Structure-activity relationships based on 3D-QSAR CoMFA/CoMSIA and design of aryloxypropanol-amine agonists with selectivity for the human β3-adrenergic receptor and anti-obesity and anti-diabetic profiles

Indexación: Scopus.Acknowledgments: This work was supported by FONDECYT No. 11130701. We would also like to thank fDoTr CthLeafbr efeora vthaeil afrbeilei tayvoafiltahbeilsitoyf towfa trheer seoqfutwireadret orecqaulciureladt etothcealAcuDla(thet ttph:e/ A/dDt c(lhatbt.pw:/e/dbstc.cloabm.w/seobfst.wcoamre/-stoofotlws aarned-tools and http://teqip.jdvu.ac.in/QSAR_Tools/). SDG. Conflicts of Interest: The authors declare no conflict of interest. Conflicts of Interest: The authors declare no conflict of interest.The wide tissue distribution of the adrenergic β3 receptor makes it a potential target for the treatment of multiple pathologies such as diabetes, obesity, depression, overactive bladder (OAB), and cancer. Currently, there is only one drug on the market, mirabegron, approved for the treatment of OAB. In the present study, we have carried out an extensive structure-activity relationship analysis of a series of 41 aryloxypropanolamine compounds based on three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. This is the first combined comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) study in a series of selective aryloxypropanolamines displaying anti-diabetes and anti-obesity pharmacological profiles. The best CoMFA and CoMSIA models presented values of r2 ncv = 0.993 and 0.984 and values of r2 test = 0.865 and 0.918, respectively. The results obtained were subjected to extensive external validation (q2, r2, r2 m, etc.) and a final series of compounds was designed and their biological activity was predicted (best pEC50 = 8.561). © 2018 by the authors.https://www.mdpi.com/1420-3049/23/5/119

Working time satisfaction in aging nurses

Satisfaction with working time could represent an index of good balance between work and life and predict satisfactory work ability and endurance of aged workers. This study is aimed at checking whether elderly nurses who were satisfied with working hours had a better work ability index than those unsatisfied, and finding which factors were related to satisfaction of working time with reference to general \u201cwell being\u201d and/or \u201cprivate life\u201d. The study sample consisted of 3,174 female nurses recruited in six European countries within the Nurses\u2019 Early Exit Study. All were rotating shiftworkers (nights included) and 12.95 % were over 45 years of age. A composite questionnaire, including demands at work and in private life, working conditions, individual resources and alternatives to nursing profession, was administered to the participants at baseline and 1 yr later (Time 1). Work ability index (WAI) at time 1 was used as outcome, whereas age groups and satisfaction of working time at baseline were used as predictors, after adjusting for family status and number of children < 7yrs of age. Also \u201csatisfaction with working time\u201d at Time 1 was used as outcome, whereas working hours, job demand, leisure time, influence on planning rotas, family status, number of children, work/family conflicts, sleep at Time 0 were included as potential determinants. Conditional Random Forest analysis was used to evaluate high, moderate or weak importance of these determinants. Nurses satisfied with working time at time 0 showed a higher WAI (time1) than those unsatisfied in all age groups, also over 50. Less work/family conflicts and better quality and quantity sleep turned out to be the best predictors of satisfaction with working time. Consistently, the importance of the other predictors differs when the outcome is \u201csatisfaction with working time\u201d related to general well-being rather than to private life

A New Kind of Quinonic-Antibiotic Useful Against Multidrug-Resistant S. aureus and E. faecium Infections

Indexación: Scopus.A rapid emergence of resistant bacteria is occurring worldwide, endangering the efficacy of antibiotics and reducing the therapeutic arsenal available for treatment of infectious diseases. In the present study, we developed a new class of compounds with antibacterial activity obtained by a simple, two step synthesis and screened the products for in vitro antibacterial activity against ATCC® strains using the broth microdilution method. The compounds exhibited minimum inhibitory concentrations (MIC) of 1⁻32 μg/mL against Gram-positive ATCC® strains. The structure⁻activity relationship indicated that the thiophenol ring is essential for antibacterial activity and the substituents on the thiophenol ring module, for antibacterial activity. The most promising compounds detected by screening were tested against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF) clinical isolates. We found remarkable activity against VREF for compounds 7 and 16, were the MIC50/90 were 2/4 µg/mL and 4/4 µg/mL, respectively, while for vancomycin the MIC50/90 was 256/512 µg/mL. Neither compound affected cell viability in any of the mammalian cell lines at any of the concentrations tested. These in vitro data show that compounds 7 and 16 have an interesting potential to be developed as new antibacterial drugs against infections caused by VREF.https://www.mdpi.com/1420-3049/23/7/177

