The Antiobesity Effects of Rosehip (Rosa canina) Flesh by Antagonizing the PPAR Gamma Activity in High-Fat Diet-Fed Mice.

SCOPE: The rosehip (Rosa canina) is a perennial shrub with a reddish pseudofruit that has demonstrated antidiabetic, antiatherosclerotic, and antiobesogenic effects in rodent models but there is low information about the molecular mechanisms underlying these effects on the onset and progression of diet-induced obesity. METHODS AND RESULTS: Four-week-old C57BL/6J male mice are subjected to a high-fat diet (HFD)-supplemented or not with R. canina flesh for 18 weeks. The results indicated that the R. canina flesh exerts a preventive effect on HFD-induced obesity with a significant reduction in body-weight gain and an improvement of hyperglycemia and insulin resistance caused by a HFD. At the tissue level, subcutaneous white adipose tissue exhibits a higher number of smaller adipocytes, with decreased lipogenesis. On its side, the liver shows a significant decrease in lipid droplet content and in the expression of genes related to lipogenesis, fatty acid oxidation, and glucose metabolism. Finally, the data suggest that most of these effects agree with the presence of a putative Perosxisome proliferator-activated receptor gamma (PPARγ) antagonist in the R. canina flesh. CONCLUSIONS: R. canina flesh dietary supplementation slows down the steatotic effect of a HFD at least in part through the regulation of the transcriptional activity of PPARγ.

Reducing lipid bilayer stress by monounsaturated fatty acids protects renal proximal tubules in diabetes.

In diabetic patients, dyslipidemia frequently contributes to organ damage such as diabetic kidney disease (DKD). Dyslipidemia is associated with both excessive deposition of triacylglycerol (TAG) in lipid droplets (LDs) and lipotoxicity. Yet, it is unclear how these two effects correlate with each other in the kidney and how they are influenced by dietary patterns. By using a diabetes mouse model, we find here that high-fat diet enriched in the monounsaturated oleic acid (OA) caused more lipid storage in LDs in renal proximal tubular cells (PTCs) but less tubular damage than a corresponding butter diet with the saturated palmitic acid (PA). This effect was particularly evident in S2/S3 but not S1 segments of the proximal tubule. Combining transcriptomics, lipidomics, and functional studies, we identify endoplasmic reticulum (ER) stress as the main cause of PA-induced PTC injury. Mechanistically, ER stress is caused by elevated levels of saturated TAG precursors, reduced LD formation, and, consequently, higher membrane order in the ER. Simultaneous addition of OA rescues the cytotoxic effects by normalizing membrane order and increasing both TAG and LD formation. Our study thus emphasizes the importance of monounsaturated fatty acids for the dietary management of DKD by preventing lipid bilayer stress in the ER and promoting TAG and LD formation in PTCs.

La soledad como determinante de salud en las personas mayores de 60 años en un entorno semirrural / Loneliness as a determinant of health in people over 60 in a semi-rural environment

La soledad es un fenómeno emergente relacionado con la pérdida funcional de las capacidades básicas (ABVD), el riesgo de desarrollar enfermedades y el aumento de la morbimortalidad. Objetivo principal: describir la prevalencia del sentimiento de soledad en las personas > 60 años de un entorno semirrural. Objetivos secundarios: estudiar la relación de la soledad con factores personales y uso de los servicios médicos. Estudio transversal en el ámbito de la Atención Primaria. Población de estudio: personas entre 60 y 85 años usuarias del Centre d'Atenció Primaria Palafrugell. La variable principal es la soledad medida con una escala validada en España (Escala De Jong y Gierveld de 11 ítems [DJGS-11]). Se pasó la escala a los usuarios del centro de salud mediante entrevista telefónica. Obtuvimos una muestra aleatoria de 149 pacientes estratificada por edad y sexo. El 54,4% de las personas estudiadas se sienten solas en Palafrugell. Existe más riesgo de probabilidad (RP) de sentirse solo entre las personas de 71-85 años que entre las de 60-70 años (p > 0,05; RP = 1,41), entre aquellos que tienen una mala percepción de la salud (p < 0,05; RP = 1,65), viven solos (p < 0,05, RP = 1,48) y no tienen carné de conducir (p < 0,05; RP = 1,48). Las personas solas visitan el doble las urgencias hospitalarias (p < 0,05; RP = 1,98). La soledad es un determinante de salud importante en la población anciana, ya que una de cada dos de estas personas experimenta soledad. Se han observado tendencias como la relación entre soledad y uso de los servicios sanitarios, pero son necesarios más estudios en esta dirección

