Immunogenic cell death triggered by impaired deubiquitination in multiple myeloma relies on dysregulated type I interferon signaling

Introduction Proteasome inhibition is first line therapy in multiple myeloma (MM). The immunological potential of cell death triggered by defects of the ubiquitin-proteasome system (UPS) and subsequent perturbations of protein homeostasis is, however, less well defined. Methods In this paper, we applied the protein homeostasis disruptors bortezomib (BTZ), ONX0914, RA190 and PR619 to various MM cell lines and primary patient samples to investigate their ability to induce immunogenic cell death (ICD). Results Our data show that while BTZ treatment triggers sterile type I interferon (IFN) responses, exposure of the cells to ONX0914 or RA190 was mostly immunologically silent. Interestingly, inhibition of protein de-ubiquitination by PR619 was associated with the acquisition of a strong type I IFN gene signature which relied on key components of the unfolded protein and integrated stress responses including inositol-requiring enzyme 1 (IRE1), protein kinase R (PKR) and general control nonderepressible 2 (GCN2). The immunological relevance of blocking de-ubiquitination in MM was further reflected by the ability of PR619-induced apoptotic cells to facilitate dendritic cell (DC) maturation via type I IFN-dependent mechanisms. Conclusion Altogether, our findings identify de-ubiquitination inhibition as a promising strategy for inducing ICD of MM to expand current available treatments

Preliminary in vitro assessment of the potential toxicity and antioxidant activity of Ceiba speciosa (A. St.-Hill) Ravenna (Paineira)

The bark tea of Ceiba speciosa, a tropical tree of the Malvaceae family, is used in the Northwestern Region of Rio Grande do Sul state, Brazil, to reduce blood cholesterol levels. However, there are no scientific data on the efficacy and safety of this plant. The aim of the present study was to evaluate the in vitro antioxidant and toxic potential of bark extracts of C. speciosa. We performed a preliminary phytochemical analysis by high-performance liquid chromatography-diode array detection (HPLC-DAD) and evaluated the oxidative damage to proteins and lipids, the radical scavenging effect, and genotoxicity of the lyophilized aqueous extract (LAECs) and the precipitate obtained from the raw ethanol extract (Cs1). The phytochemical profile demonstrated the presence of phenolic and flavonoid compounds. The LAECs and Cs1 prevented damage to lipids and proteins at concentrations of 50 and 10 µg/mL. They also showed a scavenging effect on 2,2-diphenyl-1-pricril-hydrazyl (DPPH) radicals in a concentration-dependent manner. Furthermore, no genotoxic effect was observed at concentrations of 10, 5 and 2 µg/mL in the Comet assay. The present study is the first evaluation regarding the characterization of C. speciosa and its safety, and the results demonstrate its antioxidant potential and suggest that its therapeutic use may be relatively safe

Climate change and potato production in contrasting South African agro-ecosystems 3. Effects on relative development rates of selected pathogens and pests

A set of daily weather data simulations for 1961 to 2050 were used to calculate past and future trends in pest and disease pressure in potato cropping systems at three agro-ecologically distinct sites in South Africa: the Sandveld, the Eastern Free State and Limpopo. The diseases and pests modelled were late blight, early blight and brown spot, blackleg and soft rot, root-knot nematodes and the peach-potato aphid Myzus persicae (as indicator of Potato virus Y and Potato leaf roll virus). The effects of climate on trends in relative development rates of these pathogens and pests were modelled for each pathogen and pest using a set of quantitative parameters, which included specific temperature and moisture requirements for population growth, compiled from literature. Results showed that the cumulative relative development rate (cRDR) of soft rot and blackleg, root-knot nematodes and M. persicae will increase over the 90-year period in the areas under consideration. The cRDR of early blight and brown spot is likely to increase in the wet winter and wet summer crops of the Sandveld and Eastern Free State, respectively, but remains unchanged in the dry summer and dry winter crops of the Sandveld and Limpopo, respectively. Climate change will decrease the cRDR of late blight in all of the cropping systems modelled, except in the wet winter crop of the Sandveld. These results help to set priorities in research and breeding, specifically in relation to management strategies for diseases and pests.Potatoes South Africa and the Netherlands Ministry of Economy, Agriculture and Innovation Agriculture.http://link.springer.com/journal/11540hb201

