal molecular perturbations following RIC compared to non-RIC at the transcriptome level, which was mirrored at the proteome level. In particular, we noted that RIC resulted in suppression of tissue inflammatory profiles. Furthermore, an accumulation of muscle extracellular matrix assembly proteins in kidney tissues was detected at the protein level, which may be in response to muscle tissue damage and/or fibrosis. However, the majority of these protein changes did not reach significance (p<0.05). ConclusionsOur data identifies subtle molecular phenotypes in porcine kidneys following RIC and this knowledge could potentially aid optimization of remote ischemic conditioning protocols in renal transplantation.

physiology↗

bioRxiv2021

The impact of viral mutations on recognition by SARS-CoV-2 specific T-cells

We identify amino acid variants within dominant SARS-CoV-2 T-cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T-cells assessed by IFN-{gamma} and cytotoxic killing assays. These data demonstrate the potential for T-cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T-cell as well as humoral immunity.

immunology↗

bioRxiv2021

The shifting of dominating roles between structural cells and immune cells are key regulators of human adipose tissues aging

Adipose tissue is a highly dynamic organ with complex cellular composition. Aging induces adipose tissue function decline and relocation of peripheral adipose tissue to abdominal compartment, which often associated with inflammation and metabolic disorders. Here we performed single-cell RNA sequencing to comprehensively and unbiasedly deconvolve how subcutaneous adipose tissue (SAT) responses to aging. We collected >25,000 stromal vascular cells from abdominal and gluteofemoral SAT of young and old donors. Analyses of transcription signatures and cell networks uncovered impaired adipogenesis and extracellular matrix synthesis capacity of APC, altered metabolic phenotype of immune cells and shifted tissue-dominating cells that can be used to predict adipose tissue aging. We also reported aging-associated distinct transcriptional program between gluteofemoral SAT and abdominal SAT. Our work thus reveals unanticipated cellular, immunological, metabolic and site-specific aspects of human adipose tissues aging process, providing valuable resource for better understanding of aging-associated adipose tissue dysfunction.

pathology↗

bioRxiv2020

Transferrin receptor (Tfr1) ablation in satellite cells impacts skeletal muscle regeneration through the activation of ferroptosis

Satellite cells (SCs) are critical to the postnatal development and skeletal muscle regeneration. Inactivation of SCs is linked with the skeletal muscle loss. Leveraging on the RNAseq screening, transferrin receptor (Tfr1) is identified to be associated with muscle/SC ageing and the declined regeneration potential. Muscle-specific deletion of Tfr1 results in the growth retardation, metabolic disorder and lethality, shedding light on the importance of Tfr1 in skeletal muscle physiology. Here, our investigation reported that conditional SC-ablation of Tfr1 leads to the SCs inactivation and skeletal muscle regeneration defects, followed by the labile iron accumulation, de novo lipogenesis via fibroadipogenic progenitors (FAPs) and Gpx4/Nrf2-mediated ROS-scavenger defects. These abnormal phenomena, such as Hmox1-mediated myoglobin degradation, Tfr1-Slc39a14 functional switch and the activation of unsaturated fatty acid biosynthesis pathway are orchestrated with the occurrence of ferroptosis in skeletal muscle. Ferroptosis may further prevent SC proliferation and skeletal muscle regeneration. Ferrostatin-1, a ferroptosis inhibitor could not rescue Tfr1-ablation induced ferroptosis. However, intramuscular administration of lentivirus expressing Tfr1 could partially reduce labile iron accumulation, decrease de novo lipogenesis and promote skeletal muscle regeneration. Most importantly, Tfr1/Slc39a14 functional switch, labile iron accumulation and fatty acid biosynthesis are recapitulated in aged skeletal muscle of rodents, indicating that ferroptosis occurs in the skeletal muscles of aged rodents. The present study also bridges the gap between pathogenesis of iron and functional defects in the skeletal muscle, providing mechanistic information to develop anti-aging strategies. One Sentence SummaryConditional ablation of Tfr1 in satellite cells (SCs) results in the SC inactivation, skeletal muscle regeneration defects, labile iron accumulation, and unsaturated fatty acid biosynthesis, leading to the activation of ferroptosis, which is recapitulated in skeletal muscles of aged rodents to be a new cell death form identified in skeletal muscle and sheds light on the development of novel anti-ageing strategies.

cell biology↗

bioRxiv2020

Myeloid cell-associated resistance to PD-1/PD-L1 blockade in urothelial cancer revealed through bulk and single-cell RNA sequencing

