High Fitness Scores Research Articles

In silico screening for novel inhibitors of DNA polymerase III alpha subunit of Mycobacterium tuberculosis (MtbDnaE2, H37Rv).

Tuberculosis, a pandemic disease is caused by Mycobacterium tuberculosis (Mtb). DNA polymerase III encoded by DnaE2 of Mtb is specifically required for its survival in vivo, and hence can be considered to be a potential drug target. Amino acid sequence analysis of the MtbDnaE2 and its human counterpart does not show any significant similarity. Therefore, a 3D model of the MtbDnaE2 was generated using Modeller 9v10 with the template structure of E. Coli DNA polymerase III alpha subunit (2HNH_A). The generated models were validated using a number of programmes such as RAMPAGE/PROCHECK, VERIFY_3D, and ProSA. MtbDnaE2 has few conserved residues and four conserved domains similar to that present in DNA polymerase III of E. coli. In silico screening was performed with bioactive anti-tuberculosis compounds and 6-AU (a known inhibitor of DNA polymerase III of Bacillus subtilis) and its analogues against the modeled MtbDnaE2 structure. Docking was performed using GOLD v5.2 software which resulted in the identification of top ten compounds with high GOLD fitness scores and binding affinity (X-Score). To further evaluate the efficacy of these compounds, in silico ADMET analysis was performed using MedChem Designer v3. Given their high binding affinity to the targeted MtbDnaE2, which is essential for DNA replication in the Mtb and good ADMET properties, these compounds are promising candidates for further evaluation and development as anti-tubercular agents.

CRF19_cpx is an Evolutionary fit HIV-1 Variant Strongly Associated With Rapid Progression to AIDS in Cuba

BackgroundClinicians reported an increasing trend of rapid progression (RP) (AIDS within 3years of infection) in Cuba. MethodsRecently infected patients were prospectively sampled, 52 RP at AIDS diagnosis (AIDS-RP) and 21 without AIDS in the same time frame (non-AIDS). 22 patients were sampled at AIDS diagnosis (chronic-AIDS) retrospectively assessed as >3years infected. Clinical, demographic, virological, epidemiological and immunological data were collected. Pol and env sequences were used for subtyping, transmission cluster analysis, and prediction of resistance, co-receptor use and evolutionary fitness. Host, immunological and viral predictors of RP were explored through data mining. FindingsSubtyping revealed 26 subtype B strains, 6 C, 6 CRF18_cpx, 9 CRF19_cpx, 29 BG-recombinants and other subtypes/URFs. All patients infected with CRF19 belonged to the AIDS-RP group. Data mining identified CRF19, oral candidiasis and RANTES levels as the strongest predictors of AIDS-RP. CRF19 was more frequently predicted to use the CXCR4 co-receptor, had higher fitness scores in the protease region, and patients had higher viral load at diagnosis. InterpretationCRF19 is a recombinant of subtype D (C-part of Gag, PR, RT and nef), subtype A (N-part of Gag, Integrase, Env) and subtype G (Vif, Vpr, Vpu and C-part of Env). Since subtypes D and A have been associated with respectively faster and slower disease progression, our findings might indicate a fit PR driving high viral load, which in combination with co-infections may boost RANTES levels and thus CXCR4 use, potentially explaining the fast progression. We propose that CRF19 is evolutionary very fit and causing rapid progression to AIDS in many newly infected patients in Cuba.

E-Pharmacophore and Molecular Dynamics Study of Flavonols and Dihydroflavonols as Inhibitors Against DiHydroOrotate DeHydrogenase

DiHydroOrotate DeHydrogenase [huDHODH] is a therapeutic target for Rheumatoid arthritis [RA]. Leflunomide [A771726] is a widely used synthetic inhibitor against huDHODH. We to find more efficient lead like compounds. A four featured E-Pharmacophore A1D4H6R7 was built based on the inhibitor A771726. This pharmacophore was validated by checking its ability to identify known highly active inhibitors of huDHODH and assigning higher fitness scores to them. A reverse validation was also performed where random 4 featured pharmacophores were built and its efficiency in identifying actives was compared with our E-Pharmacophore. Our Epharmacophore was very efficient, since it passed both validations by picking the known active molecules with high fitness scores. This validated E- pharmacophore was searched against the KEGG phytochemicals subset database. This search resulted in 18 molecules which were subjected to docking with huDHODH. The molecules with docking score greater than that of A771726 were selected. The docking results were further validated using MM/GBSA which gave similar ranking with high binding free energy values. The four molecules 6-Methoxytaxifolin, Rhamnetin, Rhamnazin and Pinoquercetin were taken for explicit 3ns simulation and it was observed that all four molecules had acceptable RMSD values and stable interactions. Thus our study, suggests four phytomolecules that might inhibit huDHODH more efficiently than A771726. Interestingly, some of the obtained hits have already been proven in vitro anti-inflammatory activity which confirms that, the developed E-pharmacophore can be used to identify novel small molecules against inflammatory target, huDHODH.