An ACACB variant implicated in diabetic nephropathy associates with body mass index and gene expression in obese subjects

Acetyl coenzyme A carboxylase B gene (ACACB) single nucleotide polymorphism (SNP) rs2268388 is reproducibly associated with type 2 diabetes (T2DM)-associated nephropathy (DN). ACACB knock-out mice are also protected from obesity. This study assessed relationships between rs2268388, body mass index (BMI) and gene expression in multiple populations, with and without T2DM. Among subjects without T2DM, rs2268388 DN risk allele (T) associated with higher BMI in Pima Indian children (n = 2021; p-additive = 0.029) and African Americans (AAs) (n = 177; p-additive = 0.05), with a trend in European Americans (EAs) (n = 512; p-additive = 0.09), but not Germans (n = 858; p-additive = 0.765). Association with BMI was seen in a meta-analysis including all non-T2DM subjects (n = 3568; p-additive = 0.02). Among subjects with T2DM, rs2268388 was not associated with BMI in Japanese (n = 2912) or EAs (n = 1149); however, the T allele associated with higher BMI in the subset with BMI≥30 kg/m(2) (n = 568 EAs; p-additive = 0.049, n = 196 Japanese; p-additive = 0.049). Association with BMI was strengthened in a T2DM meta-analysis that included an additional 756 AAs (p-additive = 0.080) and 48 Hong Kong Chinese (p-additive = 0.81) with BMI≥30 kg/m(2) (n = 1575; p-additive = 0.0033). The effect of rs2268388 on gene expression revealed that the T risk allele associated with higher ACACB messenger levels in adipose tissue (41 EAs and 20 AAs with BMI\u3e30 kg/m(2); p-additive = 0.018) and ACACB protein levels in the liver tissue (mixed model p-additive = 0.03, in 25 EA bariatric surgery patients with BMI\u3e30 kg/m(2) for 75 exams). The T allele also associated with higher hepatic triglyceride levels. These data support a role for ACACB in obesity and potential roles for altered lipid metabolism in susceptibility to DN

Developing assessments for child exposure to intimate partner violence in Switzerland – A study of medico-legal reports in clinical settings

Purpose: Evidence to inform assessment of needs of children exposed to intimate partner violence (IPV) in health settings is limited. A Swiss hospital-based medico-legal consultation for adult victims of violence also detects children’s exposure to IPV and refers cases to the Pediatrics Child Abuse and Neglect Team. Based on a conceptual ecological framework, this study examined the nature and circumstances of children’s exposure to IPV described in accounts collected by nurses in consultations with adult IPV victims. Methods: From 2011-2014, 438 parents (88% female) of 668 children aged 0 to 18 sought medico-legal care from the Violence Medical Unit in Lausanne Switzerland, following assaults by intimate partners (85% male). As part of the consultation, nurses completed a semi-structured questionnaire with victimized parents, recording their answers in the patient file. Victims’ statements about the abuse, their personal, family and social contexts, and their children’s exposure to IPV were analyzed. Descriptive statistics and qualitative thematic content analyses were conducted to identify, from the victimized parents’ accounts, elements useful to understand the nature and circumstances of children’s exposure and involvement during violent events. Results: Parent statements on specific violent events described children being present in 75% of the cases. Children were said to be exposed to, and responded to, severe physical violence, serious threats and insults, in the context of repeated assaults and coercive control. Families, especially mothers, were often coping with additional socio-economic vulnerabilities. Conclusions: Implications for further developing assessments of children living with IPV, especially in health settings were identified

Loss-of-function variants in the KCNQ5 gene are implicated in genetic generalized epilepsies

