Radiative contribution to neutrino masses and mixing in μν\mu\nuSSM

In an extension of the minimal supersymmetric standard model (popularly known as the $\mu\nu$SSM), three right handed neutrino superfields are introduced to solve the $\mu$-problem and to accommodate the non-vanishing neutrino masses and mixing. Neutrino masses at the tree level are generated through $R-$parity violation and seesaw mechanism. We have analyzed the full effect of one-loop contributions to the neutrino mass matrix. We show that the current three flavour global neutrino data can be accommodated in the $\mu\nu$SSM, for both the tree level and one-loop corrected analyses. We find that it is relatively easier to accommodate the normal hierarchical mass pattern compared to the inverted hierarchical or quasi-degenerate case, when one-loop corrections are included.Comment: 51 pages, 14 figures (58 .eps files), expanded introduction, other minor changes, references adde

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Prostaglandin profiling reveals a role for haematopoietic prostaglandin D synthase in adipose tissue macrophage polarisation in mice and humans.

BACKGROUND/OBJECTIVES: Obesity has been associated with both changes in adipose tissue lipid metabolism and inflammation. A key class of lipid-derived signalling molecules involved in inflammation are the prostaglandins. In this study, we aimed to determine how obesity affects the levels of prostaglandins within white adipose tissue (WAT) and determine which cells within adipose tissue produce them. To avoid the effects of cellular stress on prostaglandin levels, we developed a multivariate statistical approach in which metabolite concentrations and transcriptomic data were integrated, allowing the assignment of metabolites to cell types. SUBJECTS/METHODS: Eicosanoids were measured by liquid chromatography-tandem mass spectrometry and mRNA levels using real-time PCR. Eicosanoid levels and transcriptomic data were combined using principal component analysis and hierarchical clustering in order to associate metabolites with cell types. Samples were obtained from C57Bl/6 mice aged 16 weeks. We studied the ob/ob genetically obese mouse model and diet-induced obesity model. We extended our results in mice to a cohort of morbidly obese humans undergoing bariatric surgery. RESULTS: Using our modelling approach, we determined that prostglandin D₂ (PGD₂) in adipose tissue was predominantly produced in macrophages by the haematopoietic isoform of prostaglandin D synthase (H-Pgds). Analysis of sub-fractionated WAT confirmed that H-Pgds was expressed in adipose tissue macrophages (ATMs). Furthermore, H-Pgds expression in ATMs isolated from lean and obese mice was consistent with it affecting macrophage polarisation. Functionally, we demonstrated that H-PGDS-produced PGD₂ polarised macrophages toward an M2, anti-inflammatory state. In line with a potential anti-inflammatory role, we found that H-PGDS expression in ATMs was positively correlated with both peripheral insulin and adipose tissue insulin sensitivity in humans. CONCLUSIONS: In this study, we have developed a method to determine the cellular source of metabolites within an organ and used it to identify a new role for PGD₂ in the control of ATM polarisation.HQL-79 was a kind gift of Professor Yoshihiro Urade. Professor Vidal-Puig was funded by the BHF, MRC and BBSRC. Dr Virtue was funded by the BBSRC and the BHF. Dr Eiden, Dr Masoodi and Dr Griffin were funded by the MRC. Dr Mok was funded by the Wellcome Trust.This is the final published version. It first appeared at http://www.nature.com/ijo/journal/vaop/ncurrent/full/ijo201534a.htm

Inhibition of renal cell carcinoma angiogenesis and growth by antisense oligonucleotides targeting vascular endothelial growth factor