An Accelerated Step Test to Assess Dancer Pre-season Aerobic Fitness

As the technical performance demands of dance increase, professional companies and pre-professional schools are implementing pre-season screenings that require an efficient, cost effective way to measure dancer aerobic fitness. The aim of this study was to assess an accelerated 3-minute step test (112 beats·min(-1)) by comparing it to the well-studied YMCA step test (96 beats·min(-1)) and a benchmark standard, an incremental treadmill test, using heart rate (HR) and oxygen consumption (VO2) as variables. Twenty-six professional and pre- professional dancers (age 20 ± 2.02 years) were fitted with a telemetric gas analysis system and HR monitor. They were tested in the following order: 96 step, 112 step, and treadmill test, with rest to return to baseline heart rate between each test. The step and treadmill tests were compared using Intra-class Correlation Coefficients [ICC (3, k)] calculated with analysis of variance (p < 0.05). To determine whether there was a relationship between peak and recovery HR (HRpeak, HRrecov) and VO2(VO2peak, VO2recov) variables, Pearson product moment correlations were used. Differences due to gender or group (pre- professionals versus professionals) were explored with MANOVAs for HRpeak, VO2peak, HRrecov, VO2recov, and fitness category. The 112 step test produced higher HRpeak and VO2peak values than the 96 step test, reflecting a greater workload (p < 0.001). For HRpeak, there were high correlations (r = 0.71) and for HRrecov, moderate correlations (r = 0.60) between the 112 step test and treadmill test. For VO2peak and VO2recov, there were moderate correlations between the 112 step test and treadmill test (r = 0.65 and 0.73). No differences between genders for VO2peak values were found for either step test, but males displayed lower HRpeak values for both step tests and higher VO2peak values during the treadmill test (p < 0.001). Recovery HR was lower in males for the 96 and 112 step tests (p < 0.05). This was reflected in higher fitness scores. There were no differences between groups in any of the variables when only females were compared. For the 112 step test, correlations between HRpeak and HRrecov were high (r = 0.85), and correlations between HRpeak and fitness category were very high (r = 0.98). It is concluded that the 112 step test provides an efficient, acceptable tool for testing dance populations, though further testing in larger groups of dancers representing a diverse range of genres and training levels is needed.

Discovery of HIV‐1 Integrase Inhibitors: Pharmacophore Mapping, Virtual Screening, Molecular Docking, Synthesis, and Biological Evaluation

HIV-1 integrase enzyme plays an important role in the life cycle of HIV and responsible for integration of virus into human genome. Here, both computational and synthetic approaches were used to design and synthesize newer HIV-1 integrase inhibitors. Pharmacophore mapping was performed on 20 chemically diverse molecules using DISCOtech, and refinement was carried out using GASP. Ten pharmacophore models were generated, and model 2, containing four features including two donor sites, one acceptor atom, and one hydrophobic region, was considered the best model as it has the highest fitness score. It was used as a query in NCI and Maybridge databases. Molecules having more than 99% Q(fit) value were used to design 30 molecules bearing pteridine ring and were docked on co-crystal structure of HIV-1 integrase enzyme. Among these, six molecules, showing good docking score compared with the reference standards, were synthesized by conventional as well as microwave-assisted methods. All compounds were characterized by physical and spectral data and evaluated for in vitro anti-HIV activity against the replication of HIV-1 (IIIB) in MT-4 cells. The used approach of molecular docking and anti-HIV activity data of designed molecules will provide significant insights to discover novel HIV-1 Integrase Inhibitors.

