PDE4B Missense Variant Increases Susceptibility to Post-traumatic Stress Disorder-Relevant Phenotypes in Mice.

Large-scale genome-wide association studies (GWASs) have associated intronic variants in , encoding cAMP-specific phosphodiesterase-4B (PDE4B), with increased risk for post-traumatic stress disorder (PTSD), as well as schizophrenia and substance use disorders that are often comorbid with it. However, the pathophysiological mechanisms of genetic risk involving PDE4B are poorly understood. To examine the effects of PDE4B variation on phenotypes with translational relevance to psychiatric disorders, we focused on PDE4B missense variant M220T, which is present in the human genome as rare coding variant rs775201287.

Beta-amyloid interacts with and activates the long-form phosphodiesterase PDE4D5 in neuronal cells to reduce cAMP availability.

Inhibition of the cyclic-AMP degrading enzyme phosphodiesterase type 4 (PDE4) in the brains of animal models is protective in Alzheimer's disease (AD). We show for the first time that enzymes from the subfamily PDE4D not only colocalize with beta-amyloid (Aβ) plaques in a mouse model of AD but that Aβ directly associates with the catalytic machinery of the enzyme. Peptide mapping suggests that PDE4D is the preferential PDE4 subfamily for Aβ as it possesses a unique binding site.

ATOMDANCE: Kernel-based denoising and choreographic analysis for protein dynamic comparison.

Comparative methods in molecular evolution and structural biology rely heavily upon the site-wise analysis of DNA sequence and protein structure, both static forms of information. However, it is widely accepted that protein function results from nanoscale nonrandom machine-like motions induced by evolutionarily conserved molecular interactions. Comparisons of molecular dynamics (MD) simulations conducted between homologous sites representative of different functional or mutational states can potentially identify local effects on binding interaction and protein evolution.

Nucleus accumbens dopamine release reflects the selective nature of pair bonds.

In monogamous species, prosocial behaviors directed toward partners are dramatically different from those directed toward unknown individuals and potential threats. Dopamine release in the nucleus accumbens has a well-established role in social reward and motivation, but how this mechanism may be engaged to drive the highly divergent social behaviors directed at a partner or unfamiliar conspecific remains unknown. Using monogamous prairie voles, we first employed receptor pharmacology in partner preference and social operant tasks to show that dopamine is critical for the appetitive drive for social interaction but not for low-effort, unconditioned consummatory behaviors.

Case Report: Shewanella Algae Pneumonia and Bacteremia in an Elderly Male Living at a Long-Term Care Facility.

Shewanella algae is a gram-negative, nonfermenting, oxidase-positive, motile bacillus that is ubiquitous in aquatic ecosystems. Human infections are rare and the immunocompromised are left most vulnerable. Risk factors for this infection include exposure to seawater, consumption of raw seafood, and underlying comorbid conditions such as hepatobiliary disease and chronic cutaneous ulcers.

A neuronal signature for monogamous reunion.

Pair-bond formation depends vitally on neuromodulatory signaling within the nucleus accumbens, but the neuronal dynamics underlying this behavior remain unclear. Using 1-photon in vivo Ca imaging in monogamous prairie voles, we found that pair bonding does not elicit differences in overall nucleus accumbens Ca activity. Instead, we identified distinct ensembles of neurons in this region that are recruited during approach to either a partner or a novel vole.

Antioxidant and pro-oxidant mechanisms of (+) catechin in microsomal CYP2E1-dependent oxidative stress.

The objectives of this work were to evaluate the effects of catechin on cytochrome P450 2E1 (CYP2E1)-dependent oxidative stress. Microsomes co-expressing human CYP2E1 with NADPH cytochrome P450 reductase and cytochrome b5 were incubated with NADPH and DTPA at pH 7.0.

Increase in Ca current by sustained cAMP levels enhances proliferation rate in GH3 cells.

Aims: Ca and cAMP are important intracellular modulators. In order to generate intracellular signals with various amplitudes, as well as different temporal and spatial properties, a tightly and precise control of these modulators in intracellular compartments is necessary. The aim of this study was to evaluate the effects of elevated and sustained cAMP levels on voltage-dependent Ca currents and proliferation in pituitary tumor GH3 cells.

Selective inhibition of phosphodiesterases 4, 5 and 9 induces HSP20 phosphorylation and attenuates amyloid beta 1-42-mediated cytotoxicity.

Phosphodiesterase (PDE) inhibitors are currently under evaluation as agents that may facilitate the improvement of cognitive impairment associated with Alzheimer's disease. Our aim was to determine whether inhibitors of PDEs 4, 5 and 9 could alleviate the cytotoxic effects of amyloid beta 1-42 (Aβ) via a mechanism involving the small heatshock protein HSP20. We show that inhibition of PDEs 4, 5 and 9 but not 3 induces the phosphorylation of HSP20 which, in turn, increases the colocalisation between the chaperone and Aβ to significantly decrease the toxic effect of the peptide.

