C6orf10 low-frequency and rare variants in italian multiple sclerosis patients

In light of the complex nature of multiple sclerosis (MS) and the recently estimated contribution of low-frequency variants into disease, decoding its genetic risk components requires novel variant prioritization strategies. We selected, by reviewing MS Genome Wide Association Studies (GWAS), 107 candidate loci marked by intragenic single nucleotide polymorphisms (SNPs) with a remarkable association (p-value <= 5 x 10(-6)). A whole exome sequencing (WES)-based pilot study of SNPs with minor allele frequency (MAF) <= 0.04, conducted in three Italian families, revealed 15 exonic low-frequency SNPs with affected parent-child transmission. These variants were detected in 65/120 Italian unrelated MS patients, also in combination (22 patients). Compared with databases (controls gnomAD, dbSNP150, ExAC, Tuscany-1000 Genome), the allelic frequencies of C6orf10 rs 16870005 and IL2RA rs12722600 were significantly higher (i.e., controls gnomAD, p = 9.89 x 10(-7) and p < 1 x 10(-20)). TET2 rs61744960 and TRAF3 rs138943371 frequencies were also significantly higher, except in Tuscany-1000 Genome. Interestingly, the association of C6orf10 rs16870005 (Ala431Thr) with MS did not depend on its linkage disequilibrium with the HLA-DRB1 locus. Sequencing in the MS cohort of the C6orf10 3' region revealed 14 rare mutations (10 not previously reported). Four variants were null, and significantly more frequent than in the databases. Further, the C6orf10 rare variants were observed in combinations, both intra-locus and with other low-frequency SNPs. The C6orf10 Ser389Xfr was found homozygous in a patient with early onset of the MS. Taking into account the potentially functional impact of the identified exonic variants, their expression in combination at the protein level could provide functional insights in the heterogeneous pathogenetic mechanisms contributing to MS.In light of the complex nature of multiple sclerosis (MS) and the recently estimated contribution of low-frequency variants into disease, decoding its genetic risk components requires novel variant prioritization strategies. We selected, by reviewing MS Genome Wide Association Studies (GWAS), 107 candidate loci marked by intragenic single nucleotide polymorphisms (SNPs) with a remarkable association (p-value ≤ 5 × 10−6). A whole exome sequencing (WES)-based pilot study of SNPs with minor allele frequency (MAF) ≤ 0.04, conducted in three Italian families, revealed 15 exonic low-frequency SNPs with affected parent-child transmission. These variants were detected in 65/120 Italian unrelated MS patients, also in combination (22 patients). Compared with databases (controls gnomAD, dbSNP150, ExAC, Tuscany-1000 Genome), the allelic frequencies of C6orf10 rs16870005 and IL2RA rs12722600 were significantly higher (i.e., controls gnomAD, p = 9.89 × 10−7 and p < 1 × 10−20). TET2 rs61744960 and TRAF3 rs138943371 frequencies were also significantly higher, except in Tuscany-1000 Genome. Interestingly, the association of C6orf10 rs16870005 (Ala431Thr) with MS did not depend on its linkage disequilibrium with the HLA-DRB1 locus. Sequencing in the MS cohort of the C6orf10 3′ region revealed 14 rare mutations (10 not previously reported). Four variants were null, and significantly more frequent than in the databases. Further, the C6orf10 rare variants were observed in combinations, both intra-locus and with other low-frequency SNPs. The C6orf10 Ser389Xfr was found homozygous in a patient with early onset of the MS. Taking into account the potentially functional impact of the identified exonic variants, their expression in combination at the protein level could provide functional insights in the heterogeneous pathogenetic mechanisms contributing to MS

Clash-VLT: Insights on the mass substructures in the frontier fields cluster MACS J0416.1-2403 through accurate strong lens modeling

We present a detailed mass reconstruction and a novel study on the substructure properties in the core of the Cluster Lensing And Supernova survey with Hubble (CLASH) and Frontier Fields galaxy cluster MACS J0416.1\u20132403. We show and employ our extensive spectroscopic data set taken with the VIsible Multi-Object Spectrograph instrument as part of our CLASH-VLT program, to confirm spectroscopically 10 strong lensing systems and to select a sample of 175 plausible cluster members to a limiting stellar mass of log (M */M &09) ~= 8.6. We reproduce the measured positions of a set of 30 multiple images with a remarkable median offset of only 0.''3 by means of a comprehensive strong lensing model comprised of two cluster dark-matter halos, represented by cored elliptical pseudo-isothermal mass distributions, and the cluster member components, parameterized with dual pseudo-isothermal total mass profiles. The latter have total mass-to-light ratios increasing with the galaxy HST/WFC3 near-IR (F160W) luminosities. The measurement of the total enclosed mass within the Einstein radius is accurate to ~5%, including the systematic uncertainties estimated from six distinct mass models. We emphasize that the use of multiple-image systems with spectroscopic redshifts and knowledge of cluster membership based on extensive spectroscopic information is key to constructing robust high-resolution mass maps. We also produce magnification maps over the central area that is covered with HST observations. We investigate the galaxy contribution, both in terms of total and stellar mass, to the total mass budget of the cluster. When compared with the outcomes of cosmological N-body simulations, our results point to a lack of massive subhalos in the inner regions of simulated clusters with total masses similar to that of MACS J0416.1\u20132403. Our findings of the location and shape of the cluster dark-matter halo density profiles and on the cluster substructures provide intriguing tests of the assumed collisionless, cold nature of dark matter and of the role played by baryons in the process of structure formation. This work is based in large part on data collected at ESO VLT (prog. ID 186.A-0798) and NASA HST