A Comparison of Deployed Occupational Tasks Performed by Different Types of Military Battalions and Resulting Low Back Pain

With deployment Soldiers must now wear body armor and additional equipment while performing occupational tasks, representing a large demand that has not been considered when studying military occupations. The purpose of this study was to: (1) describe tasks required by different occupational battalions within a Brigade Combat Team; (2) establish the incidence of low back pain (LBP) in each battalion and; (3) determine which tasks predict LBP within the different battalions. This was a prospective cohort study investigating 805 Soldiers in a Brigade Combat Team deployed to Afghanistan for 1 year. Demographic, occupational, and fitness variables were recorded. There was no difference in time spent on fitness training between the battalions. Occupational tasks performed by deployed Soldiers vary in the level of physical demand between battalions. Infantry had the highest fitness score (257); wore the heaviest equipment (70 lb.); spent the most time wearing body armor (49 hours/week), performing dismounted patrol (29 hours/week), and lifting objects (35 hours/week); spent the least amount of time working at a desk (14 hours/week); but had a similar incidence of LBP (77%) compared to other battalions. History of LBP and time spent wearing body armor were the two most consistent predictors of LBP across battalion types.

Structure modeling and docking study of HCV NS5B-3a RNA polymerase for the identification of potent inhibitors

Homology modeling in combination with molecular docking studies has been applied to predict the binding modes of the Hepatitis C virus (HCV) NS5B-3a inhibitors within the pocket of NS5B polymerase of HCV genotype 3a. Structure modeling and docking using Genetic Optimization for Ligand Docking (GOLD) were carried out to understand the ligand binding properties of NS5B-3a and to identify a potent inhibitor against it. The three-dimensional homology model of Pakistani strain is not available and was built based on the HCV-J4 NS5B polymerase structure. Compound 1 possessing high GOLD fitness score of 62.17 with IC50 value of 0.04 μM was selected as the potent inhibitor. The docking analysis depicted that hydrogen bonding, ionic and hydrophobic interactions contributed significantly for its ligand binding and the amino acid residues Arg442 and His403 seemed to be the anchor residues for receptor recognition. For developing a connection between the experimental bioactivities and GOLD fitness scores, a squared correlation coefficient was calculated and found as acceptable with the value of r2 = 0.67. These findings may act as potent lead in designing effective NS5B-3a inhibitors.

Cardiorespiratory fitness in males, and upper limbs muscular strength in females, are positively related with 25-hydroxyvitamin D plasma concentrations in European adolescents: the HELENA study

High prevalence of vitamin D insufficiency (<75 nmol/l) has been previously reported in European adolescents. Vitamin D deficiency has been related to physical fitness and adiposity but it is not clearly known whether this relationship applies to growing children and adolescents. To determine how body composition and physical fitness are related to 25-hydroxyvitamin D [25(OH)D] concentrations in European adolescents. The HEalthy Lifestyle in Europe by Nutrition in Adolescence-CSS study was a multi-centre cross-sectional study. Plasma 25(OH)D, body composition and physical fitness measures were obtained in 1006 European adolescents (470 males) aged 12.5-17.5 years. Stepwise regression and ANCOVA were performed by gender using 25(OH)D as dependent variable, with body composition, physical fitness as independent variables controlling for age, seasonality and latitude. For males, maximum oxygen consumption (VO2max) (B = 0.189) and body mass index (BMI) (B = -0.124) were independently associated with 25(OH)D concentrations (both P < 0.05). For females, handgrip strength (B = 0.168; P < 0.01) was independently associated with 25(OH)D concentrations. Those adolescents at lower BMI and high fitness score presented significant higher 25(OH)D concentrations than those at lower fitness score in the other BMI groups (P < 0.05). Cardiorespiratory fitness and upper limbs muscular strength are positively associated with 25(OH)D concentrations in male and female adolescents, respectively. Adiposity in males and low fat free mass in females are related to hypovitaminosis D. The interaction between fitness and BMI has a positive effect on 25(OH)D concentrations. Therapeutic interventions to correct the high rates of vitamin D deficiency in adolescents should consider physical fitness.

QSTR mathematical models for the toxicity of aliphatic carboxylic acids on tetrahymena pyriformis

The present work represents an attempt to improve QSTR models for aquatic toxicity of 3838 aliphatic carboxylic acids tested in the Tetrahymena pyriformis population growth assay, using the topological index ZEP and the following nine main electrotopological and molecular descriptors: acidic dissociation constant, 1-octanol/water partition coefficient, the energy of the lowest unoccupied molecular orbital, acidic dissociation constant, molar refractivity, refraction index, surface tension, polarizability and, electrotopological states. Several different relations between toxicity [loglog(IGC50-1)] and the molecular and topological properties were examined, and a group of multiple linear regression models with high fitness scores were generated.

