Central CCL2 signaling onto MCH neurons mediates metabolic and behavioral adaptation to inflammation

Sickness behavior defines the endocrine, autonomic, behavioral, and metabolic responses associated with infection. While inflammatory responses were suggested to be instrumental in the loss of appetite and body weight, the molecular underpinning remains unknown. Here, we show that systemic or central lipopolysaccharide (LPS) injection results in specific hypothalamic changes characterized by a precocious increase in the chemokine ligand 2 (CCL2) followed by an increase in pro‐inflammatory cytokines and a decrease in the orexigenic neuropeptide melanin‐concentrating hormone (MCH). We therefore hypothesized that CCL2 could be the central relay for the loss in body weight induced by the inflammatory signal LPS. We find that central delivery of CCL2 promotes neuroinflammation and the decrease in MCH and body weight. MCH neurons express CCL2 receptor and respond to CCL2 by decreasing both electrical activity and MCH release. Pharmacological or genetic inhibition of CCL2 signaling opposes the response to LPS at both molecular and physiologic levels. We conclude that CCL2 signaling onto MCH neurons represents a core mechanism that relays peripheral inflammation to sickness behavior.     

An unexpectedly long history of sexual selection in birds-of-paradise

Background  

The birds-of-paradise (Paradisaeidae) form one of the most prominent avian examples of sexual selection and show a complex biogeographical distribution. The family has accordingly been used as a case-study in several significant evolutionary and biogeographical syntheses. As a robust phylogeny of the birds-of-paradise has been lacking, these hypotheses have been tentative and difficult to assess. Here we present a well supported species phylogeny with divergence time estimates of the birds-of-paradise. We use this to assess if the rates of the evolution of sexually selected traits and speciation have been excessively high within the birds-of-paradise, as well as to re-interpret biogeographical patterns in the group.     

Assessing weight-related quality of life in adolescents

Objective : The development of a new weight‐related measure to assess quality of life in adolescents [Impact of Weight on Quality of Life (IWQOL)‐Kids] is described. Research Methods and Procedures : Using a literature search, clinical experience, and consultation with pediatric clinicians, 73 items were developed, pilot tested, and administered to 642 participants, 11 to 19 years old, recruited from weight loss programs/studies and community samples (mean z‐BMI, 1.5; range, ?1.2 to 3.4; mean age, 14.0; 60% female; 56% white). Participants completed the 73 items and the Pediatric Quality of Life Inventory and were weighed and measured. Results : Four factors (27 items) were identified (physical comfort, body esteem, social life, and family relations), accounting for 71% of the variance. The IWQOL‐Kids demonstrated excellent psychometric properties. Internal consistency coefficients ranged from 0.88 to 0.95 for scales and equaled 0.96 for total score. Convergent validity was demonstrated with strong correlations between IWQOL‐Kids total score and the Pediatric Quality of Life Inventory (r = 0.76, p < 0.0001). Significant differences were found across BMI groups and between clinical and community samples, supporting the sensitivity of this measure. Participants in a weight loss camp demonstrated improved IWQOL‐Kids scores, suggesting responsiveness of the IWQOL‐Kids to weight loss/social support intervention. Discussion : The present study provides preliminary evidence regarding the psychometric properties of the IWQOL‐Kids, a weight‐related quality of life measure for adolescents. Given the rise of obesity in youth, the development of a reliable and valid weight‐related measure of quality of life is timely.     

Dengue Virus Uses a Non‐Canonical Function of the Host GBF1‐Arf‐COPI System for Capsid Protein Accumulation on Lipid Droplets

Dengue viruses cause the most important human viral disease transmitted by mosquitoes. In recent years, a great deal has been learned about molecular details of dengue virus genome replication; however, little is known about genome encapsidation and the functions of the viral capsid protein. During infection, dengue virus capsid progressively accumulates around lipid droplets (LDs) by an unknown mechanism. Here, we examined the process by which the viral capsid is transported from the endoplasmic reticulum (ER) membrane, where the protein is synthesized, to LDs. Using different methods of intervention, we found that the GBF1‐Arf1/Arf4‐COPI pathway is necessary for capsid transport to LDs, while the process is independent of both COPII components and Golgi integrity. The transport was sensitive to Brefeldin A, while a drug resistant form of GBF1 was sufficient to restore capsid subcellular distribution in infected cells. The mechanism by which LDs gain or lose proteins is still an open question. Our results support a model in which the virus uses a non‐canonical function of the COPI system for capsid accumulation on LDs, providing new ideas for antiviral strategies.      

