IN SILICO STUDY OF NOVEL SULFONAMIDE DERIVATIVES BEARING A 1, 2, 4-TRIAZOLE MOIETY ACT AS CARBONIC ANHYDRASE INHIBITORS WITH PROMISING ANTI-CANCER ACTIVITY.

OBJECTIVE: Aim: To evaluate the theoretical binding affinities of four synthetic compounds that target the carbonic anhydrase IX enzyme in solid tumors. PATIENTS AND METHODS: Materials and Methods: To accurately depict the molecular structure, we utilized the Chem Draw Professional 12.0 program. We downloaded the carbonic anhydrase IX enzyme (29.25 KDa) (PDB code: 4YWP) from the Protein Data Bank into the Molecular Operating Environment software. Then, the S-score and rmsd were calculated for the proposed compounds. RESULTS: Results: The theoretically synthesized compounds demonstrated good binding affinities with the receptor active pockets Sa, Sb, and Sd, with S-scores of -7.6491, -8.3789, and -8.3218, respectively. Substitutions improve compound orientation. The substituted triazoles ring increases flexibility and receptor interaction. In addition, the benzyl chloride derivatives play an important role in the interaction, with varying effects dependent on the groups substituted at position 4 of the benzene ring. CONCLUSION: Conclusions: The synthesized compounds Sb with para Br substitution (S-score = -8.37) and Sd with para Cl substitution (S-score = -8.32) are considered the best ones as they exhibit a high affinity for the receptor.

Inhibitory behavior and adsorption of asparagine dipeptide amino acid on the Fe(111) surface.

CONTEXT: The inhibitory effect of asparagine (Asn) and its derivatives on iron (Fe) corrosion was studied by performing density functional theory (DFT) calculations. In this paper, the global and local reactivity descriptors of Asn in the protonated and neutral forms were evaluated. Also, the changes in reactivity were investigated when dipeptides were combined with Asn. Due to the increase in the reaction centers within their molecular structure, there was an enhancement in the inhibitory effect of these dipeptides. Moreover, the adsorption energies (Eads) and the adsorption configurations of Asn and small peptides (SPs) with most stability were determined on the surface of Fe(111). It was found that dipeptides had a chemical adsorption on these substrates. In the protonated forms, there was an enhancement in the absolute values of Eads between the inhibitors and the Fe(111) surfaces. Peptides were more likely to be adsorbed on the Fe surfaces, showing the great inhibitory effect of these moieties. The results of the current research demonstrate the possibility of utilizing SPs as efficient "green" corrosion inhibitors. METHODS: DFT computations were undertaken by employing the BIOVIA Material Studio with B3LYP-D3 functional and 6-31 + G* basis set. The theoretical evaluation of the inhibitory effect of asparagine (Asn) dipeptides, and the potential analysis of small peptides to protect against the corrosion of Fe, was done.

Exploring the role of 2D-C2N monolayers in potassium ion batteries.

CONTEXT: In recent years, undivided attention has been given to the unique properties of layered nitrogenated holey graphene (C2N) monolayers (C2NMLs), which have widespread applications (e.g., in catalysis and metal-ion batteries). Nevertheless, the scarcity and impurity of C2NMLs in experiments and the ineffective technique of adsorbing a single atom on the surface of C2NMLs have significantly limited their investigation and thus their development. Within this research study, we proposed a novel model, i.e., atom pair adsorption, to inspect the potential use of a C2NML anode material for KIBs through first-principles (DFT) computations. The maximum theoretical capacity of K ions reached 2397 mA h g-1, which was greater in contrast with that of graphite. The results of Bader charge analysis and charge density difference revealed the creation of channels between K atoms and the C2NML for electron transport, which increased the interactions between them. The fast process of charge and discharge in the battery was due to the metallicity of the complex of C2NML/K ions and because the diffusion barrier of K ions on the C2NML was low. Moreover, the C2NML has the advantages of great cycling stability and low open-circuit voltage (approximately 0.423 V). The current work can provide useful insights into the design of energy storage materials with high efficiency. METHODS: In this research, we used B3LYP-D3 functional and 6-31 + G* basis with GAMESS program to calculate adsorption energy, open-circuit voltage, and maximum theoretical capacity of K ions on the C2NML.

