Investigating the effectiveness of forensic genetics and population genetic diversity using a multi-InDel system in Chinese Hezhou and Southern Shaanxi Han populations.

INTRODUCTION: Multiple insertion-deletion (multi-InDel) has greater potential in forensic genetics than InDel, and its efficacy in kinship testing, individual identification, DNA mixture detection and ancestry inference remains to be explored. METHODS: Consequently, we designed an efficient and robust system consisting of 41 multi-InDels to evaluate its efficacy in forensic applications in Chinese Hezhou Han (HZH) and Southern Shaanxi Han (SNH) populations and explore the genetic relationships between the SNH, HZH, and 26 reference populations. RESULTS AND CONCLUSION: The obtained results showed that 38 out of the 41 multi-InDels had fairly high genetic variations. The the cumulative probability of discrimination and exclusion values of the multi-InDels (except MI38) in HZH and SNH populations both exceeded 1-e-25 and 1-e-6, correspondingly. The genetic compositions of HZH and SNH individuals were similar to that of East Asians and the Naive Bayes model could well distinguish East Asians, Africans and Americans. These results indicated that the multi-InDel systerm can serve as an effective tool to provide important evidence for the development of multi-InDels in forensic practice and better analyse the genetic background of the Han Chinese populations.

Fasting mimicking diet extends lifespan and improves intestinal and cognitive health.

Caloric restriction is an effective means of extending a healthy lifespan. Fasting mimicking diet (FMD) is a growing pattern of caloric restriction. We found that FMD significantly prolonged the lifespan of prematurely aging mice. In naturally aging mice, FMD improved cognitive and intestinal health. Through a series of behavioral experiments, we found that FMD relieved anxiety and enhanced cognition in aged mice. In the intestine, the FMD cycles enhanced the barrier function, reduced senescence markers, and maintained T cell naïve-memory balance in the lamina propria mucosa. To further explore the causes of immune alterations, we examined changes in the stool microbiota using 16S rRNA sequencing. We found that FMD remodeled gut bacterial composition and significantly expanded the abundance of Lactobacillus johnsonii. Our research revealed that FMD has in-depth investigative value as an anti-aging intervention for extending longevity and improving cognition, intestinal function, and gut microbiota composition.

Microbial metabolite enhances immunotherapy efficacy by modulating T cell stemness in pan-cancer.

The immune checkpoint blockade (ICB) response in human cancers is closely linked to the gut microbiota. Here, we report that the abundance of commensal Lactobacillus johnsonii is positively correlated with the responsiveness of ICB. Supplementation with Lactobacillus johnsonii or tryptophan-derived metabolite indole-3-propionic acid (IPA) enhances the efficacy of CD8+ T cell-mediated αPD-1 immunotherapy. Mechanistically, Lactobacillus johnsonii collaborates with Clostridium sporogenes to produce IPA. IPA modulates the stemness program of CD8+ T cells and facilitates the generation of progenitor exhausted CD8+ T cells (Tpex) by increasing H3K27 acetylation at the super-enhancer region of Tcf7. IPA improves ICB responsiveness at the pan-cancer level, including melanoma, breast cancer, and colorectal cancer. Collectively, our findings identify a microbial metabolite-immune regulatory pathway and suggest a potential microbial-based adjuvant approach to improve the responsiveness of immunotherapy.

The myelination-associated G protein-coupled receptor 37 is regulated by Zfp488, Nkx2.2, and Sox10 during oligodendrocyte differentiation.

Oligodendrocyte differentiation and myelination in the central nervous system are controlled and coordinated by a complex gene regulatory network that contains several transcription factors, including Zfp488 and Nkx2.2. Despite the proven role in oligodendrocyte differentiation little is known about the exact mode of Zfp488 and Nkx2.2 action, including their target genes. Here, we used overexpression of Zfp488 and Nkx2.2 in differentiating CG4 cells to identify aspects of the oligodendroglial expression profile that depend on these transcription factors. Although both transcription factors are primarily described as repressors, the detected changes argue for an additional function as activators. Among the genes activated by both Zfp488 and Nkx2.2 was the G protein-coupled receptor Gpr37 that is important during myelination. In agreement with a positive effect on Gpr37 expression, downregulation of the G protein-coupled receptor was observed in Zfp488- and in Nkx2.2-deficient oligodendrocytes in the mouse. We also identified several potential regulatory regions of the Gpr37 gene. Although Zfp488 and Nkx2.2 both bind to one of the regulatory regions downstream of the Gpr37 gene in vivo, none of the regulatory regions was activated by either transcription factor alone. Increased activation by Zfp488 or Nkx2.2 was only observed in the presence of Sox10, a transcription factor continuously present in oligodendroglial cells. Our results argue that both Zfp488 and Nkx2.2 also act as transcriptional activators during oligodendrocyte differentiation and cooperate with Sox10 to allow the expression of Gpr37 as a modulator of the myelination process.

