关键词： ACMG/AMP   AlphaMissense   BP4   PP3   TP53   bioinformatic predictions   protein stability   relative solvent accessibility   variant classification   ΔΔG  

摘要： The clinical classification of germline missense variants and single-amino-acid deletions is challenging. The BayesDel and Align-GVGD bioinformatic prediction tools currently used for ClinGen TP53 variant curation expert panel (VCEP) classification do not directly capture changes in protein folding stability, measured using computed destabilization energies (ΔΔG scores). The AlphaMissense tool recently developed by Google DeepMind to predict pathogenicity for all human proteome missense variants is trained in part using AlphaFold2 architecture. Our study investigated whether protein folding stability and/or AlphaMissense scores could improve impact prediction for p53 missense and single-amino-acid deletion variants. ΔΔG scores were calculated for missense variants using FoldX and for single-amino-acid deletions using an AlphaFold2/RosettaRelax protocol. Residue surface exposure was categorized using relative solvent accessibility (RSA) measures. The predictive values of ΔΔG scores, AlphaMissense, BayesDel, and Align-GVGD were examined using Boruta and binary logistic regression based on functionally defined reference sets. The likelihood ratio (LR) toward pathogenicity was estimated and used to refine optimal categories for predicting variant pathogenicity for different RSA values. We showed that current VCEP predictive approaches for missense variants were improved by integrating ΔΔG scores ≥2.5 kcal/mol for partially buried and buried residues, but better performance was achieved using AlphaMissense with ΔΔG and RSA. For deletion variants, ΔΔG scores ≥4.8 Rosetta energy unit (REU) in buried residues outperformed currently used predictive approaches. Future TP53 VCEP specifications for p53 missense impact prediction may consider AlphaMissense, ΔΔG score, and RSA combined for substitution variants and ΔΔG score alone for deletion variants.

关键词： Iterative methods  

摘要： Allosteric signaling in proteins allows perturbations at one locale to modulate activity at an orthosteric distant site. This may explain how distal mutations disrupt protein activity and offer pathways for the development of allosteric therapeutics, a novel class of restorative compounds to reactivate native function. Despite the ubiquitous presence of allosteric control in nature and the promises that it holds for treating currently untreatable diseases, quantitative theory of the mechanism of allostery is lacking. Working to fill this critical gap, we have developed a novel method to identify groups of covarying residues which the sector hypothesis suggests are capable of transmitting allosteric signals in proteins. A major problem with sectors computed from covariance measures is the selection relies upon a full covariance matrix rather than on the covariance among the residues posited to be in the sector. We demonstrate a novel method which constructs sectors on the basis of cohesion within the residues in the sector to eliminate the incongruity between the sector idea and the way it is calculated. Furthermore, the refinement can be iteratively applied, enabling the extraction of more than one sector in a well-defined, systematic manner. In this study, we report on the development of MD multi-sector selector and its application to allosteric signaling in the tumor suppressor protein p53. We consider the implications of our findings on our long-term goal of allosterically reactivating mutant p53 as a means of curing cancer, and critically assess the broader applicability of MD multi-sector selector across diverse fields.

关键词： 早期口腔运动干预   早产儿   喂养   Meta分析  

摘要： 目的系统、科学地评价和分析早期口腔运动干预(oral motor intervention,OMI)对早产儿喂养效果影响的相关研究,为喂养护理研究实践提供参考依据。方法通过计算机检索PubMed、Embase、Cochrane Library、Web of Science、Clinical Trial、中国生物医学文献数据库、中国知网、万方数据库和维普数据库中对早产儿实施早期口腔运动干预的相关研究,检索时间为建库至2024年3月。由至少2名学者独立完成文献筛选、数据提取和分析,采用RevMan 5.4软件对纳入研究进行Meta分析。结果共纳入19篇随机对照试验,共计1429例早产儿。Meta分析结果显示,与早产儿常规护理干预相比,早期口腔运动干预可以显著减少早产儿完全经口喂养过渡时间[MD=-3.08,95%CI(-4.96,-4.17),P<0.001],缩短住院时间[MD=-3.40,95%CI(-4.02,-2.77),P<0.001],提高喂养效率[MD=1.79,95%CI(1.45,2.13),P<0.001],增加摄奶量比[MD=0.07,95%CI(0.02,0.12),P<0.001],降低喂养不耐受发生率[RR=0.36,95%CI(0.24,0.53),P<0.001]。结论对早产儿实施早期口腔运动干预,可以有效降低部分早产儿喂养不耐受发生率,缩短早产儿对完全经口实施喂养要求的住院过渡时间、住院恢复时间,提高早产儿喂养活动的完成效率和总摄奶量占比,建议临床推广使用。