Evaluation of a biosensor-based graphene oxide-DNA nanohybrid for lung cancer.

Lung cancer is nowadays among the most prevalent diseases worldwide and features the highest mortality rate among various cancers, indicating that early diagnosis of the disease is of paramount importance. Given that the conventional methods of cancer detection are expensive and time-consuming, special attention has been paid to the provision of less expensive and faster techniques. In recent years, the dramatic advances in nanotechnology and the development of various nanomaterials have led to activities in this context. Recent studies indicate that the graphene oxide (GO) nanomaterial has high potential in the design of nano biosensors for lung cancer detection owing to its unique properties. In the current article, a nano biosensor based on a DNA-GO nanohybrid is introduced to detect deletion mutations causing lung cancer. In this method, mutations were detected using a FAM-labeled DNA probe with fluorescence spectrometry. GO was synthesized according to Hummers' method and examined and confirmed using Fourier Transform Infrared (FT-IR) Spectrometry and UV-vis spectrometry methods and Transmission Electron Microscopy (TEM) images.

Sex moderates the associations between physical activity intensity and attentional control in older adolescents.

INTRODUCTION: The relationship between physical activity (PA) intensity and executive functions in older adolescents remains poorly understood. This study aimed to examine the associations between PA intensity, volume, attentional control, and working memory and the moderating effects of sex in older adolescents. METHOD: We analyzed baseline data from 418 participants (211 females, Mage  = 16.5 ± 0.40 years) from the Burn 2 Learn trial. Adolescents wore GT9X Link accelerometers on a non-dominant wrist for 7 days, 24-h·d-1 . PA intensity was expressed as intensity gradient (IG) and moderate-to-vigorous PA (MVPA, Hildebrand cut-points); PA volume was expressed as average acceleration (AvACC). Attentional control was measured with a standard deviation (SDRT) and a coefficient of variation (CVRT) of the reaction time on the incongruent trials of a flanker task. Working memory was expressed as a d prime (a signal discrimination index) on the 2-back task. The moderating effects of sex on the PA-executive functions associations, adjusting for age, BMI z-score, and cardiorespiratory fitness, were tested using multilevel random intercept models. RESULTS: After controlling for AvACC, sex moderated the relationships between IG and incongruent SDRT (B = 0.53, 95% CI: 0.12, 0.94) and CVRT (B = 0.63, 95% CI: 0.22, 1.05; ps ≤ 0.002). Only girls with higher IG showed smaller incongruent SDRT and CVRT (Bs ≤ -0.26, ps ≤ 0.01). IG was not related to working memory. AvACC and MVPA were not associated with attentional control or working memory. CONCLUSION: Our findings reveal a novel association between higher-intensity PA and superior attentional control among adolescent girls.

Galangin/ß-Cyclodextrin Inclusion Complex as a Drug-Delivery System for Improved Solubility and Biocompatibility in Breast Cancer Treatment.

The purpose of this study was to evaluate the potential of a newly modified cyclodextrin derivative, water-soluble ß-cyclodextrin-epichlorohydrin (ß-CD), as an effective drug carrier to enhance the poor solubility and bioavailability of galangin (GAL), a poorly water-soluble model drug. In this regard, inclusion complexes of GAL/ß-CDP were prepared. UV-VIS spectrophotometry, Fourier-transform infrared spectroscopy (FTIR), X-ray crystallography (XRD), zeta potential analysis, particle size analysis, field emission scanning electron microscopy (FESEM), and transmission electron microscopy (TEM) were applied to characterize the synthesized GAL/ß-CD. Michigan Cancer Foundation-7 (MCF-7; human breast cancer cells) and rat embryo fibroblast (REF; normal cells) were employed to examine the in vitro cytotoxic effects of GAL/ß-CD using various parameters. The dye-based tests of MTT and crystal violet clearly exhibited that GAL/ß-CD-treated cells had a reduced proliferation rate, an influence that was not found in the normal cell line. The cells' death was found to follow apoptotic mechanisms, as revealed by the dye-based test of acridine orange/ethidium bromide (AO/EtBr), with the involvement of the mitochondria via caspase-3-mediated events, as manifested by the Rh 123 test. We also included a mouse model to examine possible in vivo toxic effects of GAL/ß-CD. It appears that the inclusion complex does not have a significant influence on normal cells, as indicated by serum levels of kidney and liver enzymatic markers, as well as thymic and splenic mass indices. A similar conclusion was reached on the histological level, as manifested by the absence of pathological alterations in the liver, kidney, thymus, spleen, heart, and lung.