Single-cell multi-omics analysis of lineage development and spatial organization in the human fetal cerebellum.

Human cerebellum encompasses numerous neurons, exhibiting a distinct developmental paradigm from cerebrum. Here we conducted scRNA-seq, scATAC-seq and spatial transcriptomic analyses of fetal samples from gestational week (GW) 13 to 18 to explore the emergence of cellular diversity and developmental programs in the developing human cerebellum. We identified transitory granule cell progenitors that are conserved across species. Special patterns in both granule cells and Purkinje cells were dissected multidimensionally. Species-specific gene expression patterns of cerebellar lobes were characterized and we found that PARM1 exhibited inconsistent distribution in human and mouse granule cells. A novel cluster of potential neuroepithelium at the rhombic lip was identified. We also resolved various subtypes of Purkinje cells and unipolar brush cells and revealed gene regulatory networks controlling their diversification. Therefore, our study offers a valuable multi-omics landscape of human fetal cerebellum and advances our understanding of development and spatial organization of human cerebellum.

Using two self-developed InDel panels to explore forensic traits and ancestral components in the Hui group.

To address the challenges faced by forensic examiners in degraded DNA analysis, we have developed two different panels for various forensic applications, encompassing an AIM-InDel panel for ancestry inference and a Multi-InDel panel for individual identification, respectively. Herein, the efficiencies of these two panels were tested in the Chinese Hui group. By calculating forensic parameters and simulating family relationships, we verified that the Multi-InDel panel could be an effective tool for individual identification, paternity testing, and could assist in kinship identification in the Hui group. For full siblings, the true positive rate of kinship discrimination was 96.553%, when the threshold of log10LR was 1. The cumulative probability of matching as well as cumulative probability of exclusion were 3.8117 × 10-26 and 0.999999722, respectively. Meanwhile, we found that the AIM-InDel panel was effective for bio-geographic ancestry inference, with the vast majority of loci contributing significantly to distinguish East Asian, African, and European populations. By studying the population structure of the Hui ethnic minority, the genetic distance to the Beijing Han population was the closest among the 26 reference populations, which was similar to previous reports. In summary, we have developed two panels which can be effectively applied to the Hui group for individual identification, parentage testing and bio-geographic ancestry inference.

Targeted sequencing of high-density SNPs provides an enhanced tool for forensic applications and genetic landscape exploration in Chinese Korean ethnic group.

BACKGROUND: In this study, we present a NGS-based panel designed for sequencing 1993 SNP loci for forensic DNA investigation. This panel addresses unique challenges encountered in forensic practice and allows for a comprehensive population genetic study of the Chinese Korean ethnic group. To achieve this, we combine our results with datasets from the 1000 Genomes Project and the Human Genome Diversity Panel. RESULTS: We demonstrate that this panel is a reliable tool for individual identification and parentage testing, even when dealing with degraded DNA samples featuring exceedingly low SNP detection rates. The performance of this panel for complex kinship determinations, such as half-sibling and grandparent-grandchild scenarios, is also validated by various kinship simulations. Population genetic studies indicate that this panel can uncover population substructures on both global and regional scales. Notably, the Han population can be distinguished from the ethnic minorities in the northern and southern regions of East Asia, suggesting its potential for regional ancestry inference. Furthermore, we highlight that the Chinese Korean ethnic group, along with various Han populations from different regional areas and certain northern ethnic minorities (Daur, Tujia, Japanese, Mongolian, Xibo), exhibit a higher degree of genetic affinities when examined from a genomic perspective. CONCLUSION: This study provides convincing evidence that the NGS-based panel can serve as a reliable tool for various forensic applications. Moreover, it has helped to enhance our knowledge about the genetic landscape of the Chinese Korean ethnic group.

Hollow-Architected Heteroatom-Doped Carbon-Supported Nanoscale Cu/Co as an Enhanced Magnetic Activator for Oxone to Degrade Toxicants in Water.

