血清Cys-C、TBiL、MR-proADM、AGEs与老年慢性心力衰竭患者心功能和心脏再同步化治疗应答的关系研究

摘要 目的：探讨血清胱抑素C（Cys-C）、总胆红素（TBiL）、肾上腺髓质中段肽（MR-proADM）、晚期糖基化终末产物（AGEs）与老年慢性心力衰竭（CHF）患者心功能和心脏再同步化治疗（CRT）应答的关系。方法：选择2020年3月至2022年1月我院收治的151例接受CRT治疗的老年CHF患者为研究对象,随访6个月,统计治疗应答情况。CRT治疗前检测血清Cys-C、TBiL、MR-proADM、AGEs水平,超声心动图检测心功能,分析血清Cys-C、TBiL、MR-proADM、AGEs与心功能的相关性以及与老年CHF患者CRT治疗应答的关系。结果：151例患者失访1例,余150例患者中无应答48例（无应答组）,应答102例（应答组）。无应答组血清Cys-C、TBiL、MR-proADM、AGEs水平均高于应答组（P＜0.05）,且与左心室射血分数（LVEF）呈负相关（P＜0.05）,与左室舒张末期内径（LVEDD）和左室收缩末期内径（LVESD）呈正相关（P＜0.05）。多因素Logistic回归分析结果显示缺血性心肌病、血清Cys-C、TBiL、MR-proADM、AGEs是老年CHF患者CRT治疗无应答的危险因素（P＜0.05）,LVEF是保护因素（P＜0.05）。结论：CRT治疗无应答老年CHF患者血清Cys-C、TBiL、MR-proADM、AGEs水平升高,且与心功能下降有关。血清Cys-C、TBiL、MR-proADM、AGEs是CRT治疗无应答的危险因素,可为CRT治疗效果评估提供一定的参考。     

铜蓝蛋白、鳞状细胞癌相关抗原与慢性肾功能衰竭的关系及对病情进展的预测价值研究

摘要 目的：分析铜蓝蛋白（CER）、鳞状细胞癌相关抗原（SCCA）与慢性肾功能衰竭的关系及对病情进展的预测价值。方法：选择我院自2019年4月至2021年4月接诊的169例慢性肾功能衰竭患者作为研究对象,根据24 h尿白蛋白定量分为微量白蛋白尿组（＜200 mg/24 h,102例）和大量白蛋白尿组（＞200 mg/24 h,67例）。比较两组各项实验室指标及血清CER、SCCA水平,分析CER、SCCA与慢性肾功能衰竭患者肾功能指标的关系。随访12个月,观察病情进展,使用受试者工作特征曲线（ROC）评价血清CER联合SCCA对病情进展的预测效能。结果：大量白蛋白尿组血清肌酐（Scr）、血尿素氮（BUN）水平均明显高于微量白蛋白尿组,肾小球滤过率（GFR）低于微量白蛋白尿组（P＜0.05）;大量白蛋白尿组血清CER、SCCA水平均高于微量白蛋白尿组（P＜0.05）;经Pearson相关性分析,慢性肾功能衰竭患者血清CER、SCCA水平均与Scr、BUN呈正相关,与GFR呈负相关（P＜0.05）;经多因素Logistic回归分析,GFR、CER、SCCA均是慢性肾功能衰竭患者病情进展的独立预测因素（P＜0.05）;经ROC曲线分析,血清CER联合SCCA预测慢性肾功能衰竭患者病情进展的AUC为0.925,明显大于GFR的0.620（P＜0.05）。结论：血清CER、SCCA水平与慢性肾功能衰竭患者肾功能呈负相关,联合预测病情进展效能较好,值得临床予以重视应用。     

新生血管性年龄相关性黄斑变性对抗VEGF治疗的耐药性危险因素分析

摘要 目的：探究新生血管性年龄相关性黄斑变性对抗血管内皮生长因子（VEGF）治疗的耐药性危险因素。方法：选取2019年5月至2021年5月于我院接受治疗的90例nAMD患者作为研究对象,进行VEGF治疗,根据患者的耐药情况将其分为耐药组（n=19）和非耐药组（n=71）,统计患者资料,对比分析产生耐药性的危险因素。结果：危险因素与AMD类型、PED、椭圆体带完整性、积液、出血、BCVA、眼压、CRT异常有关（P<0.05）,危险因素与性别和平均年龄无关（P>0.05）;Ⅰ型CNV患者在VEGF治疗前后CRT水平未出现显著变化（P>0.05）,II型CNV患者和混合型CNV患者治疗前后CRT水平均显著降低（P<0.05）。Logistic回归分析显示：最终进入主效应模型的因素即抗VEGF治疗的耐药性发生的多因素为积液、PED、出血、AMD类型。结论：新生血管性年龄相关性黄斑变性（nAMD）对抗VEGF治疗出现耐药性与积液、出血和AMD类型有关。     