Two New 3,4;9,10-seco-Cycloartane Type Triterpenoids fromIllicium difengpiand Their Anti-Inflammatory Activities

A pair of new 3,4;9,10-seco-cycloartane type triterpenoid stereoisomerides: 24R,25-dihydroxy-3,4;9,10-seco-4(28)-cycloarten-10,3-olide (1) named Illiciumolide A and 24S,25-dihydroxy-3,4;9,10-seco-4(28)-cycloarten-10,3-olide (2) named Illiciumolide B were isolated from the stem bark of Illicium difengpi, as well as five known biogenetically related triterpenoids, including sootepin E (3), betulinic acid (4), lupeol (5), (all-Z)-1,5,9,13,17,21-hexamethyl-1,5,9,13,17,21-cyclotertracosahexaene (6), and (all-E)-2,6,10,15,19,23-hexamethyl-2,6,10,14,18,22-tetracosahexaene (7). The structures of two new compounds were determined on the basis of spectroscopic analysis including 1D-, 2D-NMR, and MS techniques. Two assays were conducted: inhibition of tumor necrosis factor-alpha (TNF-α) and inhibition of nuclear factor kappa B (NF-κB) in RAW264. 7 cells induced by lipopolysaccharide (LPS). It was observed that compounds 1, 2 and 7 showed significant inhibition of TNF-α production and NF-κB release. The molecule docking results showed that compounds 1 and 2 got high fitness scores with dual specificity mitogen-activated protein kinase kinase 1 (MPKK1), whose activation plays a pivotal role between TNF-α and activation of NF-κB. The anti-HIV-1 potency of compounds 1–5 was also discussed, in addition to the results of computer-aided screening for targets.

The relationship between body composition and physical fitness in 14 year old adolescents residing within the Tlokwe local municipality, South Africa: The PAHL study

BackgroundLittle is known about the relationship between body composition and physical fitness in 14 year-old high school adolescents of South Africa. Baseline data from a longitudinal study on physical activity and health (PAHLS) may provide valuable information for future studies, hence to inform public health policy makers. The objectives of this study are to determine the prevalence of underweight, normal weight and overweight among adolescents aged 14 years in the Tlokwe Local Municipality of the North West Province of South Africa, and to assess the association between physical fitness and body composition separately for boys and girls, adjusted for race and locality.MethodsBody weight, height and triceps, and subscapular skinfolds of 256 adolescents (100 boys and 156 girls) aged 14 years were measured, and percentage body fat and body mass index (BMI) were calculated. BMI was used to determine underweight, normal weight and overweight based on the standard criterion. Physical fitness was assessed by standing broad jump, bent arm hang and sit-ups according to the EUROFIT fitness standard procedures. Multinomial logistic regression analyses stratified for gender and adjusted for race (black or white), and the locality (urban or township) of the schools were used to analyze the data.ResultsIn the total group 35.9% were underweight and 13.7% overweight. Boys were more underweight (44%) than girls (30.7%). The prevalence of overweight was 8% in boys and 17.3% in girls. BMI was strongly (p = 0.01) related with percentage body fat. Strong and significant positive associations between physical fitness and BMI for the underweight girls with high physical fitness scores (OR, 10.69 [95%CI: 2.81-40.73], and overweight girls with high physical fitness scores (OR, 0.11 [95%CI: 0.03-0.50]) were found. Non-significant weaker positive relationship between physical fitness and BMI for the underweight boys with high physical fitness scores (OR, 1.80 [95%CI: 0.63-5.09]), and the overweight boys with high physical fitness scores (OR, 0.18 [95%CI: 0.02-1.78]) were found.ConclusionBoth underweight and overweight among boys and girls in Tlokwe Local Municipality exist, and their effects on physical fitness performances were also noticed. As such, strategic physical activity, interventions or follow-up studies recognizing this relationship particularly in the overweight adolescents are needed. In addition, authorities in health and education departments dealing with adolescents should make use of this evidence base information in policies development.