Even though transition metals can activate Oxone to degrade toxic contaminants, bimetallic materials possess higher catalytic activities because of synergistic effects, making them more attractive for Oxone activation. Herein, nanoscale CuCo-bearing N-doped carbon (CuCoNC) can be designed to afford a hollow structure as well as CuCo species by adopting cobaltic metal organic frameworks as a template. In contrast to Co-bearing N-doped carbon (CoNC), which lacks the Cu dopant, CuCo alloy nanoparticles (NPs) are contained by the Cu dopant within the carbonaceous matrix, giving CuCoNC more prominent electrochemical properties and larger porous structures and highly nitrogen moieties. CuCoNC, as a result, has a significantly higher capability compared to CoNC and Co3O4 NPs, for Oxone activation to degrade a toxic contaminant, Rhodamine B (RDMB). Furthermore, CuCoNC+Oxone has a smaller activation energy for RDMB elimination and maintains its superior effectiveness for removing RDMB in various water conditions. The computational chemistry insights have revealed the RDMB degradation mechanism. This study reveals that CuCoNC is a useful activator for Oxone to eliminate RDMB.

Heat-inactivated Bifidobacterium adolescentis ameliorates colon senescence through Paneth-like-cell-mediated stem cell activation.

Declined numbers and weakened functions of intestinal stem cells (ISCs) impair the integrity of the intestinal epithelium during aging. However, the impact of intestinal microbiota on ISCs in this process is unclear. Here, using premature aging mice (telomerase RNA component knockout, Terc-/-), natural aging mice, and in vitro colonoid models, we explore how heat-inactivated Bifidobacterium adolescentis (B. adolescentis) affects colon senescence. We find that B. adolescentis could mitigate colonic senescence-related changes by enhancing intestinal integrity and stimulating the regeneration of Lgr5+ ISCs via Wnt/ß-catenin signaling. Furthermore, we uncover the involvement of Paneth-like cells (PLCs) within the colonic stem-cell-supporting niche in the B. adolescentis-induced ISC regeneration. In addition, we identify soluble polysaccharides (SPS) as potential effective components of B. adolescentis. Overall, our findings reveal the role of heat-inactivated B. adolescentis in maintaining the ISCs regeneration and intestinal barrier, and propose a microbiota target for ameliorating colon senescence.

Progress in the mechanism of autophagy and traditional Chinese medicine herb involved in alcohol-related liver disease.

Alcohol-related liver disease (ALD) is chronic liver damage caused by long-term heavy drinking with, extremely complicated pathogenesis. The current studies speculated that excessive alcohol and its metabolites are the major causes of liver cell toxicity. Autophagy is evolutionarily conserved in eukaryotes and aggravates alcoholic liver damage, through various mechanisms, such as cellular oxidative stress, inflammation, mitochondrial damage and lipid metabolism disorders. Therefore, autophagy plays an critical role in the occurrence and development of ALD. Some studies have shown that traditional Chinese medicine extracts improve the histological characteristics of ALD, as reflected in the improvement of oxidative stress and lipid droplet clearance, which might be achieved by inducing autophagy. This article reviews the mechanisms of quercetin, baicalin, glycycoumarin, salvianolic acid A, resveratrol, ginsenoside rg1, and dihydromyricetin inducing autophagy and their participation in the inhibition of ALD. The regulation of autophagy in ALD by these traditional Chinese medicine extracts provides novel ideas for the treatment of the disease; however, its molecular mechanism needs to be elucidated further.

Bifidobacterium adolescentis orchestrates CD143+ cancer-associated fibroblasts to suppress colorectal tumorigenesis by Wnt signaling-regulated GAS1.

