Homology modeling in drug discovery: Overview,current applications,and future perspectives

Homology modeling is one of the computational structure prediction methods that are used to determine protein 3D structure from its amino acid sequence. It is considered to be the most accurate of the computational structure prediction methods. It consists of multiple steps that are straightforward and easy to apply. There are many tools and servers that are used for homology modeling. There is no single modeling program or server which is superior in every aspect to others. Since the functionality of the model depends on the quality of the generated protein 3D structure, maximizing the quality of homology modeling is crucial. Homology modeling has many applications in the drug discovery process. Since drugs interact with receptors that consist mainly of proteins, protein 3D structure determination, and thus homology modeling is important in drug discovery. Accordingly, there has been the clarification of protein interactions using 3D structures of proteins that are built with homology modeling. This contributes to the identification of novel drug candidates. Homology modeling plays an important role in making drug discovery faster, easier, cheaper, and more practical. As new modeling methods and combinations are introduced, the scope of its applications widens.     

Acute physiological responses to physiotherapy applications pre and post autologous stem cell transplantation: an experimental study

Objective

We aimed to investigate the acute physiological responses (APR) to physiotherapy applications in patients undergoing autologous stem cell transplantation (ASCT), the difference between pre- and post-ASCT according to APR.

Methods

Twenty-six patients who were hospitalized for ASCT attended regular physiotherapy program. APR was recorded in the beginning and at the end of each exercise session. The differences in APR were calculated for each session. The mean values of the differences in APR were computed in pre-conditioning, pre-, and post-ASCT. Daily complete blood counts were also recorded during ASCT.

Results

Hemoglobin and platelet counts were significantly lower pre- and post-ASCT. Neutrophil counts were significantly lower post-ASCT. The difference in systolic blood pressure (SBP) in the beginning and at the end of the exercise sessions was significantly higher post-ASCT in comparison to pre-ASCT.

Conclusion

There was no significant change in APR except the SBP which suggests that similar level of exercise intensity could be tolerated in pre- and post-ASCT periods as well as preconditioning.     

Life-Time Adversities,Reported Thirteen Years After a Suicide Attempt: Relationship to Recovery, 5HTTLPR Genotype,and Past and Present Morbidity

In this study, we investigated how adversities related to past and present morbidity, and genotype. Forty-two, suicide attempters and 22 matched control patients were followed-up after 13 years. Life-time adversities were explored in an interview, and the patients were reassessed psychiatrically. The serotonin-transporter-linked promotor region (5-HTTLPR) was typed. More adversities were reported by suicide attempters than controls, and by still-ill than recovered suicide attempters. Adversities reported at follow-up were related to psychiatric morbidity at follow-up, but not to morbidity 13 years earlier. The 5-HTTLPR, genotype was associated with reported adversities, but not chances of recovery. Adversities potentially affected chronic morbidity. 5-HTTLPR genotype did not affect long-term recovery.     

Efficacy of carbon dioxide-insufflating colonoscopy in patients with irritable bowel syndrome: A randomized double-blind study

Background and Aim: Colonoscopy has the disadvantage of pain and discomfort for patients. It has been shown in randomized controlled trials that carbon dioxide (CO₂) insufflations significantly reduce pain and discomfort in patients undergoing colonoscopy. However, there have been no studies in which CO₂ insufflation in colonoscopy of patients with irritable bowel syndrome (IBS) was investigated. Methods: Randomized double‐blind controlled study was conducted to assess the suffering from colonoscopy in patients with IBS and the efficacy of CO₂ insufflation in colonoscopy for patients with IBS. Patients with IBS and controls who received colonoscopy were randomized into an air or CO₂ insufflation group. Patients' symptoms such as distension and pain were compared using a 10‐cm visual analog scale (VAS). Results: There were 18 patients in the IBS/air group, 19 patients in the IBS/CO₂ group, 25 patients in the control/air group and 26 patients in the control/CO₂ group. The mean value of severity of distension after colonoscopy and the mean value of severity of pain from during examination to one hour after the examination were higher in the IBS group than in the control group. The severity of these symptoms was reduced earlier in the CO₂ group. CO₂ insufflation in colonoscopy was more effective in the IBS group than in the control group from 15 min to one hour after the examination. Conclusion: Regarding colonoscopy‐related suffering, IBS patients showed significant differences from non‐IBS patients. CO₂ insufflation in colonoscopy is effective for IBS patients, particularly for patients who commence activities after colonscopy.     