Miscarriage following dengue virus 3 infection in the first six weeks of pregnancy of a dengue virus-naive traveller returning from Bali to Italy, April 2016

We report miscarriage following dengue virus (DENV)-3 infection in a pregnant woman returning from Bali to Italy in April 2016. On her arrival, the woman had fever, rash, asthenia and headache. DENV RNA was detected in plasma and urine samples collected the following day. Six days after symptom onset, she had a miscarriage. DENV RNA was detected in fetal material, but in utero fetal infection cannot be demonstrated due to possible contamination by maternal blood

The use of a genetic strategy to study the role of modulation of oxidative stress by uncoupling proteins 2 and 3 in the pathogenesis of Type 2 Diabetes

Mitochondrial dysfunction has been implicated in the early pathogenesis of Type 2 Diabetes. The uncoupling proteins 2 and 3 are mitochondrial proteins found in man that have been implicated in protecting mammals from the effects of over-nutrition. Examination of the effect of genetic variation in the UCP2-UCP3 genetic cluster has so far been inconclusive. The aim of this thesis was to examine, using a genetic strategy, the hypothesis that the role of the uncoupling proteins 2 and 3 in the pathogenesis of Type 2 Diabetes is via modification of oxidative stress. In a prospective study of nearly 3000 men the risk of type 2 diabetes at 10 years was increased for both the UCP2-866AA (1.94 [1.18-3.19]: p=0.009) and the UCP3-55TT (2.06 [1.06-3.99]: p=0.03) homozygotes. This increased risk was not explained by the association with any measured conventional risk factors. Paradoxically, in a Europe-wide cross-sectional study of 598 subjects the UCP2-866A variant was associated with lower waist-hip ratio (GX v AA,1.00 [0.06] v 0.98 [0.07]; p=0.003), although also associated with lower insulin secretion (42.6 [24.6] v 35.6 [18.6]; p=0.03). The UCP3 variant was not significantly associated with any metabolic trait. The significant heritability of plasma markers of oxidative stress (TAS 0.54, TOAS 0.49) suggests anti-oxidant function is a plausible mechanism to determine Type 2 Diabetes risk. The predictors of anti-oxidant stress in a family study were examined, as was the impact of UCP2-UCP3 gene cluster variation. Genetic variation in the UCP2-UCP3 was found to increase the risk of the Type 2 diabetes. While UCP2 may modify insulin secretion directly, the mechanism of action for UCP3 is likely to involve novel risk factors for Type 2 Diabetes such as modification of mitochondrial oxidative stress. Finally, the development of a human model is described to examine genetic influences on oxidative stress burden using a meal rich in used cooking oil.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Early co-circulation of different clades of influenza A/H1N1v pandemic virus in Northern Italy

Introduction. The spatial diffusion over time of pandemic influenza A/H1N1 virus (A/H1N1v) was surveyed in Northern Italy (nearly 10 million inhabitants) from April to December 2009, and the molecular characteristics of circulating viruses were analyzed to identify the appearance of drift variants. About 45% of analyzed samples were laboratory-confirmed cases of A/H1N1v. Sporadic cases occurred until the middle of June 2009, then, case numbers began to increase delineating distinct epidemiological phases of viral circulation. Methods. RNA was extracted using RNeasy Mini kit (QIAGEN GmbH, Germany). Virological diagnosis of A/H1N1v infection was carried out by real-time RT-PCR assay. Sequence analysis of hemagglutinin (HA) gene was performed through a RT-PCR assay specific for a 995 bp fragment (nt. 64-1,058) in the HA1 domain. The nucleotide sequences were obtained by automated DNA sequencing. The HA1 sequences were aligned with other sequences collected from GenBank database by ClustalX software. The multiple sequence alignment was used to perform a basic phylogenetic analysis and a phylogenetic tree from HA sequences was constructed. Results. The HA gene sequences of A/H1N1v analyzed segregated into three genetically distinct clades and were characterized by the appearance of amino acid variations that were progressively fixed in the field viral population under scrutiny. Conclusions. These data suggest an early co-circulation of genetically distinct A/H1N1v variants and emphasize the importance of a close molecular surveillance to detect rapidly the spread of new viral variants and to define their epidemiological impact