BACKGROUND: The interplay between gut microbiota and tumor microenvironment (TME) in the pathogenesis of colorectal cancer (CRC) is not well explored. Here, we elucidated the functional role of Bifidobacterium adolescentis (B.a) on CRC and investigated its possible mechanism on the manipulation of cancer-associated fibroblasts (CAFs) in CRC. METHODS: Different CRC animal models and various cell line models were established to explore the function of B.a on CRC. The single-cell RNA sequencing (scRNA-seq) or flow cytometry was used to detect the cell subsets in the TME of CRC. Western blot, quantitative real-time polymerase chain reaction (qRT-PCR), or immunofluorescence staining were performed to examine the activation of Wnt signaling and growth arrest specific 1 (GAS1) on CD143+ CAFs. Chromatin immunoprecipitation quantitative real-time PCR (CHIP-qPCR) was performed to investigate the regulation of transcription factor 4 (TCF4) on GAS1. Multi-immunofluorescence assay examined the expression level of CD143 and GAS1 on tissue microarray. RESULTS: We found that B.a abundance was significantly reduced in CRC patients from two independent cohorts and the bacteria database of GMrepo. Supplementation with B.a suppressed ApcMin/+ spontaneous or AOM/DSS-induced tumorigenesis in mice. scRNA-seq revealed that B.a facilitated a subset of CD143+ CAFs by inhibiting the infiltration of Th2 cells, while promoting the TNF-alpha+ B cells in TME. CD143+ CAFs highly expressed GAS1 and exhibited tumor suppressive effect. Mechanistically, GAS1 was activated by the Wnt/ß-catenin signaling in CD143+ CAFs. B.a abundance was correlated with the expression level of CD143 and GAS1. The level of CD143+ CAFs predicted the better survival outcome in CRC patients. CONCLUSIONS: These results highlighted that B.a induced a new subset of CD143+ CAFs by Wnt signaling-regulated GAS1 to suppress tumorigenesis and provided a novel therapeutic target for probiotic-based modulation of TME in CRC.

Bifidobacterium adolescentis induces Decorin+ macrophages via TLR2 to suppress colorectal carcinogenesis.

BACKGROUND: The interplay between gut microbiota and tumor microenvironment (TME) in the pathogenesis of colorectal cancer (CRC) is largely unknown. Here, we elucidated the functional role of B. adolescentis and its possible mechanism on the manipulation of Decorin+ macrophages in colorectal cancer. METHODS: The relative abundance of B. adolescentis in tumor or para-tumor tissue of CRC patients was analyzed. The role of B. adolescentis was explored in the CRC animal models. The single cell-RNA sequencing (scRNA-seq) was used to investigate the myeloid cells subsets in TME. The expression level of TLR2/YAP axis and its downstream Decorin in macrophages were tested by Western blot and qRT-PCR. Knockdown of Decorin in Raw264.7 was performed to investigate the effect of Decorin+ macrophages on subcutaneous tumor formation. Multi-immunofluorescence assay examined the number of Decorin+ macrophages on the CRC tissue. RESULTS: We found that the abundance of B. adolescentis was significantly reduced in tumor tissue of CRC patients. Supplementation with B. adolescentis suppressed AOM/DSS-induced tumorigenesis in mice. ScRNA-seq and animal experiment revealed that B. adolescentis increased Decorin+ macrophages. Mechanically, Decorin was activated by TLR2/YAP axis in macrophages. The abundance of B. adolescentis was correlated with the number of Decorin+ macrophages and the expression level of TLR2 in tumor tissue of CRC patients. CONCLUSIONS: These results highlight that B. adolescentis induced Decorin+ macrophages and provide a novel therapeutic target for probiotic-based modulation of immune microenvironment in CRC.

Hypoxia derived exosomes promote the proliferation and metastasis of colorectal cancer through the regulation of HIF-1α/miR-4299/ZBTB4.

AIMS: The biological functions of colorectal cancer (CRC) cell derived exosomes responding to hypoxic microenvironment and its underlying mechanisms remain unclear. MAIN METHODS: Extracted exosomes were confirmed. CRC cells were incubated with hypoxic and normoxic exosomes and its biological behavior were analyzed. miRNA microarray were conducted. Cells were incubated with miRNAs mimics, inhibitors, or small interfering RNAs; expression of reporter constructs was measured in luciferase assays. Cells were transfected with Lentivirus vectors containing eGFP-miR-4299 overexpression (or ZBTB4 siRNA expression plasmid) and they were injected into BALB/C nude mice subcutaneously or by tail vein and the growth of xenograft tumors or lung metastasis were measured. The clinical significance of ZBTB4 was measured in tumor tissues and adjacent non-tumor tissues. KEY FINDINGS: Hypoxic exosomes could tranfer to the recipient normoxic cells and promote the cell proliferation and migration. We found several miRNAs were significantly up-regulated in hypoxic exosomes and the expression levels of miR-4299 increased in both hypoxic cells and hypoxic exosomes. We observed that miR-4299 was upregulated in a HIF-1α dependent way. In addition, ectopic expression of miR-4299 promoted the tumor growth and metastasis in vitro and in vivo. ZBTB4, an identified direct target of miR-4299, could abrogate the effect on tumor growth and distant metastasis. The expression of ZBTB4 were decreased in tumor tissues compared with non-tumor colon tissues from patients. SIGNIFICANCE: We demonstrated that in response to hypoxia, CRC cells had an increased production of exosomes. The hypoxia derived exosomes promote the proliferation and metastasis of colorectal cancer by exporting miR-4299 and modulating its target gene ZBTB4.