醒脑开窍针法联合颞三针治疗急性脑梗死的疗效及对患者生活质量、血流动力学的影响

摘要 目的：评价醒脑开窍针法联合颞三针治疗急性脑梗死（ACI）的疗效及对患者生活质量、血流动力学的影响。方法：选入2022年1月~2022年12月我院收治的ACI患者70例,根据治疗方法不同分为常规组（常规治疗）和联合组（常规治疗+醒脑开窍针+颞三针）,各35例。评价并比较两组的临床疗效、生活质量及血流动力学等指标。结果：联合组治疗总有效率94.29 %,显著高于常规组的74.29 %（P＜0.05）;与治疗前相比,两组治疗后NIHSS评分明显降低、BI和SS-QOL评分显著升高（P＜0.05）,而联合组降低/升高幅度更大,与常规组差异显著（P＜0.05）;两组治疗前脑血流动力学指标无明显差异（P＞0.05）,而治疗后,联合组大脑中动脉Vs、Vd、Vm明显高于常规组（P＜0.05）。结论：在常规治疗基础上应用醒脑开窍针联合颞三针,可有效提高ACI的临床疗效,增加大脑局部血流量,改善神经功能缺损症状,提高日常生活能力及生活质量。     

温针灸联合平衡针刀对椎动脉型颈椎病患者椎动脉血流、颈椎关节活动度及生活质量的影响

摘要 目的：探讨椎动脉型颈椎病（CSA）患者应用温针灸联合平衡针刀治疗对椎动脉血流、颈椎关节活动度及生活质量的影响。方法：选取首都医科大学附属北京中医医院于2020年1月-2023年1月收治的150例CSA患者,按治疗方案的不同进行分组,对照组（75例）行温针灸治疗,研究组（75例）行温针灸联合平衡针刀治疗,对比两组疗效、生活质量、颈椎关节活动度、颈椎功能、椎动脉血流指标。结果：研究组96.00%（72/75）治疗总有效率高于对照组81.33%（61/75）（P＜0.05）;研究组治疗后左椎动脉收缩期峰值血流速度、右椎动脉收缩期峰值血流速度高于对照组（P＜0.05）;研究组治疗后3周屈伸活动角度、旋转活动角度高于对照组（P＜0.05）;研究组治疗后1周、2周及3周NDI评分较对照组均更低（P＜0.05）;研究组治疗后健康调查简表（SF-36）各项评分高于对照组（P＜0.05）。结论：CSA应用温针灸联合平衡针刀治疗,可改善颈椎关节活动度,促进颈椎功能恢复,有利于椎动脉血流状况改善,并提高生活质量。     