Prevalence and associated factors of COVID-19 across Italian regions: a secondary analysis from a national survey on physiotherapists

Background: Coronavirus disease 2019 (COVID-19) broke out in China in December 2019 and now is a pandemic all around the world. In Italy, Northern regions were hit the hardest during the first wave. We aim to explore the prevalence and the exposure characteristics of physiotherapists (PTs) working in different Italian regions during the first wave of COVID-19. Methods: Between April and May 2020 a structured anonymous online survey was distributed to all PTs registered in the National Professional Registry to collect prevalence data of a confirmed diagnosis of COVID-19 (i.e., nasopharyngeal swab and/or serological test). A bottom-up agglomerative nesting hierarchical clustering method was applied to identify groups of regions based on response rate. Multivariable logistic regression was used to explore personal and work-related factors associated with a confirmed diagnosis of COVID-19. Results: A total of 15,566 PTs completed the survey (response rate 43.3%). The majority of respondents (57.7%) were from Northern regions. Considering all respondents, the number of confirmed COVID-19 cases in Northern and Central Italy, was higher compared to those in Southern Italy (6.9% vs. 1.8%, P &lt; 0.001); focusing the analysis on respondents who underwent nasopharyngeal swab&nbsp;and/or serological test led to similar findings (14.1% vs. 6.4%, P &lt; 0.001). Working in Northern and Central regions was associated with a higher risk of confirmed diagnosis of COVID-19 compared to Southern regions (OR 3.4, 95%CI 2.6 to 4.3). PTs working in Northern and Central regions were more likely to be reallocated to a different unit and changing job tasks, compared to their colleagues working in the Southern regions (10.5% vs 3.7%, P &lt; 0.001). Conclusions: Work-related risk factors were differently distributed between Italian regions at the time of first pandemic wave, and PTs working in the Northern and Central regions were more at risk of a confirmed diagnosis of COVID-19, especially when working in hospitals. Preventive and organizational measures should be applied to harmonize physiotherapy services in the national context. Registration: https://osf.io/x7ch

L-serine biosynthesis in the human central nervous system: Structure and function of phosphoserine aminotransferase

Organisms from all kingdoms of life synthesize L-serine (L-Ser) from 3-phosphoglycerate through the phosphorylated pathway, a three-step diversion of glycolysis. Phosphoserine aminotransferase (PSAT) catalyzes the intermediate step, the pyridoxal 5′-phosphate-dependent transamination of 3-phosphohydroxypyruvate and L-glutamate to O-phosphoserine (OPS) and α-ketoglutarate. PSAT is particularly relevant in the central nervous system of mammals because L-Ser is the metabolic precursor of D-serine, cysteine, phospholipids, and nucleotides. Several mutations in the human psat gene have been linked to serine deficiency disorders, characterized by severe neurological symptoms. Furthermore, PSAT is overexpressed in many tumors and this overexpression has been associated with poor clinical outcomes. Here, we report the detailed functional and structural characterization of the recombinant human PSAT. The reaction catalyzed by PSAT is reversible, with an equilibrium constant of about 10, and the enzyme is very efficient, with a kcat/Km of 5.9&nbsp;× 106&nbsp;M−1&nbsp;s−1, thus contributing in driving the pathway towards the products despite the extremely unfavorable first step catalyzed by 3-phosphoglycerate dehydrogenase. The 3D X-ray crystal structure of PSAT was solved in the substrate-free as well as in the OPS-bound forms. Both structures contain eight protein molecules in the asymmetric unit, arranged in four dimers, with a bound cofactor in each subunit. In the substrate-free form, the active site of PSAT contains a sulfate ion that, in the substrate-bound form, is replaced by the phosphate group of OPS. Interestingly, fast crystal soaking used to produce the substrate-bound form allowed the trapping of different intermediates along the catalytic cycle