Interleukin-6 and C-Reactive Protein: their association with vitamin D in women with recurrent infections of reproductive system.

Aerobic bacteria can colonize the female reproductive system with harmful effects, which may lead to miscarriages, premature deliveries or continue of its growing to cause adverse reproductive systems issues. Increasing in the levels of inflammatory markers may be considered a herald of danger. High vaginal swabs were obtained from 85 women. Of these, 67 patients were suffering recurrent vaginitis and symptoms such as itching, irritation, burning, and vaginal discharged, and 18 apparently healthy controls. Swabs were cultured in a suitable media and the cultivated bacteria were diagnosed in the hospital's laboratory. At the same time of collecting the vaginal swabs, 5 ml of venous blood was withdrawn from the patients and controls. An ELISA method was applied to measure the levels of inflammatory cytokines and concentration of vitamin D. The bacterial growth showed six species of isolated bacteria, which were Staphylococcus aureus, Streptococcus spp., E. coli, S. non aureus, Proteus spp. and Klebsiella spp. The first three species were the most prevalent bacteria, and the serum levels of C reactive protein (CRP) and IL-6 were high in female patients infected with these bacteria. CRP was significantly elevated in sera of the patient's group (P= 0.016), while the increase in IL-6 was not significant. Vitamin D was correlated negatively with IL-6 and positively with CRP, but the correlations did not reach statistical significance. In conclusion, rising of CRP could be an expected result to the bacterial colonizing the reproductive system while IL-6 may develop significantly when the aerobic vaginitis continues until triggering one of the infertility issues.

Psyllium reduces inulin-induced colonic gas production in IBS: MRI and in vitro fermentation studies.

OBJECTIVE: Health-promoting dietary fibre including inulin often triggers gastrointestinal symptoms in patients with IBS, limiting their intake. Our aim was to test if coadministering psyllium with inulin would reduce gas production. DESIGN: A randomised, four-period, four-treatment, placebo-controlled, crossover trial in 19 patients with IBS. Subjects ingested a 500 mL test drink containing either inulin 20 g, psyllium 20 g, inulin 20 g+ psyllium 20 g or dextrose 20 g (placebo). Breath hydrogen was measured every 30 min with MRI scans hourly for 6 hours. Faecal samples from a subset of the patients with IBS were tested using an in vitro fermentation model. Primary endpoint was colonic gas assessed by MRI. RESULTS: Colonic gas rose steadily from 0 to 6 hours, with inulin causing the greatest rise, median (IQR) AUC(0-360 min) 3145 (848-6502) mL·min. This was significantly reduced with inulin and psyllium coadministration to 618 (62-2345) mL·min (p=0.02), not significantly different from placebo. Colonic volumes AUC(0-360 min) were significantly larger than placebo for both inulin (p=0.002) and inulin and psyllium coadministration (p=0.005). Breath hydrogen rose significantly from 120 min after inulin but not psyllium; coadministration of psyllium with inulin delayed and reduced the maximum increase, AUC(0-360 min) from 7230 (3255-17910) ppm·hour to 1035 (360-4320) ppm·hour, p=0.007.Fermentation in vitro produced more gas with inulin than psyllium. Combining psyllium with inulin did not reduce gas production. CONCLUSIONS: Psyllium reduced inulin-related gas production in patients with IBS but does not directly inhibit fermentation. Whether coadministration with psyllium increases the tolerability of prebiotics in IBS warrants further study. TRIAL REGISTRATION NUMBER: NCT03265002.

scRNA-seq of human vitiligo reveals complex networks of subclinical immune activation and a role for CCR5 in Treg function.

