Social perceptions and the stigmatization towards fifteen mental illnesses in France: a preliminary study on the role of vital force and burden

IntroductionThis study examined social perceptions and rejection towards fifteen mental illnesses, as well as a preliminary test of the SUBAR model, that hypothesized perceptions of both vital forces and burden would be negatively and positively related to social rejection, respectively.MethodsUsing an online survey with participants from France (n = 952), social rejection was assessed using a feeling thermometer and a social distance scale, while social perceptions were measured using visual analog scales.ResultsA stigma map for these different disorders is drawn up, revealing the social perceptions and levels of stigmatization specific to certain mental illnesses. Controlling for relevant social perceptions (i.e., danger, warmth, competence), we found that perception of burden was positively and significantly associated to social distance and negative feeling for 73% and 67% of mental illnesses, respectively. The perception of vital force was negatively and significantly related to social distance and negative feeling for 87% and 20% of mental illnesses, respectively. The change in R2 between model 1 (i.e. perception of danger, warmth, competence) and model 2 (i.e. model 1 + perceptions of vital force and burden) significantly improved in 100% of cases for social distance and 67% of cases for negative feeling.ConclusionThese preliminary data provide support for the SUBAR model and call for further investigations to better understand the social rejection of people with mental illnesses

Evolution of late-stage metastatic melanoma is dominated by aneuploidy and whole genome doubling

Although melanoma is initiated by acquisition of point mutations and limited focal copy number alterations in melanocytes-of-origin, the nature of genetic changes that characterise lethal metastatic disease is poorly understood. Here, we analyze the evolution of human melanoma progressing from early to late disease in 13 patients by sampling their tumours at multiple sites and times. Whole exome and genome sequencing data from 88 tumour samples reveals only limited gain of point mutations generally, with net mutational loss in some metastases. In contrast, melanoma evolution is dominated by whole genome doubling and large-scale aneuploidy, in which widespread loss of heterozygosity sculpts the burden of point mutations, neoantigens and structural variants even in treatment-naïve and primary cutaneous melanomas in some patients. These results imply that dysregulation of genomic integrity is a key driver of selective clonal advantage during melanoma progression

Molecular Pathogenesis of Post-Transplant Acute Kidney Injury: Assessment of Whole-Genome mRNA and MiRNA Profiles.

Acute kidney injury (AKI) affects roughly 25% of all recipients of deceased donor organs. The prevention of post-transplant AKI is still an unmet clinical need. We prospectively collected zero-hour, indication as well as protocol kidney biopsies from 166 allografts between 2011 and 2013. In this cohort eight cases with AKI and ten matched allografts without pathology serving as control group were identified with a follow-up biopsy within the first twelve days after engraftment. For this set the zero-hour and follow-up biopsies were subjected to genome wide microRNA and mRNA profiling and analysis, followed by validation in independent expression profiles of 42 AKI and 21 protocol biopsies for strictly controlling the false discovery rate. Follow-up biopsies of AKI allografts compared to time-matched protocol biopsies, further baseline adjustment for zero-hour biopsy expression level and validation in independent datasets, revealed a molecular AKI signature holding 20 mRNAs and two miRNAs (miR-182-5p and miR-21-3p). Next to several established biomarkers such as lipocalin-2 also novel candidates of interest were identified in the signature. In further experimental evaluation the elevated transcript expression level of the secretory leukocyte peptidase inhibitor (SLPI) in AKI allografts was confirmed in plasma and urine on the protein level (p<0.001 and p = 0.003, respectively). miR-182-5p was identified as a molecular regulator of post-transplant AKI, strongly correlated with global gene expression changes during AKI. In summary, we identified an AKI-specific molecular signature providing the ground for novel biomarkers and target candidates such as SLPI and miR-182-5p in addressing AKI

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

Ligand exchange-mediated activation and stabilization of a Re-based olefin metathesis catalyst by chlorinated alumina

International audienc

Minocycline prevents TRAIL upregulation in pDCs and CD4+ T cells by attenuating anti-viral IFN and activation responses.

<p>(A) pDCs become activated in response to TLR7/9 stimulation by HIV and secrete type I IFN, which in turn upregulates ISGs on leukocytes, including the TNF family members TRAIL and FasL and the B7 family member PDL1. These ligands induce apoptosis and/or exhaustion on target cells expressing the cognate death receptors (TRAIL/DR5; FasL/Fas; PDL1/PD1). (B–G) pDCs were isolated from blood of healthy human donors and exposed to 300 ng p24 eq./mL of AT-2 HIV with or without 20 μM minocycline for 18 hours (<i>n</i> = 6 different donors). (B, C) IFNα and IFNβ protein from pDC supernatants were measured by ELISA. (D) IFNβ mRNA was measured by qRT-PCR. (E) Mx mRNA and (F) TRAIL were measured as examples of ISGs by qRT-PCR and flow cytometry, respectively. (G) Viability of pDCs was determined by Annexin V/7AAD staining. (H) CD4+ T cells were isolated from blood of healthy human donors and activated with anti-CD3 with or without 20 μM minocycline (<i>n</i> = 6 different donors). After 24 hours, minocycline was replenished and some wells were additionally stimulated with IFNα and IFNβ. TRAIL was measured by flow cytometry after an additional 24 hours. (I) Representative flow cytometry gating of pDC purity by BDCA2+/CD123+ double staining immediately following isolation. (J) Representative gating of CD4+ T cell purity by CD4+/CD3+ double staining immediately following isolation. (K) Representative gating of pDC viability (Annexin V-/7AAD-) and TRAIL expression after 18 hours of stimulation in culture with virus and/or minocycline. (L) Representative gating of TRAIL expression in CD4+ T cells following 48 hours in culture. Parametric data were analyzed by paired <i>t</i>-test (TRAIL flow cytometry), and nonparametric data were analyzed by Wilcoxon signed-rank test (IFN ELISAs and IFNβ, Mx qRT-PCR).</p

