Several common genetic variations have been associated with type 2 diabetes, but the exact disease mechanisms are still poorly elucidated. Using congenic strains from the diabetic Goto-Kakizaki rat, we identified a 1.4-megabase genomic locus that was linked to impaired insulin granule docking at the plasma membrane and reduced beta cell exocytosis. In this locus, Adra2a, encoding the alpha2A-adrenergic receptor [alpha(2A)AR], was significantly overexpressed. Alpha(2A)AR mediates adrenergic suppression of insulin secretion. Pharmacological receptor antagonism, silencing of receptor expression, or blockade of downstream effectors rescued insulin secretion in congenic islets. Furthermore, we identified a single-nucleotide polymorphism in the human ADRA2A gene for which risk allele carriers exhibited overexpression of alpha(2A)AR, reduced insulin secretion, and increased type 2 diabetes risk. Human pancreatic islets from risk allele carriers exhibited reduced granule docking and secreted less insulin in response to glucose; both effects were counteracted by pharmacological alpha(2A)AR antagonists.

The melanocortin 4 receptor is expressed in virtually all brain regions of mammals and plays an important role in energy homeostasis. Polymorphisms in this gene may thus be related to growth and obesity. In pigs, a non-synonymous polymorphic site was described (Asp298Asn) and demonstrated to affect cAMP production and to alter adenylyl cyclase signalling. Association studies revealed significant linkage of this mutation with production trait in pigs. In this study, 207 Lithuanian White pigs were genotyped at the MC4R locus and analysed on relationships between genotype and breeding values for several performance traits. The observed allele and genotype frequencies did not deviate significantly from Hardy-Weinberg equilibrium (wildtype allele 0.59; mutant allele 0.41) and are comparable with those described in other Large White populations. The mutant Asn298 allele of the MC4R gene was significantly associated with increased test daily gain, higher lean meat percentage and lower backfat thickness. There was a trend towards an improved feed conversion ratio (p = 0.065) in animals with the mutant allele whereas no significant effect was found on lifetime daily gain. These results indicate that the MC4R polymorphism should be integrated in selection programmes in the Lithuanian White to improve carcass composition.

Beta amyloid (Ab) oligomers are thought to contribute to the pathogenesis of Alzheimer's disease. However, clinical trials using Ab immunization were unsuccessful due to strong brain inflammation, the mechanisms of which are poorly understood. In this study we tested whether monoclonal antibodies to oligomeric Ab would prevent the neurotoxicity of Ab oligomers in primary neuronal-glial cultures. However, surprisingly, the antibodies dramatically increased the neurotoxicity of Ab. Antibodies bound to monomeric Ab fragments were non-toxic to cultured neurons, while antibodies to other oligomeric proteins: hamster polyomavirus major capsid protein, human metapneumovirus nucleocapsid protein, and measles virus nucleocapsid protein, strongly potentiated the neurotoxicity of their antigens. The neurotoxicity of antibodyoligomeric antigen complexes was abolished by removal of the Fc region from the antibodies or by removal of microglia from cultures, and was accompanied by inflammatory activation and proliferation of the microglia in culture. In conclusion, we find that immune complexes formed by Ab oligomers or other oligomeric/ multimeric antigens and their specific antibodies can cause death and loss of neurons in primary neuronal-glial cultures via Fc-dependent microglial activation. The results suggest that therapies resulting in antibodies to oligomeric Ab or oligomeric brain virus proteins should be used with caution or with suppression of microglial activation.

