A common mechanism of defective channel trafficking underlying DFNA2 hearing loss result in different cell surface expression levels of KCNQ4 mutants

KCNQ4 mutations underlie DFNA2, a subtype of autosomal dominant hearing loss. We had previously identified the pore-region p.G296S mutation that impaired channel activity in two manners: it greatly reduced surface expression and abolished channel function. Moreover, G296S mutant exerted a strong dominant-negative effect on potassium currents by reducing the channel expression at the cell surface representing the first study to identify a trafficking-dependent dominant mechanism for the loss of KCNQ4 channel function in DFNA2. Here, we have investigated the pathogenic mechanism associated with all the described KCNQ4 mutations (F182L, W242X, E260K, D262V, L274H, W276S, L281S, G285C, G285S and G321S) that are located in different domains of the channel protein. F182L mutant showed a wild type-like cell-surface distribution in transiently transfected NIH3T3 fibroblasts and the recorded currents in Xenopus oocytes resembled those of the wild-type. The remaining KCNQ4 mutants abolished potassium currents, but displayed distinct levels of defective cell-surface expression in NIH3T3 as quantified by flow citometry. Co-localization studies revealed these mutants were retained in the ER, unless W242X, which showed a clear co-localization with Golgi apparatus. Interestingly, this mutation results in a truncated KCNQ4 protein at the S5 transmembrane domain, before the pore region, that escapes the protein quality control in the ER but does not reach the cell surface at normal levels. Currently we are investigating the trafficking behaviour and electrophysiological properties of several KCNQ4 truncated proteins artificially generated in order to identify specific motifs involved in channel retention/exportation. Altogether, our results indicate that a defect in KCNQ4 trafficking is the common mechanism underlying DFNA

No changes in adolescent’s sedentary behaviour across Europe between 2002 and 2017

Abstract: Background: Public health organizations have been alerted to the high levels of sedentary behaviour (SB) among adolescents as well as to the health and social consequences of excess sedentary time. However, SB changes of the European Union (EU) adolescents over time have not been reported yet. This study aimed to identify SB of the EU adolescents (15–17 years) in four-time points (2002, 2005, 2013 and 2017) and to analyse the prevalence of SB according to the sex. Methods: SB of 2542 adolescents (1335 boys and 1207 girls) as a whole sample and country-by-country was analysed in 2002, 2005, 2013, and 2017 using the Sport and Physical Activity EU Special Eurobarometers’ data. SB was measured using the sitting time question from the short version of the International Physical Activity Questionnaire (IPAQ), such that 4h30min of daily sitting time was the delineating point to determine excess SB behaviour (≥4h30min of sitting time) or not (≤4h30min of sitting time). A χ2 test was used to compare the prevalence of SB between survey years. Furthermore, SB prevalence between sexes was analysed using a Z-Score test for two population proportions. Results: The prevalence of SB among EU adolescents across each of the four survey years ranged from 74.2 and 76.8%, rates that are considered high. High levels of SB were also displayed by both sexes (girls: 76.8 to 81.2%; boys: 71.7 to 76.7%). No significant differences in the prevalence of SB among years (p > 0.05) were found for the whole sample, and for either girls or boys. Also, no significant differences in the prevalence of SB between girls and boys were found. Conclusion: The SB prevalence in European adolescents is extremely high (76.8% in 2017) with no differences between girls and boys. No significant improvements have been seen between 2002 and 2017. Eurobarometer should increase the adolescents’ sample to make possible benchmarking comparisons among the EU countries and extend the survey to the younger children population

Observing Supermassive Black Holes across cosmic time: from phenomenology to physics

In the last decade, a combination of high sensitivity, high spatial resolution observations and of coordinated multi-wavelength surveys has revolutionized our view of extra-galactic black hole (BH) astrophysics. We now know that supermassive black holes reside in the nuclei of almost every galaxy, grow over cosmological times by accreting matter, interact and merge with each other, and in the process liberate enormous amounts of energy that influence dramatically the evolution of the surrounding gas and stars, providing a powerful self-regulatory mechanism for galaxy formation. The different energetic phenomena associated to growing black holes and Active Galactic Nuclei (AGN), their cosmological evolution and the observational techniques used to unveil them, are the subject of this chapter. In particular, I will focus my attention on the connection between the theory of high-energy astrophysical processes giving rise to the observed emission in AGN, the observable imprints they leave at different wavelengths, and the methods used to uncover them in a statistically robust way. I will show how such a combined effort of theorists and observers have led us to unveil most of the SMBH growth over a large fraction of the age of the Universe, but that nagging uncertainties remain, preventing us from fully understating the exact role of black holes in the complex process of galaxy and large-scale structure formation, assembly and evolution.Comment: 46 pages, 21 figures. This review article appears as a chapter in the book: "Astrophysical Black Holes", Haardt, F., Gorini, V., Moschella, U and Treves A. (Eds), 2015, Springer International Publishing AG, Cha