Vitiligo is an autoimmune skin disease characterized by the targeted destruction of melanocytes by T cells. Cytokine signaling between keratinocytes and T cells results in CD8+ T cell infiltration of vitiligo lesions, but the full scope of signals required to coordinate autoimmune responses is not completely understood. We performed single-cell RNA sequencing on affected and unaffected skin from patients with vitiligo, as well as healthy controls, to define the role of each cell type in coordinating autoimmunity during disease progression. We confirmed that type 1 cytokine signaling occupied a central role in disease, but we also found that this pathway was used by regulatory T cells (Tregs) to restrain disease progression in nonlesional skin. We determined that CCL5-CCR5 signaling served as a chemokine circuit between effector CD8+ T cells and Tregs, and mechanistic studies in a mouse model of vitiligo revealed that CCR5 expression on Tregs was required to suppress disease in vivo but not in vitro. CCR5 was not required for Treg recruitment to skin but appeared to facilitate Treg function by properly positioning these cells within the skin. Our data provide critical insights into the pathogenesis of vitiligo and uncover potential opportunities for therapeutic interventions.

Bacterial isolation from internal organs of rats (Rattus rattus) captured in Baghdad city of Iraq.

AIM: Rats are accused in disseminating many zoonotic diseases. This study aimed to isolate and identify bacteria from internal organs of rats captured in Baghdad City, Iraq. MATERIALS AND METHODS: A total of 120 black rats (R. rattus) were trapped from different areas in Baghdad city. Rats were kept in individual plastic cages for 3 h before euthanizing. Deep pharyngeal swab, intestinal content, urine, and pieces of the liver and spleen, lung, kidney, and brain were obtained aseptically. The specimens were inoculated into peptone water and incubated at 37°C for 24 h for enrichment. A loopful of each specimen was then subcultured onto MacConkey Agar, Blood Agar, and Mannitol Salt Agar. CHROMagar O157 H7 and CHROMagar Listeria were used to detect Escherichia coli 157:7 and Listeria spp., respectively. Biochemical tests on analytical profile index, microscopic examination, and commercial kit for latex agglutination test for serotyping E. coli O157:H7 were used. RESULTS: Mixed bacterial isolates were recorded as 116, 52, 36, 28, 18, 6, and 4 from intestinal contents, deep pharyngeal, liver and spleen, urine, lung, brain, and kidney, respectively. Microorganisms included E. coli, Staphylococcus aureus, Streptococcus spp., Bacillus spp., Pseudomonas aeruginosa, Citrobacter freundii, Proteus vulgaris, E. coli O157:H7, Enterobacter cloacae, Listeria spp., Klebsiella spp., Ochrobactrum anthropi, Aeromonas spp., Brucella spp., Pseudomonas fluorescens, Escherichia fergusonii, Micrococcus spp., Morganella spp., Proteus mirabilis, Pseudomonas luteola, and Streptobacillus spp. The highest bacterial prevalence (88; 73.33%) was recorded for E. coli, where 68 isolates were identified from the intestinal contents. Of these, four isolates were E. coli O157:H7. CONCLUSION: Rats are important carriers and transmitters of a number of pathogens and can disseminate these microorganisms to humans and animals.

Spatial analysis of groundwater suitability for drinking and irrigation in Lahore, Pakistan.