Summary Background De novo missense variants in KCNQ5, encoding the voltage-gated K+ channel KV7.5, have been described to cause developmental and epileptic encephalopathy (DEE) or intellectual disability (ID). We set out to identify disease-related KCNQ5 variants in genetic generalized epilepsy (GGE) and their underlying mechanisms. Methods 1292 families with GGE were studied by next-generation sequencing. Whole-cell patch-clamp recordings, biotinylation and phospholipid overlay assays were performed in mammalian cells combined with homology modelling. Findings We identified three deleterious heterozygous missense variants, one truncation and one splice site alteration in five independent families with GGE with predominant absence seizures; two variants were also associated with mild to moderate ID. All missense variants displayed a strongly decreased current density indicating a loss-of-function (LOF). When mutant channels were co-expressed with wild-type (WT) KV7.5 or KV7.5 and KV7.3 channels, three variants also revealed a significant dominant-negative effect on WT channels. Other gating parameters were unchanged. Biotinylation assays indicated a normal surface expression of the variants. The R359C variant altered PI(4,5)P2-interaction. Interpretation Our study identified deleterious KCNQ5 variants in GGE, partially combined with mild to moderate ID. The disease mechanism is a LOF partially with dominant-negative effects through functional deficits. LOF of KV7.5 channels will reduce the M-current, likely resulting in increased excitability of KV7.5-expressing neurons. Further studies on network level are necessary to understand which circuits are affected and how this induces generalized seizures. Funding DFG/FNR Research Unit FOR-2715 (Germany/Luxemburg), BMBF rare disease network Treat-ION (Germany), foundation ‘no epilep’ (Germany)

Preliminary in vitro assessment of the potential toxicity and antioxidant activity of Ceiba speciosa (A. St.-Hill) Ravenna (Paineira)

ABSTRACT The bark tea of Ceiba speciosa, a tropical tree of the Malvaceae family, is used in the Northwestern Region of Rio Grande do Sul state, Brazil, to reduce blood cholesterol levels. However, there are no scientific data on the efficacy and safety of this plant. The aim of the present study was to evaluate the in vitro antioxidant and toxic potential of bark extracts of C. speciosa. We performed a preliminary phytochemical analysis by high-performance liquid chromatography-diode array detection (HPLC-DAD) and evaluated the oxidative damage to proteins and lipids, the radical scavenging effect, and genotoxicity of the lyophilized aqueous extract (LAECs) and the precipitate obtained from the raw ethanol extract (Cs1). The phytochemical profile demonstrated the presence of phenolic and flavonoid compounds. The LAECs and Cs1 prevented damage to lipids and proteins at concentrations of 50 and 10 µg/mL. They also showed a scavenging effect on 2,2-diphenyl-1-pricril-hydrazyl (DPPH) radicals in a concentration-dependent manner. Furthermore, no genotoxic effect was observed at concentrations of 10, 5 and 2 µg/mL in the Comet assay. The present study is the first evaluation regarding the characterization of C. speciosa and its safety, and the results demonstrate its antioxidant potential and suggest that its therapeutic use may be relatively safe

Functional significance of genes associated with fat distribution

Obesity is a growing health problem characterized by a variety of related complications like fatty liver disease, Type 2 diabetes and cardiovascular diseases. One of the major organs relevant for obesity is the adipose tissue (AT) and in the last decades it has been shown that AT is an endocrine organ located in different sites of the body. The AT is mainly distributed in two depots, the subcutaneous adipose tissue (ScAT) and visceral adipose tissue (VAT). It is well acknowledged that fat stored prominently in VAT makes subjects more prone for metabolic complications. It is also known that obesity as well as fat distribution are controlled by genetic factors including single nucleotide polymorphisms, deletions or insertions of nucleotides or sequences; but also the altered mRNA expression or epigenetic modifications like DNA methylation play a role. There is clear evidence that the majority of obesity cases have a polygenic character. This thesis aims to identify and characterize novel candidate ( HIF3A, REPIN1, IRX3/5 and KLF13) genes to gain further insights into different types of obesity and into causes and consequences of adverse FD, including related comorbidities