Synthesis of 4-sulfamoyl phenyl diazocarboxylic acid derivatives as novel non-classical inhibitors of human carbonic anhydrase II activity: an in vitro study.

The first class of carbonic anhydrase inhibitors (CAIs) discovered was sulfonamides, but their clinical use is limited due to side effects caused by their inhibition of multiple CA isoforms. To overcome this, researchers have focused on developing isoform-selective CAIs. This study involved the synthesis and characterization of novel carboxylic acid/sulfonamide derivatives. We investigated the interaction between these compounds and the human carbonic anhydrase II (hCA II) isoform using spectroscopic and computational methods. The synthesized compounds were evaluated based on their IC50, Kd and Ki values, and it was found that the inhibitory potency and binding affinity of the compounds increased with the number of carboxylic acids zinc binding groups. Specifically, the compound C4, with three carboxylic acid groups, showed the strongest inhibitory potency. Fluorescence measurements revealed that all compounds quenched the intrinsic fluorescence of hCA II through a dynamic quenching process, and each compound had one binding site in the hCA II structure. Thermodynamic analysis indicated hydrogen bonds and van der Waals interactions played key roles in the binding of these compounds to hCA II. Docking studies showed that the carboxylic acid groups directly attached to the zinc ion in the active site, displacing water/hydroxide ions and causing steric hindrance. Overall, the strengthening of inhibitory activity and the binding power of these carboxylic acid derivatives for the hCA II makes these compounds interesting for designing novel hCA II inhibitors.Communicated by Ramaswamy H. Sarma.

HealMA: a model-driven framework for automatic generation of IoT-based Android health monitoring applications.

The development of IoT-based Android health monitoring mobile applications (apps) using traditional software development methods is a challenging task. Developers need to be familiar with various programming languages to manage the heterogeneity of hardware and software systems and to support different communication technologies. To address these problems, in this paper, we first analyze the domain of health monitoring mobile applications and then propose a framework based on model-driven engineering that accelerates the development of such systems. The proposed framework, called HealMA, includes a domain-specific modeling language, a graphical modeling editor, several validation rules, and a set of model-to-code transformations, all packed as an Eclipse plugin. We evaluated the framework to assess its applicability in generating various mobile health applications, as well as its impact on software productivity. To this end, four different health monitoring applications have been automatically generated. Then, we evaluated the productivity of software developers by comparing the time and effort it takes to use HealMA compared to a code-centric process. As part of the evaluation, we also evaluated the usability of HealMA-generated apps by conducting a user study. The results show that HealMA is both applicable and beneficial for automatic generation of usable IoT-based Android health monitoring apps.

Mental Health and Prevention of Substance Use Programs in Iran: Component of the National Action Plan for Prevention and Control of Non-communicable Diseases.

Background: Mental disorders have a high prevalence and significant burden among all health conditions across the world and in Iran. Therefore, some targets in the field of mental health and substance and alcohol use prevention have been included in the National Action Plan for Prevention and Control of Non-communicable Diseases and Related Risk Factors. Methods: Keeping in mind the key priorities, important strategies have been considered for attaining the main targets in this field. These strategies fall under four categories of governance, prevention and reduction of risk factors, health care, and surveillance, and monitoring and evaluation strategies. Conclusion: The success of mental health and substance and alcohol use prevention programs in Iran can be partly related to the evidence-based approach adopted and also to the commitment of high-rank officials of the Ministry of Health and Medical Education to the principal strategy of increasing access to the general population to basic mental health services, among all other non-communicable diseases.

Purification and Characterization of an Extracellular Alkaline Solvent-stable Metalloprotease Secreted from Newly Isolated Bacillus sp. DEM05: Optimization of Protease Production.