Adaptive immunity and tumor-promoting inflammation exist in delicate balance in individual tumor microenvironments; however, the role of this balance in defining sensitivity and resistance to PD-1/PD-L1 blockade therapy in urothelial cancer and other malignancies is poorly understood. We pursued an unbiased systems biology approach using bulk RNA sequencing data to examine pre-treatment molecular features associated with sensitivity to PD-1/PD-L1 blockade in patients with metastatic urothelial cancer and identified an adaptive_immune_response module associated with response and an inflammatory_response module and stromal module associated with resistance. We mapped these gene modules onto single-cell RNA sequencing data demonstrating the adaptive_immune_response module emanated predominantly from T, NK, and B cells, the inflammatory_response module from monocytes/macrophages, and the stromal module from fibroblasts. The adaptive_immune_response:inflammatory_response module expression ratio in individual tumors, reflecting the balance between antitumor immunity and tumor-associated inflammation and coined the 2IR score, best correlated with clinical outcomes and was validated in an independent cohort. Individual monocytes/macrophages with low 2IR scores demonstrated upregulation of proinflammatory genes including IL1B and downregulation of antigen presentation genes, were unrelated to classical M1 versus M2 polarization, and were enriched in pre-treatment peripheral blood from patients with PD-L1 blockade-resistant metastatic urothelial cancer. Single sentence summaryProinflammatory monocytes/macrophages, present in tumor and blood, are associated with resistance to immune checkpoint blockade in urothelial cancer.

genomics↗

bioRxiv2020

Prunella vulgaris extract and suramin block SARS-coronavirus 2 virus Spike protein D614 and G614 variants mediated receptor association and virus entry in cell culture system

Until now, no approved effective vaccine and antiviral therapeutic are available for treatment or prevention of SARS-coronavirus 2 (SCoV-2) virus infection. In this study, we established a SCoV-2 Spike glycoprotein (SP), including a SP mutant D614G, pseudotyped HIV-1-based vector system and tested their ability to infect ACE2-expressing cells. This study revealed that a C-terminal 17 amino acid deletion in SCoV-2 SP significantly increases the incorporation of SP into the pseudotyped viruses and enhanced its infectivity, which may be helpful in the design of SCoV2-SP-based vaccine strategies. Moreover, based on this system, we have demonstrated that an aqueous extract from the Chinese herb Prunella vulgaris (CHPV) and a compound, suramin, displayed potent inhibitory effects on both wild type and mutant (G614) SCoV-2 SP pseudotyped virus (SCoV-2-SP-PVs)-mediated infection. The 50% inhibitory concentration (IC50) for CHPV and suramin on SCoV-2-SP-PVs are 30, and 40 g/ml, respectively. To define the mechanisms of their actions, we demonstrated that both CHPV and suramin are able to directly interrupt SCoV-2-SP binding to its receptor ACE2 and block the viral entry step. Importantly, our results also showed that CHPV or suramin can efficiently reduce levels of cytopathic effect caused by SARS-CoV-2 virus (hCoV-19/Canada/ON-VIDO-01/2020) infection in Vero cells. Furthermore, our results demonstrated that the combination of CHPV/suramin with an anti-SARS-CoV-2 neutralizing antibody mediated more potent blocking effect against SCoV2-SP-PVs. Overall, this study provides evidence that CHPV and suramin has anti-SARS-CoV-2 activity and may be developed as a novel antiviral approach against SARS-CoV-2 infection.

microbiology↗

bioRxiv2020

Fine-scale Population Structure and Demographic History of Han Chinese Inferred from Haplotype Network of 111,000 Genomes

ABSTRACTHan Chinese is the most populated ethnic group across the globe with a comprehensive substructure that resembles its cultural diversification. Studies have constructed the genetic polymorphism spectrum of Han Chinese, whereas high-resolution investigations are still missing to unveil its fine-scale substructure and trace the genetic imprints for its demographic history. Here we construct a haplotype network consisted of 111,000 genome-wide genotyped Han Chinese individuals from direct-to-consumer genetic testing and over 1.3 billion identity-by-descent (IBD) links. We observed a clear separation of the northern and southern Han Chinese and captured 5 subclusters and 17 sub-subclusters in haplotype network hierarchical clustering, corresponding to geography (especially mountain ranges), immigration waves, and clans with cultural-linguistic segregation. We inferred differentiated split histories and founder effects for population clans Cantonese, Hakka, and Minnan-Chaoshanese in southern China, and also unveiled more recent demographic events within the past few centuries, such as Zou Xikou and Chuang Guandong. The composition shifts of the native and current residents of four major metropolitans (Beijing, Shanghai, Guangzhou, and Shenzhen) imply a rapidly vanished genetic barrier between subpopulations. Our study yields a fine-scale population structure of Han Chinese and provides profound insights into the nation’s genetic and cultural-linguistic multiformity.Competing Interest StatementThe authors AL, KK, ST, XW, LW, TL, HW, JD, QZ, XY, and GC work for WeGene (Shenzhen Zaozhidao Technology Co. Ltd. or Shenzhen WeGene Clinical Laboratory).View Full Text

genomics↗

bioRxiv2020

Luteolin transforms the BMDM polarity to regulate the expression of inflammatory factors

