A realist synthesis of the evidence on outreach programmes for health improvement of Traveller Communities.

Background: Improving the health of Traveller Communities is an international public health concern but there is little evidence on effective interventions. This study aimed to explain how, for whom and in what circumstances outreach works in Traveller Communities.

Methods: A realist synthesis was undertaken.

Intragenic deletions of ALDH7A1 in pyridoxine-dependent epilepsy caused by Alu-Alu recombination.

Objective: To investigate the role of intragenic deletions of ALDH7A1 in patients with clinical and biochemical evidence of pyridoxine-dependent epilepsy but only a single identifiable mutation in ALDH7A1.

Methods: We designed a custom oligonucleotide array with high-density probe coverage across the ALDH7A1 gene. We performed array comparative genomic hybridization in 6 patients with clinical and biochemical evidence of pyridoxine-dependent epilepsy but only a single detectable mutation in ALDH7A1 by sequence analysis.

Androgens Attenuate Vitamin D Production Induced by UVB Irradiation of the Skin of Male Mice by an Enzymatic Mechanism.

Cutaneous exposure to UVB irradiation is an important source of vitamin D. Here, we examined sex-specific differences in cutaneous vitamin D production in mice. Both male and female mice on a vitamin D-deficient diet manifested vitamin D deficiency, with mineral abnormalities, secondary hyperparathyroidism, and osteomalacia.

A Molecular Dynamics Study of Allosteric Transitions in Leishmania mexicana Pyruvate Kinase.

A comparative molecular dynamics analysis of the pyruvate kinase from Leishmania mexicana is presented in the absence and presence of the allosteric effector fructose 2,6-bisphosphate. Comparisons of the simulations of the large 240 kDa apo and holo tetramers show that binding of fructose 2,6-bisphosphate cools the enzyme and reduces dynamic movement, particularly of the B-domain. The reduced dynamic movement of the holo form traps the pyruvate kinase tetramer in its enzymatically active state with the B-domain acting as a lid to cover the active site.

Distinct miRNA expression in dorsal striatal subregions is associated with risk for addiction in rats.

Recently, we published data using an animal model that allowed us to characterize animals into two groups, addiction vulnerable and addiction resilient, where we identified that addiction/relapse vulnerability was associated with deficits in synaptic plasticity-associated gene expression in the dorsal striatum (DS). Notable was the strong reduction in expression for activity-regulated cytoskeleton-associated protein (Arc) considered a master regulator of synaptic plasticity. In the present study, we confirmed that Arc messenger RNA was significantly decreased in the DS, but importantly, we identified that this reduction was restricted to the dorsomedial (DMS) and not dorsolateral striatum (DLS).

A qualitative investigation of the barriers to help-seeking among members of the public presented with symptoms of new-onset rheumatoid arthritis.

Objective: Treating patients with rheumatoid arthritis (RA) within 3 months of symptom onset leads to significantly improved clinical outcomes. However, many people with RA symptoms wait a long time before seeking medical attention. To develop effective health interventions to encourage people to seek help early, it is important to understand what the general public knows about RA, how they would react to the symptoms of RA, and what might delay help-seeking.

BDNF and the maturation of posttranscriptional regulatory networks in human SH-SY5Y neuroblast differentiation.

The SH-SY5Y culture system is a convenient neuronal model with the potential to elaborate human/primate-specific transcription networks and pathways related to human cognitive disorders. While this system allows for the exploration of specialized features in the human genome, there is still significant debate about how this model should be implemented, and its appropriateness for answering complex functional questions related to human neural architecture. In view of these questions we sought to characterize the posttranscriptional regulatory structure of the two-stage ATRA differentiation, BDNF maturation protocol proposed by Encinas et al.

Electrophysiological characteristics of paraventricular thalamic (PVT) neurons in response to cocaine and cocaine- and amphetamine-regulated transcript (CART).

Recent work has established that the paraventricular thalamus (PVT) is a central node in the brain reward-seeking pathway. This role is mediated in part through projections from hypothalamic peptide transmitter systems such as cocaine- and amphetamine-regulated transcript (CART). Consistent with this proposition, we previously found that inactivation of the PVT or infusions of CART into the PVT suppressed drug-seeking behavior in an animal model of contingent cocaine self-administration.

Alteration of imprinted Dlk1-Dio3 miRNA cluster expression in the entorhinal cortex induced by maternal immune activation and adolescent cannabinoid exposure.

A significant feature of the cortical neuropathology of schizophrenia is a disturbance in the biogenesis of short non-coding microRNA (miRNA) that regulate translation and stability of mRNA. While the biological origin of this phenomenon has not been defined, it is plausible that it relates to major environmental risk factors associated with the disorder such as exposure to maternal immune activation (MIA) and adolescent cannabis use. To explore this hypothesis, we administered the viral mimic poly I:C to pregnant rats and further exposed some of their maturing offsprings to daily injections of the synthetic cannabinoid HU210 for 14 days starting on postnatal day 35.

FOXO1 repression contributes to block of plasma cell differentiation in classical Hodgkin lymphoma.

The survival of classical Hodgkin lymphoma (cHL) cells depends on activation of NF-κB, JAK/STAT, and IRF4. Whereas these factors typically induce the master regulator of plasma cell (PC) differentiation PRDM1/BLIMP-1, levels of PRDM1 remain low in cHL. FOXO1, playing a critical role in normal B-cell development, acts as a tumor suppressor in cHL, but has never been associated with induction of PC differentiation.

Orexin antagonists for neuropsychiatric disease: progress and potential pitfalls.

