10 research outputs found

    Supplementary Material for: Autophagy induced by low shear stress leads to endothelial glycocalyx disruption

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    Introduction: Previous studies have confirmed that low shear stress (LSS) induces glycocalyx disruption, leading to endothelial dysfunction. However, the role of autophagy in LSS-induced glycocalyx disruption and relevant mechanism are not clear. In this study, we hypothesized that LSS may promote autophagy, disrupting the endothelium glycocalyx. Methods: Human umbilical vein endothelial cells (HUVECs) were subjected to physiological shear stress and LSS treatments, followed by the application of autophagy inducers and inhibitors. Additionally, cells were treated with specific matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) inhibitor. The expression of autophagic markers, glycocalyx, MMP-2 and MMP-9 were measured. Results: LSS impacted the expression of endothelium autophagy markers, increasing the expression of LC3II.LC3I-1 and beclin-1, and decreasing the levels of p62, accompanied by glycocalyx disturbance. Moreover, LSS upregulated the expression of MMP-2 and MMP-9 and downregulated the levels of syndecan-1 and heparan sulfate (HS). Additionally, expression of MMP-2 and MMP-9 was increased by an autophagy promoter but was decreased by autophagy inhibitor treatment under LSS. Autophagy and MMP-2 and MMP-9 further caused glycocalyx disruption. Conclusion: LSS promotes autophagy, leading to glycocalyx disruption. Autophagy increases the expression of MMP-2 and MMP-9, which are correlated with the glycocalyx destruction induced by LSS

    Supplementary Material for: The association of glaucoma with ischemic stroke and functional outcome after ischemic stroke from the perspective of causality

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    Introduction: Glaucoma may be related to ischemic stroke (IS) and poor outcomes after IS in observational studies, while the causal association remains unclear. Methods: We obtained single nucleotide polymorphisms (SNPs) related to glaucoma from the gene-wide association study (GWAS) conducted by the FinnGen consortium. The GWAS included a total of 13,614 cases and 295,540 controls. The summary-level of datasets regarding IS were collected from the MEGASTROKE consortium, including 34,217 cases and 406,111 controls. Furthermore, we acquired summary statistics datasets for functional outcomes following IS from the GWAS meta-analysis conducted by the GISCOME consortium, which involved 6,021 individuals. The genetic association estimates for functional outcomes at 90 days after IS were evaluated by the modified Rankin Score (mRS), including 3,741 cases with good functional outcomes (mRS=0-2) and 2,280 subjects with poor functional outcomes post-stroke (mRS=3-6). Inverse variance weighting (IVW) was used as the primary method, complemented by sensitivity analyses for pleiotropy and increasing robustness. Results: Genetically, glaucoma is associated with an increased risk of IS (odds ratio [OR]=1.08, 95% confidence interval [CI] = 1.02-1.14, P = 0.0039), as well as poor prognosis after IS with adjustment for severity (OR=1.64; 95% CI=1.27-2.13, P=0.0001) and functional outcome after IS (OR=1.45, 95% CI=1.12-1.87, P=0.0038). Through sensitivity analyses, we confirmed the robustness of the results. In addition, we did not identify any causal association between IS, functional outcome after IS, and glaucoma in reverse analysis. Conclusion: Our study provides evidence suggesting a potential genetic causal relationship between glaucoma and an increased risk of IS, as well as a poor functional outcome following IS. Future studies are necessary to confirm these findings

    Supplementary Material for: Adolescence predatory risk alters social behaviors and cognitive ability and central oxytocin and vasopressin expression in adult Brandt’s voles