Loneliness is an emergent social phenomenon related to a loss of basic activities of daily living (Barthel Index), increased risk of developing disease as well as morbidity and mortality rate. The main objective was to report the prevalence of loneliness in elderly people (> 60 years old) in a non-urban setting. The secondary objective was to study the relationship between personal factors and use of health services. We performed a transversal study in the scope of primary care. People aged 60 to 85 years old and users of the Primary Health Care Centre from Palafrugell were included. The De Jong and Gierveld 11-item scale was used to determine loneliness by phone interview. We obtained a random sample of 149 patients which was stratified by age and sex. The prevalence of loneliness in Palafrugell is 54,4%. There is a higher risk of feeling lonely in those people aged 71-85 years old compared to those aged 60-70 years old (p > 0,05; RP = 1,41), those who have a poor perception of one's own state of health (P < 0,05; RP = 1,65), those who live alone (p < 0,05; RP = 1,48) and do not have a driving licence (p < 0,05; RP = 1,48). Lonely people visit the casualty department twice as often (p < 0,05; RP = 1,98). Loneliness is a key health determinant in elderly people and one in two feels lonely. Trends such as the relationship between loneliness and use of health services are observed. However, further studies along these lines are needed

Pre- and post-injury job type distributions of individuals with SCI in relation to structural changes in the labor market: A comparative analysis based on findings from the Swiss Spinal Cord Injury Cohort Study.

Objective: To compare pre- and post-injury job type distributions of individuals with spinal cord injury (SCI) living in Switzerland.Design: Cross-sectional, self-report survey.Setting: Community.Participants: Two hundred sixty-three individuals reporting a pre- and 677 a post-injury job title in the Swiss SCI Cohort Study community survey.Interventions: Not applicable.Outcome Measures: Job titles were elicited by free-text questions and classified using the International Standard Classification of Occupations (ISCO-08). Frequencies across ISCO-08 major groups were calculated and compared to Swiss labor market statistics for 1995 and 2011.Results: Compared to pre-SCI, Professionals (16.3% vs 31.2%) and Clerical Support Workers (11.7% vs 19.1%) were more prevalent and Crafts and Related Workers (26.5% vs 5.4%) less common post-injury. Except for Clerical Support Workers, these results reflect recent structural changes in the Swiss labor market.Conclusion: The higher post-SCI prevalence of jobs predominantly requiring cognitive and communication skills compared to rather physically oriented jobs mirrors structural changes in the labor market, except for clerical jobs. Future return-to-work strategies should not primarily target the clerical sector with its diminishing job opportunities, but promote vocational re-training towards jobs requiring higher education and assistive technology to return individuals with limited cognitive resources to physically oriented jobs.

Molecular Basis for Autosomal-Dominant Renal Fanconi Syndrome Caused by HNF4A.

HNF4A is a nuclear hormone receptor that binds DNA as an obligate homodimer. While all known human heterozygous mutations are associated with the autosomal-dominant diabetes form MODY1, one particular mutation (p.R85W) in the DNA-binding domain (DBD) causes additional renal Fanconi syndrome (FRTS). Here, we find that expression of the conserved fly ortholog dHNF4 harboring the FRTS mutation in Drosophila nephrocytes caused nuclear depletion and cytosolic aggregation of a wild-type dHNF4 reporter protein. While the nuclear depletion led to mitochondrial defects and lipid droplet accumulation, the cytosolic aggregates triggered the expansion of the endoplasmic reticulum (ER), autophagy, and eventually cell death. The latter effects could be fully rescued by preventing nuclear export through interfering with serine phosphorylation in the DBD. Our data describe a genomic and a non-genomic mechanism for FRTS in HNF4A-associated MODY1 with important implications for the renal proximal tubule and the regulation of other nuclear hormone receptors.

SNAVA-A real-time multi-FPGA multi-model spiking neural network simulation architecture.