BACKGROUND: Proteases play an important role in food, leather, detergent, and medical technologies. OBJECTIVES: In the current study, an alkaliphilic solvent-stable thermotolerant metalloprotease was isolated from Bacillus sp. DEM05. MATERIAL AND METHODS: For culture optimization, carbon, and nitrogen sources as well as incubation temperature, pH, and time were examined. RESULTS: Herein the highest outcome for bacterial growth and protease production was obtained after 72 h incubation (pH 7) at 37 °C. DEM05 protease was successfully purified and the specific activity of the protease was 1075 U.mg-1. The purity of the enzyme was verified by SDS-PAGE electrophoresis as a single band of 30 kDa. The optimal activity of the enzyme was at pH 10 and 50 °C. H2O2, SDS, Triton X-100, Zn2+, Co2+, and Cu2+ could increase the protease activity. EDTA inhibited the protease activity, revealed that it can be classified as a metalloprotease. The enzyme was compatible with the water-miscible and water-immiscible organic solvents and proteolyzed several substrates, implying the wide substrate specificity. CONCLUSIONS: The results brought convincing evidence that DEM05 protease could be recruited as a novel prevailing protease that can be earmarked on industrial and medical technologies.

Antioxidant and glycohydrolase inhibitory behavior of curcumin-based compounds: Synthesis and evaluation of anti-diabetic properties in vitro.

Naturally occurring anti-diabetic compound curcumin can prevent diabetes complications due to antioxidant and anti-inflammatory properties as well as the attenuation of postprandial hyperglycemia. In this line, we have synthesized thirteen curcumin based derivatives (L1-L13) by multi-component reaction, characterized by IR, 1HNMR, 13C NMR, MS, elemental analysis and evaluated for possible antioxidant properties and α-glucosidase (α-Glu) and α-amylase (α-Amy) inhibitory potential. The curcumin-based pyrano[2,3-d]pyrimidine derivatives could inhibit α-Glu and α-Amy enzyme activity which showed desirable antioxidant activity. Furthermore, among the series, L5, L12, L9, L10, L8 and L11 were identified as more potent inhibitors of α-Glu enzyme than curcumin and the compounds of L12, L4, L9, L5, L10, L8, L13, and L11 were the stronger inhibitors of the α-Amy enzyme in vitro. Besides, among them, L12 had the lowest IC50 for the inhibition of both enzymes. Since strong inhibitors for pancreatic α-Amy result in the progression of severe gastrointestinal side effects, the inhibitors that show the lower α-Amy/α-Glu inhibitory ratio have attracted much attention in medicinal chemistry. Besides, considering antioxidant characteristics of synthesized compounds, the L7 derivative with the highest antioxidant activity and the lowest "α-Amy/α-Glu inhibitory" ratio could be an appropriate candidate for further study through the rational drug design to the exploration of a new class of powerful anti-diabetic drugs.

Bovine Leukemia virus (BLV) and risk of breast cancer: a systematic review and meta-analysis of case-control studies.

BACKGROUND: Breast cancer is reported as one of the most common cancers among females worldwide. Infectious agents especially viruses have been considered as role players in the development of breast cancer. Although some investigations suggest an association between bovine leukemia virus (BLV) and breast cancer, the involvement of this virus as a risk factor remains controversial. The present study aimed to find out any possible association between BLV and breast cancer through conducting a systematic review and meta-analysis. METHODS: Systematic literature search was performed by finding related case-control articles from the PubMed, Google Scholar, Web of Science, Scopus, and EMBASE databases. The heterogeneity and the multivariable-adjusted OR and corresponding 95% CI were applied by meta-analysis and forest plot across studies. All statistical analyses were performed using Stata 14.1. RESULT: Based on a comprehensive literature search, 9 case-control studies were included for meta-analysis. The combination of all included studies showed that BLV infection is associated with an increased risk of breast cancer [summary OR (95% CI) 2.57 (1.45, 4.56)]. CONCLUSION: This is the first meta-analysis to analyze a potential association between BLV infection and the risk of breast cancer. Control of the infection in cattle herds and screening of the milk and dairy products may help to reduce the transmission of the virus to humans.

Awareness and Attitude Towards Opioid and Stimulant Use and Lifetime Prevalence of the Drugs: A Study in 5 Large Cities of Iran.

