The fundamental group and torsion group of Beauville surfaces

We give a survey on the fundamental group of surfaces isogenous to a higher product. If the surfaces are regular, e.g. if they are Beauville surfaces, the first homology group is a finite group. We present a MAGMA script which calculates the first homology groups of regular surfaces isogenous to a product.Comment: 14 pages; MAGMA script included; v2: minor corrections, final version to appear in the Proceedings of the Conference "Beauville Surfaces and Groups", Newcastle University (UK), 7-9th June 201

Brainstem Auditory Evoked Potentials' Diagnostic Accuracy for Hearing Loss: Systematic Review and Meta-Analysis

Background: Microvascular decompression (MVD) utilizes brainstem auditory evoked potential (BAEP) intraoperative monitoring to reduce the risk of iatrogenic hearing loss. Studies report varying efficacy and hearing loss rates during MVD with intraoperative monitoring. Objectives: This study aims to perform a comprehensive review and study of diagnostic accuracy of BAEPs during MVD to predict hearing loss in studies published from January 1984 to December 2013. Methods: The PubMed/MEDLINE and World Science databases were searched. Studies performed MVD for trigeminal neuralgia, hemifacial spasm, glossopharyngeal neuralgia or geniculate neuralgia and monitored intraoperative BAEPs to prevent hearing loss. Retrospectively, BAEP parameters were compared with postoperative hearing. The diagnostic accuracy of significant change in BAEPs, which includes loss of response, was tested using summary receiver operative curve and diagnostic odds ratio (DOR). Results: A total of 13 studies were included in the analysis with a total of 2,540 cases. Loss of response pooled sensitivity, specificity, and DOR with 95% confidence interval being 74% (60–84%), 98% (88–100%), and 69.3 (18.2–263%), respectively. The similar significant change results were 88% (77–94%), 63% (40–81%), and 9.1 (3.9–21.6%). Conclusion: Patients with hearing loss after MVD are more likely to have shown loss of BAEP responses intraoperatively. Loss of responses has high specificity in evaluating hearing loss. Patients undergoing MVD should have BAEP monitoring to prevent hearing loss

Hydroxytriazole derivatives as potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors discovered by bioisosteric scaffold hopping approach

YesThe aldo-keto reductase 1C3 isoform (AKR1C3) plays a vital role in the biosynthesis of androgens, making this enzyme an attractive target for castration-resistant prostate cancer therapy. Although AKR1C3 is a promising drug target, no AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid, a non-steroidal anti-inflammatory drug, is known to potently inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. To diminish off-target effects, we have applied a scaffold hopping strategy replacing the benzoic acid moiety of flufenamic acid with an acidic hydroxyazolecarbonylic scaffold. In particular, differently N-substituted hydroxylated triazoles were designed to simultaneously interact with both subpockets 1 and 2 in the active site of AKR1C3, larger for AKR1C3 than other AKR1Cs isoforms. Through computational design and iterative rounds of synthesis and biological evaluation, novel compounds are reported, sharing high selectivity (up to 230-fold) for AKR1C3 over 1C2 isoform and minimal COX1 and COX2 off-target inhibition. A docking study of compound 8, the most interesting compound of the series, suggested that its methoxybenzyl substitution has the ability to fit inside subpocket 2, being involved in π-π staking interaction with Trp227 (partial overlapping) and in a T-shape π-π staking with Trp86. This compound was also shown to diminish testosterone production in the AKR1C3-expressing 22RV1 prostate cancer cell line while synergistic effect was observed when 8 was administered in combination with abiraterone or enzalutamide.University of Turin (Ricerca Locale grant 2014 and 2015) and Prostate Cancer UK grant S12-02

Potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the benzoisoxazole moiety: application of a bioisosteric scaffold hopping approach to flufenamic acid

YesThe aldo-keto reductase 1C3 (AKR1C3) isoform plays a vital role in the biosynthesis of androgens and is considered an attractive target in prostate cancer (PCa). No AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid and indomethacine are non-steroidal anti-inflammatory drugs known to inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. Recently, we employed a scaffold hopping approach to design a new class of potent and selective AKR1C3 inhibitors based on a N-substituted hydroxylated triazole pharmacophore. Following a similar strategy, we designed a new series focused around an acidic hydroxybenzoisoxazole moiety, which was rationalised to mimic the benzoic acid role in the flufenamic scaffold. Through iterative rounds of drug design, synthesis and biological evaluation, several compounds were discovered to target AKR1C3 in a selective manner. The most promising compound of series (6) was found to be highly selective (up to 450-fold) for AKR1C3 over the 1C2 isoform with minimal COX1 and COX2 off-target effects. Other inhibitors were obtained modulating the best example of hydroxylated triazoles we previously presented. In cell-based assays, the most promising compounds of both series reduced the cell proliferation, prostate specific antigen (PSA) and testosterone production in AKR1C3-expressing 22RV1 prostate cancer cells and showed synergistic effect when assayed in combination with abiraterone and enzalutamide. Structure determination of AKR1C3 co-crystallized with one representative compound from each of the two series clearly identified both compounds in the androstenedione binding site, hence supporting the biochemical data.University of Turin (Ricerca Locale grant 2015-2017) and Prostate Cancer UK grant S12-027

