Pulmonary hypertension (PH) underscores the urgent need for novel therapeutic targets. This study aimed to employ a proteome-wide Mendelian randomization (MR) approach to systematically identify circulating proteins causally associated with PH, thereby providing genetically validated candidate targets for drug development. We adopted a 2-sample MR design, integrating large-scale plasma proteomic quantitative trait loci (pQTL) data (encompassing 4148 proteins) and summary statistics from a large-scale PH genome-wide association study (2047 cases, 8301 controls). Candidate targets were screened through a multilayered analytical pipeline comprising proteomic MR, transcriptomic MR, and summary-data-based Mendelian randomization. The ultimately identified MR-Identified Causal Candidate Targets (MR-ICTs) underwent rigorous Bayesian colocalization analysis, followed by biological characterization through functional enrichment analysis, single-cell transcriptomics, and phenome-wide association studies. Through robust genetic causal inference, this study provides that circulating proteins such as LYZ, GREM2, NID1, and PF4V1 play causal roles in PH pathogenesis. These findings offer a set of rigorously genetically validated, high-priority therapeutic targets for developing novel PH treatments, specifically addressing key pathological mechanisms such as innate immunity, BMP signaling pathway dysregulation, and platelet activation. Our multi-dimensional analysis ultimately identified 6 MR-ICTs causally associated with PH. Notably, the causal associations for lysozyme C (LYZ), gremlin-2 (GREM2), nidogen-1 (NID1), and platelet factor 4 variant 1 (PF4V1) were stringently validated by Bayesian colocalization analysis (posterior probability for hypothesis 4 [PPH4], indicating a shared causal variant, > 0.99). Functional enrichment analysis revealed significant involvement of these targets in immune response and TGF-β signaling pathways. Single-cell analysis further elucidated their cell-type-specific expression, with LYZ predominantly expressed in monocytes and PF4V1 almost exclusively in platelets.

Purpose:Vacuolar protein sorting associated protein 16 (Vps16) is a key component of the Vps core complex (Vps–C) and acts as a tethering protein in membrane fusion. Nevertheless, its role in myocardial ischemia/reperfusion (I/R) remains largely unexplored. Methods:This study established a myocardial I/R model in rats and a hypoxia/reoxygenation (H/R) model using H9c2 cells. Both gain-of-function (via adenovirus-mediated Vps16 overexpression) and loss-of-function (via shRNA-mediated Vps16 knockdown) experiments were conducted. Results:This study showed that Vps16-overexpression improved autophagic flux and cardiac function following I/R in vivo and in vitro. However, the protective effect of Vps16 on cardiomyocytes against I/R injury was nullified when treated with autophagy inhibitors such as Bafilomycin A1 (BafA1). Vps16-knockdown worsened H/R-induced impairment of autophagic flux and cell death in H9c2 cardiomyocytes, while these effects could be reversed by rapamycin (Rapa), an autophagy activator. Mechanistically, Vps16 competed with Rubicon for binding to UVRAG in cardiomyocytes via the residues 333–613, subsequently promoting Rab7 activation, which is essential for the late stage of autophagy. Knockdown of Rubicon successfully mitigated the adverse impact of truncated Vps16 (lacking residues 333–613) in cardiomyocytes. Conclusion:These findings indicate that Vps16 exerts a protective effect against myocardial I/R injury, achieved by promoting autolysosome maturation of and reinstating the autophagic flux in cardiomyocytes.

