Biology subjects

Song, Y.-Q.

Publications and source records attributed to Song, Y.-Q..

7 recordsLinked to original sources

bioRxiv2024

Cerebrospinal Fluid Dynamics: Uncovering Alternative Blood Vessel Clearance Mechanisms

The pathways that run along the olfactory nerves crossing the cribriform plate and connecting to lymphatic vessels in the nasal cavity, have been identified as a crucial route for cerebrospinal fluid (CSF) outflow. However, the presence of a CSF efflux pathway through blood vessels in this region has yet to be clarified. This study aimed to elucidate the anatomical connections between the subarachnoid space and the bloodstream at the nasal epithelium and the venous drainage routes of the nasal epithelium in mice. Our findings demonstrated that CSF tracers could be drained not only through lymphatic vessels in the nasal cavity and cervical lymph nodes (CLNs), but also through the blood vessels in this area that extend to its venous drainage routes, including the facial and jugular veins. Additionally, we showed that ligation of CLNs neither impeded the influx and efflux of CSF tracers nor exacerbated Alzheimers disease (AD)-related pathology in AD mice. Our work reveals a previously unrecognized pathway for CSF drainage through blood vessels within the nasal mucosa. These findings provide insight into the efficient removal of waste products, facilitating optimal functioning of neural tissue within the susceptible tissue of our brains.

neuroscience↗

bioRxiv2023

Differentiation and migration of hematopoietic stem and progenitor cells cross multiple tissues

Hematopoiesis requires the coordinated differentiation of hematopoietic stem cells and progenitor cells (HSPCs) in multiple tissues. Although differentiation of HSPCs in bone marrow (BM) has been well-studied, our knowledge about the migration and differentiation of HSPCs cross tissues is limited. Here, we collected and integrated single-cell RNA-seq data of human CD34+ cells, which represent HSPCs, from BM, peripheral blood (PB), thymus and mobilized PB (mPB), to investigate the hematopoiesis cross tissues. We constructed a cell atlas of HSPCs cross tissues and found most HSPC subsets in BM had counterparts in PB, indicating migration of HSPCs from BM to PB has a much broad spectrum. We found B progenitors highly expressed CXCR4 for anchoring in BM, while cells with low expression of CXCR4 facilitate their migration out of BM. Among the HSPC subsets from thymus, we only found the counterparts of the earliest thymic progenitors (ETPs) in BM and PB, potentially indicating that ETPs were the subsets that migrated from BM to PB and thymus. We found interaction signaling including CD99-CD99, CXCL12-CXCR4 and CCL19-CCR7 played important roles in ETP homing to thymus. Briefly, these data provided a single unified developmental spectrum of hematopoiesis cross different tissues, connected by cell migration.

genomics↗

bioRxiv2023

Association of an estrogen-sensitive Pax1-Col11a1-Mmp3 signaling axis with adolescent idiopathic scoliosis

Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than five-fold greater risk of severe disease compared to boys. Despite its medical impact, the molecular mechanisms that drive AIS are largely unknown. We previously defined a female-specific AIS genetic risk locus in an enhancer near the PAX1 gene. Here we sought to define the roles of PAX1 and newly-identified AIS-associated genes in the developmental mechanism of AIS. In a genetic study of 10,519 individuals with AIS and 93,238 unaffected controls, significant association was identified with a variant in COL11A1 encoding collagen (1) XI (rs3753841; NM_080629.2_c.4004C>T; p.(Pro1335Leu); P=7.07e-11, OR=1.118). Using CRISPR mutagenesis we generated Pax1 knockout mice (Pax1-/-). In postnatal spines we found that PAX1 and collagen (1) XI protein both localize within the intervertebral disc (IVD)-vertebral junction region encompassing the growth plate, with less collagen (1) XI detected in Pax1-/- spines compared to wildtype. By genetic targeting we found that wildtype Col11a1 expression in costal chondrocytes suppresses expression of Pax1 and of Mmp3, encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, this suppression was abrogated in the presence of the AIS-associated COL11A1P1335L mutant. Further, we found that either knockdown of the estrogen receptor gene Esr2, or tamoxifen treatment, significantly altered Col11a1 and Mmp3 expression in chondrocytes. We propose a new molecular model of AIS pathogenesis wherein genetic variation and estrogen signaling increase disease susceptibility by altering a Pax1-Col11a1-Mmp3 signaling axis in spinal chondrocytes.

genetics↗

bioRxiv2020

Deviation from baseline mutation burden provides powerful and robust rare-variants association test for complex diseases