小檗碱对缺血性脑梗死大鼠氧化应激/炎症反应、血管生成的作用研究

摘要 目的：探讨小檗碱对缺血性脑梗死大鼠氧化应激/炎症反应、血管生成的作用。方法：选取60只SPF级SD大鼠,随机分为对照组、模型组和小檗碱组各20只。建立大鼠脑缺血再灌注损伤模型。术后及给药后7d采用Longa标准评分评估大鼠神经功能。检测各组大鼠脑组织的抗氧化活性和炎症因子水平。采用免疫组化检测脑缺血再灌注皮质微血管密度（MVD）。采用实时定量聚合酶链反应（qRT-PCR）检测低氧诱导生长因子- 1 （HIF-1 ）和血管内皮生长因子（VEGF） mRNA表达水平。采用蛋白免疫印迹试验检测VEGF和HIF-1 蛋白表达水平。结果：模型组和小檗碱组大鼠术后具有神经功能缺损症状表现,Longa评分均高于对照组。给药7 d后,模型组和小檗碱组大鼠Longa评分均高于对照组（P＜0.05）,且小檗碱组大鼠Longa评分低于模型组（P＜0.05）。与对照组比较,模型组丙二醛（MDA）水平显著升高,而谷胱甘肽过氧化物酶（GSH-Px）和超氧化物岐化酶（SOD）活性显著降低（P＜0.05）。与模型组比较,小檗碱组MDA水平显著降低,而GSH-Px和SOD活性显著升高（P＜0.05）。与对照组比较,模型组白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）水平显著升高（P＜0.05）。与模型组比较,小檗碱组IL-1β、TNF-α水平显著降低,差异有统计学意义（P＜0.05）。给药7 d后,模型组和小檗碱组MVD、VEGF mRNA和HIF-1 mRNA表达水平均高于对照组（P＜0.05）,而小檗碱组MVD、VEGF mRNA和HIF-1 mRNA表达水平高于模型组（P＜0.05）。给药7 d后,小檗碱组和模型组VEGF和HIF-1 蛋白表达水平均高于对照组（P＜0.05）,而小檗碱组VEGF和HIF-1 蛋白表达水平高于模型组（P＜0.05）。结论：小檗碱通过抑制氧化应激/炎症反应、促进血管生成从而达到脑保护作用,其机制可能与激活HIF-1 /VEGF信号通路有关。     

不同anti-VEGF药物联合玻璃体切除术治疗增殖型糖尿病性视网膜病变效果及对视力水平的影响

摘要 目的：研究不同anti-VEGF药物联合玻璃体切除术治疗增殖型糖尿病性视网膜病变（PDR）效果及对视力水平的影响。方法：随机将2016年4月～2022年6月甘肃省人民医院收治的268例PDR患者分为雷珠单抗组（88例）、康柏西普组（90例）和阿柏西普组（90例）,雷珠单抗组行雷珠单抗注射联合玻璃体切除术,康柏西普组行康柏西普注射联合玻璃体切除术,阿柏西普组行阿柏西普联合玻璃体切除术,观察三组患者的临床治疗效果,并检测其术前、术后7 d和28 d后的血管内皮细胞生长因子（VEGF）和促红细胞生长素（EPO）、最佳矫正视力（BCVA）、黄斑中心凹厚度（CMT）和眼压。结果：三组治疗总有效率比较,差异无统计学意义（P＞0.05）。康柏西普组、阿柏西普组治疗7 d后VEGF、EPO水平明显低于雷珠单抗组（P＜0.05）。康柏西普组、雷珠单抗组治疗7 d后BCVA水平明显低于阿柏西普组;康柏西普组、阿柏西普组治疗7 d后CMT水平低于雷珠单抗组（P＜0.05）。三组治疗前、治疗7 d后、治疗28 d后眼压比较,差异无统计学意义（P＞0.05）。结论：雷珠单抗、康柏西普、阿柏西普联合玻璃体切除术在PDR治疗中均具有较为显著的治疗效果,但康柏西普和阿柏西普在减少黄斑厚度方面效果更为显著,而雷珠单抗与康柏西普在改善视力方面效果更明显。     

认知康复训练联合高频重复经颅磁刺激对脑卒中后认知障碍患者认知功能和血清BDNF、VEGF的影响

摘要 目的：观察脑卒中后认知障碍（PSCI）患者在认知康复训练基础上辅助高频重复经颅磁刺激（rTMS）治疗后,其认知功能和血清脑源性神经营养因子（BDNF）、血管内皮生长因子（VEGF）水平变化。方法：选择我院2020年1月~2020年12月期间接收的300例PSCI患者,以随机数字表法将患者分为实验组（150例）、对照组（150例）。对照组在常规治疗基础上联合认知康复训练,实验组则在对照组的基础上联合高频rTMS。对比两组认知功能、日常生活能力、听觉事件相关电位、血清BDNF和VEGF水平及不良反应。结果：两组治疗4周后蒙特利尔认知评估量表（MoCA）各条目评分及总分均较治疗前升高,且实验组高于对照组（P<0.05）。两组治疗4周后改良Barthel指数（MBI）评分较治疗前升高,且实验组高于对照组（P<0.05）。实验组治疗4周后P300潜伏期短于对照组,P300波幅高于对照组（P<0.05）。两组治疗4周后血清BDNF、VEGF水平升高,且实验组高于对照组（P<0.05）。两组不良反应发生率组间对比无统计学差异（P>0.05）。结论：认知康复训练联合高频rTMS可有效改善PSCI患者认知功能,上调其血清BDNF、VEGF水平,改善听觉事件相关电位,从而提高患者日常生活能力。     

