Not Every Hit-Identification Technique Works on 1-Deoxy-D-Xylulose 5-Phosphate Synthase (DXPS):Making the Most of a Virtual Screening Campaign

In this work, we demonstrate how important it is to investigate not only on-target activity but to keep antibiotic activity against critical pathogens in mind. Since antimicrobial resistance is spreading in bacteria such as Mycobacterium tuberculosis, investigations into new targets are urgently needed. One promising new target is 1-deoxy-D-xylulose 5-phosphate synthase (DXPS) of the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway. We have recently solved the crystal structure of truncated M. tuberculosis DXPS and used it to perform a virtual screening in collaboration with Atomwise Inc. using their deep convolutional neural network-based AtomNet® platform. Of 94 virtual hit compounds only one showed interesting results in binding and activity studies. We synthesized 30 close derivatives using a straightforward synthetic route that allowed for easy derivatization. However, no improvement in activity was observed for any of the derivatives. Therefore, we tested them against a variety of pathogens and found them to be good inhibitors against Escherichia coli.</p

Impaired IL-23-dependent induction of IFN-gamma underlies mycobacterial disease in patients with inherited TYK2 deficiency

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-alpha/beta (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-gamma is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.ANRS Nord-Sud ; CIBSS ; CODI ; Comité para el Desarrollo de la Investigación ; Fulbright Future Scholarshi

Evaluation of Educational Atmosphere and Its Related Factors from the Point of View of the Students of Qom University of Medical Sciences in 2018, (Iran)

Background and Objectives: Evaluation of learning and teaching activities is one of the activities that is given emphasis and attention in the educational institutions. One of the diagnostic tools in this context is assessment of educational environment and educational space or, in other words, educational atmosphere. The aim of this study was to investigate the students' viewpoint about the educational atmosphere of Qom University of Medical Sciences.   Methods: This study was performed as a descriptive-analytical study 0n all the students studying in Qom University of Medical Sciences in 2018. Based on multi-stage sampling, 306 students were selected. Data collection tool was included a demographic characteristics questionnaire and DREEM standard questionnaire. Data were analyzed by independent t-test, one way ANOVA, Duncan's post-hoc test, and Pearson correlation coefficient at the significance level of p<0.05.   Results: The mean score of the educational atmosphere from the students' viewpoint was 114.1±23.3; 0.7% of the samples evaluated the educational atmosphere as undesirable, 24.8% semi-desirable, 69.3% desirable, and 5.2% very desirable. Based on the independent t-test results, in terms of gender, there were significant differences between the students' point of view on learning, educational environment, and social status; Also, the total score of educational atmosphere showed a significant difference in terms of gender (p<0.05). The results of ANOVA test showed that in terms of the collage, there was a significant difference between the students' viewpoint about learning (p=0.007). There was a significant positive correlation between the students' GPA and the educational atmosphere (r=0.307, p=0.022).   Conclusion: The results of this study indicated that educational atmosphere was desirable from the viewpoint of most of the students, and male students had more positive point of view on educational atmosphere of the university, compared to the female ones. In addition, students with higher GPA had more positive viewpoint about the educational atmosphere

Ex-vivo assessment of meningococcal resistance to natural immunity: serum bactericidal assays versus whole- blood assay