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    Introduction: Stress during adolescence causes long-term behavioral changes in adulthood. We previously found that adolescent exposure to predatory risk augments adolescent social contact and adult parental behavior in Brandt’s voles (Lasiopodomys brandtii). Methods: Here we determined whether this experience alters sexual behavior, pair-bond formation, and recognition ability, as well as basal HPA axis activity, central oxytocin (OT), and arginine-vasopressin (AVP) expression in adulthood. Results: In the social interaction test, repeated cat odor (CO) exposure enhanced the frequency of lordosis by female voles toward an unfamiliar opposite-sex conspecific. CO voles preferred to engage with their partners after 48 h cohabitation whereas the control groups did not, which may reflect stable pair bonds in the CO treatment group. Furthermore, adolescent exposure to CO inhibited novel object and place recognition ability, while it influenced social recognition only among adult males. No effect of adolescent CO exposure was observed for basal HPA axis activity, showing a habituation effect. Finally, we found that CO exposure increased OT and decreased AVP expression in the hypothalamus, including the paraventricular nucleus and anterior hypothalamus. The levels of OT in the medial amygdala were lower, and AVP in the lateral septum was higher in CO voles compared with the control. Discussion/Conclusion: These findings demonstrate that adolescent exposure to predator risk promotes adult reproductive behavior of Brandt’s voles. Deficits in recognition ability may necessitate alterations in reproductive strategies to enhance inclusive fitness. OT and AVP systems may play a modulatory role in the alteration of social behaviors elicited by adolescent predatory risk

    Supplementary Material for: Perilipin1 deficiency prompts lipolysis in lipid droplets and aggravates the pathogenesis of persistent immune activation in Drosophila

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    Lipid droplets (LDs) are highly dynamic intracellular organelles, which are involved in lots of biological processes. However, the dynamic morphogenesis and functions of intracellular LDs during persistent innate immune responses remain obscure. In this study, we induce long-term systemic immune activation in Drosophila through genetic manipulation. Then, the dynamic pattern of LDs is traced in the Drosophila fat body. We find that deficiency of Plin1, a key regulator of LDs’ reconfiguration, blocks LDs minimization at the initial stage of immune hyperactivation but enhances LDs breakdown at the later stage of sustained immune activation via recruiting the lipase Brummer (Bmm, homologous to human ATGL). The high wasting in LDs shortens the lifespan of flies with high-energy-cost immune hyperactivation. Therefore, these results suggest a critical function of LDs during long-term immune activation and provide a potential treatment for the resolution of persistent inflammation

    Supplementary Material for: Perilipin1 deficiency prompts lipolysis in lipid droplets and aggravates the pathogenesis of persistent immune activation in Drosophila

    No full text
    Lipid droplets (LDs) are highly dynamic intracellular organelles, which are involved in lots of biological processes. However, the dynamic morphogenesis and functions of intracellular LDs during persistent innate immune responses remain obscure. In this study, we induce long-term systemic immune activation in Drosophila through genetic manipulation. Then, the dynamic pattern of LDs is traced in the Drosophila fat body. We find that deficiency of Plin1, a key regulator of LDs’ reconfiguration, blocks LDs minimization at the initial stage of immune hyperactivation but enhances LDs breakdown at the later stage of sustained immune activation via recruiting the lipase Brummer (Bmm, homologous to human ATGL). The high wasting in LDs shortens the lifespan of flies with high-energy-cost immune hyperactivation. Therefore, these results suggest a critical function of LDs during long-term immune activation and provide a potential treatment for the resolution of persistent inflammation

    PowerPoint Slides for: Genetic Features of Chinese Patients with Gitelman Syndrome: Sixteen Novel SLC12A3 Mutations Identified in a New Cohort

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    <i>Background:</i> Gitelman syndrome (GS) is an autosomal recessive renal tubulopathy caused by inactivating mutations in the <i>SLC12A3</i> gene. Although hundreds of different mutations across the <i>SLC12A3</i> gene have been reported worldwide, data from mainland China are limited. We investigated the clinical manifestations and genetic features of Chinese patients with GS. <i>Methods:</i> Fifty-four unrelated Chinese patients with clinically diagnosed GS were included. Clinical manifestations and biochemical parameters were collected and analyzed. All exons and flanking regions of the <i>SLC12A3</i> and <i>CLCNKB</i> genes were screened by direct sequencing. <i>Results:</i>Weakness was the most commonly reported symptom in this cohort of patients with GS. In gender-based analyses, higher systolic blood pressure and urine protein excretion were observed in male patients. For genetic screening, 2 pathogenic<i>SLC12A3</i> mutations were identified in 38 patients (70.4%), 1 mutation in 11 patients (20.4%) and no mutation in 5 patients (9.3%). In total, 42 distinct pathogenic mutations throughout <i>SLC12A3</i> were identified; 16 were novel, including 9 missense, 1 deletion, 1 insertion, 3 splice site and 2 nonsense mutations. Eleven mutations were recurrently found in different patients. Among them, T60M and D486N were identified in 11 individuals. No <i>CLCNKB</i> mutations were found. <i>Conclusion:</i> Sixteen novel <i>SLC12A3</i> pathogenic mutations were identified in a cohort of Chinese patients with GS. T60M and D486N were most frequent and appear to be important candidate alleles in Chinese patients with GS

