Grandparenting Activities and Mental Health in Northern Sri Lanka

Grandparenting activities are of increasing interest to researchers seeking to understand reduced social engagement and depression among aging adults. Heterogeneity in the population and caretaking roles complicate its measurement. We piloted a measure of grandparenting activities among 79 grandparents (aged 55+) in Sri Lanka and correlated those activity levels with psychological distress. Second, we explored whether the aforementioned correlation varied by grandparent functional limitations. We found that greater engagement in generative grandparenting activities was correlated with lower distress, and that association was stronger among grandparents with more functional limitations. We discuss possible explanations and implications of these findings

A robust nanoscale RP HPLC-MS approach for sensitive Fc proteoform profiling of IgG allotypes

The conserved region (Fc) of IgG antibodies dictates the interactions with designated receptors thus defining the immunological effector functions of IgG. Amino acid sequence variations in the Fc, recognized as subclasses and allotypes, as well as post-translational modifications (PTMs) modulate these interactions. Yet, the high similarity of Fc sequences hinders allotype-specific PTM analysis by state-of-the-art bottom-up methods and current subunit approaches lack sensitivity and face co-elution of near-isobaric allotypes.To circumvent these shortcomings, we present a nanoscale reversed-phase (RP) HPLC-MS workflow of intact Fc subunits for comprehensive characterization of Fc proteoforms in an allotype- and subclass-specific manner. Polyclonal IgGs were purified from individuals followed by enzymatic digestion releasing single chain Fc subunits (Fc/2) that were directly subjected to analysis. Chromatographic conditions were optimized to separate Fc/2 subunits of near-isobaric allotypes and subclasses allowing allotype and proteoform identification and quantification across all four IgG subclasses. The workflow was complemented by a semi-automated data analysis pipeline based on the open-source software Skyline followed by post-processing in R. The approach revealed pronounced differences in Fc glycosylation between donors, besides inter-subclass and inter-allotype variability within donors. Notably, partial occupancy of the N-glycosylation site in the CH3 domain of IgG3 was observed that is generally neglected by established approaches. The described method was benchmarked across several hundred runs and showed good precision and robustness.This methodology represents a first mature Fc subunit profiling approach allowing truly subclass- and allotype-specific Fc proteoform characterization beyond established approaches. The comprehensive information obtained paired with the high sensitivity provided by the miniaturization of the approach guarantees applicability to a broad range of research questions including clinically relevant (auto)antibody characterization or pharmacokinetics assessment of therapeutic IgGs.Pathophysiology and treatment of rheumatic disease

BNCI Horizon 2020 - Towards a Roadmap for Brain/Neural Computer Interaction

In this paper, we present BNCI Horizon 2020, an EU Coordination and Support Action (CSA) that will provide a roadmap for brain-computer interaction research for the next years, starting in 2013, and aiming at research efforts until 2020 and beyond. The project is a successor of the earlier EU-funded Future BNCI CSA that started in 2010 and produced a roadmap for a shorter time period. We present how we, a consortium of the main European BCI research groups as well as companies and end user representatives, expect to tackle the problem of designing a roadmap for BCI research. In this paper, we define the field with its recent developments, in particular by considering publications and EU-funded research projects, and we discuss how we plan to involve research groups, companies, and user groups in our effort to pave the way for useful and fruitful EU-funded BCI research for the next ten years

Randomized phase I trial of antigen-specific tolerizing immunotherapy with peptide/calcitriol liposomes in ACPA+ rheumatoid arthritis

BACKGROUND. Antigen-specific regulation of autoimmune disease is a major goal. In seropositive rheumatoid arthritis (RA), T cell help to autoreactive B cells matures the citrullinated (Cit) antigen-specific immune response, generating RA-specific V domain glycosylated anti-Cit protein antibodies (ACPA VDG) before arthritis onset. Low or escalating antigen administration under “sub-immunogenic” conditions favors tolerance. We explored safety, pharmacokinetics, and immunological and clinical effects of s.c. DEN-181, comprising liposomes encapsulating self-peptide collagen II259-273 (CII) and NF-κB inhibitor 1,25-dihydroxycholecalciferol. METHODS. A double-blind, placebo-controlled, exploratory, single-ascending-dose, phase I trial assessed the impact of low, medium, and high DEN-181 doses on peripheral blood CII-specific and bystander Cit64vimentin59-71–specific (Cit-Vim–specific) autoreactive T cell responses, cytokines, and ACPA in 17 HLA-DRB1*04:01+ or *01:01+ ACPA+ RA patients on methotrexate. RESULTS. DEN-181 was well tolerated. Relative to placebo and normalized to baseline values, Cit-Vim–specific T cells decreased in patients administered medium and high doses of DEN-181. Relative to placebo, percentage of CII-specific programmed cell death 1+ T cells increased within 28 days of DEN-181. Exploratory analysis in DEN-181–treated patients suggested improved RA disease activity was associated with expansion of CII-specific and Cit-Vim–specific T cells; reduction in ACPA VDG, memory B cells, and inflammatory myeloid populations; and enrichment in CCR7+ and naive T cells. Single-cell sequencing identified T cell transcripts associated with tolerogenic TCR signaling and exhaustion after low or medium doses of DEN-181. CONCLUSION. The safety and immunomodulatory activity of low/medium DEN-181 doses provide rationale to further assess antigen-specific immunomodulatory therapy in ACPA+ RA

The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism

Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions

High power ECRH and ECCD in moderately collisional ASDEX upgrade H-modes and status of EC system upgrade

This contribution deals with H-modes with significant heat exchange between electrons and ions, but which can still show large differences between electron and ion-temperatures especially inside half minor radius. These conditions are referred to as moderately collisional. A systematic study shows that an increasing fraction of electron heating increases the transport in the ion channel mainly due to the dependence of the ITG dominated ion transport on the ratio Te/Ti in agreement with modeling. The rotational shear in the plasmas under study was so small that it hardly influences ITG stability, such that variations of the rotation profile due to a change of the heating method were of minor importance. These findings connect to studies of advanced tokamak scenarios using ECCD as a tool to modify the q-profile. The electron heating connected to the ECCD tends to increase the transport in the ion channel quite in contrast to the goal to operate at reduced current but with increased confinement. The confinement only increases as the fraction of ion heating is increased by adding more NBI. An ITER case was modeled as well. Due to the larger value of νei ・ τE the ratio Te/Ti is only moderately reduced even with strong electron heating and the confinement reduction is small even for the hypothetic case of using only ECRH as additional heating. Finally the paper discusses the ongoing upgrade of the AUG ECRH-system