清热化痰、宣肺解痉法治疗支气管哮喘的临床疗效及对气道呼吸参数、生活质量的影响

摘要 目的：探讨清热化痰、宣肺解痉法治疗支气管哮喘的临床疗效及对气道呼吸参数、生活质量的影响。方法：选取我院2019年10月到2021年9月收治的60例支气管哮喘患者作为研究对象,分为观察组与对照组,每组30例。对照组予吸入布地奈德福莫特罗粉吸入剂,观察组在对照组基础上增加清热化痰宣肺解痉法治疗,对比两组患者临床疗效,治疗前与治疗1个月后的中医证候积分变化,气道呼吸参数变化,炎症因子以及生活质量变化。结果：观察组总有效率较对照组高（P<0.05）;两组患者治疗前中医证候积分对比无差异（P＞0.05）,治疗后降低,且观察组低于对照组（P＜0.05）;两组患者治疗前第1秒用力呼气容积（FEV₁）、用力肺活量（FVC）、第1s用力呼气量/用力肺活量（FEV₁/FVC）最大呼气流速（PEF）对比无明显差异（P＞0.05）,治疗后两组患者FVC、FEV₁、FEV₁/ FVC、PEF均有提升,且观察组高于对照组（P＜0.05）;两组患者治疗前肿瘤坏死因子-α（TNF-α）、转化生长因子-β1（TGF-β1）、基质金属蛋白-9（MMP-9）、血管内皮生长因子（VEGF）、干扰素-γ（IFN-γ）、白细胞介素-4（IL-4）水平对比无明显差异（P＞0.05）,治疗后两组患者TNF-α、TGF-β1、MMP-9、VEGF、IFN-γ、IL-4水平均明显降低,且观察组低于对照组（P＜0.05）;两组患者治疗前生活质量评分对比无差异（P＞0.05）,治疗后1个月生活质量相关评分均降低,且观察组较对照组低（P＜0.05）。结论：支气管哮喘患者在常规西医治疗基础上增加清热化痰宣肺解痉法治疗可减轻患者症状。另外可改善患者呼吸功能,降低炎症因子反应,提升患者生活质量。     

超声检查参数联合血清VEGF、Tg、Gal-1对甲状腺癌的诊断价值及其与淋巴结转移的关系

摘要 目的：探讨超声检查参数联合血清血管内皮生长因子（VEGF）、甲状腺球蛋白（Tg）、半乳糖血凝素-1（Gal-1）对于甲状腺癌的临床诊断价值及其与淋巴结转移的关系。方法：回顾性分析2017年6月至2020年6月入我院就诊的158例甲状腺肿瘤患者的临床资料。77例甲状腺癌患者纳入恶性组,81例甲状腺腺瘤患者纳入良性组,比较两组的超声检查参数及血清VEGF、Tg、Gal-1水平;此外,恶性组患者亚分组为淋巴结转移组（n=51）和无淋巴结转移组（n=26）,比较两组超声检查参数及血清VEGF、Tg、Gal-1水平。以受试者工作特征（ROC）曲线分析超声检查参数联合血清VEGF、Tg、Gal-1对甲状腺癌的诊断效能。采用Sprearman相关系数分析各指标水平变化与甲状腺癌患者发生淋巴结转移的相关性。结果：恶性组患者的血管化指数（VI）、血流指数（FI）及血清VEGF、Tg、Gal-1水平均高于良性组患者（P＜0.05）;淋巴转移组患者的VI、FI及血清VEGF、Tg、Gal-1水平均高于无淋巴结转移组患者（P＜0.05）;超声检查参数VI、FI联合血清VEGF、Tg、Gal-1诊断甲状腺癌的曲线下面积为0.933、敏感度为85.50%、特异度为80.00%,均明显高于五项指标单独检测。Spearman相关性分析结果显示,超声检查参数VI、FI以及血清VEGF、Tg、Gal-1与甲状腺癌患者淋巴结转移均呈正相关（P＜0.05）。结论：联合检测超声检查参数VI、FI及血清VEGF、Tg、Gal-1对甲状腺癌有较高的早期诊断价值,且上述指标均与患者淋巴结转移密切相关。     