ABSTRACTMacrophage are indispensable regulator cells in inflammatory response. Macrophage polarization and its secreted inflammatory factors have affinity with the outcomes of inflammation. Luteolin, a flavonoid abundant in plants has anti-inflammatory activity, but whether luteolin can manipulate M1/M2 polarization of BMDM to suppress inflammation is still veiled. The purpose of this study was to observe the effects of luterolin on the polarity of BMDM derived from C57BL/6 mice and the expression of inflammatory factors, to explore the mechanism of luteolin regulating the BMDM polarity. M1-polarized BMDM were induced by LPS+IFN-γ, M2-polarization were stimulated with IL-4. BMDM morphology was observed by laser confocal microscopy; levels of BMDM differentiation and CD11c or CD206 on membrane surface were assessed by FCM; mRNA and protein of M1/M2-type inflammatory factors were performed by qPCR and ELISA, respectively; the expression of p-STAT1 and p-STAT6 protein pathways was detected by Western-blotting. The isolated mouse bone marrow cells were successfully differentiated into BMDM, LPS+IFN-γ induced BMDM M1-phenotype polarization, and IL-4 induced its M2-phenotype polarization. After M1-polarized BMDM treated with luteolin, M1-type pro-inflammatory factors including IL-6, TNF-α□iNOS, CD86 were down-regulated while M2-type anti-inflammatory factors including IL-10, Arg1, CD206 were up-regulated; the expression of M1-type surface marker CD11c decreased, nevertheless, M2-type marker CD206 increased; levels of inflammatory signaling protein p-STAT1 and p-STAT6 were attenuated and enhanced respectively. Our study suggests luteolin may transform BMDM polarity through p-STAT1/6 to regulate the expression of inflammatory mediators, thereby inhibiting inflammation. Naturally occurring luteolin hold promise as an anti-inflammatory and immunomodulatory agent.View Full Text

immunology↗

bioRxiv2020

Herbivore-induced activation of viral phosphatase disarms plant antiviral immunities for pathogen transmission

The survival of pathogens depends on their ability to overcome host immunity, especially arthropod-borne viruses (arboviruses) which must withstand the immune responses of both the host and the arthropod vector. Successful arboviruses often modify host immunity to accelerate pathogen transmission; however, few studies have explored the underlying mechanism. Here we report attracted herbivore infestation on the virus-infected plants promote transmission by the associated vector herbivore. This herbivore-induced defense suppression underpins a subversive mechanism used by Begomovirus, the largest genus of plant viruses, to compromise host defense for pathogen transmission. Begomovirus-infected plants accumulated {beta}C1 proteins in the phloem where they were bound to host defense regulators, transcription factor WRKY20 and two mitogen-activated protein kinases MPK3 and MPK6. Once perceiving whitefly herbivory or endogenous secreted peptide PEP1, the plants started dephosphorylation on serine33 and stimulated {beta}C1 protein as a phosphatase. {beta}C1 dephosphorylated MPK3/6 and WRKY20, the latter negatively regulated salicylic acid signaling and vascular callose deposition. This viral hijacking of WRKY20 accumulated more vascular callose by which enforced whitefly prolonged salivation and phloem sap ingestion, therefore impelling more virus transmission among plants. We present a scenario in which viruses dynamically respond to the presence of their vectors, suppressing host immunity and promoting pathogen transmission only when needed.

microbiology↗

bioRxiv2020

Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent COVID-19 patients.