The role and therapeutic targeting of α-, β- and γ-secretase in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia in the elderly and its prevalence is set to increase rapidly in coming decades. However, there are as yet no available drugs that can halt or even stabilize disease progression. One of the main pathological features of AD is the presence in the brain of senile plaques mainly composed of aggregated β amyloid (Aβ), a derivative of the longer amyloid precursor protein (APP).

Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling.

Atherosclerosis is primarily a disease of lipid metabolism and inflammation; however, it is also closely associated with endothelial extracellular matrix (ECM) remodelling, with fibronectin accumulating in the laminin-collagen basement membrane. To investigate how fibronectin modulates inflammation in arteries, we replaced the cytoplasmic tail of the fibronectin receptor integrin α5 with that of the collagen/laminin receptor integrin α2. This chimaera suppressed inflammatory signalling in endothelial cells on fibronectin and in knock-in mice.

The Impact of Acculturation Level on Weight Status and Weight Outcomes in Hispanic Children.

Background: Previous studies revealed that higher levels of acculturation are related to obesity in Hispanic adults. Conflicting findings exist regarding this relationship in children, and little is known about the impact of acculturation on children's success in pediatric weight management programs. The purposes of the study were to (1) examine the relationship between acculturation and overweight/obese weight status and (2) determine the impact of acculturation on the changes in weight status among overweight/obese children 12 and 24 months after having participated in a weight management intervention.

Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition.

Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippocampal formation, is a major Disrupted in Schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness.

Phosphorylation of ezrin on Thr567 is required for the synergistic activation of cell spreading by EPAC1 and protein kinase A in HEK293T cells.

Recent studies have demonstrated that the actin binding protein, ezrin, and the cAMP-sensor, EPAC1, cooperate to induce cell spreading in response to elevations in intracellular cAMP. To investigate the mechanisms underlying these effects we generated a model of EPAC1-dependent cell spreading based on the stable transfection of EPAC1 into HEK293T (HEK293T-EPAC1) cells. We found that direct activation of EPAC1 with the EPAC-selective analogue, 8-pCPT-2'-O-Me-cAMP (007), promoted cell spreading in these cells.

The phosphorylation of Hsp20 enhances its association with amyloid-β to increase protection against neuronal cell death.

Up-regulation of Hsp20 protein levels in response to amyloid fibril formation is considered a key protective response against the onset of Alzheimer's disease (AD). Indeed, the physical interaction between Hsp20 and Aβ is known to prevent Aβ oligomerisation and protects neuronal cells from Aβ mediated toxicity, however, details of the molecular mechanism and regulatory cell signalling events behind this process have remained elusive. Using both conventional MTT end-point assays and novel real time measurement of cell impedance, we show that Hsp20 protects human neuroblastoma SH-SY5Y cells from the neurotoxic effects of Aβ.

Arrestin regulation of small GTPases.

The regulation of small GTPases by arrestins is a relatively new way by which arrestin can exert influence over cell signalling cascades, hence, molecular interactions and specific binding partners are still being discovered. A pathway showcasing the regulation of GTPase activity by β-arrestin was first elucidated in 2001. Since this original study, growing evidence has emerged for arrestin modulation of GTPase activity through direct interactions and also via the scaffolding of GTPase regulatory proteins.

Real-time probing of β-amyloid self-assembly and inhibition using fluorescence self-quenching between neighbouring dyes.

The fluorescence response of the Thioflavin-T (ThT) dye and derivatives has become the standard tool for detecting β-amyloid aggregates (Aβ) in solution. However, it is accepted that ThT-based methods suffer from important drawbacks. Some of these are due to the cationic structure of ThT, which limits its application at slightly acidic conditions; whereas some limitations are related to the general use of an extrinsic-dye sensing strategy and its intrinsic requirement for the formation of a sensor-binding site during the aggregation process.

Chemical informatics uncovers a new role for moexipril as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4).

PDE4 is one of eleven known cyclic nucleotide phosphodiesterase families and plays a pivotal role in mediating hydrolytic degradation of the important cyclic nucleotide second messenger, cyclic 3'5' adenosine monophosphate (cAMP). PDE4 inhibitors are known to have anti-inflammatory properties, but their use in the clinic has been hampered by mechanism-associated side effects that limit maximally tolerated doses. In an attempt to initiate the development of better-tolerated PDE4 inhibitors we have surveyed existing approved drugs for PDE4-inhibitory activity.

The technology behind Colgate Simply White Toothpaste.

Colgate Simply White Toothpaste is a new advanced tooth whitening dentifrice that can be used every day. The synergy of abrasive stain removal with activated hydrogen peroxide delivers excellent performance in the removal of extrinsic and intrinsic tooth stain. Colgate Simply White Toothpaste provides other oral health benefits that have become the cost-of-entry into the toothpaste market: caries protection, tartar control, fresh breath, and a preferred flavor.