Allelic Discrimination of Vitamin D Receptor Polymorphisms and Risk of Type 2 Diabetes Mellitus: A Case-Controlled Study

(1) Background: Type 2 diabetes mellitus (T2DM) is one of the rapidly growing healthcare problems, and several vitamin D receptor (VDR) polymorphisms seem to modulate the risk of T2DM. Our research was designed to investigate the allelic discrimination of VDR polymorphisms and T2DM occurrence risk. (2) Methods: This case-control research included 156 patients with T2DM and 145 healthy control subjects. Most of the study population were males 56.6% vs. 62.8% in the case and control groups, respectively. Genotyping for VDR single nucleotide polymorphisms (SNPs), rs228570 (Fok1), rs7975232 (Apa1), and rs1544410 (Bsm1) was compared between both groups. (3) Results: There was a negative link between vitamin D levels and insulin sensitivity. A significant difference was noted in the allelic discrimination of VDR polymorphism rs228570 and rs1544410 between the study groups (p \u3c 0.001). No difference was observed in the allelic discrimination of VDR polymorphism rs7975232 between the groups (p = 0.063). Moreover, T2DM patients had significantly higher levels of fasting blood sugar (FBS), glycated hemoglobin HbA1c, 2-h post-prandial blood sugar (PP), serum glutamic oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT), total cholesterol, and triglycerides (p \u3c 0.001), while High-Density Lipoprotein (HDL) Cholesterol (HDL-C) was significantly decreased (p = 0.006). (4) Conclusions: VDR polymorphisms had a positive association with T2DM risk among the Egyptian population. Further large-scale research using deep sequencing of samples is strongly urged to investigate different vitamin D gene variants and interactions, as well as the influence of vitamin D on T2DM

ANTIVIRAL AND IMMUNE STIMULANT ACTIVITIES OF GLYCYRRHIZIN AGAINST DUCK HEPATITIS VIRUS

This study was conducted to investigate the effect of glycyrrhizin as an immune stimulant against duck hepatitis virus (DHV). In vitro study was carried out to determine cytotoxic and antiviral effects of glycyrrhizin in VERO cells. In vivo study was performed on 40 one-day-old White Pekin ducklings. –and the birds weres divided into 4 groups: control, glycyrrhizin treated, vaccinated with live attenuated DHV vaccine and glycyrrhizin treated and vaccinated; to investigate the changes in immunity and challenge test. Blood samples were collected from each duckling for evaluation of cellular and humeral immunity. The in vitro results revealed that glycyrrhizin had antiviral and no toxic effects till 106 dilutions. Higher antibody titer was observed from the 5th week till the end of experiment in glycyrrhizin and vaccinated group. Treatment with glycyrrhizin alone or with DHV vaccine demonstrated a pronounced lymphocytic proliferation response after 4 days post-inoculation till the end of experiment, while vaccinated group revealed a pronounced proliferation response after 24 days post-inoculation. Treatment with glycyrrhizin alone or combination with DHV vaccine revealed good immune stimulant and antiviral effect against DHV

Biological and clinical significance of PARP1 protein expression in breast cancer

Poly(ADP-ribose) polymerase-1 (PARP1) is a key facilitator of DNA repair. PARP inhibitors have gained recent attention as promising therapeutic agents for the treatment of solid tumours including breast cancer (BC). However, the biological and clinical significance of PARP1 expression in BC and its role in DNA-damage response (DDR) remain to be defined. We investigated the expression of PARP1 expression, cleaved (PARP1c) and non-cleaved (PAR1nc) forms, in a large and well-characterised cohort of clinically annotated stage I–III operable BCs (n = 1,269) and 43 BRCA1-mutated BCs using immunohistochemistry. PARP1 expression was correlated to clinicopathological variables, outcome and expression of other key DNA repair proteins (BRCA1, RAD51, Ku70/80, PIASγ and CHK1). Expression of PARP1 was exclusively nuclear. 49 and 85 % of sporadic BC showed expression PARP1nc and PARP1c, respectively. In BRCA1-mutated tumours, PARP1nc/PARP1c was highly expressed (95 and 79 %, respectively). PARP1nc expression was positively associated with premenopausal younger age patients, larger size and higher tumour grade. PARP1 was positively associated with DDR-proteins; RAD51, BRCA1, CHK1 and PIASγ (p < 0.001). Negative association was found between PARP1nc and Ki67. PARP1c was associated with ER (p < 0.001). Different associations between PARP1 and DDR-proteins were observed when stratified based on ER/BRCA1 status. PARP1 was not an independent predictor of outcome in sporadic or BRCA1-mutated BC. Our results demonstrate a potential biological role for PARP1c and PARP1nc in DNA repair in BC based on the significant association with other key DNA damage repair proteins. These associations were not restricted to ER-negative or triple-negative subgroup