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The authors investigated the association of the catechol-O-methyltransferase (COMT) gene Val 158 Met polymorphism with delirium risk and functional and cognitive outcomes among patients with complicated mild to moderate traumatic brain injury (TBI). Methods:In a prospective observational cohort study, patients were monitored for occurrence of delirium during the first 4 days of admission by using the Confusion Assessment Method. Functional and cognitive outcomes were evaluated with the Glasgow Outcome on Discharge Scale and the Montreal Cognitive Assessment test, respectively. Eightynine patients were included in the study; of these, 17 (19%) were diagnosed with delirium. Results:The COMT Val 158 /Val 158 polymorphism was associated with increased risk of delirium in multivariable regression analyses adjusted for alcohol misuse, history of neurological disorder, age, and admission Glasgow Coma Scale score (odds ratio=4.57, 95% CI=1.11, 18.9, p=0.036).The COMT Met 158 allele was associated with better functional outcomes in univariate analysis (odds ratio=2.82, 95% CI=1.10, 7.27, p=0.031) but not in multivariable analysis (odds ratio=2.33, 95% CI=0.89, 6.12, p=0.085). Cognitive outcomes were not associated with the COMT Val 158 Met polymorphism in univariate regression analysis (p=0.390). Delirium was a significant predictor of worse functional and cognitive outcomes in multivariable regression analyses adjusted for other risk factors (odds ratio=0.04, 95% CI= 0.01, 0.16, p,0.001, and b=-3.889, 95% CI=-7.55, -0.23, p= 0.038, respectively). Conclusions:The COMT genotype is important in delirium risk and functional outcomes of patients with mild to moderate TBI. Whether the COMT genotype is associated with outcomes through incident delirium remains to be determined in larger studies.

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Background: Personality traits are related with risk of hazardous alcohol use and alcohol dependence. The Substance Use Risk Profile Scale (SURPS) measures personality traits associated with addictive substance abuse. We examined psychometric properties of the SURPS in Lithuanian population. Materials and methods: Two hundred forty-seven participants (mean age 37.22 ± 0.78 years), were recruited from the local community and from an inpatient addiction treatment centre. Internal consistency, stability, factor structure, content validity, and external validity of the SURPS were examined. Hazardous alcohol use was evaluated by Alcohol Use Disorder Identification Test (AUDIT). Alcohol dependence diagnosis was established by International Classification of Diseases-10 (ICD-10). We also performed gender analyses for associations of personality traits with alcohol dependence and hazardous use of alcohol. Results: The SURPS scale demonstrated appropriate internal validity, good temporal stability, and adequate criterion validity and construct validity. The SURPS scores of hopelessness, anxiety sensitivity and impulsivity were higher in the alcohol dependence group than in the control group for both males and females. Impulsivity and sensation seeking were associated with hazardous alcohol use and these associations were more prevalent in females. Conclusions: Lithuanian translation of the SURPS scale was appropriate. The SURPS demonstrated good sensitivity for discriminating on alcohol dependence and was more sensitive for discriminating on hazardous alcohol use for females.

Background and objective: Nitric oxide (NO) is known to exert cardioprotective effects against heart ischemic damage and may be involved in ischemic pre- and postconditioning. NO-triggered cardioprotective mechanisms are not well understood but may involve regulation of mitochondrial permeability transition pore (mPTP). In this study, we aimed to identify differentially phosphorylated mitochondrial proteins possibly involved in the NO/protein kinase G (PKG)/mPTP signaling pathway that can increase the resistance of cardiomyocytes to ischemic damage. Materials and methods: Isolated hearts from Wistar rats were perfused with NO donor NOC-18 prior to induction of stop–flow ischemia. To quantify and characterize the phosphoproteins, mitochondrial proteins were resolved and analyzed by two-dimensional gel electrophoresis followed by Pro-Q Diamond phosphoprotein gel staining, excision, trypsin digestions, and mass spectrometry. Quantitative proteomic analysis coupled with liquid chromatography–tandem mass spectrometry was also performed. Results: Mitochondrial protein phosphorylation patterns in NOC-18-pretreated ischemic hearts versus ischemic hearts were compared. Pretreatment of hearts with NOC-18 caused changes in mitochondrial phosphoproteome after ischemia which involved modifications of 10 mitochondrial membrane-bound and 10 matrix proteins. Among them, α-subunit of ATP synthase and adenine nucleotide (ADP/ATP) translocase 1, both of which are considered as potential structural components of mPTP, were identified. We also found that treatment of isolated non-ischemic mitochondria with recombinant PKG did not cause the same protein phosphorylation as pretreatment of hearts with NOC-18. Conclusions: Our study suggests that pretreatment of hearts with NOC-18 causes changes in mitochondrial phosphoproteome after ischemia which involves modifications of certain proteins thought to be involved in the regulation of mPTP opening and intracellular redox state. These proteins may be potential targets for pharmacological preconditioning of the heart.