Spiking Neural Networks (SNN) for Versatile Applications (SNAVA) simulation platform is a scalable and programmable parallel architecture that supports real-time, large-scale, multi-model SNN computation. This parallel architecture is implemented in modern Field-Programmable Gate Arrays (FPGAs) devices to provide high performance execution and flexibility to support large-scale SNN models. Flexibility is defined in terms of programmability, which allows easy synapse and neuron implementation. This has been achieved by using a special-purpose Processing Elements (PEs) for computing SNNs, and analyzing and customizing the instruction set according to the processing needs to achieve maximum performance with minimum resources. The parallel architecture is interfaced with customized Graphical User Interfaces (GUIs) to configure the SNN's connectivity, to compile the neuron-synapse model and to monitor SNN's activity. Our contribution intends to provide a tool that allows to prototype SNNs faster than on CPU/GPU architectures but significantly cheaper than fabricating a customized neuromorphic chip. This could be potentially valuable to the computational neuroscience and neuromorphic engineering communities.

Action potential propagation: ion current or intramembrane electric field?

The established action potential propagation mechanisms do not satisfactorily explain propagation on myelinated axons given the current knowledge of biological channels and membranes. The flow across ion channels presents two possible effects: the electric potential variations across the lipid bilayers (action potential) and the propagation of an electric field through the membrane inner part. The proposed mechanism is based on intra-membrane electric field propagation, this propagation can explain the action potential saltatory propagation and its constant delay independent of distance between Ranvier nodes in myelinated axons.

Employment pathways of individuals with spinal cord injury living in Switzerland: A qualitative study.

BACKGROUND: Labour market participation (LMP) represents a key goal of rehabilitation for individuals with spinal cord injury (SCI). To achieve this goal, Swiss SCI rehabilitation centres seek, together with their clients, viable follow-up solutions for returning to work after initial rehabilitation. However, the long-term outcomes of such vocational follow-up solutions have not been investigated so far, and there is a paucity of knowledge regarding the various types of employment pathways that persons with SCI living in Switzerland may experience. OBJECTIVE: To examine long-term employment pathways as experienced by individuals with SCI living in Switzerland. METHODS: A qualitative descriptive study design involving narrative interviews with individuals who completed vocational rehabilitation (VR) during their initial rehabilitation. Interviews were transcribed verbatim, and data analysed using an inductive thematic analysis approach. RESULTS: The analysis of the 15 interviews revealed four employment pathways: the pathway of no paid work, the pathway of retraining, the pathway of job adaptation and the pathway of continuing work. CONCLUSIONS: Apart from three pathways leading towards paid employment, our results revealed one pathway that was characterized by permanent unemployment. Individuals facing a pathway of no paid work may benefit from more custom-made vocational follow-up solutions and prolonged job coaching after initial VR.

A low-protein diet induces body weight loss and browning of subcutaneous white adipose tissue through enhanced expression of hepatic fibroblast growth factor 21 (FGF21).

SCOPE: Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic candidate for the treatment of obesity. Since FGF21 production is regulated by various nutritional factors, we analyze the impact of low protein intake on circulating levels of this growth hormone in mice and in a sub cohort of the PREDIMED (Prevención con Dieta Mediterránea) trial. We also describe the role of hepatic FGF21 in metabolic adaptation to a low-protein diet (LPD). METHODS AND RESULTS: We fed control and liver-specific Fgf21 knockout (LFgf21KO) mice a LPD. This diet increased FGF21 production by inducing its overexpression in liver, and this correlated with a body weight decrease without changes in food intake. The LPD also caused FGF21-dependent browning in subcutaneous white adipose tissue (scWAT), as indicated by an increase in the expression of uncoupling protein 1 (UCP1). In a subgroup of 78 individuals from the PREDIMED trial, we observed an inverse correlation between protein intake and circulating FGF21 levels. CONCLUSION: Our results reinforce the involvement of FGF21 in coordinating energy homeostasis under a range of nutritional conditions. Moreover, here we describe an approach to increase the endogenous production of FGF21, which if demonstrated functional in humans, could generate a treatment for obesity.

Nutritional regulation of fibroblast growth factor 21: from macronutrients to bioactive dietary compounds.