Flap transplantation plays a vital role in wound reconstruction. However, the mechanisms by which remote ischemic preconditioning (RIPC) may improve flap survival remain incompletely understood. Rats were randomly assigned to three groups: sham, ischemia/reperfusion (I/R), and RIPC + I/R. The I/R model was established by ligating the iliopsoas and thoracodorsal arteries to induce flap ischemia, followed by reperfusion. RIPC was performed via limb clamping. A combination of high-throughput sequencing, functional cellular assays, and live imaging was used to assess gene expression, cellular functions, and flap viability. RIPC upregulated the expression of ZNF667. This protein acted as a transcriptional repressor of VHL by binding to its promoter region, where it competitively inhibited the recruitment of histone-modifying enzymes, including MLL3/4, SETD1A, and EP300. Consequently, histone methylation and acetylation were reduced, leading to suppressed VHL transcription. The downregulation of VHL diminished the ubiquitination-mediated degradation of hypoxia-inducible factor-1α (HIF-1α), which in turn enhanced the expression of stromal cell-derived factor 1 (SDF1). This signaling cascade promoted the proliferation, migration, differentiation, and tube-forming capacity of endothelial progenitor cells (EPCs). Live imaging confirmed that RIPC stimulated the recruitment of EPCs into the flap tissue, accompanied by increased microvessel density. These effects collectively enhanced angiogenesis and significantly reduced the area of flap necrosis. RIPC improves flap survival by modulating the ZNF667–VHL–SDF1 axis and augmenting the function of EPCs. These findings not only provide a potential therapeutic strategy for flap transplantation but also advance our understanding of the mechanisms underlying flap survival.

PURPOSE:While reperfusion is essential for restoring blood flow, it can paradoxically exacerbate myocardial injury by disrupting energy metabolism, leading to cell necrosis, apoptosis, and structural damage. Despite the significance of ischemia-reperfusion (I/R) injury, effective treatments remain scarce, highlighting the need for a deeper understanding of its underlying mechanisms to develop targeted therapies. METHODS:A rat model of myocardial I/R injury and a H9c2 cell-based hypoxia/reoxygenation (H/R) model were utilized for primary validation. HOXB5 was overexpressed several days prior to I/R or H/R induction. Gene and protein expression were assessed by RT-qPCR, Western blotting, immunohistochemistry, and immunofluorescence. Cell viability and apoptosis were evaluated using CCK-8 and flow cytometry. Mitochondrial function and ferroptosis were analyzed by commercial kits. The regulatory relationship among Lin28a, HOXB5, and Sirt5 was examined using RIP, ChIP-PCR, and dual-luciferase assays. RESULTS:HOXB5 expression was significantly reduced in infarcted myocardial tissue following I/R injury, of which overexpression attenuated H/R-trigged apoptosis to motivate H9c2 cell survival. Meanwhile, HOXB5 overexpression decreased mitochondrial ROS production, improved mitochondrial respiration, mitochondrial complexes (I, II, III, and V) activity, and reduced mitophagy under H/R conditions in H9c2 cells. Mechanistically, Lin28A was identified as a regulator of HOXB5, which in turn transcriptionally activated Sirt5. Furthermore, the protective effects of HOXB5 overexpression on myocardial histological damage and cardiac function through modulating ferroptosis in rats' I/R injury was abrogated by Sirt5 knockdown. CONCLUSION:Our study reveals the crucial role of HOXB5 in maintaining mitochondrial homeostasis and regulating mitophagy, which in turn protects cardiomyocytes from I/R injury through Sirt5. These findings underscore the HOXB5-Sirt5 pathway as a promising therapeutic target for mitigating I/R injury.

Myocardial injury induced by ischemia-reperfusion (I/R) remains a difficult clinical problem. However, the exact mechanisms underlying I/R-induced have yet to be clarified. CARD9 is an important cytoplasmic-binding protein. In this study, an immunocoprecipitation assay showed that SUMOylation of the CARD9 protein promoted the binding of CARD9 to HOXB5, but hindered the O-GlcNAc glycosylation of HOXB5, a predicted transcription factor of Parkin and a key factor in mitophagy. O-GlcNAc glycosylation is an important signal for translocation of proteins from the cytoplasm to the nucleus. CARD9 protein SUMOylation is regulated by PIAS3, which is related to I/R-induced myocardial injury. Therefore, we propose that knockdown of PIAS3 inhibits SUMOylation of the CARD9 protein, facilitates the dissociation of CARD9 and HOXB5, which increases the O-GlcNAc-mediated glycosylation of HOXB5, while the resulting HOXB5 nuclear translocation promotes Parkin-induced mitophagy and alleviates myocardial I/R injury.