    Supplementary Material for: Identification of 8 Novel Mutations in Nephrogenesis-Related Genes in Chinese Han Patients with Unilateral Renal Agenesis

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    <p><b><i>Background:</i></b> Few genetic studies have focused on unilateral renal agenesis (URA), which is a disorder with insidious clinical manifestations and a tendency to result in renal failure. We aimed to detect pathogenic mutations in nephrogenesis-related genes, which were identified by a literature review conducted among a large cohort of Chinese Han patients with URA. <b><i>Methods:</i></b> Totally, 86 unrelated URA patients were included. All URA patients were diagnosed by employing radiological methods. Patients with a solitary kidney owing to nephrectomy or renal atrophy due to secondary factors were excluded. Nine (10.5%) patients had a family history of abnormal nephrogenesis. Fifteen (17.4%) had other malformations in the urogenital system. All coding exons and adjacent intron regions of 25 genes were analyzed using next-generation sequencing and validated by Sanger sequencing and 100 ethnically matched healthy controls. <b><i>Results:</i></b> Ten conserved mutations (9 missense mutations and 1 deletion mutation) were identified in <i>SALL1, EYA1, RET, HNF1B, DSTYK, WNT4,</i> and<i> SIX5</i>. All mutations were novel or rare (frequency <0.1%) in the public databases and absent from the 100 healthy controls. Nine patients carried mutations in candidate genes. Most of the patients carried one single heterozygous mutation, except for 2, who respectively carried compound heterozygous mutations and 2 single heterozygous mutations. In addition, 2 patients shared the same mutation in <i>DSTYK</i>. <b><i>Conclusion:</i></b> A total of 10.5% of our URA cases could be explained by mutations in our candidate genes. The mutations in nephrogenesis-related genes in the Chinese Han patients with URA had a decentralized distribution without any hotspot mutations.</p

    Supplementary Material for: The Wound Healing of Autologous Regenerative Factor on Recurrent Benign Airway Stenosis: A Canine Experimental and Pilot Study

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    Introduction: Benign airway stenosis (BAS) is a severe pathologic condition. Complex stenosis has a high recurrence rate and requires repeated bronchoscopic interventions for achieving optimal control, leading to recurrent BAS (RBAS) due to intraluminal granulation. Methods: This study explored the potential of autologous regenerative factor (ARF) for treating RBAS using a post-intubation tracheal stenosis canine model. Bronchoscopic follow-ups were conducted, and RNA-seq analysis of airway tissue was performed. A clinical study was also initiated involving 17 patients with recurrent airway stenosis. Results: In the animal model, ARF demonstrated significant effectiveness in preventing further collapse of the injured airway, maintaining airway patency and promoting tissue regeneration. RNA-seq results showed differential gene expression, signifying alterations in cellular components and signaling pathways. The clinical study found that ARF treatment was well-tolerated by patients with no severe adverse events requiring hospitalization. ARF treatment yielded a high response rate, especially for post-intubation tracheal stenosis and idiopathic tracheal stenosis patients. Conclusion: The study concludes that ARF presents a promising, effective, and less-invasive method for treating RBAS. ARF has shown potential in prolonging the intermittent period and reducing treatment failure in patients with recurrent tracheal stenosis by facilitating tracheal mucosal wound repair and ameliorating tracheal fibrosis. This novel approach could significantly impact future clinical applications
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