Dermal cysts participate in reparative regeneration of epidermis in Hrhr/Hrhr mice

One of the phenotypic effects of mutation in the Hr gene in mice is disintegration of hair follicles and their degeneration into open funnel-shaped structures (utricles) opened on skin surface and cysts located in the depth of the dermis. The aim of the current study consists in analysis of the process of reparative regeneration of skin in homozygotous mice with one of the mutant alleles of the Hr gene—Hr ^hr . It is shown that epithelial cells that constitute the inner pavement of cysts take part in the process of epithelization of deep skin wounds. This indicates that the competence of ectodermal cells in relation to inductive signals from injured skin remains in Hr ^hr homozygote mice, in spite of the significant anatomic abnormalities of the hair follicles.     

Occurrence of N-malonyl-D-alanine in pea seedlings

One of the ninhydrin-negative alanine conjugates isolated from pea seedlings was identified as $\text{N-}\text{malonyl}\text{-}\text{D}\text{-}\text{alanine}$.The identification of this conjugate was carried out by a comparison of its gas-liquid chromatographic and mass spectrometric properties, and its nuclear magnetic resonance and infrared spectra with those of synthetic $\text{N-}\text{malonyl}\text{-}\text{D}\text{-}\text{alanine}$. The alanine in the conjugate was shown to be present as the D-isomer by enzymatic and chromatographic analyses.     

Stereochemistry of C-methylation in the biosynthesis of rhododendrin in Alnus and Betula

Using differently labelled precursors, it was established that rhododendrin (3-(4-hydroxyphenyl)-1-methylpropyl-β-D-glucopyranoside) is formed through the phenylpropane pathway via p-coumaryl alcohol, dihydro-p-coumaryl alcohol and C-methylation of the γ-C-atom of the C₆C₃ unit with methionine supplying the methyl group. It was demonstrated that the pro-(S)-hydrogen atom of dihydro-p-coumaryl alcohol is replaced stereospecifically by the methyl group.     

Desensitization of CholecystokininB Receptors in GH3 Cells

Abstract: Desensitization of the cholecystokinin (CCK) octapeptide (CCK-8)-induced rise in intracellular free calcium concentration ([Ca²⁺],) was characterized in GH₃ cells, a pituitary tumor cell line, which are known to possess CCK_B receptor subtype. The CCK-8-induced [Ca²⁺], transient was reduced following the initial application of CCK-8. A similar desensitization of the CCK-8-induced response was observed following the first application of thyrotropin-releasing hormone (TRH). By contrast, the TRH- induced response was not desensitized by the preceding application of CCK-8. Desensitization of the CCK-8-induced [Ca²⁺], transient was associated with diminished inositol 1,4,5-trisphosphate formation. The recovery of desensitization of the CCK-8-induced response was delayed by a phosphoserine/phosphothreonine phosphatase inhibitor, calyculin A (100 n M ). The responsiveness to CCK-8 was also reduced by phorbol 12, 13-dibutyrate (PDBu), and this effect of PDBu was completely abolished by preincubation with staurosporine. Staurosporine significantly attenuated the desensitization caused by preincubation with CCK-8, but this effect was too small to attribute the desensitization to the protein kinase C transduction pathway alone. It is likely that desensitization of CCK receptors involves multiple transduction pathways.     

Quantitation of Group-specificaAntigen in Hepatitis B Vaccines by Anti-HBs/aMonoclonal Antibody