Role of Neurokinin B and Dynorphin A in pituitary gonadotroph and somatolactotroph cell lines

The role of Neurokinin B (NKB) and Dynorphin A (Dyn) in the regulation of the hypothalamic pituitary axis is an important area of recent investigation. These peptides are critical for the rhythmic release of GnRH, which subsequently stimulates the secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The present study utilized the gonadotroph cell line LβT2 and the somatolactotroph GH3 cell line to examine the possible role of these peptides in pituitary hormone secretion. The NKB receptor (NK3R) and the Dyn receptor (the κ-opiate receptor (KOR)) were both detected in LβT2 cells and GH3 cells. NKB, by itself, failed to increase gonadotropin LHβ and FSHβ promoter activities and did not modulate the effects of GnRH on gonadotropin promoter activity. In GH3 cells, NKB significantly increased TRH-induced PRL promoter activity although NKB alone did not have an effect on basal PRL promoter activity. Dyn had no effect on gonadotropin promoters alone or in combination with GnRH stimulation. PRL promoters stimulated by TRH were not significantly changed by Dyn. TRH-induced PRL promoter activity was further increased in the presence of higher concentrations of NKB, whereas Dyn did not have a significant effect on the PRL promoter even at a high concentration. In addition, TRH-induced ERK (Extracelluar signal-regulated kinase) activation was enhanced in the presence of NKB. Our current study demonstrated that NKB had a stimulatory effect on PRL expression in a PRL-producing cell, but had no effect on gonadotropin secretion from a gonadotroph cell line.     

Trial using pig cells with the H–D antigen knocked down

Purpose

This report describes an attempt to reduce the expression level of Hanganutziu–Deicher (H–D) antigens by small interfering RNA (siRNA) for pig cytidine monophospho-N-acetylneuraminic acid hydroxylase (pCMAH).

Methods

A pig endothelial cell (PEC) line, and PEC and fibroblasts from an α1,3galactosyltransferase knockout (GalT-KO) piglet were used. Real-time PCR was used to evaluate the degradation of mRNA by siRNA. The H–D antigen was stained, and then the cells were incubated with human serum for the FACS analysis. The extent of lysis in human serum was next calculated using an LDH assay.

Results

Suppression of the mRNA of pCMAH by each siRNA was first determined. The mixture of siRNAs for pCMAH reduced the expressions of the H–D antigen on the PEC and fibroblasts to a considerable extent. The further reduction in the xenoantigenicity for human serum of the GalT-KO cells was then confirmed. In addition, the PEC line showed a significant downregulation in complement-dependent cytotoxicity by the siRNAs, thus indicating that the anti-H–D antigen in human serum is capable of causing lysis of the pig cells.

Conclusion

pCMAH silencing by siRNA reduced the expression of the H–D antigen and its antigenicity, thus confirming that the H–D antigen is one of the major non-Gal antigens in this situation.     

Increased parietal activity after training of interference control

Recent studies suggest that computerized cognitive training leads to improved performance in related but untrained tasks (i.e. transfer effects). However, most study designs prevent disentangling which of the task components are necessary for transfer. In the current study, we examined whether training on two variants of the adaptive dual n-back task would affect untrained task performance and the corresponding electrophysiological event-related potentials (ERPs). Forty three healthy young adults were trained for three weeks with a high or low interference training variant of the dual n-back task, or they were assigned to a passive control group. While n-back training with high interference led to partial improvements in the Attention Network Test (ANT), we did not find transfer to measures of working memory and fluid intelligence. ERP analysis in the n-back task and the ANT indicated overlapping processes in the P3 time range. Moreover, in the ANT, we detected increased parietal activity for the interference training group alone. In contrast, we did not find electrophysiological differences between the low interference training and the control group. These findings suggest that training on an interference control task leads to higher electrophysiological activity in the parietal cortex, which may be related to improvements in processing speed, attentional control, or both.