1, 2,1 2 (Received 4 Dec, 2008; Accepted 14 Feb, 2009)AbstractBackground and purpose: Literature review indicates that antibiotic resistance of bacteria may be associated with the resistance to host natural immunity. In the previous study we found that: all meningococcal isolates of meningitis cases are less sensitive to typical anti-meningococcal antibiotics. In present study, the association of the above characters was analyzed in an ex-vivo “case-control” study.Materials and methods: A randomized controlled trial compared effect two dietary treatments (low glycemic index & low fat) in 46 adults, ages 18-55 years old, BMI >27,who proceed to motahary clinic in shiraz, Iran. Body weight, BMI, WHR (waist/hip ratio), fast and post-prandial Plasma lipid profile (Triacylglycerol, total Cholesterol, LDL-C, HDL-C concentration) level of obese women measured at the beginning and at the end 6 weeks.Results: The resistance of both groups against selected sera were similar in the ratio 1:2- by SIC and SBC methods. The growth of “test” and “control” groups in the pooled sera were stopped at the ratios 1:512 and 1:1024 respectively. In SBA the population of “test” and “control” groups decreased in parallel to each other. However, the invasive (test) meningococcal strains established slower reduction in WBA.Conclusion: Studies on the correlation between antibiotic resistance of bacteria and the resistance to the natural immunity have ended with different results. According to our experience, it seems that for ex- vivo investigation of natural immunity against meningococci the WBA is more reliable. J Mazand Univ Med Sci 2009; 19(68):48-57 (Persian

The relationship between financial development indicators and human capital in Iran

Human capital is considered as one of the major factors to promote economic stability, especially in developing countries. Furthermore, one of the most important factors in developing human capital is taking the advantage of facilities and economic capabilities in the Instruction Sector. Development of financial system provides such abilities for the prospective countries. This paper studies the influence of financial development on human capital in Iran over period 1977-2010 with the application of a VAR model. The results show that the cash flow in Iran has a negative effect on human capital, which could be because of the increase in inflation and ends increase in costs of long-term investment and human capital is taken into account as long term investment. However, the facilities provided by the banking system has negative effect on human capital due to the lack of the best financial resource allocation. However, since most of university graduate students in Iran practically have adequate skills and education, they do not have enough capital to start a business. Providing financial assistance for the private sector can lead to a business in which they can use their skills and education towards promoting production

Does carotid intima-media thickness have relationship with polycystic ovary syndrome?

Background: Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder associated with cardiovascular disease (CVD) risk factors and metabolic disturbances and a genetically heterogeneous disease. Intima-media thickness (IMT) is an indicator of atherosclerosis. This study aimed to determine the relation between IMT and PCOS in women. Methods: This cross-sectional study was performed on 44 PCOS patients and 44 healthy women. Data collection included lipid profiles, blood pressure, waist circumference, body mass index (BMI), and common and internal IMT of carotid artery which were measured in studied subjects. IMT was measured by a radiologist using a linear 12 MHz ultrasound probe (LOGIC S6, GE) in carotid setting. Results: IMT of common carotid artery (56.8 ΁ 7.6 in cases versus 49.8 ΁ 7.3 in controls), internal carotid artery (56.9 ΁ 6.03 in cases versus 49.6 ΁ 6.9 in controls), and both common and internal carotid artery (56.6 ΁ 6.7 in cases versus 49.7 ΁ 6.9 in controls) were significantly higher in PCOS patients than healthy women (P < 0.001). Conclusions: In summary, results demonstrated that carotid artery thickness as a risk for premature atherosclerosis in patients with PCOS is higher than healthy subjects. And hence care and monitoring of PCOS women with these risk factors sounds to be important and necessary

The Level of Internet Dependence among Medical Students in Qom University of Medical Sciences, 2016 (Iran)

Background and Objectives: Considering the fact that internet is a necessity in today&rsquo;s life and using the internet for different purposes can lead to addiction and dependence, this research was conducted to determine the level of internet addiction among medical students in Qom University of Medical Sciences. &nbsp; Methods: This descriptive cross-sectional study, was carried out on all medical students studying in Qom University of Medical Sciences in 2016. In this study, 116 students were selected by convenience sampling. Data collection tool included personal characteristics questionnaire and standard internet addiction questionnaire of Young. Data were analyzed by central statistics indices, independent t-test, and ANOVA, at the significance level of lower than 0.05. &nbsp; Results: In this study, most of the samples were female (68.1%) and the mean age of the participants was 20.5&plusmn;2.7, and only 10.3% of the participants were married and 60.3% used the internet at home. Also, the majority (57.8%) of the subjects, were mildly dependent on the Internet. According to the independent t-test, the mean score of internet addiction was significantly higher in males than females (p=0.001), and it was also significantly higher in singles than the married ones (p=0.001). &nbsp; Conclusion: The results of this research were indicative of high level of internet dependence among the studied students; so that familiarization of the student with internet dependency, proper use of this technology, and its usage management, seem necessary. &nbsp