BACKGROUND: Providing population-based data on awareness, attitude and practice of drug and stimulant use has policy implications. A national study was conducted among Iranian general population to explore life time prevalence, awareness and attitudes toward opioids and stimulant use. METHODS: We recruited subjects from 5 provinces with heterogenic pattern of drug use. Participants were selected using stratified multistage cluster sampling. Data were collected using a validated self-administered questionnaire. Logistic regression model was applied to identify the variables that are associated with drug and stimulant use. RESULTS: In total 2065 respondents including 1155 men (33.96 ± 10.40 years old) and 910 women (35.45 ± 12.21 years old) were recruited. Two-third of respondents had good awareness about adverse effects of opioid use. Corresponding figure in terms of stimulants was 81.4%. Almost 95% of participants reported a negative attitude towards either opioid or stimulant use. The lifetime prevalence of opioid use and stimulant use were 12.9% (men: 21.5%, women: 4.0%) and 7.3% (men: 9.6%, women: 4.9%), respectively. Gender (adjusted odds ratio [AOR]M/W=6.92; 95% CI: 2.92, 16.42), education (AORundergraduate/diploma or less =0.49; 95% CI: 0.26, 0.90), and marital status (AORothers/single=2.13; 95% CI: 1.36, 3.33) were significantly related with opioid use. With respect to stimulant use, age was negatively associated with the outcome (AOR60+/20-29 years = 0.08: 95% CI; 0.01, 0.98) and men were 2 times more likely than women to use stimulants (ORM/W=2.15: 95% CI: 0.83, 5.56). In addition, marital status (AOROthers/singles = 3.45; 95% CI: 1.09, 10.93), and awareness (AORWeak and moderate/good =0.40; 95% CI: 0.25, 0.61) were independently correlated with stimulants use. CONCLUSION: While the attitude of Iranian adults toward opioid and stimulant use was negative, their awareness was not that adequate to prevent the drug use. Men and those with lower socio-economic status (SES) should be the focus of health promotion programs regarding opioid use. However, regarding stimulants use, promotion programs should target younger age groups and those with higher SES status.

Prevalence and Correlates of Lifetime Alcohol Use among Adult Urban Populations in Iran: A Knowledge, Attitude, and Practice Study.

Globally, alcohol use is one of the leading contributors to the burden of disease. The aim of this study was to provide data on prevalence and correlates of lifetime alcohol use among Iranian adults living in urban areas. This cross-sectional study investigated knowledge, attitude, and practice (KAP) of Iranian adults towards drug and alcohol use. Participants were recruited from the capital cities of five provinces-Tehran, West Azerbaijan, Markazi, Kerman, and Khorasan Razavi-in 2015. We used multivariate logistic regression models to conduct data analysis. Completing the questionnaire were 2,065 participants (44.06% female). Prevalence of lifetime alcohol use was 28% (95% CI: 25-29%). Lifetime alcohol use was significantly associated with male gender (Odds Ratio (OR) = 1.74, 95% Confidence Interval (CI): 1.26- 2.39), positive attitude towards alcohol (OR = 2.15, CI: 1.60-4.34), lifetime stimulants use (OR = 5.73, CI: 3.56- 9.23), and lifetime opioids use (OR = 4.47, CI: 3.12- 6.39). Estimated lifetime prevalence of alcohol use in our study was higher than the regional average. Primary alcohol prevention programs need to target sub- populations who are at risk for alcohol use and provide services that impede the development of positive attitudes towards alcohol.

Active Role of the Necrotic Zone in Desensitization of Hypoxic Macrophages and Regulation of CSC-Fate: A hypothesis.

Fast-proliferating cancer cells in the hypoxic region face a shortage of oxygen and nutrients, undergo necrotic cell death, and release numerous signaling components. Hypoxia-induced chemo-attractants signal for macrophages/monocytes to clear debris and return the system to steady state. Accordingly, macrophages arrange into pre-necrotic positions, where they are continuously exposed to stress signals. It can thus be hypothesized that gradual alteration of gene expression in macrophages eventually turns off their phagocytic machinery. Uncleared cell corpses within the hypoxic region potentially provide a rich source of building blocks for anaerobic metabolism of cancer stem cells via macropinocytosis, and are conceivably implicated in tumor progression and invasion.

