Stratification of candidate genes for Parkinson's disease using weighted protein-protein interaction network analysis

Background: Genome wide association studies (GWAS) have helped identify large numbers of genetic loci that significantly associate with increased risk of developing diseases. However, translating genetic knowledge into understanding of the molecular mechanisms underpinning disease (i.e. disease-specific impacted biological processes) has to date proved to be a major challenge. This is primarily due to difficulties in confidently defining candidate genes at GWAS-risk loci. The goal of this study was to better characterize candidate genes within GWAS loci using a protein interactome based approach and with Parkinson’s disease (PD) data as a test case. // Results: We applied a recently developed Weighted Protein-Protein Interaction Network Analysis (WPPINA) pipeline as a means to define impacted biological processes, risk pathways and therein key functional players. We used previously established Mendelian forms of PD to identify seed proteins, and to construct a protein network for genetic Parkinson’s and carried out functional enrichment analyses. We isolated PD-specific processes indicating ‘mitochondria stressors mediated cell death’, ‘immune response and signaling’, and ‘waste disposal’ mediated through ‘autophagy’. Merging the resulting protein network with data from Parkinson’s GWAS we confirmed 10 candidate genes previously selected by pure proximity and were able to nominate 17 novel candidate genes for sporadic PD. // Conclusions: With this study, we were able to better characterize the underlying genetic and functional architecture of idiopathic PD, thus validating WPPINA as a robust pipeline for the in silico genetic and functional dissection of complex disorders

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

This paper is a personal account on the discovery and characterization of the 5-HT2C receptor (first known as the 5- HT1C receptor) over 30 years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT2C receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT1CR, the 5-HT2CR was discovered while studying the pharmacological features and the distribution of [3H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [3H]mesulergine-labelling to the rat choroid plexus. [3H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT2 binding, the new binding site was called 5-HT1C because of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HT1CR (later named 5- HT2C) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HT2CR is a GPCR, with a very complex gene structure. It constitutes a rarity in theGPCR family: many 5-HT2CR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT2CR splice variants. Intense research led to therapeutically active 5-HT2C receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5- HT2CR antagonists/inverse agonists. Agomelatine, a 5-HT2CR antagonist is registered for the treatment of major depression. The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction, especially nicotine/ smoking. There is good evidence that the 5-HT2CR is involved in spinal cord injury-induced spasms of the lower limbs, which can be treated with 5-HT2CR antagonists/inverse agonists such as cyproheptadine or SB206553. The 5-HT2CR may play a role in schizophrenia and epilepsy. Vabicaserin, a 5-HT2CR agonist has been in development for the treatment of schizophrenia and obesity, but was stopped. As is common, there is potential for further indications for 5-HT2CR ligands, as suggested by a number of preclinical and/or genome-wide association studies (GWAS) on depression, suicide, sexual dysfunction, addictions and obesity. The 5-HT2CR is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychotic-induced weight gain

Bovine myofiber characteristics are influenced by postweaning nutrition

This study determined the extent to which bovine longissimus lumborum muscle (LLM) myofibers are influenced by nutrition for 120 d from weaning and the time-course of recovery after severe postweaning nutritional restriction. After weaning, 3 groups of Belmont Red cattle, a tropically adapted breed, were fed to achieve rapid growth (RG, ≥0.6 kg of BW gain/d; n = 16), slow growth (SG, 0.2 kg of BW gain/d; n = 17), or BW loss (WL, 10% loss of weaning weight; n = 17) over 120 d. They were then grazed as 1 group at pasture with forage supplementation for 600 d until slaughter at approximately 500 kg of BW. Samples of LLM were taken from 8 to 12 animals per treatment 6 d before (baseline) and 115, 204, 324, and 476 d after commencement of the study and from all cattle at slaughter (d 721). Myofiber characteristics were determined by immunocytochemical staining of myosin heavy chains. Cross-sectional areas (CSA) of the major myofiber types 1, 2A, and 2X in WL were reduced at d 115 compared with baseline and with the growth groups (all P 0.10). Differences in CSA of the major myofiber types between WL and the growth groups at 115 d were smallest for type 1 (slow oxidative) and greatest for type 2X (fast glycolytic). Consequently, the relative area (percentage of total myofiber area) of type 1 myofibers in WL was significantly greater at 115 d than in the growth groups (P 0.10), and by 721 d CSA of myofiber types differed little between the treatment groups, although SG had greater CSA of type 1 (

Haematological values of young male rusa deer (Cervus timorensis)

Objective To measure haematological values of clinical significance for rusa deer and provide reference data for farmed animals. Design Blood samples were collected regularly from eight male rusa deer from 14 days to 27 months old. Procedure Blood samples, collected by venipuncture, were analysed within 6 hours of collection for red cell count, haemoglobin, packed cell volume, plasma glucose, white cell count and differentials. Results Haemoglobin concentrations appeared to increase with age and ranged from 6.0 to 20.9 g/dL. Packed cell volume and plasma glucose concentration did not appear to vary with age. White cell counts ranged from 6.3 to 7.0 x 10(9)/L and differential counts indicated neutrophils > lymphocytes > monocytes > eosinophils > basophils. In general, the values for packed cell volume, red cell count, mean cell volumes and mean cell haemoglobin concentrations were within ranges previously reported for captive or sedated rusa deer. Conclusions Physical restraint and resultant stress was sufficient to generate some of the effects previously reported for physically immobilised or agitated deer. The values reported here do not differ greatly from those previously reported for rusa deer and can be used as reference values for clinically healthy young farmed male rusa deer

A hedonic modelling of land property value based on the effect of flooding: a case for peninsular Malaysia

The effect of flooding on land property value is a major concern of all landowners. Numerous studies have already discussed the risk of potential decline in the value of land property situated in flood-prone areas; however, those that focused on the impact of flooding on land property in Malaysia are still limited. This chapter investigates the effect of flood on the value of agricultural and industrial land properties in Peninsular Malaysia. This chapter’s results suggest that a metre increase in flood depth significantly decreases land property value by 44.6%. This result helps policymakers in designing and developing the policies of land property development that would minimize land property devaluation due to flood depth and help landowners in understanding the effect of flood on land property values