关键词： 3D打印   传统经皮微创接骨板内固定术   复杂肱骨近端骨折   对比  

摘要： 分析3D打印与传统经皮微创接骨板内固定术治疗复杂肱骨近端骨折对比。方法 选择我院2023年6月-2024年6月复杂肱骨近端骨折患者共108例,随机分2组比对,对照组以传统经皮微创接骨板内固定术治疗,观察组在对照组基础上增加3D打印。比较两组手术时间和骨折愈合时间、肩关节功能、并发症。结果 观察组手术时间短于对照组,P<0.05,骨折愈合时间两组无显著差异,P>0.05。观察组肩关节功能优于对照组,P<0.05。两组无明显差异,P>0.05。结论 3D打印技术与传统经皮微创接骨板内固定术的结合,为复杂肱骨近端骨折患者提供了一种全新的治疗选择。它不仅能够有效缩短手术时间,还能显著改善患者的肩关节功能,同时保持较高的手术安全性。这一发现无疑为未来的骨折治疗开辟了新的道路,为更多的患者带来了康复的希望。

关键词： 2型糖尿病   代谢综合征   司美格鲁肽   达格列净   腹部脂肪分布   白脂素   Spexin  

摘要： 目的探讨司美格鲁肽联合达格列净对2型糖尿病(T2DM)合并代谢综合征(MS)患者腹部脂肪分布及血清白脂素(Asprosin)、Spexin水平的影响。方法选取2022年1月—2024年1月新疆克拉玛依市中西医结合医院(市人民医院)内分泌肾病科诊治T2DM合并MS患者104例,按治疗方案不同分为2组。以接受达格列净治疗的患者52例为对照组,以接受司美格鲁肽联合达格列净治疗的患者52例为观察组,均治疗3个月,比较2组治疗前后糖代谢指标[空腹血糖(FPG)、糖化血红蛋白(HbA _(1c))]、胰岛功能相关指标[胰岛素抵抗指数(HOMA-IR)、胰岛β细胞功能指数(HOMA-β)]、脂代谢指标[总胆固醇(TC)、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)]、体质量、内脏脂肪面积(VFA)、皮下脂肪面积(SFA)、血清Asprosin与Spexin水平及不良反应发生率。结果与治疗前比较,治疗3个月后2组FPG、HbA _(1c)降低,且观察组低于对照组(t/P=4.579/<0.001,4.714/<0.001);2组HOMA-IR较治疗前降低,HOMA-β较治疗前升高,且观察组降低/升高幅度大于对照组(t/P=6.109/<0.001,6.771/<0.001);2组TC、TG、LDL-C较治疗前降低,HDL-C较治疗前升高,且观察组降低/升高幅度大于对照组(t/P=4.725/<0.001,7.748/<0.001,4.647/<0.001,6.596/<0.001);2组体质量、VFA及SFA较治疗前降低,且观察组低于对照组(t/P=2.363/0.020,6.089/<0.001,4.116/<0.001);2组血清Asprosin水平较治疗前降低,血清Spexin水平较治疗前升高,且观察组降低/升高大于对照组(t/P=6.111/<0.001,5.007/<0.001);2组不良反应发生率比较,差异无统计学意义(P>0.05)。结论司美格鲁肽联合达格列净治疗T2DM合并MS患者,可调节血清Asprosin、Spexin水平,改善糖脂代谢及胰岛素抵抗,同时可以降低体质量及VFA、SFA,且安全性高。