A non-exercise testing method for estimating cardiorespiratory fitness: associations with all-cause and cardiovascular mortality in a pooled analysis of eight population-based cohorts

Cardiorespiratory fitness (CRF) is a key predictor of chronic disease, particularly cardiovascular disease (CVD), but its assessment usually requires exercise testing which is impractical and costly in most health-care settings. Non-exercise testing cardiorespiratory fitness (NET-F)-estimating methods are a less resource-demanding alternative, but their predictive capacity for CVD and total mortality has yet to be tested. The objective of this study is to examine the association of a validated NET-F algorithm with all-cause and CVD mortality. The participants were 32,319 adults (14,650 men) aged 35-70 years who took part in eight Health Survey for England and Scottish Health Survey studies between 1994 and 2003. Non-exercise testing cardiorespiratory fitness (a metabolic equivalent of VO2max) was calculated using age, sex, body mass index (BMI), resting heart rate, and self-reported physical activity. We followed participants for mortality until 2008. Two thousand one hundred and sixty-five participants died (460 cardiovascular deaths) during a mean 9.0 [standard deviation (SD) = 3.6] year follow-up. After adjusting for potential confounders including diabetes, hypertension, smoking, social class, alcohol, and depression, a higher fitness score according to the NET-F was associated with a lower risk of mortality from all-causes (hazard ratio per SD increase in NET-F 0.85, 95% confidence interval: 0.78-0.93 in men; 0.88, 0.80-0.98 in women) and CVD (men: 0.75, 0.63-0.90; women: 0.73, 0.60-0.92). Non-exercise testing cardiorespiratory fitness had a better discriminative ability than any of its components (CVD mortality c-statistic: NET-F = 0.70-0.74; BMI = 0.45-0.59; physical activity = 0.60-0.64; resting heart rate = 0.57-0.61). The sensitivity of the NET-F algorithm to predict events occurring in the highest risk quintile was better for CVD (0.49 in both sexes) than all-cause mortality (0.44 and 0.40 for men and women, respectively). The specificity for all-cause and CVD mortality ranged between 0.80 and 0.82. The net reclassification improvement of CVD mortality risk (vs. a standardized aggregate score of the modifiable components of NET-F) was 27.2 and 21.0% for men and women, respectively. The CRF-estimating method NET-F that does not involve exercise testing showed consistent associations with all-cause and cardiovascular mortality, and it had good discrimination and excellent risk reclassification improvement. As such, it merits further attention as a practical and potentially and useful risk prediction tool.

3D QSAR pharmacophore modeling, in silico screening, and density functional theory (DFT) approaches for identification of human chymase inhibitors.

Human chymase is a very important target for the treatment of cardiovascular diseases. Using a series of theoretical methods like pharmacophore modeling, database screening, molecular docking and Density Functional Theory (DFT) calculations, an investigation for identification of novel chymase inhibitors, and to specify the key factors crucial for the binding and interaction between chymase and inhibitors is performed. A highly correlating (r = 0.942) pharmacophore model (Hypo1) with two hydrogen bond acceptors, and three hydrophobic aromatic features is generated. After successfully validating “Hypo1”, it is further applied in database screening. Hit compounds are subjected to various drug-like filtrations and molecular docking studies. Finally, three structurally diverse compounds with high GOLD fitness scores and interactions with key active site amino acids are identified as potent chymase hits. Moreover, DFT study is performed which confirms very clear trends between electronic properties and inhibitory activity (IC50) data thus successfully validating “Hypo1” by DFT method. Therefore, this research exertion can be helpful in the development of new potent hits for chymase. In addition, the combinational use of docking, orbital energies and molecular electrostatic potential analysis is also demonstrated as a good endeavor to gain an insight into the interaction between chymase and inhibitors.

Ligand and structure based pharmacophore modeling to facilitate novel histone deacetylase 8 inhibitor design

Over expression of histone deacetylases (HDACs) leads to the suppression of various gene expressions including cancer suppressor gene. Thus, novel inhibitors of these enzymes can be a valid method to treat cancers. To facilitate the discovery of novel HDAC8 inhibitors, pharmacophore models were generated using ligand and receptor based approaches and validated with a database of active and inactive compounds. These validated pharmacophores have effectively been used in search of three databases and final hits were subjected to molecular docking using GOLD 4.1 program. Hit compounds that scored high GOLD fitness scores and showed interactions with catalytically important residues and metal ions were considered. Finally, three compounds have been reported as novel virtual leads to design potent HDAC8 inhibitors.