The Impact of Social Structures on Deviant Behaviors: The Study of 402 High Risk Street Drug Users in Iran.

This study is a sociological analysis of the three dimensions of social structure including institutional, relational, and embodied structures that have an impact on the individuals' deviant behaviors in the society. The authors used a mix method to analyze the qualitative and quantitative data of 402 high risk abandoned substance users in 2008 in Tehran, capital city of Iran. The leading reasons of substance use were categorized into four fundamental themes as follows: stress, deviant social networks, and low social capital and weak social support sources. In addition, the epidemiology model of regression analysis provides a brief explanation to assess the association between the demographical and etiological variables, and the drug users' deviant behaviors. In sum, substance use is discussed as a deviant behavior pattern which stems from a comorbidity of weak social structures.

Spirituality Concept by Health Professionals in Iran: A Qualitative Study.

Background. For years, researchers have sought to provide a clear definition of spirituality and its features and consequences, but the definitions provided of this concept still lack transparency. The present qualitative research was conducted to clarify this concept within the religious-cultural context of Iran. Materials and Methods. The present conventional qualitative content analysis was conducted with an inductive approach. Data were collected through semistructured interviews with 17 spiritual health experts and activists selected through purposive sampling. Results. Three themes emerged from the analysis of the data, including (1) the structure of spirituality, (2) defects in the conceptualization of spirituality, and (3) spirituality in practice, which are explained in this paper with their relevant subthemes and codes. The definition which this study proposes for this concept is that "spirituality is the sublime aspect of human existence bestowed on all humans in order for them to traverse the path of transcendence that is closeness to God (Allah)." Conclusion. The definition provided by this study is similar to the previous definitions of this concept in its main part (transcendence) and in incorporating a God-centered view of spirituality within the context of an Islamic society. This definition has implications for health services' education, research, and practice in similar societies.

LMTK3 escapes tumour suppressor miRNAs via sequestration of DDX5.

Lemur tyrosine kinase-3 (LMTK3) plays an important role in cancer progression and is associated with breast, lung, gastric and colorectal cancer. MicroRNAs (miRNAs) are small endogenous non-coding RNAs that typically repress target genes at post-transcriptional level and have an important role in tumorigenesis. By performing a miRNA expression profile, we identified a subset of miRNAs modulated by LMTK3. We show that LMTK3 induces miR-34a, miR-196-a2 and miR-182 levels by interacting with DEAD-box RNA helicase p68 (DDX5). LMTK3 binds via DDX5 to the pri-miRNA of these three mature miRNAs, thereby sequestrating them from further processing. Ectopic expression of miR-34a and miR-182 in LMTK3-overexpressing cell lines (MCF7-LMTK3 and MDA-MB-231-LMTK3) inhibits breast cancer proliferation, invasion and migration. Interestingly, miR-34a and miR-182 directly bind to the 3'UTR of LMTK3 mRNA and consequently inhibit both its stability and translation, acting as tumour suppressor-like miRNAs. In aggregate, we show that LMTK3 is involved in miRNA biogenesis through modulation of the Microprocessor complex, inducing miRNAs that target LMTK3 itself.

The sociological study of nurse-physician professional relationship in Iran.

BACKGROUND: During recent decades, various factors have modified the nurse-physician professional relationship pattern in hospital settings. The present study investigates the typology and dynamics of this relationship as well as the effects of social structures and the actors' agency by considering the gender variable in two professional groups of nurse and physician. MATERIALS AND METHODS: A survey was conducted in 2009 using a quota sampling method of 100 female nurses and male physicians in four hospitals in Tehran. RESULTS: The study revealed three distinct patterns of nurse-physician professional relationship including "dependence-independence," "nondominance-dominance," and "cooperation-participation." Occupational socialization, gender stereotypes, organization support, and actors' agency were discovered as the most effective factors. CONCLUSIONS: Observing caution in generalizing the results, the predominant relationship pattern was derived from the persistence of gender stereotypes in the occupational context. Although there is a paradigm shift in the relational and embodied structures, balancing power resources are being formed by younger nurses who require more organizational support to improve the professional fulfilment and authority.