Amino acids stimulate cholecystokinin release through the Ca2+-sensing receptor

Cholecystokinin (CCK) is produced by discrete endocrine cells in the proximal small intestine and is released following the ingestion of food. CCK is the primary hormone responsible for gallbladder contraction and has potent effects on pancreatic secretion, gastric emptying, and satiety. In addition to fats, digested proteins and aromatic amino acids are major stimulants of CCK release. However, the cellular mechanism by which amino acids affect CCK secretion is unknown. The Ca(2+)-sensing receptor (CaSR) that was originally identified on parathyroid cells is not only sensitive to extracellular Ca(2+) but is activated by extracellular aromatic amino acids. It has been postulated that this receptor may be involved in gastrointestinal hormone secretion. Using transgenic mice expressing a CCK promoter driven/enhanced green fluorescent protein (GFP) transgene, we have been able to identify and purify viable intestinal CCK cells. Intestinal mucosal CCK cells were enriched >200-fold by fluorescence-activated cell sorting. These cells were then used for real-time PCR identification of CaSR. Immunohistochemical staining with an antibody specific for CaSR confirmed colocalization of CaSR to CCK cells. In isolated CCK cells loaded with a Ca(2+)-sensitive dye, the amino acids phenylalanine and tryptophan, but not nonaromatic amino acids, caused an increase in intracellular Ca(2+) ([Ca(2+)](i)). The increase in [Ca(2+)](i) was blocked by the CaSR inhibitor Calhex 231. Phenylalanine and tryptophan stimulated CCK release from intestinal CCK cells, and this stimulation was also blocked by CaSR inhibition. Electrophysiological recordings from isolated CCK-GFP cells revealed these cells to possess a predominant outwardly rectifying potassium current. Administration of phenylalanine inhibited basal K(+) channel activity and caused CCK cell depolarization, consistent with changes necessary for hormone secretion. These findings indicate that amino acids have a direct effect on CCK cells to stimulate CCK release by activating CaSR and suggest that CaSR is the physiological mechanism through which amino acids regulate CCK secretion.     

Differences in skeletal muscle between men and women with chronic heart failure

Men with chronic heart failure (CHF) have alterationsin their skeletal muscle that are partially responsible for a decreased exercise tolerance. The purpose of this study was to investigate whether skeletal muscle alterations in women with CHF are similar tothose observed in men and if these alterations are related to exerciseintolerance. Twenty-five men and thirteen women with CHFperformed a maximal exercise test for evaluation of peak oxygen consumption (O₂) and resting leftventricular ejection fraction, after which a biopsy of the vastuslateralis was performed. Twenty-one normal subjects (11 women, 10 men)were also studied. The relationship between muscle markers and peakO₂ was consistent for CHF men and women.When controlling for gender, analysis showed that oxidative enzymes andcapillary density are the best predictors of peak O_2. These results indicatethat aerobically matched CHF men and women have no differences inskeletal muscle biochemistry and histology. However, when CHF groupswere separated by peak exercise capacity of 4.5 metabolic equivalents(METs), CHF men with peak O₂ >4.5METs had increased citrate synthase and 3-hydroxyacyl-CoA dehydrogenasecompared with CHF men with peak O₂ <4.5METs. CHF men with a lower peak O₂ hadincreased capillary density compared with men with higher peakO₂. These observations were notreproduced in CHF women. This suggests that differences may existin how skeletal muscle adapts to decreasing peakO₂ in patients with CHF.

     

Penaeid and carid community changes in the St Lucia estuarine lake system,South Africa,under low water level,extended closed periods and marine reconnection conditions

Penaeid and carid communities were assessed in St Lucia over a wide range of saline conditions, water level conditions and mouth states, including a six-month marine connection and various connections to the Mfolozi Estuary. Samples were collected biannually in spring and autumn from November 2004 to May 2012 using seine nets. Seven penaeid and seven carid species were recorded, of which Palaemon pacificus, P. peringueyi, Penaeus indicus and Metapenaeus monoceros were the most abundant. The decline from 2004 to 2007 in both species recorded and densities of freshwater, estuarine and marine species during the initial closed period was linked to increased salinity, lack of recruitment and reduced estuarine surface area. Increased wave action and high seas following Cyclone Gamede opened the mouth in March 2007 after a 57-month closed period, resulting in recruitment of marine species, predominantly P. indicus, followed by a decline in densities after reclosure in August 2007. Increases in marine and freshwater species were evident after Mfolozi flood connections during 2008, 2009 and 2010. Highest densities were recorded after breaching in 2007 and after flood connections, highlighting the importance of a marine link to maintain the recruitment of penaeid species.     

The identification of novel acid isostere based inhibitors of the VPS10P family sorting receptor Sortilin

Using fragment based and structure based drug discovery strategies a series of novel Sortilin inhibitors has been identified. The inhibitors are based on the N-substituted 1,2,3-triazol-4-one/ol heterocyclic template. X-ray crystallography shows that the 1,2,3-triazol-4-one/ol acts as a carboxylic acid isostere, making a bi-dentate interaction with an arginine residue of Sortilin, an interaction which has not been previously characterised for this heterocycle.