Tetranuclear Zn/4f coordination clusters as highly efficient catalysts for Friedel-Crafts alkylation

A series of custom-designed, high yield, isoskeletal tetranuclear Zn/4f coordination clusters showing high efficiency as catalysts with low catalytic loadings in Friedel-Crafts alkylation are described for the first time. The possibility of altering the 4f centers in these catalysts without altering the core topology allows us to further confirm their stability via EPR and NMR, as well to gain insights into the plausible reaction mechanism, showcasing the usefulness of these bimetallic systems as catalysts

Insight into the effects of H2SO4 and HNO3 acidification processes on the properties of coal as an enhanced adsorbent for ciprofloxacin residuals: Steric and energetic studies

A sub-bituminous natural coal sample (R.C) was treated with sulfuric acid (S.C) and nitric acid (N.C) as modified products and enhanced adsorbents for obtaining ciprofloxacin (CFX) antibiotic residuals from water. The characterization studied demonstrates enhancement in the surface area and the incorporation of new active oxygenated, sulfur-bearing, and nitrogen-bearing chemical groups into the structure of coal samples. This was reflected in the adsorption capacities that were enhanced from 164.08 mg/g (R.C) to 489.2 mg/g and 518.5 mg/g for N.C and S.C, respectively. The impact of the acid modification processes was evaluated based on the energetic and steric properties of their adsorption systems considering the parameters of the advanced monolayer equilibrium model with one energy site. The determined occupied active sites’ density of R.C (46.32–61.44 mg/g), N.C (168.7–364.9 mg/g), and S.C (159.2–249.9 mg/g) reflects an increase in the quantities of active centers after the acid treatment processes, especially with HNO3. The higher efficiencies of the active sites of S.C to adsorb more CFX molecules (n = 2.08–2.31) than N.C (n = 1.41–2.16) illustrate its higher adsorption capacity. The energetic investigation [adsorption (˂40 kJ/mol) and Gaussian (˂8 kJ/mol) energies] suggested adsorption of CFX by N.C and S.C mainly by physical processes such as van der Waals forces, hydrogen bonding, dipole bonding, and π–π interactions. Moreover, the determined thermodynamic functions including entropy, internal energy, and free enthalpy reflect the spontaneous and endothermic uptake of CFX on the surfaces of N.C and S.C

HER2/neu expression status of post BCG recurrent non-muscle-invasive bladder urothelial carcinomas in relation to their primary ones

Background: Transurethral resection (TUR) followed by adjuvant therapy is still the treatment of choice of Non-Muscle-Invasive Bladder Urothelial Carcinoma (NMIBUC). However, recurrence is one of the most troublesome features of these lesions. Early second resection and adjuvant BCG therapy has been shown to improve the outcome. Objective: To evaluate the prognostic value of C-erbB-2 (HER2/neu) expression status in Non-Muscle-Invasive Bladder Urothelial Carcinoma cases, before and after intravesical Bacillus Calmette Guerin (BCG immunotherapy). Materials and methods: HER2/neu expression was studied in 120 (Ta-T1) Non-Muscle-Invasive Urothelial Carcinoma cases. The expression was evaluated and compared to the expression after Bacillus Calmette Guerin (BCG) immunotherapy. Results: HER2/neu expression in low and high grade of the Non- Muscle-Invasive Urothelial Carcinoma was (38%) and (83%) respectively. The difference of the expression rates by tumor grade was statistically significant. In recurring lesions post BCG therapy, C-erbB-2 expression was markedly decreased (31.6%) when compared to its expression before therapy (65%). Conclusions: The HER2/neu expression increased as the tumor grade rose. The reduction in expression following BCG treatment in Non-Invasive transitional cell carcinoma cases could reflect a reduction of the potential malignancy of the tumor

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Unlocking the potential of approved drugs for the allosteric inhibition of tropomyosin-receptor kinase A using molecular docking and molecular dynamics studies