Differentiation of human skin-derived precursor cells into functional islet-like insulin-producing cell clusters.

Advances in cell-replacement strategies for diabetes have focused on renewable sources of glucose-responsive, insulin-producing cells (IPCs). One of the most proper alternatives is multipotent skin-derived precursors cells (SKPs), which can be differentiated into IPCs. In this study, we reported the isolation and expansion of human skin-derived precursors (hSKPs) followed by their differentiation into IPCs in vitro, through exposure to suitable differentiation factors. The gene expression of endocrine ß cell markers was analyzed by reverse transcriptase-polymerase chain reaction. In addition, insulin production was examined immunocytochemically, and insulin and C-peptide secretion were examined using enzyme-linked immunosorbent assay. Dithizone-stained cellular clusters were observed after approximately 20 d. The clusters were found to be immunoreactive to insulin and expressed multiple genes related to pancreatic ß cell development and function: insulin, Pdx-1, Islet-1, NeuroD, Glut-2, Pax-4, Ngn-3, and Nkx2.2, but not to other pancreas-specific hormones such as glucagon and somatostatin. Cellular clusters were also able to secrete detectable amounts of insulin and C-peptide in a glucose dose-dependent manner. These findings suggest that human SKPs can differentiate into functional IPCs. This may offer a safer cell source for future stem cell-based therapies.

Effect of aquatic exercise training on fatigue and health-related quality of life in patients with multiple sclerosis.

OBJECTIVE: To examine the effectiveness of aquatic exercise training on fatigue and health-related quality of life (HRQOL) in women with multiple sclerosis (MS). DESIGN: Randomized controlled trial, 4-week and 8-week follow-up. SETTING: Referral center of a multiple sclerosis society. PARTICIPANTS: Women (N=32) diagnosed with relapsing-remitting MS (mean age ± SD, 32.6±8.0y) were recruited into this study. After undergoing baseline testing by a neurologist, participants were randomly assigned to either an intervention (aquatic exercise) or a control group. INTERVENTIONS: The intervention consisted of 8 weeks supervised aquatic exercise in a swimming pool (3 times a week, each session lasting 60min). MAIN OUTCOME MEASURES: At baseline, 4 weeks, and 8 weeks, fatigue and HRQOL were assessed by a blind assessor using the Modified Fatigue Impact Scale and the Multiple Sclerosis Quality of Life-54 questionnaire, respectively. A mixed-model approach to repeated-measures analysis of variance was used to detect within- and between-subject effects. RESULTS: Findings are based on 21 patients (10 from the exercise group and 11 from the control group) who had data available on outcomes. There was no significant difference between the 2 groups at the baseline. Patients in the aquatic exercise group showed significant improvements in fatigue and subscores of HRQOL after 4 and 8 weeks compared with the control group. Results obtained from the intention-to-treat analysis were consistent with those of per-protocol analysis. CONCLUSIONS: The findings suggest that aquatic exercise training can effectively improve fatigue and HRQOL of patients with MS and should be considered in the management of this relatively common public health problem.

A distinct subset of human NK cells expressing HLA-DR expand in response to IL-2 and can aid immune responses to BCG.

Subsets of NK cells can have distinct functions. Here, we report that >25% of human peripheral blood NK cells express HLA-DR after culture with IL-2. This can be driven by an expansion of a small subset of NK cells expressing HLA-DR, in contrast to previous assumptions that HLA-DR is upregulated on previously negative cells. HLA-DR-expressing NK cells showed enhanced degranulation to susceptible target cells and expressed chemokine receptor CXCR3, which facilitated their enrichment following exposure to CXCL11/I-TAC. Suggesting HLA-DR-expressing NK cells have an important role in an immune response, stimulation of PBMCs with Mycobacterium bovis BCG (BCG) triggered expansion of this subset. Importantly, the magnitude of an individual's NK cell IFN-γ response triggered by BCG was associated with the initial frequency of HLA-DR-expressing NK cells in PBMCs. More directly indicating the importance of HLA-DR-expressing NK cells, enriching the frequency of this subset in PBMCs substantially augmented the IFN-γ response to BCG. Thus, HLA-DR expression marks a distinct subset of NK cells, present at low frequency in circulating blood but readily expanded by IL-2, that can play an important role during immune responses to BCG.