Identification of potent virtual leads to design novel indoleamine 2,3-dioxygenase inhibitors: Pharmacophore modeling and molecular docking studies

Indoleamine 2,3-dioxygenase, a heme-containing enzyme, is emerging as a vital target for the treatment of cancer, chronic viral infections, and other diseases. The aim of this study is to identify novel scaffolds and utilize them in designing potent IDO inhibitors. Pharmacophore hypotheses were developed. The highly correlating ( r = 0.958) hypothesis with two hydrogen bond acceptor, one hydrogen bond donor and one hydrophobic aromatic features was selected, validated and used in virtual screening. Hit compounds were subjected to various drug-like filtrations and molecular docking studies. Finally, three structurally diverse compounds with high GOLD fitness scores and interactions with critical active site amino acids were identified. These final hits may act as potent virtual leads in effective IDO inhibitor designing.

Binding of 2CA1P (nocturnal inhibitor) to the active site of RubisCO using genetic algorithm (GA).

Ribulose-1, 5- Bisphosphate carboxylase/ oxygenase (RubisCO) catalyzes the first step in net photosynthetic assimilation and photorespiratory carbon oxidation. The activity of this enzyme is modulated in response to changes in light intensity as suggested in a number of early reports. Several studies found that the natural inhibitor 2CA1P is involved in the inhibition of the enzyme under reduced light intensity in rice (Oryza sativa). Due to the lack of studies and information on the interaction between this inhibitor and the active site of the enzyme, we attempted to predict the interaction between the amino acids in the active site and the inhibitor using both Hyperchem7.5 and GOLD software. After the docking; three possibilities having the highest fitness score were found (65.71, 64.72, 62.04), in these possibilities the inhibitor was bound to the enzyme, the phosphate and carboxylate groups in the same positions with a clear difference in the position of OH. In order to confirm the accuracy of the genetic algorithm, the artificial inhibitor 2CABP was docked back in the active site of the enzyme using the same parameters used in the case of the 2CA1P and the algorithm's predictions were compared with the experimentally observed binding mode. The results showed that the difference in the active sites before and after the docking was in the range of 0.93 A which indicated that the results were very accurate. Depending on this result it was concluded that the results obtained in the case of the 2CA1P were close to the experimental results.

THE ROBUST LINEAR REGRESSION MODEL BETWEEN SATELLITE-DERIVED URBAN HEAT ISLAND AND UNDERLYING SURFACE PARAMETERS

Using Landsat TM imagery,the author investigated urban surface temperature and its relationship with such underlying surface parameters as NDVI,SAVI,NDBI,NDMI,Tasseled Cap Brightness(TCB),Greenness(TCG) and Wetness(TCW),total shortwave albedo,and visible and near-IR broadband albedos in Jinan City,Shandong province.The results show that the mean land surface temperature(Ts) in the built-up areas is 11.04℃,higher than that in the suburban areas.Simple linear models between landcover parameters and Ts derived from Landsat TM thermal image were built by using robust LTS regression and classic least-squares regression.Ts is negatively correlated with vegetation indices(NDVI,SAVI and TCG),wetness indices(NDMI and TCW) and near-IR broadband albedo and positively correlated with brightness indices(NDBI and TCB) and visible broadband albedo at the significant level of α=0.05.However,simple linear relationship between Ts and total shortwave albedo does not exist.Most of the regression models have high fitness score,except only for the two models associated with TCW and TCB.It is also shown that the linear regression model between NDMI and Ts is most robust,while the regression equations associated with visible and near-IR broadband albedo,TCW and TCB are not robust.

An improved QSPR study of the toxicity of aliphatic carboxylic acids using genetic algorithm

Toxicity of 38 aliphatic carboxylic acids was studied by using a quantitative structure–activity relationship (QSAR) method and the following molecular and topological properties: acidic dissociation constant, electrotopological states, molar refractivity, refraction index, log Kow, ELUMO, surface tension, and polarizability. Application of realistic molecular quantities that can express the toxicities of the molecules is the idea behind the choice of these topological and physicochemical descriptors. To obtain a proper model for relating the toxicity values of aliphatic carboxylic acids to their structural properties a genetic algorithm (GA) coupled with the partial least-squares (PLS) method were utilized. All different possible relations between toxicity [log (IGC50−1)] and the molecular properties up to forth order were examined, and a group of multiple regression models with high fitness scores were generated. Acidic dissociation constant, surface tension, log Kow, and the electrotopological state of the methyl group were selected as significant descriptors, using a backward elimination method on the top descriptors obtained from the genetic algorithm. The selected descriptors and the orders chosen for them are shown to be good for assessing the toxicity of aliphatic carboxylic acids. It was also verified that, in equations in several variable, using higher-order relationships (i.e., square, cubic, and/or quadratic) gives an excellent accuracy.