Minocycline attenuates type I IFN production and TRAIL expression in lymphocytes.

<p>PBMCs were isolated from the blood of healthy human donors, pretreated for two hours <i>in vitro</i> with 0, 20, or 40 μM minocycline, and exposed to increasing amounts of either AT-2 inactivated HIV (<i>n</i> = 4 different donors) or infectious influenza virus (<i>n</i> = 3 different donors). After overnight culture, supernatants were analyzed for secreted IFNα (<b>A, D</b>) and IFNβ protein (<b>B, E</b>) by ELISA. (<b>C, F</b>) Lymphocytes were analyzed by flow cytometry for TRAIL expression. (<b>G</b>) Representative flow cytometry gating of lymphocyte TRAIL expression in PBMC mixed cultures following AT-2 HIV stimulation. (<b>H</b>) Representative gating of lymphocyte TRAIL expression in PBMC mixed cultures following influenza stimulation. A two-way repeated measures ANOVA was used to compare the effect of different doses of minocycline (<i>p</i>-value shown on graph) and varying levels of AT-2 HIV or influenza on levels of TRAIL, IFNα, and IFNβ.</p

Minocycline prevents CTLA-4 and IDO expression in CD4+ T cells and pDCs.

<p>(<b>A</b>) IDO can be induced in pDCs by engagement of B7 receptors with CTLA-4 on CD4+ T cells or by stimulation with IFNα, β, γ, TNFα, TGFβ, or HIV. IDO converts the amino acid tryptophan (TRP) into L-formylkynurenine, initiating the production of a cascade of TRP metabolites that block T cell proliferation, induce T cell apoptosis, and convert CD4+ cells into Tregs. KYN: kynurenine; PIC: picolinic acid; TRP: tryptophan; 3HAA: 3-hydroxy anthranilic acid. (<b>B</b>) CD4+ T cells were isolated from blood of healthy human donors and activated with anti-CD3 with or without 20 μM minocycline (<i>n</i> = 6 different donors). After 24 hours minocycline was replenished and some wells were stimulated with IFNα and IFNβ. After 48 hours total cells were analyzed by flow cytometry for CTLA-4. (<b>C</b>) pDCs were isolated from blood of healthy human donors and exposed to AT-2 HIV with or without 20 μM minocycline (<i>n</i> = 6 different donors). After 18 hours RNA was harvested for IDO1 qRT-PCR. CTLA-4 data were analyzed by paired <i>t</i>-test. IDO mRNA was analyzed by Wilcoxon signed-rank test. (<b>D</b>) Representative flow cytometry gating of CTLA-4 expression on isolated CD4+ T cells.</p

Attenuation of Pathogenic Immune Responses during Infection with Human and Simian Immunodeficiency Virus (HIV/SIV) by the Tetracycline Derivative Minocycline

<div><p>HIV immune pathogenesis is postulated to involve two major mechanisms: 1) chronic innate immune responses that drive T cell activation and apoptosis and 2) induction of immune regulators that suppress T cell function and proliferation. Both arms are elevated chronically in lymphoid tissues of non-natural hosts, which ultimately develop AIDS. However, these mechanisms are not elevated chronically in natural hosts of SIV infection that avert immune pathogenesis despite similarly high viral loads. In this study we investigated whether minocycline could modulate these pathogenic antiviral responses in non-natural hosts of HIV and SIV. We found that minocycline attenuated <i>in vitro</i> induction of type I interferon (IFN) and the IFN-stimulated genes indoleamine 2,3-dioxygenase (IDO1) and TNF-related apoptosis inducing ligand (TRAIL) in human plasmacytoid dendritic cells and PBMCs exposed to aldrithiol-2 inactivated HIV or infectious influenza virus. Activation-induced TRAIL and expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4) in isolated CD4+ T cells were also reduced by minocycline. Translation of these <i>in vitro</i> findings to <i>in vivo</i> effects, however, were mixed as minocycline significantly reduced markers of activation and activation-induced cell death (CD25, Fas, caspase-3) but did not affect expression of IFNβ or the IFN-stimulated genes IDO1, FasL, or Mx in the spleens of chronically SIV-infected pigtailed macaques. TRAIL expression, reflecting the mixed effects of minocycline on activation and type I IFN stimuli, was reduced by half, but this change was not significant. These results show that minocycline administered after infection may protect against aspects of activation-induced cell death during HIV/SIV immune disease, but that <i>in vitro</i> effects of minocycline on type I IFN responses are not recapitulated in a rapid progressor model <i>in vivo</i>.</p></div