Matched sizes of activating and inhibitory receptor/ligand pairs are required for optimal signal integration by human natural killer cells.

It has been suggested that receptor-ligand complexes segregate or co-localise within immune synapses according to their size, and this is important for receptor signaling. Here, we set out to test the importance of receptor-ligand complex dimensions for immune surveillance of target cells by human Natural Killer (NK) cells. NK cell activation is regulated by integrating signals from activating receptors, such as NKG2D, and inhibitory receptors, such as KIR2DL1. Elongating the NKG2D ligand MICA reduced its ability to trigger NK cell activation. Conversely, elongation of KIR2DL1 ligand HLA-C reduced its ability to inhibit NK cells. Whereas normal-sized HLA-C was most effective at inhibiting activation by normal-length MICA, only elongated HLA-C could inhibit activation by elongated MICA. Moreover, HLA-C and MICA that were matched in size co-localised, whereas HLA-C and MICA that were different in size were segregated. These results demonstrate that receptor-ligand dimensions are important in NK cell recognition, and suggest that optimal integration of activating and inhibitory receptor signals requires the receptor-ligand complexes to have similar dimensions.

Multiple mechanisms downstream of TLR-4 stimulation allow expression of NKG2D ligands to facilitate macrophage/NK cell crosstalk.

The activating receptor NKG2D recognizes proteins that are not normally expressed at the surface of most cells but are expressed during a cellular "stress" response (e.g., upon induction of the DNA damage pathway). This establishes recognition of "induced self" as an important strategy for surveillance of infections or tumor transformation. However, NKG2D ligands can also be induced on human macrophages by TLR stimulation, which has been far less studied. In this paper, we clarify that LPS, which ligates TLR-4, preferentially upregulated MICA and not MICB; CL097, which ligates TLR-7/8, upregulated both MICA and MICB; and polyinosinic-polycytidylic acid, which ligates TLR-3, upregulated neither. To probe how LPS stimulation triggers MICA expression, we determined that the stability of MICA mRNA was much longer than that of MICB mRNA, but neither was changed by LPS stimulation. This finding suggests that increased levels of MICA mRNA following LPS stimulation resulted from increased transcription. However, it was not sufficient for surface protein expression, which was controlled posttranscriptionally via a separate pathway involving the ataxia telangiectasia mutated/ataxia telangiectasia and Rad3 related kinases. Moreover, LPS stimulation decreased expression of microRNAs (miRNA)--miR-17-5, miR-20a, and miR-93--which target MICA, implicating a novel role for miRNAs in NKG2D ligand expression. Thus, TLR stimulation allows expression of NKG2D ligands through multiple pathways, including downmodulation of specific miRNAs.

Natural killer cell signal integration balances synapse symmetry and migration.

Natural killer (NK) cells discern the health of other cells by recognising the balance of activating and inhibitory ligands expressed by each target cell. However, how the integration of activating and inhibitory signals relates to formation of the NK cell immune synapse remains a central question in our understanding of NK cell recognition. Here we report that ligation of LFA-1 on NK cells induced asymmetrical cell spreading and migration. In contrast, ligation of the activating receptor NKG2D induced symmetrical spreading of ruffled lamellipodia encompassing a dynamic ring of f-actin, concurrent with polarization towards a target cell and a "stop" signal. Ligation of both LFA-1 and NKG2D together resulted in symmetrical spreading but co-ligation of inhibitory receptors reverted NK cells to an asymmetrical migratory configuration leading to inhibitory synapses being smaller and more rapidly disassembled. Using micropatterned activating and inhibitory ligands, signals were found to be continuously and locally integrated during spreading. Together, these data demonstrate that NK cells spread to form large, stable, symmetrical synapses if activating signals dominate, whereas asymmetrical migratory "kinapses" are favoured if inhibitory signals dominate. This clarifies how the integration of activating and inhibitory receptor signals is translated to an appropriate NK cell response.