Towards the Assessment of an Ecological Index for Quantifying Sustainability of Day Life. A Case Study of the Environmental Consequences of Dietary and Transport in a Standard Workday

e-Conferenc

Structural communication between the GTPase Sec4p and its activator Sec2p: Determinants of GEF activity and early deformations to nucleotide release

Ras GTPases are molecular switches that cycle between OFF and ON states depending on the bound nucleotide (i.e. GDP-bound and GTP-bound, respectively).The Rab GTPase, Sec4p, plays regulatory roles in multiple steps of intracellular vesicle trafficking. Nucleotide release is catalyzed by the Guanine Nucleotide Exchange Factor (GEF) Sec2p.Here, the integration of structural information with molecular dynamics (MD) simulations addressed a number of questions concerning the intrinsic and stimulated dynamics of Sec2p and Sec4p as well as the chain of structural deformations leading to GEF-assisted activation of the Rab GTPase.Sec2p holds an intrinsic ability to adopt the conformation found in the crystallographic complexes with Sec4p, thus suggesting that the latter selects and shifts the conformational equilibrium towards a pre-existing bound-like conformation of Sec2p.The anchoring of Sec4p to a suitable conformation of Sec2p favors the Sec2p-assisted pulling on itself of the a1/switch 1 (SWI) loop and of SWI, which loose any contact with GDP. Those deformations of Sec4p would occur earlier. Formation of the final Sec2p-Sec4p hydrophobic interface, accomplishes later. Disruption of the nucleotide cage would cause firstly loss of interactions with the guanine ring and sec-ondly loss of interactions with the phosphates.The ease in sampling the energy landscape and adopting a bound-like conformation likely favors the catalyzing ability of GEFs for Ras GTPases.(c) 2022 Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Bio-technology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/)

hbv genotype must be included in treatment algorithm

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SARS-CoV-2 Circulation in the School Setting: A Systematic Review and Meta-Analysis

The contribution of children to viral spread in schools is still debated. We conducted a systematic review and meta-analysis of studies to investigate SARS-CoV-2 transmission in the school setting. Literature searches on 15 May 2021 yielded a total of 1088 publications, including screening, contact tracing, and seroprevalence studies. MOOSE guidelines were followed, and data were analyzed using random-effects models. From screening studies involving more than 120,000 subjects, we estimated 0.31% (95% confidence interval (CI) 0.05–0.81) SARS-CoV-2 point prevalence in schools. Contact tracing studies, involving a total of 112,622 contacts of children and adults, showed that onward viral transmission was limited (2.54%, 95% CI 0.76–5.31). Young index cases were found to be 74% significantly less likely than adults to favor viral spread (odds ratio (OR) 0.26, 95% CI 0.11–0.63) and less susceptible to infection (OR 0.60; 95% CI 0.25–1.47). Lastly, from seroprevalence studies, with a total of 17,879 subjects involved, we estimated that children were 43% significantly less likely than adults to test positive for antibodies (OR 0.57, 95% CI 0.49–0.68). These findings may not applied to the Omicron phase, we further planned a randomized controlled trial to verify these results

SARS-CoV-2 Circulation in the School Setting: A Systematic Review and Meta-Analysis

The contribution of children to viral spread in schools is still debated. We conducted a systematic review and meta-analysis of studies to investigate SARS-CoV-2 transmission in the school setting. Literature searches on 15 May 2021 yielded a total of 1088 publications, including screening, contact tracing, and seroprevalence studies. MOOSE guidelines were followed, and data were analyzed using random-effects models. From screening studies involving more than 120,000 subjects, we estimated 0.31% (95% confidence interval (CI) 0.05–0.81) SARS-CoV-2 point prevalence in schools. Contact tracing studies, involving a total of 112,622 contacts of children and adults, showed that onward viral transmission was limited (2.54%, 95% CI 0.76–5.31). Young index cases were found to be 74% significantly less likely than adults to favor viral spread (odds ratio (OR) 0.26, 95% CI 0.11–0.63) and less susceptible to infection (OR 0.60; 95% CI 0.25–1.47). Lastly, from seroprevalence studies, with a total of 17,879 subjects involved, we estimated that children were 43% significantly less likely than adults to test positive for antibodies (OR 0.57, 95% CI 0.49–0.68). These findings may not applied to the Omicron phase, we further planned a randomized controlled trial to verify these results

HER2 Copy Number and Resistance Mechanisms in Patients with HER2-positive Advanced Gastric Cancer Receiving Initial Trastuzumab-based Therapy in JACOB Trial