Microbiology of airway disease in a cohort of patients with Cystic Fibrosis

BACKGROUND: Recent reports document an increasing incidence of new Gram-negative pathogens such as Stenotrophomonas maltophilia and Alcaligenes xylosoxidans isolated from patients with Cystic Fibrosis, along with an increase in common Gram-negative pathogens such as Pseudomonas aeruginosa and Burkholderia cepacia complex. Furthermore, the increase in multidrug-resistance of such organisms makes the therapeutic management of these patients more problematic. Therefore, careful isolation and identification, and accurate studies of susceptibility to antibiotics are critical for predicting the spread of strains, improving therapeutic measures and facilitating our understanding of the epidemiology of emerging pathogens. The first aim of this study was to determine the incidence and the prevalence of colonization by Gram-negative organisms isolated from respiratory samples of Cystic Fibrosis patients in the Regional Referral Cystic Fibrosis Centre of Naples; the second was to evaluate the spectrum of multidrug-resistance of these organisms. METHODS: Patients (n = 300) attending the Regional Cystic Fibrosis Unit were enrolled in this study over 3 years. Sputum was processed for microscopic tests and culture. An automated system, Phoenix (Becton Dickinson, Sparks, Maryland, USA), was used for phenotypic identification of all strains; the API 20 NE identification system (bioMérieux, Marcy l'Etoile, France) was used when the identification with the Phoenix system was inaccurate. A PCR-RFLP method was used to characterize the organisms in the Burkholderia cepacia complex. A chemosusceptibility test on microbroth dilutions (Phoenix) was used. Primary outcomes such as FEV1 were correlate with different pathogens. RESULTS: During the period of study, 40% of patients was infected by Pseudomonas aeruginosa, 7% by Burkholderia cepacia complex, 11% by Stenotrophomonas maltophilia and 7% by Alcaligenes xylosoxidans. Of the strains isolated, 460 were multidrug-resistant. Multiresistant were Pseudomonas aeruginosa and Burkholderia cepacia complex. CONCLUSION: The results confirm previously reported data; in particular, they show an increase the isolation of non-fermentative Gram-negative bacteria in Cystic Fibrosis patients. They also demonstrate increased resistance to antibiotics. Beta-lactams are rarely effective, with exception of ceftazidime, which is the most efficacious agent against multiresistant strains. Aminoglycosides and quinolones are poorly efficacious

Dietary intakes in infertile women a pilot study

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Disruption of tumor necrosis factor alpha receptor 1 signaling accelerates NAFLD progression in mice upon a high-fat diet

Obesity is accompanied by a low-grade inflammation state, characterized by increased proinflammatory cytokines levels such as tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL-1β). In this regard, there exists a lack of studies in hepatic tissue about the role of TNFα receptor 1 (TNFR1) in the context of obesity and insulin resistance during the progression of nonalcoholic fatty liver disease (NAFLD). The aim of this work was to evaluate the effects of high-caloric feeding (HFD) (40% fat, for 16 weeks) on liver inflammation-induced apoptosis, insulin resistance, hepatic lipid accumulation and its progression toward nonalcoholic steatohepatitis (NASH) in TNFR1 knock-out and wild-type mice. Mechanisms involved in HFD-derived IL-1β release and impairment of insulin signaling are still unknown, so we determined whether IL-1β affects liver insulin sensitivity and apoptosis through TNFα receptor 1 (TNFR1)-dependent pathways. We showed that knocking out TNFR1 induces an enhanced IL-1β plasmatic release upon HFD feed. This was correlated with higher hepatic and epididymal white adipose tissue mRNA levels. In vivo and in vitro assays confirmed an impairment in hepatic insulin signaling, in part due to IL-1β-induced decrease of AKT activation and diminution of IRS1 levels, followed by an increase in inflammation, macrophage (resident and recruited) accumulation, hepatocyte apoptotic process and finally hepatic damage. In addition, TNFR1 KO mice displayed higher levels of pro-fibrogenic markers. TNFR1 signaling disruption upon an HFD leads to an accelerated progression from simple steatosis to a more severe phenotype with many NASH features, pointing out a key role of TNFR1 in NAFLD progression.This work was supported by research grants from Consejo Nacional de Investigaciones Científicas y Técnicas (PIP-CONICET 112201500508, to C.E.C.) and SAF2016-75004-R and SAF2015-70270-REDT (MINECO, Spain)to P.M.S. and O.M.Peer reviewe