Exosome-Based Regimen Rescues Endometrial Fibrosis in Intrauterine Adhesions Via Targeting Clinical Fibrosis Biomarkers.

Intrauterine adhesions (IUA), which is characterized by endometrial fibrosis, continue to be the most common cause of uterine infertility globally. Our work revealed that 3 fibrotic progression markers (Vimentin, COL5A2, and COL1A1) were significantly increased in the endometrium of IUA patients. Mesenchymal stem cell-derived exosomes (EXOs) have been recently revealed as a cell-free therapy for fibrosis diseases. Nevertheless, the application of EXOs is restricted by the short residency duration in the target tissue. To overcome this limitation, herein, we reported an exosome-based regimen (EXOs-HP) that thermosensitive poloxamer hydrogel possessed the ability to efficiently promote the residency duration of EXOs in the uterine cavity. By downregulating fibrotic progression markers (Vimentin, COL5A2, and COL1A1), EXOs-HP could significantly restore the function and structure of the injured endometrium in the IUA model. Our work provides the theoretical and experimental foundation of EXOs-HP in treating IUA, highlighting the clinical potential of topical EXOs-HP delivery system in IUA patients.

Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability.

MYC-driven medulloblastomas are highly aggressive childhood brain tumors, however, the molecular and genetic events triggering MYC amplification and malignant transformation remain elusive. Here we report that mutations in CTDNEP1, a CTD nuclear-envelope-phosphatase, are the most significantly enriched recurrent alterations in MYC-driven medulloblastomas, and define high-risk subsets with poorer prognosis. Ctdnep1 ablation promotes the transformation of murine cerebellar progenitors into Myc-amplified medulloblastomas, resembling their human counterparts. CTDNEP1 deficiency stabilizes and activates MYC activity by elevating MYC serine-62 phosphorylation, and triggers chromosomal instability to induce p53 loss and Myc amplifications. Further, phosphoproteomics reveals that CTDNEP1 post-translationally modulates the activities of key regulators for chromosome segregation and mitotic checkpoint regulators including topoisomerase TOP2A and checkpoint kinase CHEK1. Co-targeting MYC and CHEK1 activities synergistically inhibits CTDNEP1-deficient MYC-amplified tumor growth and prolongs animal survival. Together, our studies demonstrate that CTDNEP1 is a tumor suppressor in highly aggressive MYC-driven medulloblastomas by controlling MYC activity and mitotic fidelity, pointing to a CTDNEP1-dependent targetable therapeutic vulnerability.

Follicular fluid progesterone downregulated HPGD and COX2 in granulosa cells via suppressing NF-ĸB in endometriosis†.

Increasing evidences showed that ovulatory dysfunction, possibly caused by luteinized unruptured follicular follicle syndrome (LUFS), is one of the reasons for endometriosis-related infertility. The present study was conducted to explore the potential effect of elevated progesterone in follicular fluid (FF) on ovulation in endometriosis. A prospective study including 50 ovarian endometriosis patients and 50 control patients with matched pairs design was conducted with alterations in FF and peritoneal fluid (PF) components identified by metabolomics analyses and differentially expressed genes in granulosa cells (GCs) identified by transcriptome analysis. Patients with endometriosis exhibited a significantly higher progesterone level in serum, FF, and PF. Granulosa cells from endometriosis patients revealed decreased expression of HPGD, COX-2, and suppressed NF-ĸB signaling. Similarly, progesterone treatment in vitro downregulated HPGD and COX2 expression and suppressed NF-ĸB signaling in granulosa tumor-like cell line KGN (Bena Culture Collection, China) and primarily cultured GCs, as manifested by decreased expressions of IL1R1, IRAK3, reduced pIĸBα/IĸBα ratio, and nucleus translocation of p65. On the contrary, TNF-α treatment increased expression of IL1R1, IRAK3, pIĸBα, p65, and HPGD in GCs. One potential p65 binding site was identified in the promoter region of HPGD by chromatin immunoprecipitation. In conclusion, we found that intrafollicular progesterone might downregulate HPGD and COX-2 in GCs via suppressing the NF-ĸB signaling pathway, shedding light on the mechanism underlying the endometriosis-related ovulatory dysfunction.