Cross-cultural adaptation of the Tailored Activity Program (TAP) for Brazilian Portuguese

Introduction: The Tailored Activity Program (TAP) is an intervention program in Occupational Therapy for individuals with dementia and their caregivers. It is based on 8 home-based sessions, during 3 or 4 months. Brazil lacks an Occupational Therapy methodology of action, which justifies the cross-cultural adaptation of the TAP. Objective: To adapt the TAP reference materials "Intervention Manual" and the "Caregiver Notebook" to the Brazilian culture. Method: The methodology used proposes the translation, back translation, evaluation of semantic, idiomatic, conceptual and cultural equivalences and the pre-test of materials for production in Portuguese. Results: The translation phase adapted 17 itemsthe back-translation process identified distortions. In the evaluation of the semantic and idiomatic equivalence of the Manual Intervention, 74 items of 374 items evaluated were discordantand in the Caregivers Notebook 96 items of 2051 items evaluated were discordant. Regarding to conceptual and cultural equivalence, in the Manual Intervention, 62 of 374 items evaluated were discordant and in the Caregivers Notebook, 57 of 2051 items. The discordant items were modified from suggestions given by the reviewers. After the evaluation of the committee of reviewers, we conducted a pre-test of the Portuguese versions and two items were adapted. Conclusion: The TAP has been adapted to the Brazilian culture and kept the original proposal for intervention with 8 sessions during a period of 3 to 4 months.Univ Fed Sao Paulo Unifesp, Dept Gestao & Cuidados Saude, Baixada Santista, SP, BrazilJohns Hopkins Univ, Sch Nursing, Ctr Innovat Care Aging, Baltimore, MD USAUniv Fed Sao Paulo Unifesp, Dept Gestao & Cuidados Saude, Baixada Santista, SP, BrazilWeb of Scienc

Onset of Mediterranean outflow into the North Atlantic

Sediments cored along the southwestern Iberian margin during Integrated Ocean Drilling Program Expedition 339 provide constraints on Mediterranean Outflow Water (MOW) circulation patterns from the Pliocene epoch to the present day. After the Strait of Gibraltar opened (5.33 million years ago), a limited volume of MOW entered the Atlantic. Depositional hiatuses indicate erosion by bottom currents related to higher volumes of MOW circulating into the North Atlantic, beginning in the late Pliocene. The hiatuses coincide with regional tectonic events and changes in global thermohaline circulation (THC). This suggests that MOW influenced Atlantic Meridional Overturning Circulation (AMOC), THC, and climatic shifts by contributing a component of warm, saline water to northern latitudes while in turn being influenced by plate tectonics

A reference time scale for Site U1385 (Shackleton Site) on the SW Iberian Margin

We produced a composite depth scale and chronology for Site U1385 on the SW Iberian Margin. Using log(Ca/Ti) measured by core scanning XRF at 1-cm resolution in all holes, a composite section was constructed to 166.5 meters composite depth (mcd) that corrects for stretching and squeezing in each core. Oxygen isotopes of benthic foraminifera were correlated to a stacked δ^18O reference signal (LR04) to produce an oxygen isotope stratigraphy and age model. Variations in sediment color contain very strong precession signals at Site U1385, and the amplitude modulation of these cycles provides a powerful tool for developing an orbitally-tuned age model. We tuned the U1385 record by correlating peaks in L* to the local summer insolation maxima at 37^oN. The benthic δ^18O record of Site U1385, when placed on the tuned age model, generally agrees with other time scales within their respective chronologic uncertainties. The age model is transferred to down-core data to produce a continuous time series of log(Ca/Ti) that reflect relative changes of biogenic carbonate and detrital sediment. Biogenic carbonate increases during interglacial and interstadial climate states and decreases during glacial and stadial periods. Much of the variance in the log(Ca/Ti) is explained by a linear combination of orbital frequencies (precession, tilt and eccentricity), whereas the residual signal reflects suborbital climate variability. The strong correlation between suborbital log(Ca/Ti) variability and Greenland temperature over the last glacial cycle at Site U1385 suggests that this signal can be used as a proxy for millennial-scale climate variability over the past 1.5 Ma. Millennial climate variability, as expressed by log(Ca/Ti) at Site U1385, was a persistent feature of glacial climates over the past 1.5 Ma, including glacial periods of the early Pleistocene (‘41-kyr world’) when boundary conditions differed significantly from those of the late Pleistocene (‘100-kyr world’). Suborbital variability was suppressed during interglacial stages and enhanced during glacial periods, especially when benthic δ^18O surpassed ~ 3.3-3.5‰. Each glacial inception was marked by appearance of strong millennial variability and each deglaciation was preceded by a terminal stadial event. Suborbital variability may be a symptomatic feature of glacial climate or, alternatively, may play a more active role in the inception and/or termination of glacial cycles.This research was supported by the Natural Environmental Research Council Grant NE/K005804/1 to DH and LS and NE/J017922/1 to DH.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.gloplacha.2015.07.00

