Mapping molecular binding by means of conformational dynamics measurements

Protein–protein interactions are key in virtually all biological processes. The study of these interactions and the interfaces that mediate them play a key role in the understanding of biological function. In particular, the observation of protein–protein interactions in their dynamic environment is technically difficult. Here two surface analysis techniques, dual polarization interferometry and quartz crystal microbalance with dissipation monitoring, were paired for real-time mapping of the conformational dynamics of protein–protein interactions. Our approach monitors this dynamics in real time and in situ, which is a great advancement within technological platforms for drug discovery. Results agree with the experimental observations of the interaction between the TRIM21α protein and circulating autoantibodies via a bridging bipolar mechanism. This work provides a new chip-based method to monitor conformational dynamics of protein–protein interactions, which is amenable to miniaturized high-throughput determination.

Protein–protein interactions are key in virtually all biological processes.     

Intramolecular radical cyclization approach to access highly substituted indolines and 2,3-dihydrobenzofurans under visible-light

The combination of visible-light and tris(trimethylsilyl)silane promoting intramolecular reductive cyclization protocol for the synthesis of functionalized indolines and 2,3-dihydrobenzofurans has been developed. The transformations occur in the absence of transition metal and additional photocatalyst. In addition, quantum yield (Φ) was determined and electron paramagnetic resonance spectroscopy was performed to better understand the reaction pathway.

The combination of visible-light and tris(trimethylsilyl)silane promoting intramolecular reductive cyclization protocol for the synthesis of functionalized indolines and 2,3-dihydrobenzofurans has been developed.     

Frailty Syndrome in Association with Depressive Symptoms and Functional Disability among Hospitalized Elderly

ABSTRACT

We sought to examine the frailty association with depression and functional disability in hospitalized older adults. In particular, we compared non-frail, pre-frail, and frail elderly hospitalized individuals. We performed a cross-sectional study with 255 hospitalized Brazilian elderly patients. We used a structured instrument to assess socio-economic data, the Fried frailty phenotype and used morbidity scales (Geriatric Depression; Katz; Lawton and Brody). The adjusted analysis revealed that frail elderly exhibit increased odds ratios (OR) for depressive symptoms (OR = 2.72, 95% CI: 1.12–6.62), disability related to basic activities (OR = 3.50, 95% CI: 1.26–9.60), and instrumental daily living (OR = 2.70, 95% CI: 1.12–6.44). Frailty in hospitalized older adults is associated with depressive symptomatology and functional disability.     

BKCa Channel Activation Attenuates the Pathophysiological Progression of Monocrotaline-Induced Pulmonary Arterial Hypertension in Wistar Rats

Cardiovascular Drugs and Therapy - In the present study, the therapeutic efficacy of a selective BKCa channel opener (compound X) in the treatment of monocrotaline (MCT)-induced pulmonary arterial...     

Neuronal activity regulated pentraxin (narp) and GluA4 subunit of AMPA receptor may be targets for fluoxetine modulation

Fluoxetine is the foremost prescribed antidepressant. Drugs acting on monoaminergic system may also regulate glutamatergic system. Indeed, the investigation of proteins associated with this system, such as Narp (neuronal activity-dependent pentraxin) and GluA4 subunit of AMPA receptor may reveal poorly explored modulations triggered by conventional antidepressants. This study aimed to uncover neurochemical mechanisms underlying the chronic fluoxetine treatment, mainly by evaluating these protein targets in the prefrontal cortex and in the hippocampus. Mice received a daily administration of fluoxetine (0.1, 1 or 10 mg/kg, p.o.) or potable water (vehicle group) for 21 days. These animals were submitted to the forced swim test (FST) to verify antidepressant-like responses and the open-field test (OFT) to assess locomotor activity. Modulation of signaling proteins was analyzed by western blot. Chronic treatment with fluoxetine (1 and 10 mg/kg) was effective, since it reduced the immobility time in the FST, without altering locomotor activity. Fluoxetine 10 mg/kg increased CREB phosphorylation and BDNF expression in the prefrontal cortex and hippocampus. Noteworthy, in the hippocampus fluoxetine also promoted Akt activation and augmented Narp expression. In the prefrontal cortex, a significant decrease in the expression of the GluA4 subunit and Narp were observed following fluoxetine administration (10 mg/kg). The results provide evidence of novel molecular targets potentially involved in the antidepressant effects of fluoxetine, since in mature rodents Narp and GluA4 are mainly expressed in the GABAergic parvalbumin-positive (PV+) interneurons. This may bring new insights into the molecular elements involved in the mechanisms underlying the antidepressant effects of fluoxetine.

     

Water-based resistance training program with isolated concentric action improves physical functional capacity and muscular strength in older women

Background

Resistance training has proven to be an excellent method for counteracting aging physical dysfunctions. However, its application in the liquid environment is not yet fully elucidated.

