Comparative study of the unbinding process of some HTLV-1 protease inhibitors using unbiased molecular dynamics simulations.

The HTLV-1 protease is one of the major antiviral targets to overwhelm this virus. Several research groups have developed protease inhibitors, but none has been successful. In this regard, developing new HTLV-1 protease inhibitors to fix the defects in previous inhibitors may overcome the lack of curative treatment for this oncovirus. Thus, we decided to study the unbinding pathways of the most potent (compound 10, PDB ID 4YDF, Ki = 15 nM) and one of the weakest (compound 9, PDB ID 4YDG, Ki = 7900 nM) protease inhibitors, which are very structurally similar. We conducted 12 successful short and long simulations (totaling 14.8 µs) to unbind the compounds from two monoprotonated (mp) forms of protease using the Supervised Molecular Dynamics (SuMD) without applying any biasing force. The results revealed that Asp32 or Asp32' in the two forms of mp state similarly exert powerful effects on maintaining both potent and weak inhibitors in the binding pocket of HTLV-1 protease. In the potent inhibitor's unbinding process, His66' was a great supporter that was absent in the weak inhibitor's unbinding pathway. In contrast, in the weak inhibitor's unbinding process, Trp98/Trp98' by pi-pi stacking interactions were unfavorable for the stability of the inhibitor in the binding site. In our opinion, these results will assist in designing more potent and effective inhibitors for the HTLV-1 protease.

Complete reconstruction of dasatinib unbinding pathway from c-Src kinase by supervised molecular dynamics simulation method; assessing efficiency and trustworthiness of the method.

Over the past years, rational drug design has gained lots of attention since employing it gave the world targeted therapy and more effective treatment solutions. Structure-based drug design (SBDD) is an excellent tool in rational drug design that takes advantage of accurate methods such as unbiased molecular dynamics (UMD) simulation for designing and optimizing molecular entities by understanding the binding and unbinding pathways of the binders. Supervised molecular dynamics (SuMD) simulation is a branch of UMD in which long-duration simulations are turned into short simulations, called replica, and a specific parameter is monitored throughout the simulation. In this work, we utilized this strategy to reconstruct the unbinding pathway of the anticancer drug dasatinib from its target protein, the c-Src kinase. Several unbinding events with valuable details were achieved. Then, to assess the efficiency and trustworthiness of the SuMD method, the unbinding pathway was also reconstructed by conventional UMD simulation, which uncovered some of the limitations of this method, such as limited sampling of the active site and finding the metastable states in the unbinding pathway. Furthermore, in times like these, when the world is desperate to find treatments for the Covid-19 disease, we think these methods are of exceptional value.Communicated by Ramaswamy H. Sarma.

Efficacy and safety of pentoxifylline combination therapy in major depressive disorder: a randomized, double-blind, placebo-controlled clinical trial.

In this randomized, double-blind, placebo-controlled clinical trial, we assessed the efficacy and safety of pentoxifylline combination therapy with sertraline in treatment of major depressive disorder (MDD). A total of 56 patients with MDD were assigned into two parallel groups to receive sertraline (100 mg/day) plus placebo or sertraline (100 mg/day) plus pentoxifylline (400 mg three times daily) for six weeks. Patients were evaluated with the Hamilton rating scale for depression (HAM-D) at baseline and weeks 2, 4 and 6. The sertraline plus pentoxifylline group demonstrated greater improvement in HAM-D scores from baseline to all three study time points (P = 0.013, 0.007 and 0.016 for week 2, 4 and 6, respectively). Response to treatment rate was also significantly higher in the sertraline plus pentoxifylline group compared to the sertraline plus placebo group at week 4 [57.1 vs. 21.4%, P = 0.013] and the study endpoint [96.4 vs. 57.1%, P = 0.001]. However, the remission rate, time to remission and time to treatment response did not show any significant difference between trial groups. Our findings support the efficacy and safety of pentoxifylline combination therapy in patients with MDD.

Development of neural fractional order PID controller with emulator.

This paper focuses on tuning parameters of fractional order PID controller (FOPID) by using neural networks (NNs). For tuning the coefficients of the controller and orders of fractional derivative and integrator, five exclusive NNs are employed. Moreover, an emulator is used to identify the plant's behavior. Extended Kalman Filter (EKF) algorithm is used to update the weights of the controller's NNs, and Back Propagation (BP) algorithm is used for the weight updating procedure of the emulator's NNs. The proposed neural fractional order PID controller (NFOPID) is capable of being applied to various plants. Thus, two plants with different dynamics are examined. One is vibration damping of a Euler-Bernoulli beam, which has a fast dynamic, and the other is a time-delayed system like temperature control of a tempered glass furnace. The controller could deal appropriately with these tasks and is compared for accuracy and robustness with other controllers. The results were satisfactory for both systems.

A boosted unbiased molecular dynamics method for predicting ligands binding mechanisms: probing the binding pathway of dasatinib to Src-kinase.

SUMMARY: Small molecules such as metabolites and drugs play essential roles in biological processes and pharmaceutical industry. Knowing their interactions with biomacromolecular targets demands a deep understanding of binding mechanisms. Dozens of papers have suggested that discovering of the binding event by means of conventional unbiased molecular dynamics (MD) simulation urges considerable amount of computational resources, therefore, only one who holds a cluster or a supercomputer can afford such extensive simulations. Thus, many researchers who do not own such resources are reluctant to take the benefits of running unbiased MD simulation, in full atomistic details, when studying a ligand binding pathway. Many researchers are impelled to be content with biased MD simulations which seek its validation due to its intrinsic preconceived framework. In this work, we have presented a workable stratagem to encourage everyone to perform unbiased (unguided) MD simulations, in this case a protein-ligand binding process, by typical desktop computers and so achieve valuable results in nanosecond time scale. Here, we have described a dynamical binding's process of an anticancer drug, the dasatinib, to the c-Src kinase in full atomistic details for the first time, without applying any biasing force or potential which may lead the drug to artificial interactions with the protein. We have attained multiple independent binding events which occurred in the nanosecond time scales, surprisingly as little as ∼30 ns. Both the protonated and deprotonated forms of the dasatinib reached the crystallographic binding mode without having any major intermediate state during induction. AVAILABILITY AND IMPLEMENTATION: The links of the tutorial and technical documents are accessible in the article. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Evaluation of serum natural autoantibodies reaction in different hematological disorders with prospective view to their probable utilization in predictive medicine.

