G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage.

Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials.

A need for multi-sector and multi-pronged solutions to address the many barriers inhibiting change from unhealthy food environments in publicly funded recreation facilities: a mixed-method study.

Public recreation facilities are preferred gathering places for families to participate in physical, social, intellectual, and creative pursuits, and the importance of food environments in these facilities is gaining recognition. Evidence from other Canadian jurisdictions describes such food environments as unsupportive of health, which contradicts national recreation priorities to have healthy choices as the easy choices. This study aimed to characterize food environments in a convenient sample of Saskatchewan public recreation facilities.

Clinical validation of a novel bioluminescence imaging technology for aiding the assessment of carious lesion activity status.

Objectives: Clinical validation of a bioluminescence imaging system (Cis) as measured by the level of agreement between clinician visual and tactile assessment of carious lesion presence and activity and the presence/absence of elevated luminescence on a tooth surface determined from intraoral image mapping.

Materials And Methods: This was a regulatory clinical study designed in consultation with the FDA. The design was a prospective, five-investigator, nonrandomized, post-approval, clinical study utilizing the Cis to provide images of elevated calcium ion concentration (indicative of active demineralization) on tooth surfaces via use of a photoprotein.

Amyloid Accumulation Drives Proteome-wide Alterations in Mouse Models of Alzheimer's Disease-like Pathology.

Amyloid beta (Aβ) peptides impair multiple cellular pathways and play a causative role in Alzheimer's disease (AD) pathology, but how the brain proteome is remodeled by this process is unknown. To identify protein networks associated with AD-like pathology, we performed global quantitative proteomic analysis in three mouse models at young and old ages. Our analysis revealed a robust increase in Apolipoprotein E (ApoE) levels in nearly all brain regions with increased Aβ levels.

Structural basis for integration of GluD receptors within synaptic organizer complexes.

Ionotropic glutamate receptor (iGluR) family members are integrated into supramolecular complexes that modulate their location and function at excitatory synapses. However, a lack of structural information beyond isolated receptors or fragments thereof currently limits the mechanistic understanding of physiological iGluR signaling. Here, we report structural and functional analyses of the prototypical molecular bridge linking postsynaptic iGluR δ2 (GluD2) and presynaptic β-neurexin 1 (β-NRX1) via Cbln1, a C1q-like synaptic organizer.

Molecular dissection of the interaction between the AMPA receptor and cornichon homolog-3.

Cornichon homologs (CNIHs) are AMPA-type glutamate receptor (AMPAR) auxiliary subunits that modulate AMPAR ion channel function and trafficking. Mechanisms underlying this interaction and functional modulation of the receptor complex are currently unclear. Here, using proteins expressed from mouse and rat cDNA, we show that CNIH-3 forms a stable complex with tetrameric AMPARs and contributes to the transmembrane density in single-particle electron microscopy structures.

Differences in AMPA and kainate receptor interactomes facilitate identification of AMPA receptor auxiliary subunit GSG1L.

AMPA receptor (AMPA-R) complexes consist of channel-forming subunits, GluA1-4, and auxiliary proteins, including TARPs, CNIHs, synDIG1, and CKAMP44, which can modulate AMPA-R function in specific ways. The combinatorial effects of four GluA subunits binding to various auxiliary subunits amplify the functional diversity of AMPA-Rs. The significance and magnitude of molecular diversity, however, remain elusive.

Complex systems, evolution, and animal models.

In this paper, we respond to arguments made concerning our position regarding animal models (Shelley, 2010) by briefly examining the fact that animals (human and nonhuman) are complex systems that have different evolutionary trajectories. This historical fact has implications for using animals as predictive models for human response to drugs and disease.

The impact of air pollution on hospital admission for respiratory and cardiovascular diseases in an oil and gas-rich country.

Objectives: Aim of this study was to evaluate the impact of air pollution on hospital admissions for respiratory and cardiovascular diseases in an oil rich developing country, State of Qatar.

Methods: A prospective cohort population based study was conducted at different stations of Qatar during the period (2002-2005) for recording the concentration of air pollutants daily for sulphur dioxide (SO2), nitric oxide (NO), nitrogen dioxide (NO2), carbon monoxide (CO), ozone (O3) and particulate matter (PM10). Hospital admission data were collected from the inpatient discharge database of the Medical Records Department, Hamad General Hospital.

Contribution of the global subunit structure and stargazin on the maturation of AMPA receptors.

Subunit assembly governs regulation of AMPA receptor (AMPA-R) synaptic delivery and determines biophysical parameters of the ion channel. However, little is known about the molecular pathways of this process. Here, we present single-particle EM three-dimensional structures of dimeric biosynthetic intermediates of the GluA2 subunit of AMPA-Rs.

The impact of air pollution on hospital admission for respiratory and cardiovascular diseases in an oil-rich country.

Objectives: Aim of this study was to evaluate the impact of air pollution on hospital admissions for respiratory and cardiovascular diseases in an oil rich developing country, State of Qatar.

Methods: A prospective cohort population based study was conducted at different stations of Qatar during the period (2002-2005) for recording the concentration of air pollutants daily for sulphur dioxide (SO2), nitric oxide (NO), nitrogen dioxide (NO2), carbon monoxide (CO), ozone (O3) and particulate matter (PM10). Hospital admission data were collected from the inpatient discharge database of the Medical Records Department, Hamad General Hospital.

Are animal models predictive for humans?

It is one of the central aims of the philosophy of science to elucidate the meanings of scientific terms and also to think critically about their application. The focus of this essay is the scientific term predict and whether there is credible evidence that animal models, especially in toxicology and pathophysiology, can be used to predict human outcomes. Whether animals can be used to predict human response to drugs and other chemicals is apparently a contentious issue.