Background Polycystic ovary syndrome (PCOS) is a frequent and complicated endocrine disease that remains a major reason for infertility. Bushenhuoluo Decotion (BSHLD) has been validated to exhibit curative effects on PCOS. This study was aimed to explore the potential mechanism underlying the therapeutic action of BSHLD. Methods PCOS rat model was induced by dehydroepiandrosterone (DHEA). Serum hormone and cytokines levels and ovarian pathological alterations were measured to assess ovarian function. Exosomes (Exos) were identified by Transmission electron microscopy and Nanoparticle Tracking Analysis. RT-qPCR, Western blotting, immunohistochemical staining, and immunofluorescence staining were performed to detect molecule expressions. Proliferation and pyroptosis of granulosa cells (GCs) were evaluated by CCK-8 and flow cytometry, respectively. The binding relationship between miR-30a-5p and suppressor of cytokine signaling 3 (SOCS3) was verified by dual luciferase reporter and RIP assays. Results BSHLD treatment improved serum hormone abnormality, insulin sensitivity, and ovarian morphologic changes of PCOS rats. Moreover, BSHLD treatment restrained the excessive autophagy and pyroptosis in ovarian tissues of PCOS rats. Moreover, BSHLD reduced the expression of miR-30a-5p in serum, serum-derived Exos, and ovarian tissues, thus inhibiting autophagy and NLRP3-mediated pyroptosis in GCs. Mechanistically, SOCS3 was proved as a target of miR-30a-5p and could activate mTOR/P70S6K pathway to repress autophagy. The inhibitory effect of miR-30a-5p deficiency on autophagy and pyroptosis of GCs was attenuated by rapamycin. Conclusion Collectively, BSHLD suppressed autophagy and pyroptosis to improve POCS by regulating exosomal miR-30a-5p/SOCS3/mTOR signaling.

在中医药高职院校临床医学专业中,《人体解剖学》作为其中一门基础性课程,在医学教育中占据非常重要的地位,同时也是学生接触医学人文教育的重要课程,在《人体解剖学》教学中,蕴含各种各样的思政教育元素,将思政教育融入人体解剖学中具有一定的教学必要性.就此本文针对中医药高职院校临床医学专业《人体解剖学》课程思政的实践进行探讨,旨在为相关医学专业教育人士提供几点有价值的参考.

目的:观察艾灸阳明经穴对变应性鼻炎(AR)大鼠最轻持续性炎症(MPI)状态的调节,探索其改善AR发作期的症状及炎症反应的机制.方法:将50只清洁级SD大鼠随机分为空白组(10只)、模型组(10只)、艾灸阳明经穴组(20只)和鼻用激素组(10只).对除空白组外的其余组大鼠采用卵清蛋白腹腔注射联合滴鼻强化致敏制备MPI期AR模型,艾灸阳明经穴组及鼻用激素组进入MPI维持阶段后7d(致敏第43天)分别进行干预,艾灸阳明经穴组取手、足阳明经之迎香(双)、足三里(双)穴,鼻用激素组采用布地奈德混悬液进行滴鼻,2组均以7 d为1个疗程,均干预2个疗程.对空白组、模型组、艾灸阳明经穴组进行行为学评分,检测艾灸阳明经穴组、空白组及模型组大鼠鼻黏膜嗜酸性粒细胞(EOS)及细胞间黏附分子-1(ICAM-1)的改变及血清白细胞介素-4(IL-4)及白细胞介素-5(IL-5)、干扰素-γ(IFN-γ)水平.艾灸阳明经穴组及鼻用激素组继续采用卵清蛋白滴鼻激发速发相反应,2周后评估2组行为学评分及血清IL-4、IFN-γ 水平.结果:MPI期干预结束后,与空白组比较,模型组大鼠喷嚏、流涕次数增多,行为学评分升高(P＜0.01);其鼻黏膜上皮破坏明显,纤毛脱落,黏膜上皮深面固有层可见大量EOS浸润,腺体增生及水肿;血清中IL-4、IL-5含量升高,IFN-γ含量降低(P＜0.01).与模型组比较,艾灸阳明经穴组大鼠喷嚏、流涕频次减少(P＜0.05);鼻黏膜上皮损伤、纤毛紊乱程度、腺体增生及水肿有所改善,黏膜下EOS数量显著减少;血清中IL-4、IL-5含量降低,IFN-y含量升高(P＜0.05).激发速发相反应后,鼻用激素组与艾灸阳明经穴组比较,2组行为学评分,血清IL-4、IFN-γ含量比较,差异均无统计学意义(P＞0.05).结论:MPI期采用艾灸干预,可下调促炎性细胞因子分泌,减轻嗜酸性粒细胞的浸润程度,抑制鼻黏膜组织重塑,减轻炎症反应进程,改善AR发作期的症状及炎症反应,发挥其免疫调节作用.