An Insilico approach to High Altitude Pulmonary Edema - Molecular modeling of human β2 adrenergic receptor and its interaction with Salmeterol &amp; Nifedipine

Knowledge of the three-dimensional structures of protein targets from genomic data has the potential to accelerate researches pertaining to drug discovery. Human beta(2) adrenergic receptor is a G-protein-coupled receptor with seven transmembrane helices, and is important in pharmaceutical targeting on pulmonary and cardiovascular diseases. The human beta(2) adrenergic receptor has been found to play a very important role in the pathogenesis of high altitude pulmonary edema (HAPE). In the present study, a high quality of protein 3D structure has been predicted for the human beta(2) adrenergic receptor sequence with primary accession number P07550. Homologous template protein sequence with known 3D structure was identified and the template-query protein sequence validation was done by multiple sequence alignment method. The homology model was performed through Modeller and depended on the quality of the sequence alignment by BLAST, template structure and the consolidated result performed by Gene silico meta-server. The statistical verification of the generated model was evaluated by PROCHECK which revealed that the structure modeled through Modeller to be of good quality with 84.1% of residues in the most favored region. Docking studies were carried out after modeling with two well known ligands namely Salmeterol and Nifedipine, and the fitness score revealed that Salmeterol has a higher fitness score than Nifedipine. Estimation of binding affinity by X-Score revealed that Salmeterol had -10.40 binding affinity while Nifedipine showed -9.62 binding affinity. From the present study, it can be concluded that the generated model of human beta(2) adrenergic receptor can be used for further studies related to this receptor and Salmeterol was found to have a high binding affinity with human beta(2) adrenergic receptor.

Differences In Physical Activity And Physical Fitness In Children By Levels Of Urbanization

PURPOSE The purpose of this study was to examine the effects of different geographical settings on physical activity (PA) and physical fitness (PF) in children. METHODS Data were obtained from 61 elementary schools that were involved in a large statewide surveillance study known as PANARY (Physical Activity and Nutrition Among Rural Youth). Physical activity data were obtained from 1014 boys and 1057 girls (grades 4–6) using the Physical Activity Questionnaire for Children (PAQ-C). Physical fitness data were obtained from 846 boys and 912 girls using the PACER aerobic shuttle run. Degree of urbanization was determined by county Beale codes that range from 0–9. Codes of 0–2 defined large urban areas (UA), codes of 3–5 defined small cities (SC) and codes of 6–9 defined rural areas (RA). Two-way (gender × urbanization) Analysis of Covariance (ANCOVA) were used to test for differences in the PA and PF outcomes with age controlled as a covariate. Effect Sizes (ES) were used to report the magnitudes of the effects. RESULTS For PA, there were significant main effects for gender (p <.01) and degree of urbanization (p <.01). Boys had higher physical activity levels than girls in all three categories of urbanization, although the effect sizes were small (ES ∼ .20). Participants from UA areas reported the lowest levels of physical activity and these levels were significantly different than those from participants in SC (ES = −.39) and RA (ES = −.28). For PF, the gender × urbanization interaction was significant (p = .013). Boys in SC and RA had higher fitness levels than boys in UA (ES = .52 and .28, respectively). In contrast, Girls in SC and UA had higher fitness levels than girls in RA (ES ∼ .23). Boys had higher fitness scores than girls in SC (ES = .52), and RA (ES = .54) but not in UA. CONCLUSION There were differences in PA and PF levels by degree of urbanization but some of this effect may be due to socioeconomic status (SES). The SC schools had lower percentages of children eligible for free or reduced lunch (24%) than UA (29%) or RA (40%). Access to parks and programs, and quality of school physical education may also account for differences in the samples. Additional research is needed to understand possible environmental influences on PA and PF.