Fluoxetine inhibits corticotropin-releasing factor (CRF)-induced behavioural responses in rats.

Corticotropin-releasing factor (CRF) is a potent neuromodulator of stress-related behaviour but the neural mechanisms underlying these effects are not clear. Studies were designed to test the hypothesis that CRF-induced behavioural arousal involves interactions with brainstem serotonergic systems. To examine interactions between CRF and serotonergic systems in the regulation of behaviour, CRF (1 microg, intracerebroventricular (i.

Relationship of early childhood illness with adult cortisol in the Barry Caerphilly Growth (BCG) cohort.

Background: The developmental origins hypothesis suggests that pre- and postnatal exposures may influence vulnerability to later disease. The hypothalamic-pituitary-adrenal (HPA) axis is one pathway by which this may occur. Analyses were conducted in the Barry Caerphilly Growth (BCG) cohort to explore whether the postnatal exposure of childhood infections was related to HPA axis activity in adulthood.

Impact of asthma and air pollution on school attendance of primary school children: are they at increased risk of school absenteeism?

Aim: The aim of this study was to determine the impact of asthma and air pollution on school attendance of primary school children 6 to 12 years of age in Qatar.

Study Design: This was a cross-sectional population-based study.

Subjects: The total 31,400 Qatari school children at the primary school (16,130 boys and 15,270 girls) 6 to 12 of age were studied to investigate school absenteeism caused by asthma and wheezing during the academic year October 2003 to July 2004.

Evolution and medicine: the long reach of "Dr. Darwin".

In this review we consider the new science of Darwinian medicine. While it has often been said that evolutionary theory is the glue that holds the disparate branches of biological inquiry together and gives them direction and purpose, the links to biomedical inquiry have only recently been articulated in a coherent manner. Our aim in this review is to make clear first of all, how evolutionary theory is relevant to medicine; and secondly, how the biomedical sciences have enriched our understanding of evolutionary processes.

Oxytocin attenuates stress-induced c-fos mRNA expression in specific forebrain regions associated with modulation of hypothalamo-pituitary-adrenal activity.

We reported previously that the neuropeptide oxytocin attenuates stress-induced hypothalamo-pituitary-adrenal (HPA) activity and anxiety behavior. This study sought to identify forebrain target sites through which oxytocin may mediate its anti-stress effects. Ovariectomized, estradiol-treated rats received intracerebroventricular infusions of oxytocin (1 or 10 ng/hr) or vasopressin (10 ng/hr), and the patterns of neuronal activation after restraint stress were determined by semiquantitative mapping of c-fos mRNA expression.

Chronic stress accelerates atherosclerosis in the apolipoprotein E deficient mouse.

Conventional cardiovascular risk factors such as cholesterol and blood pressure do not account fully for variation in coronary heart disease suggesting the involvement of additional mechanisms. We have examined the effects of a chronic psychological stress protocol on the development of atherosclerosis in the apolipoprotein E knockout mouse. We observed a 3-fold increase in staining for atheroma accompanied by a 10-fold increase in corticosterone concentrations in mice stressed for 12 weeks.

Enhancement of antibody responses to influenza vaccination in the elderly following a cognitive-behavioural stress management intervention.

Background: Previous research has demonstrated that the psychological morbidity experienced by informal caregivers is associated with increased vulnerability to infectious diseases, in particular influenza. A pragmatic trial was conducted to examine whether a stress management intervention (SMI) could reduce psychological morbidity and enhance the antibody response to influenza vaccination in the elderly, and whether changes in immune response of SMI participants were associated with hypothalamic-pituitary-adrenal (HPA) axis activity.

Methods: Forty-three elderly spousal carers of dementia patients and 27 non-carer controls were recruited.

Anatomical and functional evidence for a stress-responsive, monoamine-accumulating area in the dorsomedial hypothalamus of adult rat brain.

The dorsomedial hypothalamus (DMH) plays an important role in relaying information to neural pathways mediating neuroendocrine, autonomic, and behavioral responses to stress. Evidence suggests that the DMH is a structurally and functionally diverse integrative structure that contributes to both facilitation and inhibition of the hypothalamo-pituitary-adrenal axis, depending on the nature of the stimulus and the specific neural circuits involved. Previous studies have determined that stress or stress-related stimuli elevate tissue concentrations of serotonin (5-hydroxytryptamine; 5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine, and noradrenaline selectively within the DMH.

Dexamethasone-induced effects on lymphocyte distribution and expression of adhesion molecules in treatment-resistant depression.

Alterations in immune function are associated with major depression and have been related to changes in endocrine function. We investigated whether alterations in immune function were associated with altered basal hypothalamic-pituitary-adrenal (HPA) function (salivary cortisol) and lymphocyte sensitivity to dexamethasone (DEX) intake (1 mg PO). The latter was explored by comparing the impact of DEX-induced changes on peripheral lymphocyte redistribution and expression of adhesion molecules (beta2 integrins and L-selectin).

Early life environment: does it have implications for predisposition to disease?

Early life environmental factors have been associated with altered predisposition to a variety of pathologies. A considerable literature examines pre- and postnatal factors associated with increased risk of cardiovascular, metabolic (i.e.

Altered glucocorticoid immunoregulation in treatment resistant depression.

Alterations in cellular immune function are associated with depression and have been related to changes in endocrine function. We carried out a study to: (i) reliably assess the hypothalamic-pituitary-adrenal (HPA) axis function in treatment resistant depression (TRP); (ii) evaluate whether depression was associated with changes on T-cell proliferation and cytokine production; and (iii) assessed the sensitivity of lymphocytes to glucocorticoids (GC)s in vitro. Thirty-six pharmacologically treated inpatients diagnosed with TRP and 31 healthy controls took part in the study.