This study used a total of 474 groundwater samples analyzed from 2014 data to evaluate the distribution of groundwater quality in the Water and Sanitation Agency (WASA) jurisdiction of Lahore city, Pakistan. The study further assessed the variations in suitability of groundwater for drinking (emphasis on arsenic and fluoride) and irrigation using spatial correlation technique in GIS. The hydrochemical analysis revealed a predominance of Mg-Ca-HCO3-SO4 and Ca-Mg-HCO3-SO4 type. Distribution analysis indicated relatively higher salinity (TDSmax = 1667 mg/L), total hardness (THmax = 558 mg/L), and alkalinity (HCO3-max = 584 mg/L) in the south-eastern region of the city, while the central part displayed the highest levels of SO4 and NO3. Also, the eastern region (north-south) of Lahore had significantly elevated As concentrations (up to 86 µg/L). The order of exceedance in terms of arsenic was Gunj Bakhsh town (17.4%), Nishter town (16.4%), Iqbal town (9.8%), Aziz Batti and Shalimar town (8.1%), and Ravi town (3%). The groundwater was classified as average saline to highly saline, except few samples in Aziz Batti/Shalimar town that were in non-saline group. Otherwise, the various indices classified the groundwater for irrigation as generally acceptable. With the various irrigation quality indices displaying discernible variations for the entire study area, it was observed from the distribution maps that the groundwater suitability for irrigation is relatively excellent in the areas away from industries and landfill locations. Also, the chloride analysis shows 98.7% of the groundwater samples belong to the very fresh and fresh water class. Thus, continued monitoring and studying the changes in groundwater quality in Lahore is imperative.

UDP-sugars activate P2Y14 receptors to mediate vasoconstriction of the porcine coronary artery.

AIMS: UDP-sugars can act as extracellular signalling molecules, but relatively little is known about their cardiovascular actions. The P2Y14 receptor is a Gi/o-coupled receptor which is activated by UDP-glucose and related sugar nucleotides. In this study we sought to investigate whether P2Y14 receptors are functionally expressed in the porcine coronary artery using a selective P2Y14 receptor agonist, MRS2690, and a novel selective P2Y14 receptor antagonist, PPTN (4,7-disubstituted naphthoic acid derivative). METHODS AND RESULTS: Isometric tension recordings were used to evaluate the effects of UDP-sugars in porcine isolated coronary artery segments. The effects of the P2 receptor antagonists suramin and PPADS, the P2Y14 receptor antagonist PPTN, and the P2Y6 receptor antagonist MRS2578, were investigated. Measurement of vasodilator-stimulated phosphoprotein (VASP) phosphorylation using flow cytometry was used to assess changes in cAMP levels. UDP-glucose, UDP-glucuronic acid UDP-N-acetylglucosamine (P2Y14 receptor agonists), elicited concentration-dependent contractions of the porcine coronary artery. MRS2690 was a more potent vasoconstrictor than the UDP-sugars. Concentration dependent contractile responses to MRS2690 and UDP-sugars were enhanced in the presence of forskolin (activator of cAMP), where the level of basal tone was maintained by addition of U46619, a thromboxane A2 mimetic. Contractile responses to MRS2690 were blocked by PPTN, but not by MRS2578. Contractile responses to UDP-glucose were also attenuated by PPTN and suramin, but not by MRS2578. Forskolin-induced VASP-phosphorylation was reduced in porcine coronary arteries exposed to UDP-glucose and MRS2690, consistent with P2Y14 receptor coupling to Gi/o proteins and inhibition of adenylyl cyclase activity. CONCLUSIONS: Our data support a role of UDP-sugars as extracellular signalling molecules and show for the first time that they mediate contraction of porcine coronary arteries via P2Y14 receptors.

Bacterial and viral co-infections complicating severe influenza: Incidence and impact among 507 U.S. patients, 2013-14.