Obesity is a worldwide health problem mainly due to its associated comorbidities. Fibroblast growth factor 21 (FGF21) is a peptide hormone involved in metabolic homeostasis in healthy individuals and considered a promising therapeutic candidate for the treatment of obesity. FGF21 is predominantly produced by the liver but also by other tissues, such as white adipose tissue (WAT), brown adipose tissue (BAT), skeletal muscle, and pancreas in response to different stimuli such as cold and different nutritional challenges that include fasting, high-fat diets (HFDs), ketogenic diets, some amino acid-deficient diets, low protein diets, high carbohydrate diets or specific dietary bioactive compounds. Its target tissues are essentially WAT, BAT, skeletal muscle, heart and brain. The effects of FGF21 in extra hepatic tissues occur through the fibroblast growth factor receptor (FGFR)-1c together with the co-receptor ß-klotho (KLB). Mechanistically, FGF21 interacts directly with the extracellular domain of the membrane bound cofactor KLB in the FGF21- KLB-FGFR complex to activate FGFR substrate 2α and ERK1/2 phosphorylation. Mice lacking KLB are resistant to both acute and chronic effects of FGF21. Moreover, the acute insulin sensitizing effects of FGF21 are also absent in mice with specific deletion of adipose KLB or FGFR1. Most of the data show that pharmacological administration of FGF21 has metabolic beneficial effects. The objective of this review is to compile existing information about the mechanisms that could allow the control of endogenous FGF21 levels in order to obtain the beneficial metabolic effects of FGF21 by inducing its production instead of doing it by pharmacological administration.

FGF21 mediates the lipid metabolism response to amino acid starvation.

Lipogenic gene expression in liver is repressed in mice upon leucine deprivation. The hormone fibroblast growth factor 21 (FGF21), which is critical to the adaptive metabolic response to starvation, is also induced under amino acid deprivation. Upon leucine deprivation, we found that FGF21 is needed to repress expression of lipogenic genes in liver and white adipose tissue, and stimulate phosphorylation of hormone-sensitive lipase in white adipose tissue. The increased expression of Ucp1 in brown adipose tissue under these circumstances is also impaired in FGF21-deficient mice. Our results demonstrate the important role of FGF21 in the regulation of lipid metabolism during amino acid starvation.

PGC-1ß regulates mouse carnitine-acylcarnitine translocase through estrogen-related receptor α.

Carnitine/acylcarnitine translocase (CACT) is a mitochondrial-membrane carrier proteins that mediates the transport of acylcarnitines into the mitochondrial matrix for their oxidation by the mitochondrial fatty acid-oxidation pathway. CACT deficiency causes a variety of pathological conditions, such as hypoketotic hypoglycemia, cardiac arrest, hepatomegaly, hepatic dysfunction and muscle weakness, and it can be fatal in newborns and infants. Here we report that expression of the Cact gene is induced in mouse skeletal muscle after 24h of fasting. To gain insight into the control of Cact gene expression, we examine the transcriptional regulation of the mouse Cact gene. We show that the 5'-flanking region of this gene is transcriptionally active and contains a consensus sequence for the estrogen-related receptor (ERR), a member of the nuclear receptor family of transcription factors. This sequence binds ERRαin vivo and in vitro and is required for the activation of Cact expression by the peroxisome proliferator-activated receptor gamma coactivator (PGC)-1/ERR axis. We also demonstrate that XTC790, the inverse agonist of ERRα, specifically blocks Cact activation by PGC-1ß in C2C12 cells.

Domain sets and measurement instruments on participation and environmental factors in spinal cord injury research.

The understanding and measurement of participation and environmental context in spinal cord injury (SCI) is critically important. However, there is limited understanding of the environment-participation relationship in SCI research. There is little consensus on what is and on how to measure participation and its environmental determinants in the SCI. The objective of this article is to develop a set of International Classification of Functioning, Disability and Health (ICF)-based SCI Participation and Environment Domain Set and measurement instruments that intend to measure those domains. ICF categories from the ICF components of activities and participation and environmental factors based on the comprehensive ICF Core Set for SCI and the ICF Core Set for vocational rehabilitation were merged. Measurement instruments were selected based on published systematic reviews of measurement instruments in SCI. There were 128 ICF categories or domains in total (38 for environmental factors and 90 for activities and participation). There were six measurement instruments on environmental factors and six for participation based on existing systematic reviews. This article presents a domain set that is relevant to conducting research on the social and environmental perspectives, in an effort to understand and measure functioning in SCI (i.e., "SCI participation domain set" and "SCI environment domain set," respectively). The sample of SCI Participation and Environment Measurement Instruments gathered indicate the comprehensiveness and depth of the different domains. Guiding principles on the utilization of these measurement instruments depending on the purpose and design of a research study are highly recommended to investigators.