A reference time scale for Site U1385 (Shackleton Site) on the SW Iberian Margin

Variations in sediment color contain very strong precession signals at Site U1385, and the amplitude modulation of these cycles provides a powerful tool for developing an orbitally-tuned age model. We tuned the U1385 record by correlating peaks in L* to the local summer insolation maxima at 37°N. The benthic δ18O record of Site U1385, when placed on the tuned age model, generally agrees with other time scales within their respective chronologic uncertainties. The age model is transferred to down-core data to produce a continuous time series of log(Ca/Ti) that reflect relative changes of biogenic carbonate and detrital sediment. Biogenic carbonate increases during interglacial and interstadial climate states and decreases during glacial and stadial periods. Much of the variance in the log(Ca/Ti) is explained by a linear combination of orbital frequencies (precession, tilt and eccentricity), whereas the residual signal reflects suborbital climate variability. The strong correlation between suborbital log(Ca/Ti) variability and Greenland temperature over the last glacial cycle at Site U1385 suggests that this signal can be used as a proxy for millennial-scale climate variability over the past 1.5 Ma. Millennial climate variability, as expressed by log(Ca/Ti) at Site U1385, was a persistent feature of glacial climates over the past 1.5 Ma, including glacial periods of the early Pleistocene (‘41-kyr world’) when boundary conditions differed significantly from those of the late Pleistocene (‘100-kyr world’). Suborbital variability was suppressed during interglacial stages and enhanced during glacial periods, especially when benthic δ18O surpassed ~ 3.3–3.5‰. Each glacial inception was marked by appearance of strong millennial variability and each deglaciation was preceded by a terminal stadial event. Suborbital variability may be a symptomatic feature of glacial climate or, alternatively, may play a more active role in the inception and/or termination of glacial cycles

Clinical Features, Cardiovascular Risk Profile, and Therapeutic Trajectories of Patients with Type 2 Diabetes Candidate for Oral Semaglutide Therapy in the Italian Specialist Care

Introduction: This study aimed to address therapeutic inertia in the management of type 2 diabetes (T2D) by investigating the potential of early treatment with oral semaglutide. Methods: A cross-sectional survey was conducted between October 2021 and April 2022 among specialists treating individuals with T2D. A scientific committee designed a data collection form covering demographics, cardiovascular risk, glucose control metrics, ongoing therapies, and physician judgments on treatment appropriateness. Participants completed anonymous patient questionnaires reflecting routine clinical encounters. The preferred therapeutic regimen for each patient was also identified. Results: The analysis was conducted on 4449 patients initiating oral semaglutide. The population had a relatively short disease duration (42%  60% of patients, and more often than sitagliptin or empagliflozin. Conclusion: The study supports the potential of early implementation of oral semaglutide as a strategy to overcome therapeutic inertia and enhance T2D management

VizieR Online Data Catalog: CLASH-VLT: the FF cluster MACS J0416.1-2403 (Balestra+, 2016)

The cluster MACS J0416.1-2403 was observed between 2012 December and 2014 November as part of the ESO Large Programme 186.A-0798 "Dark Matter Mass Distributions of Hubble Treasury Clusters and the Foundations of ΛCDM Structure Formation Models" (P.I.: Piero Rosati) using VIMOS at the ESO VLT. A total of 21 masks were observed (15 LR-Blue (low-resolution) masks and 6 MR (medium-resolution) masks). The LR-Blue masks cover the spectral range 3700-6700Å with a resolution of R=180, while the MR masks cover the range 4800-10000Å with a resolution of R=580. The massive cluster has been observed with the Hubble Space Telescope (HST) as part of the Multi-Cycle Treasury program Cluster Lensing And Supernova survey with Hubble (CLASH; P.I.: M. Postman; Postman et al. 2012, J/ApJS/199/25). The HST survey is nicely complemented by Subaru wide-field imaging

Collins and Sivers asymmetries in muonproduction of pions and kaons off transversely polarised protons

Measurements of the Collins and Sivers asymmetries for charged pions and charged and neutral kaons produced in semi-inclusive deep-inelastic scattering of high energy muons off transversely polarised protons are presented. The results were obtained using all the available COMPASS proton data, which were taken in the years 2007 and 2010. The Collins asymmetries exhibit in the valence region a non-zero signal for pions and there are hints of non-zero signal also for kaons. The Sivers asymmetries are found to be positive for positive pions and kaons and compatible with zero otherwise. © 2015