Aim

To investigate the effects of water-based resistance training (WBRT) with the concentric phase performed as fast as possible, compared to conventional resistance training (CRT), on physical functional capacity, muscle strength, and body composition in older women.

Methods

Thirteen healthy older women participated in the WBRT and 11 in the CRT. Estimation statistics focused on the effect size of the experiment/intervention were used. We also analyzed the intervention effect based on the percentage delta between WBRT and CRT.

Results

The WBRT group showed a negative large effect (d?=?? 0.922; p?=?0.0274) for the timed up and go, and a large effect for chair rise in 30″ and the elbow flex test (d?=?1.58; p?=?0.0012; d?=?2.8; p?=?0.01) respectively. Intervention comparisons based on the delta percentage between WBRT and CRT presented an intermediate effect (d?=?0.606; p?=?0.157) for the stair climb, a large effect (d?=?0.988; p?=?0.0282) for the timed up and go, and a large negative effect [d?=?? 1.32 (90.0% CI ? 1.92, ? 0.646); p?=?0.0038] for the elbow flex test. Concentric extensor-flexor peak torque (60°/s) showed an intermediate effect (d?=?0.749; p?=?0.0876; d?=?0.65; p?=?0.122 respectively). Body fat (%) demonstrated an intermediate effect (d?=?0.523; p?=?0.234).

Conclusion

WBRT with the concentric phase performed as fast as possible was able to improve physical functional capacity and maximal knee extension strength of older women.

     

Binding of heme by glutathione S-transferase: a possible role of the erythrocyte enzyme

Human erythrocyte glutathione S-transferase activity is inhibited, probably competitively, by hemin with a Ki of 10(-7) M. It is postulated that glutathione S-transferase functions physiologically as a hemin-binding and/or transport protein in developing erythroid cells.     

乐胃煎逆转胃癌前病变AgNOR及细胞图像分析

目的研究乐胃煎逆转胃癌前病变不完全结肠型肠化和／或中度异型增生的疗效．方法胃镜病理证实为不完全结肠型肠化和／或中度异型增生４６例．治疗组３０例用乐胃煎，对照组１６例用德诺（Ｄｅ＿Ｎｏｌ）．治疗前后胃镜活检胃窦固定部位粘膜标本作ＡｇＮＯＲ染色及细胞图像分析．结果乐胃煎对不完全结肠型肠化及中度异型增生总有效率均高于Ｄｅ＿Ｎｏｌ，分别为７２％比２５％（Ｐ＜００５）和８９５％比４４４％（Ｐ＜００５）．乐胃煎治疗前后，ＡｇＮＯＲ计数分别为７３０±１１６和４８１±１５０（Ｐ＜００１），Ｄｅ＿Ｎｏｌ组为７７３±０９２和７０５±１０２（Ｐ＜００１）．两组治疗前后ＡｇＮＯＲ计数差值均数相比，统计学上也有显著性差异，分别为２５２±１５４和０６９±０４８（Ｐ＜００１）．乐胃煎组中２０例作细胞图像分析，治疗后各参数（长轴、短轴、核浆比、结构异型指数等）均有不同程度的降低，有显著性差异．结论乐胃煎确有较好地逆转胃癌前病变的功效．     

Treatment of iron deficiency anemia with liposomal iron in inflammatory bowel disease: efficacy and impact on quality of life

International Journal of Clinical Pharmacy - Background Anemia is a clinical condition frequently seen in patients with inflammatory bowel disease, which is responsible for a significant loss of...     

Complement factor H gene (CFH) polymorphisms C-257T,G257A and haplotypes are associated with protection against severe dengue phenotype,possible related with high CFH expression

Four genetic polymorphisms located at the promoter (C-257T) and coding regions of CFH gene (exon 2 G257A, exon 14 A2089G and exon 19 G2881T) were investigated in 121 dengue patients (DENV-3) in order to assess the relationship between allele/haplotypes variants and clinical outcomes. A statistical value was found between the CFH-257T allele (TT/TC genotypes) and reduced susceptibility to severe dengue (SD). Statistical associations indicate that individuals bearing a T allele presented significantly higher protein levels in plasma. The −257T variant is located within a NF-κB binding site, suggesting that this variant might have effect on the ability of the CFH gene to respond to signals via the NF-κB pathway. The G257A allelic variant showed significant protection against severe dengue. When CFH haplotypes effect was considered, the ancestral CG/CG promoter-exon 2 SNP genotype showed significant risk to SD either in a general comparison (ancestral × all variant genotypes), as well as in individual genotypes comparison (ancestral × each variant genotype), where the most prevalent effect was observed in the CG/CG × CA/TG comparison. These findings support the involvement of −257T, 257A allele variants and haplotypes on severe dengue phenotype protection, related with high basal CFH expression.