Anticancer drug delivery systems based on specific interactions between albumin and polyglycerol

Here, we report for the first time on a facile method for preparation of a novel drug delivery systems based on supramolecular interactions between \u3b2-cyclodextrin-polyglycerol conjugates (\u3b2-CD-g-PG) and human serum albumin (HSA). The results obtained by combined experimental/modeling studies showed that the main driving leading to the formation of HSA/\u3b2-CD-g-PG supramolecular entities are host-guest interactions between \u3b2-CD-g-PG and the aromatic side-chains of HSA residues. Due to these interactions, HSA undergoes a partial conformational transition, leading to a greater exposition of hydrophobic domains for hydrophobic drugs. Next, the binding affinity and loading capacity of the HSA/\u3b2-CD-g-PG supermolecular nanovector for doxorubicin (DOX) and paclitaxel (PTX) were investigated. Both drug/HSA binding constants (Kb,HSA/DOX = 3.24 7103 M-1 and Kb,HSA/PTX = 5.65 7101 M-1) sensibly increased in the presence of \u3b2-CD-g-PG (Kb, HSA/\u3b2-CD-g-PG/DOX = 2.78 7104 M-1 and Kb,HSA/\u3b2-CD-g-PG/PTX = 2.82 7102 M-1). In line, both protein drug loading increased about 20% upon HSA/\u3b2-CD-g-PG interaction (80% and 71% for DOX and PTX, respectively) with respect to the loading capacity of the bare HSA (60% and 50%). Due to the improved loading capacity with minimal changes in the structure of HSA, this system is a promising vector for future cancer therap

Fabrication of magnetic niosomal platform for delivery of resveratrol: potential anticancer activity against human pancreatic cancer Capan-1 cell

Abstract Recently, the presence of different nanoparticles (NPs) has developed targeting drug delivery in treatment of cancer cell. Targeted drug delivery systems using NPs have shown great promise in improving the efficacy of intracellular uptake as well as local concentration of therapeutics with minimizing side effects. The current study planned to synthesized resveratrol-loaded magnetic niosomes nanoparticles (RSV-MNIONPs) and evaluate their cytotoxicity activity in pancreatic cancer cells. For this aim, magnetic nanoparticles (MNPs) were synthesized and loaded into niosomes (NIOs) by the thin film hydration technique and then characterized via DLS, FT-IR, TEM, SEM and VSM techniques. Moreover, the cytotoxic activity of the RSV-MNIONPs on the Capan-1 cells line was assessed by the MTT test. The distribution number of RSV-MNIONPs was gained about 80 nm and 95 nm with surface charge of − 14.0 mV by SEM and TEM analysis, respectively. RSV loading efficacy in NIOs was about 85%, and the drug releases pattern displayed a sustained discharge with a maximum amount about 35% and 40%, within 4 h in pH = 7.4 and pH = 5.8, respectively. The cytotoxicity of the RSV-MNIONPs in the presence of an external magnetic field is higher than that of the RSV, indicating enhanced cellular uptake in their encapsulated states. Furthermore, RSV loaded MNNPs were found to induce more cell cycle arrest at the G0/G1 checkpoint than free RSV. Compared with RSV-treated cells, the mRNA expression levels of BAX, Bcl2, FAS, P 53, Cyclin D and hTERT, were significantly changed in cells treated with RSV loaded MNNPs. The niosomes NPs approaches have been widely used to attain higher solubility, improved bioavailability, enhanced stability, and control delivery of RSV. Our formulation displayed antitumor activity and can be considered an appropriate carrier with a great potential for future usage in cancer therapy