新时期,教育改革活动向现代育人工作提出了新的任务:教育的价值从来不在于全盘灌输,让学生学会独立思考,针对学生素质授予学习方法,开发学生的自学能力,教学活动才能被不断优化.组织学与胚胎学的有关教学较为复杂,繁琐的理论知识对学生的理性思维与学习能力提出了更高的要求.开发学生的自主学习能力,可以让学习者主动认识人体的微细结构,为未来的自主发展提供新的机会.本文分析了当代学生的学习现状,探讨如何在组织学与胚胎学的教学中培养学生的自主学习能力.

ABSTRACT:This study aimed to determine whether endoplasmic reticulum (ER) stress is involved in impaired autophagy after myocardial ischemia/reperfusion (M-I/R) and elucidate the underlying mechanisms. The expression levels of stimulator of interferon gene (STING) and interferon regulatory transcription factor 3 (IRF3) phosphorylation increased in M-I/R heart tissues and hypoxia-treated/reoxygenation-treated H9c2 cells. The ER stress inhibitor 4-phenylbutyric acid (4-PBA) significantly suppressed the stimulation of STING-IRF3 transcription and alleviated cardiac dysfunction caused by M-I/R injury. In addition, 4-PBA reversed ischemia-induced/reperfusion-induced autophagic flux dysfunction, as demonstrated by a decrease in p 62 and LC3 levels. Similarly, the protective effect of STING deficiency on myocardial cell damage was achieved by the recovery of autophagic flux. Conversely, the protective effect of 4-PBA against hypoxia/reoxygenation injury in cardiomyocytes was offset by STING overexpression, wherein the activated STING-IRF3 pathway promoted the expression of Rubicon (a negatively-regulated autophagic molecule) by binding to the Rubicon promoter. Rubicon ablation effectively counteracts the adverse effects of STING overexpression in cardiomyocytes. The data showed that STING-IRF3 signaling of ER stress receptors is particularly important in the progression of physiological M-I/R caused by the inhibition of autophagic flow in vivo and in vitro.

健康中国理念提出了全面服务中国医疗体系建设的战略要求.健康中国理念以满足国家的医疗需求、加快本土医疗服务改革为基本切入点,给现代的医疗建设、医疗教育提出了新的任务.要想全面落实健康中国理念,学校必须基于新的时代要求,创新医疗人才培养机制,将"新医科"的开发提上日程,为健康中国的全面落实提供素质过硬、能力出色的人才储备军.本文以健康中国为背景,探讨在全新的要求下推动"新医科"建设的有效策略.

背景:内质网应激与心肌缺血再灌注(I/R)损伤的进展有关,然而,它是否参与心肌I/R后的自噬流受损尚未完全阐明.目的:文章探讨抑制内质网应激对心肌I/R后心肌自噬流的影响及其作用机制.方法:采用小鼠冠状动脉I/R损伤模型和H9c2心肌细胞缺氧复氧(H/R)模型,观察内质网应激抑制剂4-苯基丁酸(4-PBA)对心脏功能和心肌自噬流以及STING-IRF3信号通路活化的影响.结果:我们发现4-苯基丁酸(4-PBA)预处理可减轻I/R损伤引起的心肌损伤和心功能障碍,以及逆转了I/R诱导的自噬流受损,表现为p62和Rubicon表达明显降低;此外,在心肌I/R作用下,STING和磷酸化IRF3的表达增加,活化的IRF3通过与Rubicon启动子结合,促进自噬负调控分子Rubicon的表达;4-PBA抑制STING-IRF3信号通路的激活.这些结果表明,内质网应激介导的STING-IRF3信号通路通过抑制自噬流在心肌I/R损伤病理进程中发挥了关键作用,4-PBA可下调STING-IRF3信号通路的活化,从而保护心肌细胞.