Comprehensive Understanding the Forensic Systematic Effectiveness in Chinese Yunnan Hani Group and Intercontinental Population Architecture Differentiation Analyses via a Novel Set of Autosomal InDel Markers.

BACKGROUND: Chinese Yunnan Hani group is an East Asian ethnic group mainly distributed in China, Thailand, Laos, Vietnam, and Burma. The genetic makeup of Chinese Yunnan Hani ethnic group remains to be further investigated. The insertion/deletion (InDel) polymorphism genetic markers are highlighted by their merits such as shorter amplified fragments, lower mutation rates, and are considered effective tools for population genetic investigations. METHODS: The 221 individuals of Chinese Yunnan Hani group were enrolled to obtain the genetic data and polymorphic profiles of 57 autosomal InDels through multiplex amplification and genotyping. Population genetic analyses were performed between Chinese Yunnan Hani group and 30 global reference populations. RESULTS: The forensic parameters, especially cumulative power of discrimination and combined probability of exclusion values, which were 0.9999999999999999999999968 and 0.999958, separately, illustrated that this novel InDel multiplex amplification system could be utilized as a powerful tool for personal identification and paternity testing in Chinese Yunnan Hani group. The results of population genetic analyses indicated that Chinese Yunnan Hani group showed relatively smaller genetic distances and similar genetic structures with the reference East Asian populations. CONCLUSIONS: The genetic polymorphisms and results of intercontinental population architecture differentiation analyses demonstrated the high efficiency of this novel InDel multiplex amplification system. The genomic data and findings of this research will contribute to the ongoing genetic exploration of Chinese Yunnan Hani group and increase our insights into the genetic architecture of worldwide populations.

Ticagrelor for patients undergoing coronary artery bypass grafting: A meta-analysis of randomized controlled trials.

OBJECTIVE: Ticagrelor may be an alternative to aspirin as it provides robust and consistent platelet inhibition. However, the effect of ticagrelor treatment in patients undergoing coronary artery bypass grafting (CABG) has not been well confirmed. We conducted a meta-analysis to appraise whether ticagrelor therapy affects outcomes in CABG patients. METHODS: We searched PubMed, Embase, EBSCO, and Cochrane databases from its inception up to 4 December 2020 for randomized controlled trials that assessed ticagrelor versus non-ticagrelor in patients undergoing CABG. The primary outcome was the incidence of saphenous vein graft (SVG) occlusion at 1 year after CABG. Secondary outcomes were SVG occlusion at 7 days, major adverse cardiovascular events (MACE), and bleeding requiring reoperation. RESULTS: Seven trials including 4305 patients (2153 randomized to ticagrelor therapy and 2152 to non-ticagrelor therapy) were included. One-hundred and thirty of 1140 patients (11.4%) randomized to the ticagrelor group versus 175 of 1220 patients (14.3%) randomized to the non-ticagrelor group experienced SVG occlusion at 1 year after CABG. Compared to the control group, ticagrelor therapy yielded a significantly lower risk of SVG occlusion [RR 0.79 (0.64-0.97), p = 0.03]. In the subgroup analysis, ticagrelor plus aspirin compared with aspirin alone did not decrease the risk of SVG occlusion after 1 year [RR 0.65 (0.40-1.07), p = 0.09]. There was no difference in the incidence of SVG occlusion at 7 days [RR 0.67 (0.42-1.06), p = 0.09], MACE up to 1 year [RR 0.99 (0.81-1.21), p = 0.90], or bleeding requiring reoperation [RR 1.16 (0.80-1.70), p = 0.44]. CONCLUSIONS: Compared with non-ticagrelor therapy, ticagrelor decreased the risk of saphenous vein graft occlusion after 1 year in patients undergoing elective CABG with saphenous vein grafting.

Human fetal cerebellar cell atlas informs medulloblastoma origin and oncogenesis.

Medulloblastoma (MB) is the most common malignant childhood brain tumour1,2, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella3-5 have not fully defined the compositional heterogeneity of MBs. Here we undertook single-cell profiling of freshly isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group 3 and metastatic tumours. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group 3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group 3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group 3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs show potential cell populations predisposed to transformation and regulatory circuitries underlying tumour cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.