Clinical expression of cystic fibrosis in a large cohort of Italian siblings

Background: A clinical heterogeneity was reported in patients with Cystic Fibrosis (CF) with the same CFTR genotype and between siblings with CF. Methods: We investigated all clinical aspects in a cohort of 101 pairs of siblings with CF (including 6 triplets) followed since diagnosis. Results: Severe lung disease had a 22.2% concordance in sib-pairs, occurred early and the FEV1% at 12 years was predictive of the severity of lung disease in the adulthood. Similarly, CF liver disease occurred early (median: 15 years) and showed a concordance of 27.8% in sib-pairs suggesting a scarce contribution of genetic factors; in fact, only 2/15 patients with liver disease in discordant sib-pairs had a deficiency of alpha-1-antitrypsin (a known modifier gene of CF liver phenotype). CF related diabetes was found in 22 pairs (in 6 in both the siblings). It occurred later (median: 32.5 years) and is strongly associated with liver disease. Colonization by P. aeruginosa and nasal polyposis that required surgery had a concordance > 50% in sib-pairs and were poorly correlated to other clinical parameters. The pancreatic status was highly concordant in pairs of siblings (i.e., 95.1%) but a different pancreatic status was observed in patients with the same CFTR mutations. This suggests a close relationship of the pancreatic status with the "whole" CFTR genotype, including mutations in regulatory regions that may modulate the levels of CFTR expression. Finally, a severe course of CF was evident in a number of patients with pancreatic sufficiency. Conclusions: Physicians involved in care of patients with CF and in genetic counseling must be aware of the clinical heterogeneity of CF even in sib-pairs that, at the state of the art, is difficult to explain

Connected macroalgal‐sediment systems: blue carbon and food webs in the deep coastal ocean

Macroalgae drive the largest CO2 flux fixed globally by marine macrophytes. Most of the resulting biomass is exported through the coastal ocean as detritus and yet almost no field measurements have verified its potential net sequestration in marine sediments. This gap limits the scope for the inclusion of macroalgae within blue carbon schemes that support ocean carbon sequestration globally, and the understanding of the role their carbon plays within distal food webs. Here, we pursued three lines of evidence (eDNA sequencing, Bayesian Stable Isotope Mixing Modeling, and benthic‐pelagic process measurements) to generate needed, novel data addressing this gap. To this end, a 13‐month study was undertaken at a deep coastal sedimentary site in the English Channel, and the surrounding shoreline of Plymouth, UK. The eDNA sequencing indicated that detritus from most macroalgae in surrounding shores occurs within deep, coastal sediments, with detritus supply reflecting the seasonal ecology of individual species. Bayesian stable isotope mixing modeling [C and N] highlighted its vital role in supporting the deep coastal benthic food web (22–36% of diets), especially when other resources are seasonally low. The magnitude of detritus uptake within the food web and sediments varies seasonally, with an average net sedimentary organic macroalgal carbon sequestration of 8.75 g C·m−2·yr−1. The average net sequestration of particulate organic carbon in sediments is 58.74 g C·m−2·yr−1, the two rates corresponding to 4–5% and 26–37% of those associated with mangroves, salt marshes, and seagrass beds, systems more readily identified as blue carbon habitats. These novel data provide important first estimates that help to contextualize the importance of macroalgal‐sedimentary connectivity for deep coastal food webs, and measured fluxes help constrain its role within global blue carbon that can support policy development. At a time when climate change mitigation is at the foreground of environmental policy development, embracing the full potential of the ocean in supporting climate regulation via CO2 sequestration is a necessity

Detection of Inconspicuous Power Quality Disturbances through Step Changes in rms Voltage Profile

Power quality disturbances commonly observed in power systems have been studied for decades, resulting in numerous algorithms for detecting the events that affect the voltage and/or current waveforms. However, a considerable amount of disturbances is not visually observable in the raw waveforms, especially switching operations. These events must be detected through an alternative feature, such as abrupt variations in the root-mean-square (rms) voltage profile. This study examines the methods commonly used for detecting power quality disturbances in the waveform or rms voltage profile domains and identifies their limitations. Afterwards, a novel step change detector is proposed based on a modified median filter and rms voltage gradient values to overcome the deficiencies of the existing methods. The effectiveness of the proposed method is assessed by applying it to both simulated and field data. This assessment shows that the method detects all switching events with no false positives for the datasets under analysis