BACKGROUND: Influenza acts synergistically with bacterial co-pathogens. Few studies have described co-infection in a large cohort with severe influenza infection. OBJECTIVES: To describe the spectrum and clinical impact of co-infections. STUDY DESIGN: Retrospective cohort study of patients with severe influenza infection from September 2013 through April 2014 in intensive care units at 33 U.S. hospitals comparing characteristics of cases with and without co-infection in bivariable and multivariable analysis. RESULTS: Of 507 adult and pediatric patients, 114 (22.5%) developed bacterial co-infection and 23 (4.5%) developed viral co-infection. Staphylococcus aureus was the most common cause of co-infection, isolated in 47 (9.3%) patients. Characteristics independently associated with the development of bacterial co-infection of adult patients in a logistic regression model included the absence of cardiovascular disease (OR 0.41 [0.23-0.73], p=0.003), leukocytosis (>11K/µl, OR 3.7 [2.2-6.2], p<0.001; reference: normal WBC 3.5-11K/µl) at ICU admission and a higher ICU admission SOFA score (for each increase by 1 in SOFA score, OR 1.1 [1.0-1.2], p=0.001). Bacterial co-infections (OR 2.2 [1.4-3.6], p=0.001) and viral co-infections (OR 3.1 [1.3-7.4], p=0.010) were both associated with death in bivariable analysis. Patients with a bacterial co-infection had a longer hospital stay, a longer ICU stay and were likely to have had a greater delay in the initiation of antiviral administration than patients without co-infection (p<0.05) in bivariable analysis. CONCLUSIONS: Bacterial co-infections were common, resulted in delay of antiviral therapy and were associated with increased resource allocation and higher mortality.

Severe Influenza in 33 US Hospitals, 2013-2014: Complications and Risk Factors for Death in 507 Patients.

BACKGROUND: Influenza A (H1N1) pdm09 became the predominant circulating strain in the United States during the 2013-2014 influenza season. Little is known about the epidemiology of severe influenza during this season. METHODS: A retrospective cohort study of severely ill patients with influenza infection in intensive care units in 33 US hospitals from September 1, 2013, through April 1, 2014, was conducted to determine risk factors for mortality present on intensive care unit admission and to describe patient characteristics, spectrum of disease, management, and outcomes. RESULTS: A total of 444 adults and 63 children were admitted to an intensive care unit in a study hospital; 93 adults (20.9%) and 4 children (6.3%) died. By logistic regression analysis, the following factors were significantly associated with mortality among adult patients: older age (>65 years, odds ratio, 3.1 [95% CI, 1.4-6.9], P=.006 and 50-64 years, 2.5 [1.3-4.9], P=.007; reference age 18-49 years), male sex (1.9 [1.1-3.3], P=.031), history of malignant tumor with chemotherapy administered within the prior 6 months (12.1 [3.9-37.0], P<.001), and a higher Sequential Organ Failure Assessment score (for each increase by 1 in score, 1.3 [1.2-1.4], P<.001). CONCLUSION: Risk factors for death among US patients with severe influenza during the 2013-2014 season, when influenza A (H1N1) pdm09 was the predominant circulating strain type, shifted in the first postpandemic season in which it predominated toward those of a more typical epidemic influenza season.

Ca(2+) activation and tension cost in myofilaments from mouse hearts ectopically expressing enteric gamma-actin.

To determine the significance of actin isoforms in chemomechanical coupling, we compared tension and ATPase rate in heart myofilaments from nontransgenic (NTG) and transgenic (TG) mice in which enteric gamma-actin replaced >95% of the cardiac alpha-actin. Enteric gamma-actin was expressed against three backgrounds: mice expressing cardiac alpha-actin, heterozygous null cardiac alpha-actin mice, and homozygous null cardiac alpha-actin mice. There were no differences in maximum Ca(2+) activated tension or maximum rate of tension redevelopment after a quick release and rapid restretch protocol between TG and NTG skinned fiber bundles. However, compared with NTG controls, Ca(2+) sensitivity of tension was significantly decreased and economy of tension development was significantly increased in myofilaments from all TG hearts. Shifts in myosin isoform population could not fully account for this increase in the economy of force production of TG myofilaments. Our results indicate that an exchange of cardiac alpha-actin with an actin isoform differing in only five amino acids has a significant impact on both Ca(2+) regulation of cardiac myofilaments and the cross-bridge cycling rate.