Balb/c mice were immunized with aluminium hydroxide [alum, Al(OH)₃]-adjuvanted hepatitis B (HB) vaccines of subtypesadr,ayworadw. Spleen cells from the immune animals were fused with SP2/O cells. Eight hybridoma clones producing antibodies specific or HB surface antigen (HBsAg) were selected. Monoclonal antibodies (mAbs) of four clones were specific for group-specific antigen/a, and the other of four clones were specific for subtype antigen/d,y,r, orw. The anti-HBs/amAbs were classified into three non-competitive groups.Quantitation of group-specific determinantaof HBsAg (HBsAg/a) was performed by sandwich enzyme-linked immunosorbent assay (ELISA), in which a solid phase of anti-HBs guinea-pig polyclonal antibodies (pAb), the HBsAg for testing, anti-HBs/amouse mAb and horseradish peroxidase (HRP)-conjugated anti-mouse IgG were used.The unadsorbed HBsAg was used to establish the standard curve HBsAg/a. The lower detection limits were 0·5 to 1 ng/ml of HBsAg. Methods of solubilization of alum were investigated to quantify HBsAg/ain adsorbed HB vaccines. The recovery rate was more than 60% if vaccines were prediluted. The recovery of HBsAg/ain HB vaccines produced by the same manufacturer showed the similar recovery rate, and the contents of HBsAg/ain adsorbed HB vaccines could be estimated by the recovery rate determined for adsorbed HB vaccines.     

Effects of tRNALeu1 overproduction in Escherichia coli

Strains of Escherichia coli have been produced which express very high levels of the tRNA^leu₁ isoacceptor. This was accomplished by transforming cells with plasmids containing the leuV operon which encodes three copies of the tRNA^Leu₁ gene. Most transformants grew very slowly and exhibited a 15-fold increase in cellular concentrations of tRNA^Leu₁ As a result, total cellular tRNA concentration was approximately doubled and 56% of the total was tRNA^Leu₁. We examined a number of parameters which might be expected to be affected by imbalances in tRNA concentration: in vivo tRNA charging levels, misreading, ribosome step time, and tRNA modification. Surprisingly, no increase in intracellular ppGpp levels was detected even though only about 40% of total leucyl tRNA was found to be charged in vivo. Gross ribosomal misreading was not detected, and it was shown that ribosomal step times were reduced between two- and threefold. Analyses of leucyl tRNA isolated from these slow-growing strains showed that at least 90% of the detectable tRNA^Leu₁ was hypomodified as judged by altered mobility on RPC-5 reverse-phase columns, and by specific modification assays using tRNA(m¹G)-methyltransferase and pseudo-uridylate synthetase. Analysis of fast-growing revertants demonstrated that tRNA concentration per se may not explain growth inhibition because selected revertants which grew at wild-type growth rates displayed levels of tRNA comparable to that of control strains bearing the leuV operon. A synthetic tRNA^Leu₁ operon under the control of the T7 promoter was prepared which, when induced, produced six- to sevenfold increases in tRNA^Leu₁ levels. This level of tRNA^Leu₁ titrated the modification system as judged by RPC-5 column chromatography. Overall, our results suggest that hypomodified tRNA may explain, in part, the observed effects on growth, and that the protein-synthesizing system can tolerate an enormous increase in the concentration of a single tRNA.     

Engineered biosynthesis of bacteriochlorophyll gF in Rhodobacter sphaeroides

Engineering photosynthetic bacteria to utilize a heterologous reaction center that contains a different (bacterio) chlorophyll could improve solar energy conversion efficiency by allowing cells to absorb a broader range of the solar spectrum. One promising candidate is the homodimeric type I reaction center from Heliobacterium modesticaldum. It is the simplest known reaction center and uses bacteriochlorophyll (BChl) g, which absorbs in the near-infrared region of the spectrum. Like the more common BChls a and b, BChl g is a true bacteriochlorin. It carries characteristic C3-vinyl and C8-ethylidene groups, the latter shared with BChl b. The purple phototrophic bacterium Rhodobacter (Rba.) sphaeroides was chosen as the platform into which the engineered production of BChl g_F, where F is farnesyl, was attempted. Using a strain of Rba. sphaeroides that produces BChl b_P, where P is phytyl, rather than the native BChl a_P, we deleted bchF, a gene that encodes an enzyme responsible for the hydration of the C3-vinyl group of a precursor of BChls. This led to the production of BChl g_P. Next, the crtE gene was deleted, thereby producing BChl g carrying a THF (tetrahydrofarnesol) moiety. Additionally, the bchG^Rs gene from Rba. sphaeroides was replaced with bchG^Hm from Hba. modesticaldum. To prevent reduction of the tail, bchP was deleted, which yielded BChl g_F. The construction of a strain producing BChl g_F validates the biosynthetic pathway established for its synthesis and satisfies a precondition for assembling the simplest reaction center in a heterologous organism, namely the biosynthesis of its native pigment, BChl g_F.