传统的医学教育活动重视学生学习能力与专业技能的开发,但并不考虑学生进入岗位后的实践服务问题.在组织教学活动的过程中,医学教育本身存在的片面化、短期化问题并没有得到有效解决,医学教育的实施与创新还需要进一步的探索."新医科"背景下,现代医学教育活动围绕着人才素质、教学要求、社会大环境逐步发力,教学本身的互动价值与科学育人功能得到了进一步的保障.以"新医科"背景下的医学教育为对象,思考基于"新医科"的有关要求推动医学教育改革、加大人才培养力度的有效方法.

目的：调查了解株洲市在校大学生对于基本急救知识和急救技能的掌握程度，明确急救教育培训的相关方向，为规范在校大学生急救教育培训提供参考。方法：用微信小程序调查问卷随机抽样的方式选取湖南中医药高等专科学校在校大学生140名（年龄19～24岁），对该校在校大学生进行急救理论知识与技能操作培训，在实施培训完成的先后分别采用微信小程序问卷调查法对急救相关的了解及掌握的情况以及对急救知识学习要求进行研究调查。结果：调查发现，84.23%的学生从微信公众平台、网络视频等媒体平台上获取急救相关知识，但是学习的效果欠佳。而

为更好的适应当前新时代背景下对高等教育改革提出的要求，引领大学生树立正确思想观念，高职医学院校任用具有一定专业能力、德才兼备的专任教师担任临床医学专业班主任，与辅导员共同加强对班级的管理，旨在以此为国家医学事业的发展培养更多优秀的应用型人才。就此本文通过对高职医学院校班辅协同育人对临床医学专业应用型人才的培养实践进行探讨，以此为相关教育人士提供有价值的参考。

We investigate the protective effect of ginsenoside Rb3 on skin flap microvasculature following ischemia-reperfusion (I/R) injury and its regulatory mechanism. We used a rat model of I/R injury with the right iliolumbar artery and oxidative stress model of human dermal microvascular endothelial cells. The effects of Rb3 on skin flap tissue and endothelial cell survival, STING-IRF3 pathway activation, and endothelial cell adhesion were measured. Following reperfusion, the survival rate of rat perforator flaps in the Rb3-treated group gradually increased with increasing Rb3 concentration. The treatment also reduced the amount of STING protein, phosphorylated IRF3, and P-selectin in skin flap tissue, with this change being most obvious in microvascular endothelial cells. In vitro, activated IRF3 binds to the P-selectin promoter and induces P-selectin expression. Our results suggest that Rb3 plays a role in reducing I/R flap damage through negatively regulating STING-IRF3 activation to limit leukocyte-endothelial cell adhesion.

We assessed the effects and potential mechanism of romote ischemic preconditioning (RIPC) on leukocytes-endothelium cell adhesion in the flap microvessel after ischemia-reperfusion (I/R) injury. Eight hours after reperfusion, edema and intravascular leukocyte aggregation were reduced and microvessels were more obvious in the group with superficial inferior epigastric artery (SIEA) perforator flap (SIEA-flap) subjected to RIPC than in the I/R group. Zinc finger protein 667 (ZNF667) was significantly increased but P-selectin was decreased in the flaps subjected to RIPC, compared to those in the I/R group. The low expression of P-selectin was associated with ZNF667 expression and activation in human dermal microvascular endothelial cells in response to hypoxic preconditioning. ZNF667 bound to the P-selectin promoter region, suppressing its transcription through a special core sequence. The ablation of P-selectin by small interfering RNA effectively prevented the leukocytes-endothelium cell adhesion effect of ZNF667-knockdown. ZNF667 upregulation attenuates leukocyte-endothelial cell adhesion by negatively regulating the expression of P-selectin in SIEA-flap subjected to RIPC.