BACKGROUND: There are some antibodies which are present in healthy individuals without any former exposure to foreign antigens; they are known as natural autoantibodies (NAAbs). In recent years, it was shown that they probably contribute to the homeostasis of the whole body and might be present before beginning of some diseases. Thus, as new biomarkers, they are promising factors to diagnose diseases. MATERIALS AND METHODS: In this study, we drew upon samples of 924 individuals (600 controls and 324 cases) with underlying diseases of anemia, polycythemia, leukocytosis, thrombocytopenia, thrombocytosis, and pancytopenia. For detection of NAAbs against red blood cell, plasma samples were incubated with their own red cell suspension in 4°C for 18 h. Then, positive samples were evaluated for antibody screening and titration. RESULTS: Fifty-two (8.6%) controls and 58 (17.9%) cases showed positive reaction (Pv < 0.001). The prevalence of positive antibody screens among auto-positive controls was 53% and 100% among cases; moreover, strength of antibody screen reaction had a mean rank of 22.5 in controls and a mean rank of 38.5 in cases (Pv < 0.001). A significant relation was also observed between ABO blood group and prevalence of NAAbs in controls but not in cases (Pv < 0.05). CONCLUSION: The prevalence and potency of NAAbs increased along with hematological changes; moreover, the antibody reactions' pattern and titration showed significant differences between the two groups and these may be useful as biomarker for monitoring and prediction of some hematological diseases.

Accuracy of emergency transfusion score in prediction need for blood transfusion among multiple trauma patients: A cross-sectional study from Iran.

OBJECTIVE: Prediction of blood transfusion requirement in trauma patients is a dilemma in most trauma centers. The aim of the current study was assessing the accuracy of emergency transfusion score (ETS) in detecting patients' need for blood transfusion in ED. METHODS: In this cross-sectional study, all multiple trauma patients referred to the emergency department (ED) of Imam Hossein Hospital, Tehran, Iran, from March to August 2014, were enrolled. ETS parameters including low blood pressure, free fluid on ultrasound, clinical instability of the pelvic ring, age, admission from the scene, and trauma mechanism were recorded for all patients. ETS was calculated for all patients and compared with patients who received blood transfusion to estimate the accuracy of ETS. RESULTS: Of the 793 patients included in the study, 54 (6%) received blood in the ED. The mean of ETS for all patients was 3.91 ± 0.93. There was a significant correlation between ETS more than 3 and amount of blood transfusion (P = 0.004). The sensitivity, specificity, positive, and negative predictive value of ETS was 98.1%, 13.8%, 7.7%, and 99%, respectively. CONCLUSION: ETS may be considered as a useful instrument for prioritizing multiple trauma patients' need for blood transfusion in Iran. Therefore, by implementing this score, it may be prevented from inappropriate requests for blood transfusion.

Investigation of association between oipA and iceA1/iceA2 genotypes of Helicobacter pylori and gastric cancer in Iran.

BACKGROUND: H pylori is the main causative agent of Gastric cancer and chronic gastritis. Genetic diversity of H. pylori has major contribution in its pathogenesis. We investigated the prevalence of oipA and iceA1/iceA2 positive strains of H. pylori among patients with gastric cancer and gastritis. MATERIALS AND METHODS: Sampling performed by means of endoscopy from 86 patients. DNA was extracted from tissue samples using DNA extraction kit. PCR assay was performed and products were monitored by Agarose Gel Electrophoresis. RESULTS: Urease Test and 16S rRNA PCR did not show significant differences in detection of H. pylori. The frequency of iceA1 allele in patients with gastric cancer was significantly higher than those with gastritis (p<0.05). However, there was no significant difference in prevalence of oipA and iceA2 genes among the two groups of patients (p>0.05). CONCLUSIONS: The iceA1 gene, but the oipA and iceA2 genes , is associated with H. pylori-induced gastric cancer. However, confirmatory studies must be performed in future.

Outcomes of fasciotomy in patients with crush-induced acute kidney injury after Bam earthquake.

INTRODUCTION. Fasciotomy may increase the morbidity and mortality in patients with crush-induced acute kidney injury (AKI), by creating an open wound, increasing the risk of bleeding, coagulopathy, and potentially fatal sepsis. This study evaluates the outcomes of fasciotomy in these patients after Bam earthquake in Iran. MATERIALS AND METHODS. We reviewed medical records of victims of Bam earthquake complicated with crush-induced AKI. Demographic, biochemical, and clinical data of patients who underwent fasciotomy were evaluated and compared with other patients with AKI. RESULTS. Fasciotomy was performed for 70 of 200 patients with crush-induced AKI (35.0%). There were no significant differences regarding sex, age, time under the rubble, and muscle enzymes level between these patients and those without fasciotomy. They did not experience higher rates of disseminated intravascular coagulopathy, sepsis, adult respiratory distress syndrome, amputation, and dialysis session. Neither did they have a longer hospitalization period or higher death rate. CONCLUSIONS. This study showed that fasciotomy did not have any deteriorating effect on morbidity and mortality of patients with crush-induced AKI after Bam earthquake.