COVID-19 is an ongoing global crisis in which the development of effective vaccines and therapeutics will depend critically on understanding the natural immunity to the virus, including the role of SARS-CoV-2-specific T cells. We have conducted a study of 42 patients following recovery from COVID-19, including 28 mild and 14 severe cases, comparing their T cell responses to those of 16 control donors. We assessed the immune memory of T cell responses using IFN{gamma} based assays with overlapping peptides spanning SARS-CoV-2 apart from ORF1. We found the breadth, magnitude and frequency of memory T cell responses from COVID-19 were significantly higher in severe compared to mild COVID-19 cases, and this effect was most marked in response to spike, membrane, and ORF3a proteins. Total and spike-specific T cell responses correlated with the anti-Spike, anti-Receptor Binding Domain (RBD) as well as anti-Nucleoprotein (NP) endpoint antibody titre (p<0.001, <0.001 and =0.002). We identified 39 separate peptides containing CD4+ and/or CD8+ epitopes, which strikingly included six immunodominant epitope clusters targeted by T cells in many donors, including 3 clusters in spike (recognised by 29%, 24%, 18% donors), two in the membrane protein (M, 32%, 47%) and one in the nucleoprotein (Np, 35%). CD8+ responses were further defined for their HLA restriction, including B*4001-restricted T cells showing central memory and effector memory phenotype. In mild cases, higher frequencies of multi-cytokine producing M- and NP-specific CD8+ T cells than spike-specific CD8+ T cells were observed. They furthermore showed a higher ratio of SARS-CoV-2-specific CD8+ to CD4+ T cell responses. Immunodominant epitope clusters and peptides containing T cell epitopes identified in this study will provide critical tools to study the role of virus-specific T cells in control and resolution of SARS-CoV-2 infections. The identification of T cell specificity and functionality associated with milder disease, highlights the potential importance of including non-spike proteins within future COVID-19 vaccine design.

immunology↗

bioRxiv2020

Gamma secretase inhibitors inhibit ovarian cancer development and enhance olaparib's anti-ovarian cancer activity and its mechanism

BackgroundOvarian cancer is the fifth leading cause of cancer-related deaths in women. Although cytoreductive surgery combined with chemotherapy and / or targeted therapy has achieved a certain effect, but advanced patients have limited clinical benefits and are prone to relapse. Among them, Notch / jagged1 and Wnt / {beta}-catenin signal transduction plays an important role in the development of ovarian cancer and chemotherapy resistance, and it is very important to find new effective therapeutic drugs to inhibit tumor development and increase tumor chemotherapy sensitivity. MethodsTo establish ovarian cancer xenotransplantation model, to detect the effects of {gamma}-secretase inhibitor, olaparib and combination drugs on the development of ovarian cancer, and to detect the proliferation and apoptosis of ovarian cancer cells with {gamma}-secretase inhibitor, olaparib and combination drugs .After knocking down Jagged1 or {beta}-catenin, the protein expression levels of related signaling pathways under different drug treatments were analyzed by immunoblotting, and related gene expression changes were analyzed. ResultsDAPT reduced {beta}-catenin expression in a proteasome-synthetic pathway-dependent manner, thereby inhibiting the synthesis and transcription of Jagged1 protein, thereby inhibiting the expression of Notch signal transduction pathway-related proteins and gene transcription, inhibiting the activity of ovarian cancer cells and inducing cell apoptosis death, enhance the anti-ovarian cancer activity of olaparib. ConclusionDAPT inhibits cell proliferation, induces cell apoptosis, inhibits tumor development in vivo through {beta}-catenin / Jagged1 inhibition, and exerts anti-ovarian cancer activity sensitizing effect of olaparib.

cancer biology↗

bioRxiv2020

Three distinct neural mechanisms support movement-induced analgesia

Pain is essential for our survival by protecting us from severe injuries. Pain signals may be exacerbated by continued physical activities but can also be interrupted or over-ridden by physical movements, a process called movement-induced analgesia. A number of neural mechanisms have been proposed to account for this effect, including the reafference principle, the gate control theory of pain, and the top-down psychological modulation. Given that the analgesic effects of these mechanisms are temporally overlapping, it is unclear whether movement-induced analgesia results from a single neural mechanism or the joint action of multiple neural mechanisms. To address this question, we conducted five experiments on 130 healthy human subjects. First, the frequency of hand shaking was manipulated in order to quantify the relationship between the strength of the voluntary movement and the analgesic effect. Second, the temporal delay (between hand shaking and nociceptive laser stimuli) and the stimulated side (nociceptive laser stimuli were delivered on the hand ipsilateral or contralateral to the shaken one) were manipulated to quantify the temporal and spatial characteristics of the analgesic effect induced by voluntary movement. Combining psychophysics and electroencephalographic recordings, we demonstrated that movement-induced analgesia is a result of the joint action of multiple neural mechanisms. This investigation is the first to disentangle the distinct contributions of different neural mechanisms to the analgesic effect of voluntary movement. These findings extend our understanding of sensory attenuation arising from voluntary movement and may prove instrumental in the development of new strategies in pain management.

neuroscience↗