Anthropogenic Space Weather

Anthropogenic effects on the space environment started in the late 19th century and reached their peak in the 1960s when high-altitude nuclear explosions were carried out by the USA and the Soviet Union. These explosions created artificial radiation belts near Earth that resulted in major damages to several satellites. Another, unexpected impact of the high-altitude nuclear tests was the electromagnetic pulse (EMP) that can have devastating effects over a large geographic area (as large as the continental United States). Other anthropogenic impacts on the space environment include chemical release ex- periments, high-frequency wave heating of the ionosphere and the interaction of VLF waves with the radiation belts. This paper reviews the fundamental physical process behind these phenomena and discusses the observations of their impacts.Comment: 71 pages, 35 figure

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

The Caravan Rolls On

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68409/2/10.1177_107554707900100103.pd

Safety and nutritional value of a dried killed bacterial biomass from Escherichia coli (FERM BP‐10942) (PT73 (TM)) as a feed material for pigs, ruminants and salmonids

PT73 (TM) is a dried, heat-inactivated bacterial biomass used as a feed material produced from an Escherichia coli K-12 strain, which was genetically modified to overproduce threonine. The recipient organism E. coli MG 1655 is considered to be safe. The traits introduced in the final modified strain E. coli FERM BP-10942 are mainly limited to the overproduction of threonine. No full-length antibiotic resistance genes or other sequences of concern remain in the modified strain. In conclusion, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP): does not identify risks for human and animal health or the environment from this biomass regarding the genetic modification of the strain. The proposed recommended use level for dairy cows (8% PT73 (TM) of feed dry matter (~ 7% in complete feed)) and salmonids (13%) is considered safe for these target animals. The conclusion form dairy cows could be extended to other ruminants (from the beginning of rumination). Complete feed for pigs for fattening may contain up to 10% PT73 (TM). The toxicological data indicate effects of PT73 (TM) on blood coagulation and liver, which are considered to be adverse. As a consequence, the FEEDAP Panel is unable to conclude on the safety for the consumer of products derived from animals receiving feed containing PT73 (TM). PT73 (TM) is not considered a skin/eye irritant but should be considered as a potential skin and respiratory sensitiser. Moreover, any exposure of users to dust from the product via the inhalation route should be considered a serious risk. The FEEDAP Panel considers that substitution of PT73 (TM) for other protein-rich feed materials will not adversely affect the environment

Safety and nutritional value of a dried killed bacterial biomass from Escherichia coli (FERM BP‐10941) (PL73 (LM)) as a feed material for pigs, ruminants and salmonids

PL73 (LM) is a dried, heat-inactivated bacterial biomass used as a feed material produced from an Escherichia coli K-12 strain, which was genetically modified to overproduce lysine. The recipient organism E. coli K-12S B-7 is considered to be safe. The traits introduced in the final modified strain E. coli FERM BP-10941 are mainly limited to the overproduction of lysine. No full-length antibiotic resistance genes or other sequences of concern remain in the modified strain. In conclusion, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) does not identify risks for human and animal health or the environment from the biomass regarding the genetic modification of the strain. Although considering the zootechnical end-points only, the maximum safe level for dairy cows would be 6% PL73 (LM) of feed dry matter (~ 5% in complete feed) and for pigs for fattening up to 6% PL73 (LM), the unexplained effects on blood coagulation, on plasma lipoproteins in dairy cows and on total plasma bilirubin and liver weight in pigs prevent a clear conclusion of safe dietary levels for ruminants and pigs for fattening. PL73 (LM) is safe for salmonids up to a dietary concentration of 13%. The toxicological data indicate adverse effects of PL73 (LM) on blood coagulation and liver, which also occur in target species. As a consequence, the FEEDAP Panel is unable to conclude on the safety for the consumer of products derived from animals receiving feed containing PL73 (LM). PL73 (LM) is not considered a skin/eye irritant but should be considered as a potential skin and respiratory sensitiser. Moreover, any exposure of users to dust from the product via the inhalation route should be considered a serious risk. The FEEDAP Panel considers that substitution of PL73 (LM) for other protein-rich feed materials will not adversely affect the environment

Justify your alpha

Benjamin et al. proposed changing the conventional “statistical significance” threshold (i.e.,the alpha level) from p ≤ .05 to p ≤ .005 for all novel claims with relatively low prior odds. They provided two arguments for why lowering the significance threshold would “immediately improve the reproducibility of scientific research.” First, a p-value near .05provides weak evidence for the alternative hypothesis. Second, under certain assumptions, an alpha of .05 leads to high false positive report probabilities (FPRP2 ; the probability that a significant finding is a false positive

Role of age and comorbidities in mortality of patients with infective endocarditis

Purpose: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. Methods: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015. Patients were stratified into three age groups:<65 years, 65 to 80 years, and = 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. Results: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 = 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients =80 years who underwent surgery were significantly lower compared with other age groups (14.3%, 65 years; 20.5%, 65-79 years; 31.3%, =80 years). In-hospital mortality was lower in the <65-year group (20.3%, <65 years;30.1%, 65-79 years;34.7%, =80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%, =80 years; p = 0.003).Independent predictors of mortality were age = 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI = 3 (HR:1.62; 95% CI:1.39–1.88), and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared, the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. Conclusion: There were no differences in the clinical presentation of IE between the groups. Age = 80 years, high comorbidity (measured by CCI), and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group