Resistance mechanisms; Advanced gastric cancer; TrastuzumabMecanismos de resistencia; Cáncer gástrico avanzado; TrastuzumabMecanismes de resistència; Càncer gàstric avançat; TrastuzumabPurpose: In JACOB trial, pertuzumab added to trastuzumab-chemotherapy did not significantly improve survival of patients with HER2-positive metastatic gastric cancer, despite 3.3 months increase versus placebo. HER2 copy-number variation (CNV) and AMNESIA panel encompassing primary resistance alterations (KRAS/PIK3CA/MET mutations, KRAS/EGFR/MET amplifications) may improve patients’ selection for HER2 inhibition. Experimental Design: In a post hoc analysis of JACOB on 327 samples successfully sequenced by next-generation sequencing (NGS; Oncomine Focus DNA), HER2 CNV, HER2 expression by IHC, and AMNESIA were correlated with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) by univariable/multivariable models. Results: Median HER2 CNV was 4.7 (interquartile range, 2.2–16.9). HER2 CNV-high versus low using the median as cutoff was associated with longer median PFS (10.5 vs. 6.4 months; HR = 0.48; 95% confidence interval: 0.38–0.62; P < 0.001) and OS (20.3 vs. 13.0 months; HR = 0.54; 0.42–0.72; P < 0.001). Combining HER2 CNV and IHC improved discriminative ability, with better outcomes restricted to HER2-high/HER2 3+ subgroup. AMNESIA positivity was found in 51 (16%), with unadjusted HR = 1.35 (0.98–1.86) for PFS; 1.43 (1.00–2.03) for OS. In multivariable models, only HER2 CNV status remained significant for PFS (P < 0.001) and OS (P = 0.004). Higher ORR was significantly associated with IHC 3+ [61% vs. 34% in 2+; OR = 3.11 (1.89–5.17)] and HER2-high [59% vs. 43% in HER2-low; OR = 1.84 (1.16–2.94)], with highest OR in the top CNV quartile. These biomarkers were not associated with treatment effect of pertuzumab. Conclusions: HER2 CNV-high assessed by NGS may be associated with better ORR, PFS, and OS in a JACOB subgroup, especially if combined with HER2 3+. The negative prognostic role of AMNESIA requires further clinical validation

Effect of CYP4F2, VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single-Patient Data Meta-Analysis in More Than 15,000 Individuals

The cytochrome P450 (CYP)4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at the individual patients level to capture the possible effect of ethnicity, gene—gene interaction, or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients’ data. The final collection consists of 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95% confidence interval (CI) 7–10%), with a higher effect in women, in patients taking acenocoumarol, and in white patients. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived

The beneficial effects of physical exercise on visuospatial working memory in preadolescent children

The relationship between physical exercise and improvement in specific cognitive domains in children and adolescents who play sport has been recently reported, although the effects on visuospatial abilities have not yet been well explored. This study is aimed at evaluating in school-age children practicing artistic gymnastics the visuospatial memory by using a table version of the Radial Arm Maze (table-RAM) and comparing their performances with those ones who do not play any sport. The visuospatial performances of 14 preadolescent girls practicing artistic gymnastics aged between 7 and 10 years and those of 14 preadolescent girls not playing any sport were evaluated in the table-RAM forced-choice paradigm that allows disentangling short-term memory from working memory abilities. Data showed that the gymnasts obtained better performances than control group mainly in the parameters evaluating working memory abilities, such as within-phase errors and spatial span. Our findings emphasizing the role of physical activity on cognitive performances impel to promote physical exercise in educational and recreational contexts as well as to analyse the impact of other sports besides gymnastics on cognitive functioning

Cardiovascular Risk Evaluation through Heart Rate Variability (HRV) Analysis in Patients with Psoriasis before and after 12 Weeks of Etanercept Therapy: A Preliminary Prospective Study

Background The association between psoriasis and cardiovascular diseases is suggested by epidemiological studies. The sub-inflammatory systemic state that characterizes both psoriasis and atherosclerosis has been proposed as the link between these conditions; it cannot, however, explain the increased incidence of sudden cardiac death reported in young patients with severe psoriasis without common cardiovascular risk factors. In a previous study we reported higher levels of autonomic dysregulation in psoriatic patients, concluding that the prevalence of the sympathetic arm over the para-sympathetic one could increase cardiovascular risk. Objectives To assess the influence of etanercept, an anti-TNFα agent, on the autonomic cardiovascular regulation in young patients with moderate-to-severe psoriasis without cardiovascular risk factors. Methods Five-minute ECG recordings were collected at rest conditions before and after 12 weeks of therapy with etanercept in 19 young psoriatic patients without cardiovascular risk factors. The Cardiolab CE pocket PC ECG system was used for linear methods of heart rate variability (HRV) analysis. Results No significant change in HRV analysis parameters was apparent after 12 weeks of etanercept therapy. Conclusion Our data suggest that treatment with etanercept in patients with moderate-to-severe psoriasis doesn\u27t affect cardiovascular autonomic regulation, and subsequently the cardiovascular risk.</p

Properties of Some Variants of Human β2-Microglobulin and Amyloidogenesis

Three variants of human beta(2)-microglobulin (beta(2)-m) were compared with wild-type protein. For two variants, namely the mutant R3Abeta(2)-m and the form devoid of the N-terminal tripeptide (DeltaN3beta(2)-m), a reduced unfolding free energy was measured compared with wild-type beta(2)-m, whereas an increased stability was observed for the mutant H31Ybeta(2)-m. The solution structure could be determined by (1)H NMR spectroscopy and restrained modeling only for R3Abeta(2)-m that showed the same conformation as the parent species, except for deviations at the interstrand loops. Analogous conclusions were reached for H31Ybeta(2)-m and DeltaN3beta(2)-m. Precipitation and unfolding were observed over time periods shorter than 4-6 weeks with all the variants and, sometimes, with wild-type protein. The rate of structured protein loss from solution as a result of precipitation and unfolding always showed pseudo-zeroth order kinetics. This and the failure to observe an unfolded species without precipitation suggest that a nucleated conformational conversion scheme should apply for beta(2)-m fibrillogenesis. The mechanism is consistent with the previous and present results on beta(2)-m amyloid transition, provided a nucleated oligomeric species be considered the stable intermediate of fibrillogenesis, the monomeric intermediate being the necessary transition step along the pathway from the native protein to the nucleated oligomer