The identification of rare variants that contribute to complex diseases is challenging due to low statistical power. Here we propose a novel and powerful rare variants association test based on the deviation of the observed mutational burden in a genomic region from a baseline mutation burden predicted by weighted recursive truncated negative-binomial regression (RUNNER) on genomic features available from public data. Simulation studies show that RUNNER is substantially more powerful than state-of-the-art rare variant association methods (including SKAT, CMC and KBAC), while maintaining correct type 1 error rates under population stratification and in small samples. Applied to real data, RUNNER “rediscovered” known genes of Hirschsprung disease missed by current methods, and detected promising new candidate genes, including NXPE4 for Hirschsprung disease and CXCL16 for Alzheimer’s disease. The proposed approach provides a powerful and robust method to identify rare risk variants for complex diseases.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genetics↗

bioRxiv2018

Trans-ethnic polygenic analysis supports genetic overlaps of lumbar disc degeneration with height, body mass index, and bone mineral density

Lumbar disc degeneration (LDD) is age-related break-down in the fibrocartilaginous joints between lumbar vertebrae. It is a major cause of low back pain and is conventionally assessed by magnetic resonance imaging (MRI). Like most other complex traits, LDD is likely polygenic and influenced by both genetic and environmental factors. However, genome-wide association studies (GWASs) of LDD have uncovered few susceptibility loci due to the limited sample size. Previous epidemiology studies of LDD also reported multiple heritable risk factors, including height, body mass index (BMI), bone mineral density (BMD), lipid levels, etc. Genetics can help elucidate causality between traits and suggest loci with pleiotropic effects. One such approach is polygenic score (PGS) which summarizes the effect of multiple variants by the summation of alleles weighted by estimated effects from GWAS. To investigate genetic overlaps of LDD and related heritable risk factors, we calculated the PGS of height, BMI, BMD and lipid levels in a Chinese population-based cohort with spine MRI examination and a Japanese case-control cohort of lumbar disc herniation (LDH) requiring surgery. Because most large-scale GWASs were done in European populations, PGS of corresponding traits were created using weights from European GWASs. We calibrated their prediction performance in independent Chinese samples, then tested associations with MRI-derived LDD scores and LDH affection status. The PGS of height, BMI, BMD and lipid levels were strongly associated with respective phenotypes in Chinese, although phenotype variances explained were lower than in Europeans which would reduce the power to detect genetic overlaps. Despite of this, the PGS of BMI and lumbar spine BMD were significantly associated with LDD scores; and the PGS of height was associated with the increased the liability of LDH. Furthermore, linkage disequilibrium score regression suggested that, osteoarthritis, another degenerative disorder that shares common features with LDD, also showed genetic correlations with height, BMI and BMD. The findings suggest a common key contribution of biomechanical stress to the pathogenesis of LDD and will direct the future search for pleiotropic genes.

genetics↗

bioRxiv2018

Germline genetics encode the resistance, risk, and lymphatic metastasis of triple-negative breast cancer in the southern Chinese population

Early identification of the risk for triple-negative breast cancer (TNBC) at the asymptomatic phase could lead to better prognosis. Here we developed a machine learning method to quantify systematic impact of all rare germline mutations on each pathway. We collected 106 TNBC patients and 287 elder healthy women controls. The spectra of activity profiles in multiple pathways were mapped and most pathway activities exhibited globally suppressed by the portfolio of individual germline mutations in TNBC patients. Accordingly, all individuals were delineated into two types: A and B. Type A patients could be differentiated from controls (AUC = 0.89) and sensitive to BRCA1/2 damages; Type B patients can be also differentiated from controls (AUC = 0.69) but probably being protected from BRCA1/2 damages. Further we found that Individuals with the lowest activity of selected pathways had extreme high relative risk (up to 21.67 in type A) and increased lymph node metastasis in these patients. Our study showed that genomic DNA contains information of unimaginable pathogenic factors. And this information is in a distributed form that could be applied to risk assessment for more cancer types. SignificanceWe identified individuals who are more susceptible to triple negative breast cancer. Our method performs much better than previous assessments based on BRCA1/2 damages, even polygenic risk scores. We disclosed previously unimaginable pathogens in a distributed form on genome and extended risk prediction to scenarios for other cancers.

cancer biology↗

bioRxiv2018

Role of anterograde motor Kif5b in clathrin-coated vesicle uncoating and clathrin-mediated endocytosis

Kif5b-driven anterograde transport and clathrin-mediated endocytosis (CME) are responsible for opposite intracellular trafficking, contributing to plasma membrane homeostasis. However, whether and how the two trafficking processes coordinate remain unclear. Here, we show that Kif5b directly interacts with clathrin heavy chain (CHC) at a region close to that for uncoating catalyst (Hsc70) and preferentially localizes on large clathrin-coated vesicles (CCVs). Uncoating in vitro is decreased for CCVs from the cortex of kif5b conditional knockout (mutant) mouse and facilitated by adding CHC-binding Kif5b fragments, while cell peripheral distribution of CHC or Hsc70 keeps unaffected by Kif5b depletion. Furthermore, cellular entry of vesicular stomatitis virus that internalized into large CCV is inhibited in cells by Kif5b depletion or introducing a dominant-negative Kif5b fragment. These findings showed a new role of Kif5b in CCV uncoating and CME, indicating Kif5b as a molecular knot connecting anterograde transport to CME.

cell biology↗