关键词： MN9D细胞   帕金森病   长链非编码RNA   HOTAIRM1   细胞凋亡  

摘要： 目的:探讨长链非编码RNA(lncRNA)骨髓特异性HOX基因转录本反义RNA 1(HOTAIRM1)对1-甲基-4-苯基吡啶离子(MPP+)处理后的MN9D细胞活力和凋亡的影响。方法:将不同浓度(0、0.25、0.5、1、1.25、2.5 mmol/L)的MPP+作用于MN9D细胞不同时间(0、24、48和72 h)后,采用CCK-8检测各组细胞活力,选择MPP+最适浓度和最佳作用时间进行后续试验。选用siRNA进行转染,将MN9D细胞分为对照组、MPP+处理组(1 mmol/L MPP+处理24 h)、siRNA对照组(siRNA阴性对照序列转染1 h后用1 mmol/L MPP+处理24 h),和siR-HOTAIRM1干扰组(siR-HOTAIRM1转染1 h后用1 mmol/L MPP+处理24 h)。分别采用CCK-8检测各组细胞活力;实时荧光定量逆转录PCR(qRT-PCR)检测各组细胞中lncRNA HOTAIRM1的表达;流式细胞术检测各组细胞凋亡情况。结果:与对照组比较,不同浓度MPP+处理24 h,细胞活力随浓度的升高而降低(P<0.05),而lncRNA HOTAIRM1表达水平逐渐升高(P<0.05);1 mmol/L MPP+处理不同时间后,细胞活力明显下降(P<0.05),lncRNA HOTAIRM1表达水平先升高后降低(P<0.05),故选择1 mmol/L MPP+处理24 h进行后续试验。与转染siRNA阴性对照序列组相比,siR-HOTAIRM1干扰之后,lncRNA HOTAIRM1表达显著降低(P<0.01),但显著增强MPP+处理后的MN9D细胞的活力(P<0.01);明显抑制MPP+处理后的MN9D细胞的凋亡(P<0.01),从而保护MN9D细胞。结论:干扰lncRNA HOTAIRM1的表达可增强MPP+处理后的MN9D细胞活力,并抑制细胞凋亡。lncRNA HOTAIRM1敲低对MPP+处理后的MN9D细胞损伤具有保护作用。

关键词： 高渗盐水   甘露醇   颅内压   创伤性   Meta分析  

摘要： 目的系统评价高渗盐水与甘露醇治疗创伤性颅高压的安全性和有效性。方法利用计算机检索PubMed、Embase、The Cochrane Library、万方数据知识服务平台、中国知网等数据库关于高渗盐水与甘露醇治疗创伤性颅高压疗效的随机对照研究,检索时间截至2023年9月25日。根据异质性检验结果采用固定效应模型或随机效应模型分析高渗盐水与甘露醇降低颅内压效果、血清钠、血清渗透压、血清尿素氮、死亡率和功能预后良好(格拉斯哥预后评分4~5分)率等方面的差异。结果共纳入文献7篇创伤性颅高压患者479例,包括高渗盐水组256例,甘露醇组223例。两组患者在降低颅内压效果[加权平均差(WMD)=-0.19,95%CI:-0.61~0.24]、血清渗透压(WMD=-0.26,95%CI:-2.98~2.47)、血清尿素氮(WMD=-1.42,95%CI:-3.86~1.03)、死亡率(RR=0.71,95%CI:0.43~1.18)、功能预后良好率(RR=0.92,95%CI:0.61~1.38)方面比较,差异均无统计学意义(均P>0.05);高渗盐水组血清钠明显高于甘露醇组,差异有统计学意义(WMD=7.49,95%CI:4.67~10.31,P<0.001)。结论高渗盐水治疗创伤性颅高压具有良好的临床疗效和安全性,可作为甘露醇的替代药物。