Tropomyosin-receptor kinase A (TrkA) is the primary isoform among the tropomyosin-receptor kinases that have been associated with human cancer development, contributing to approximately 7.4% of all cancer cases. TrkA represents an attractive target for cancer treatment; however, currently available TrkA inhibitors face limitations in terms of resistance development and potential toxicity. Hence, the objective of this study was to identify new allosteric-approved inhibitors of TrkA that can overcome these challenges and be employed in cancer therapy. To achieve this goal, a screening of 9,923 drugs from the ChEMBL database was conducted to assess their repurposing potential using molecular docking. The top 49 drug candidates, exhibiting the highest docking scores (−11.569 to −7.962 kcal/mol), underwent MM-GBSA calculations to evaluate their binding energies. Delanzomib and tibalosin, the top two drugs with docking scores of −10.643 and −10.184 kcal/mol, respectively, along with MM-GBSA dG bind values of −67.96 and −50.54 kcal/mol, were subjected to 200 ns molecular dynamic simulations, confirming their stable interactions with TrkA. Based on these findings, we recommend further experimental evaluation of delanzomib and tibalosin to determine their potential as allosteric inhibitors of TrkA. These drugs have the potential to provide more effective and less toxic therapeutic alternatives. The approach employed in this study, which involves repurposing drugs through molecular docking and molecular dynamics, serves as a valuable tool for identifying novel drug candidates with distinct therapeutic uses. This methodology can contribute to reducing the attrition rate and expediting the process of drug discovery

Global, regional, and national burden of rheumatoid arthritis, 1990–2020, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021

Background Rheumatoid arthritis is a chronic autoimmune inflammatory disease associated with disability and premature death. Up-to-date estimates of the burden of rheumatoid arthritis are required for health-care planning, resource allocation, and prevention. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021, we provide updated estimates of the prevalence of rheumatoid arthritis and its associated deaths and disability-adjusted life-years (DALYs) by age, sex, year, and location, with forecasted prevalence to 2050. Methods Rheumatoid arthritis prevalence was estimated in 204 countries and territories from 1990 to 2020 using Bayesian meta-regression models and data from population-based studies and medical claims data (98 prevalence and 25 incidence studies). Mortality was estimated from vital registration data with the Cause of Death Ensemble model (CODEm). Years of life lost (YLL) were calculated with use of standard GBD lifetables, and years lived with disability (YLDs) were estimated from prevalence, a meta-analysed distribution of rheumatoid arthritis severity, and disability weights. DALYs were calculated by summing YLLs and YLDs. Smoking was the only risk factor analysed. Rheumatoid arthritis prevalence was forecast to 2050 by logistic regression with Socio-Demographic Index as a predictor, then multiplying by projected population estimates. Findings In 2020, an estimated 17·6 million (95% uncertainty interval 15·8–20·3) people had rheumatoid arthritis worldwide. The age-standardised global prevalence rate was 208·8 cases (186·8–241·1) per 100 000 population, representing a 14·1% (12·7–15·4) increase since 1990. Prevalence was higher in females (age-standardised female-to-male prevalence ratio 2·45 [2·40–2·47]). The age-standardised death rate was 0·47 (0·41–0·54) per 100 000 population (38 300 global deaths [33 500–44 000]), a 23·8% (17·5–29·3) decrease from 1990 to 2020. The 2020 DALY count was 3 060 000 (2 320 000–3 860 000), with an age-standardised DALY rate of 36·4 (27·6–45·9) per 100 000 population. YLDs accounted for 76·4% (68·3–81·0) of DALYs. Smoking risk attribution for rheumatoid arthritis DALYs was 7·1% (3·6–10·3). We forecast that 31·7 million (25·8–39·0) individuals will be living with rheumatoid arthritis worldwide by 2050. Interpretation Rheumatoid arthritis mortality has decreased globally over the past three decades. Global age-standardised prevalence rate and YLDs have increased over the same period, and the number of cases is projected to continue to increase to the year 2050. Improved access to early diagnosis and treatment of rheumatoid arthritis globally is required to reduce the future burden of the disease.publishedVersio

Energy Estimation of Cosmic Rays with the Engineering Radio Array of the Pierre Auger Observatory

The Auger Engineering Radio Array (AERA) is part of the Pierre Auger Observatory and is used to detect the radio emission of cosmic-ray air showers. These observations are compared to the data of the surface detector stations of the Observatory, which provide well-calibrated information on the cosmic-ray energies and arrival directions. The response of the radio stations in the 30 to 80 MHz regime has been thoroughly calibrated to enable the reconstruction of the incoming electric field. For the latter, the energy deposit per area is determined from the radio pulses at each observer position and is interpolated using a two-dimensional function that takes into account signal asymmetries due to interference between the geomagnetic and charge-excess emission components. The spatial integral over the signal distribution gives a direct measurement of the energy transferred from the primary cosmic ray into radio emission in the AERA frequency range. We measure 15.8 MeV of radiation energy for a 1 EeV air shower arriving perpendicularly to the geomagnetic field. This radiation energy -- corrected for geometrical effects -- is used as a cosmic-ray energy estimator. Performing an absolute energy calibration against the surface-detector information, we observe that this radio-energy estimator scales quadratically with the cosmic-ray energy as expected for coherent emission. We find an energy resolution of the radio reconstruction of 22% for the data set and 17% for a high-quality subset containing only events with at least five radio stations with signal.Comment: Replaced with published version. Added journal reference and DO