Angiogenesis is critical for growth and metastatic spread of solid tumours. It is tightly controlled by specific regulatory factors. Vascular endothelial growth factor has been implicated as the key factor in tumour angiogenesis. In the present studies we evaluated the effects of blocking vascular endothelial growth factor production by antisense phosphorothioate oligodeoxynucleotides on the growth and angiogenic activity of a pre-clinical model of renal cell carcinoma (Caki-1). In vitro studies showed that treating Caki-1 cells with antisense phosphorothioate oligodeoxynucleotides directed against vascular endothelial growth factor mRNA led to a reduction in expressed vascular endothelial growth factor levels sufficient to impair the proliferation and migration of co-cultured endothelial cells. The observed effects were antisense sequence specific, dose dependent, and could be achieved at a low, non-toxic concentration of phosphorothioate oligodeoxynucleotides. When vascular endothelial growth factor antisense treated Caki-1 cells were injected into nude mice and evaluated for their angiogenic potential, the number of vessels initiated were approximately half that induced by untreated Caki-1 cells. To test the anti-tumour efficacy of vascular endothelial growth factor antisense, phosphorothioate oligodeoxynucleotides were administrated to nude mice bearing macroscopic Caki-1 xenografts. The results showed that the systemic administration of two doses of vascular endothelial growth factor antisense phosphorothioate oligodeoxynucleotides given 1 and 4 days after the tumours reached a size of ∼200 mm3 significantly increased the time for tumours to grow to 1000 mm3

Cholinergic receptor pathways involved in apoptosis, cell proliferation and neuronal differentiation

Acetylcholine (ACh) has been shown to modulate neuronal differentiation during early development. Both muscarinic and nicotinic acetylcholine receptors (AChRs) regulate a wide variety of physiological responses, including apoptosis, cellular proliferation and neuronal differentiation. However, the intracellular mechanisms underlying these effects of AChR signaling are not fully understood. It is known that activation of AChRs increase cellular proliferation and neurogenesis and that regulation of intracellular calcium through AChRs may underlie the many functions of ACh. Intriguingly, activation of diverse signaling molecules such as Ras-mitogen-activated protein kinase, phosphatidylinositol 3-kinase-Akt, protein kinase C and c-Src is modulated by AChRs. Here we discuss the roles of ACh in neuronal differentiation, cell proliferation and apoptosis. We also discuss the pathways involved in these processes, as well as the effects of novel endogenous AChRs agonists and strategies to enhance neuronal-differentiation of stem and neural progenitor cells. Further understanding of the intracellular mechanisms underlying AChR signaling may provide insights for novel therapeutic strategies, as abnormal AChR activity is present in many diseases

Anatomy-Specific Pancreatic Stump Management to Reduce the Risk of Pancreatic Fistula After Pancreatic Head Resection.

BACKGROUND: The anatomical status of the pancreatic remnant after a pancreatic head resection varies greatly among patients. The aim of the present study was to improve management of the pancreatic remnant for reducing pancreatic fistula after pancreatic head resection. METHODS: Ninety-five consecutive patients who underwent an end-to-side, duct-to-mucosa pancreaticojejunostomy after pancreatic head resection were included in the study. To approximate the pancreatic stump to the jejunum, the transfixing and interrupted suture techniques were used in 51 and 44 patients, respectively. We modified the interrupted suture technique according to the anatomical status of the pancreatic remnant, i.e., the shape of the pancreatic stump and the location of the pancreatic duct. RESULTS: There was no operative mortality in this study. Overall, 14 patients (15%) developed a clinically relevant pancreatic fistula. Certain anatomical features, including a small pancreatic duct, a soft, nonfibrotic pancreatic gland, and a pancreatic duct adjacent to the posterior cut edge, were significantly associated with pancreatic fistula. The fistula rate in the interrupted suture group was 7%, lower than that (22%) in the transfixing suture group (P = 0.036), and it was not influenced by pancreatic anatomy. Multivariate analysis identified a nonfibrotic pancreas (versus fibrotic pancreas; odds ratio [OR] 12.58, 95% CI 1.2-23.9; P = 0.001), a soft pancreas (versus hard pancreas; OR 4.67, CI 1.2-51.1; P = 0.006), and the transfixing suture technique (versus interrupted suture technique; OR 9.91, CI 1.7-57.5; P = 0.003) as significant predictors of clinically relevant pancreatic fistula. CONCLUSIONS: Pancreatic anastomosis modified according to the pancreatic anatomy is effective in reducing the risk of pancreatic fistula formation with end-to-side, duct-to-mucosa pancreaticojejunostomy after pancreatic head resection