The tight regulation of sleep/wake states is critical for mental and physiological wellbeing. For example, dysregulation of sleep/wake systems predisposes individuals to metabolic disorders such as obesity and psychiatric problems, including depression. Contributing to this understanding, the last decade has seen significant advances in our appreciation of the complex interactions between brain systems that control the transition between sleep and wake states.

mTORC1 inhibition in the nucleus accumbens 'protects' against the expression of drug seeking and 'relapse' and is associated with reductions in GluA1 AMPAR and CAMKIIα levels.

The mechanistic target of rapamycin complex 1 (mTORC1) is necessary for synaptic plasticity, as it is critically involved in the translation of synaptic transmission-related proteins, such as Ca(2+)/Calmodulin-dependent kinase II alpha (CAMKIIα) and AMPA receptor subunits (GluAs). Although recent studies have implicated mTORC1 signaling in drug-motivated behavior, the ineffectiveness of rapamycin, an mTORC1 inhibitor, in suppressing cocaine self-administration has raised questions regarding the specific role of mTORC1 in drug-related behaviors. Here, we examined mTORC1's role in three drug-related behaviors: cocaine taking, withdrawal, and reinstatement of cocaine seeking, by measuring indices of mTORC1 activity and assessing the effect of intra-cerebroventricular rapamycin on these behaviors in rats.

Under-reporting of socioeconomic status of patients in stroke trials: adherence to CONSORT principles.

Background And Purpose: The 2001 Revised Consolidated Standards of Reporting of Trials (CONSORT) statement requires reporting of Randomized Controlled Trials (RCTs) to include participants' baseline demographics. This enables comparison of intervention and control groups on potential confounding variables as well as assessment of study generalizability. Socioeconomic status (SES) is associated with access to care and outcomes (mortality, functional outcome, recurrent stroke, and hospital readmission) poststroke.

The resolution of inflammation.

In 2012, Nature Reviews Immunology organized a conference that brought together scientists and clinicians from both academia and industry to discuss one of the most pressing questions in medicine--how do we turn off rampant, undesirable inflammation? There is a growing appreciation that, similarly to the initiation of inflammation, the resolution of inflammation is an intricate and active process. Can we therefore harness the mediators involved in resolution responses to treat patients with chronic inflammatory or autoimmune diseases? Here, we ask five of the speakers from the conference to share their thoughts on this emerging field.

Cocaine potentiates excitatory drive in the perifornical/lateral hypothalamus.

The hypothalamus is a critical controller of homeostatic responses and plays a fundamental role in reward-seeking behaviour. Recently, hypothalamic neurones in the perifornical/lateral hypothalamic area (PF/LHA) have also been implicated in drug-seeking behaviour through projections to extra-hypothalamic sites such as the ventral tegmental area. For example, a population of neurones that expresses the peptide orexin has been strongly implicated in addiction-relevant behaviours.

Targeting FKBP isoforms with small-molecule ligands.

The FK506 binding protein (FKBP) family of proteins provide an interesting series of drug targets since different isoforms modulate diverse cellular pathways. There are therapeutic opportunities in the fields of cancer therapy, neurodegenerative conditions and psychiatric disorders. X-ray crystallographic or NMR data are available for eight of fourteen human FKBPs covering ten of the twenty-two different FKBP domains.

MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers.

Chromosomal translocations are critically involved in the molecular pathogenesis of B-cell lymphomas, and highly recurrent and specific rearrangements have defined distinct molecular subtypes linked to unique clinicopathological features. In contrast, several well-characterized lymphoma entities still lack disease-defining translocation events. To identify novel fusion transcripts resulting from translocations, we investigated two Hodgkin lymphoma cell lines by whole-transcriptome paired-end sequencing (RNA-seq).

Estimating the affinity of protein-ligand complex from changes to the charge-state distribution of a protein in electrospray ionization mass spectrometry.

The detection of low affinity interactions between proteins and ligands by biophysical methods is challenging. It is often necessary to use competition methods that are time consuming and require well characterized known binders. A mass spectrometry approach is presented for identifying low affinity protein-ligand binding which does not require direct detection of the parent protein-ligand complex but depends on characteristic changes observed in the protein mass spectrum.

EDULISS: a small-molecule database with data-mining and pharmacophore searching capabilities.

We present the relational database EDULISS (EDinburgh University Ligand Selection System), which stores structural, physicochemical and pharmacophoric properties of small molecules. The database comprises a collection of over 4 million commercially available compounds from 28 different suppliers. A user-friendly web-based interface for EDULISS (available at http://eduliss.

Ligand discovery and virtual screening using the program LIDAEUS.

This paper discusses advances in docking and scoring approaches with examples from the high-throughput virtual screening program LIDAEUS. We describe the discovery of small molecule inhibitors for the immunophilin CypA, the cyclin-dependent kinase CDK2 and the cyclapolin series of potent Polo-like kinase inhibitors. These results are discussed in the context of advances in massively parallel computing and in the development of annotated databases.

Structure-based discovery of a family of synthetic cyclophilin inhibitors showing a cyclosporin-A phenotype in Caenorhabditis elegans.

Cyclophilins, which are found in all cellular compartments and with diverse biological roles, are now drug targets for a number of diseases including HIV infection, malaria and ischaemia. We used the database-mining program LIDAEUS and in silico screening to discover the dimedone family of inhibitors which show a conserved 'ball and socket' binding mode with a dimethyl group in the hydrophobic binding pocket of human cyclophilin A (CypA) mimicking a key interaction of the natural inhibitor cyclosporin A (CsA). The most potent derivative binds CypA with a K(d) of 11.