班级管理效率的高低对学生专业学习成绩有着直接的影响，于学生而言至关重要。本文立足于高职高专班级管理实践活动， 分别从“师生增强沟通，建立和谐关系”“制定班级制度，做好预防工作”“注重个人修养，实施言传身教”“突出学生主体，激发约束意 识”这四个方面入手，针对新时代背景下医学类高职高专班级管理工作进行了初步地分析和探索。

Background: Nucleolin has multiple functions within cell survival and proliferation pathways. Our previous studies have revealed that nucleolin can significantly reduce myocardial ischemia-reperfusion injury by promoting myocardial angiogenesis and reducing myocardial apoptosis. In this study, we attempted to determine the role of nucleolin in myocardial infarction (MI) injury recovery and the underlying mechanism. Methods: Male BALB/c mice aged 6–8 weeks were used to set up MI models by ligating the left anterior descending coronary artery. Nucleolin expression in the heart was downregulated by intramyocardial injection of a lentiviral vector expressing nucleolin-specific small interfering RNA. Macrophage infiltration and polarization were measured by real-time polymerase chain reaction, flow cytometry, and immunofluorescence. Cytokines were detected by enzyme-linked immunosorbent assay. Results: Nucleolin expression in myocardium after MI induction decreased a lot at early phase and elevated at late phase. Nucleolin knockdown impaired heart systolic and diastolic functions and decreased the survival rate after MI. Macrophage infiltration increased in the myocardium after MI. Most macrophages belonged to the M1 phenotype at early phase (2 days) and the M2 phenotype increased greatly at late phase after MI. Nucleolin knockdown in the myocardium led to a decrease in M2 macrophage polarization with no effect on macrophage infiltration after MI. Furthermore, Notch3 and STAT6, key regulators of M2 macrophage polarization, were upregulated by nucleolin in RAW 264.7 macrophages. Conclusions: Lack of nucleolin impaired heart function during recovery after MI by reducing M2 macrophage polarization. This finding probably points to a new therapeutic option for ischemic heart disease.

Autophagy in cardiomyocyte is involved in myocardial ischemia/reperfusion (M-I/R) injury. Caspase recruitment domain-containing protein 9 (CARD9) plays a critical role in cardiovascular diseases (CVDs) such as hypertension and cardiac fibrosis. However, its role in autophagy following M-I/R injury is yet to be fully elucidated. Here, we found that CARD9 expression increased in M-I/R mouse hearts, and in H9c2 or neonatal rat ventricular myocytes (NRVMs) in response to hypoxia/reoxygenation (H/R) or H2O2. CARD9−/− mice exhibited a significant cardiac dysfunction following M-I/R injury (30 min of left ascending coronary (LAD) ischemia and 12 h of reperfusion) compared to wild-type (WT) mice. CARD9 deletion impaired autophagy during M-I/R in vivo and in vitro, evidenced by decrease of microtubule-associated protein 1 light chain 3 (LC3) lipidation and p62 accumulation. Conversely, CARD9 overexpression increased autophagic flux as indicated by enhanced expression of LC3 II/LC3 I and a reduction in p62. The protective effect of CARD9 on cardiomyocytes against H/R-induced oxidative stress was abolished by treatment with autophagy inhibitors, 3-methyladenine (3-MA) or Bafilomycin A1(BafA1). CARD9 interacted with RUN domain Beclin-1-interacting cysteine-rich-containing (Rubicon), a negative regulator of autophagy, and enhanced UV-irradiation-resistance-associated gene (UVRAG)-Beclin1-phosphatidylinositol 3-kinase catalytic subunit type 3 (PI3KC3) interaction and UVRAG-Vps16-mediated Rab7 activation to promote autophagosome formation, maturation, and endocytosis. Ablation of Rubicon by siRNA effectively prevented the detrimental effect of CARD9 knockdown on cardiomyocytes. These results suggest that CARD9 has protective effects on the myocardium against M-I/R injury by activating autophagy and restoring autophagic flux in vivo and in vitro.