Pharmacological activation of the nuclear receptor REV-ERB reverses cognitive deficits and reduces amyloid-β burden in a mouse model of Alzheimer’s disease

Alzheimer’s disease currently lacks treatment options that effectively reverse the biological/anatomical pathology and cognitive deficits associated with the disease. Loss of function of the nuclear receptor REV-ERB is associated with reduced cognitive function in mouse models. The effect of enhanced REV-ERB activity on cognitive function has not been examined. In this study, we tested the hypothesis that enhanced REV-ERB function may enhance cognitive function in a model of Alzheimer’s disease. We utilized the REV-ERB agonist SR9009 to pharmacologically activate the activity of REV-ERB in the SAMP8 mouse model of Alzheimer’s disease. SR9009 reversed cognitive dysfunction of an aged SAMP8 mouse in several behavioral assays including novel object recognition, T-maze foot shock avoidance, and lever press operant conditioning task assessments. SR9009 treatment reduced amyloid-β 1–40 and 1–42 levels in the cortex, which is consistent with improved cognitive function. Furthermore, SR9009 treatment led to increased hippocampal PSD-95, cortical synaptophysin expression and the number of synapses suggesting improvement in synaptic function. We conclude that REV-ERB is a potential target for treatment of Alzheimer’s disease.</div

The S. pombe translation initiation factor eIF4G is sumoylated and associates with the SUMO protease Ulp2

SUMO is a small post-translational modifier, that is attached to lysine residues in target proteins. It acts by altering proteinprotein interactions, protein localisation and protein activity. SUMO chains can also act as substrates for ubiquitination, resulting in proteasome-mediated degradation of the target protein. SUMO is removed from target proteins by one of a number of specific proteases. The processes of sumoylation and desumoylation have well documented roles in DNA metabolism and in the maintenance of chromatin structure. To further analyse the role of this modification, we have purified protein complexes containing the S. pombe SUMO protease, Ulp2. These complexes contain proteins required for ribosome biogenesis, RNA stability and protein synthesis. Here we have focussed on two translation initiation factors that we identified as co-purifying with Ulp2, eIF4G and eIF3h. We demonstrate that eIF4G, but not eIF3h, is sumoylated. This modification is increased under conditions that produce cytoplasmic stress granules. Consistent with this we observe partial co-localisation of eIF4G and SUMO in stressed cells. Using HeLa cells, we demonstrate that human eIF4GI is also sumoylated; in vitro studies indicate that human eIF4GI is modified on K1368 and K1588, that are located in the C-terminal eIF4A- and Mnk-binding sites respectively

Hemodynamic effects of partial ventricular support in chronic heart failure: Results of simulation validated with in vivo data

ObjectiveCurrent left ventricular assist devices are designed to provide full hemodynamic support for patients with end-stage failing hearts, but their use has been limited by operative risks, low reliability, and device-related morbidity. Such concerns have resulted in minimum use of left ventricular assist devices for destination therapy. We hypothesize that partial circulatory support, which could be achieved with small pumps implanted with less-invasive procedures, might expand the role of circulatory support devices for treatment of heart failure.MethodsWe examine the hemodynamic effects of partial left ventricular support using a previously described computational model of the cardiovascular system. Results from simulations were validated by comparison with an in vivo hemodynamic study.ResultsSimulations demonstrated that partial support (2-3 L/min) increased total cardiac output (left ventricular assist device output plus native heart output) by more than 1 L/min and decreased left ventricular end-diastolic pressure by 7 to 10 mm Hg with moderate-to-severe heart failure. Analyses showed that the hemodynamic benefits of increased cardiac output and decreased left ventricular end-diastolic pressure are greater in less-dilated and less-dysfunctional hearts. Both the relationships between ventricular assist device flow and cardiac output and ventricular assist device flow and left atrial pressure predicted by the model closely approximated the same relationships obtained during hemodynamic study in a bovine heart failure model.ConclusionsResults suggest that a pump with a flow rate of 2 to 3 L/min could meaningfully affect cardiac output and blood pressure in patients with advanced compensated heart failure. The development of small devices capable of high reliability and minimal complications that can be implanted with less-invasive techniques is supported by these findings

Statistical independence of the colocalized association signals for type 1 diabetes and RPS26 gene expression on chromosome 12q13

Following the recent success of genome-wide association studies in uncovering disease-associated genetic variants, the next challenge is to understand how these variants affect downstream pathways. The most proximal trait to a disease-associated variant, most commonly a single nucleotide polymorphism (SNP), is differential gene expression due to the cis effect of SNP alleles on transcription, translation, and/or splicing gene expression quantitative trait loci (eQTL). Several genome-wide SNP–gene expression association studies have already provided convincing evidence of widespread association of eQTLs. As a consequence, some eQTL associations are found in the same genomic region as a disease variant, either as a coincidence or a causal relationship. Cis-regulation of RPS26 gene expression and a type 1 diabetes (T1D) susceptibility locus have been colocalized to the 12q13 genomic region. A recent study has also suggested RPS26 as the most likely susceptibility gene for T1D in this genomic region. However, it is still not clear whether this colocalization is the result of chance alone or if RPS26 expression is directly correlated with T1D susceptibility, and therefore, potentially causal. Here, we derive and apply a statistical test of this hypothesis. We conclude that RPS26 expression is unlikely to be the molecular trait responsible for T1D susceptibility at this locus, at least not in a direct, linear connection

Bioelectrical impedance vector analysis, phase-angle assessment and relationship with malnutrition risk in a cohort of frail older hospital patients in the United Kingdom

AbstractObjective Bioelectrical impedance vector analysis (BIVA) and phase angle (PA) have been shown previously to indicate relative nutritional status in patients. The aim of this study was to investigate the application of {BIVA} and {PA} assessments in a cohort of frail older hospital patients and compare these assessments with malnutrition risk screening by {MUST} (Malnutrition Universal Screening Tool), and the MNA-SF® (Mini-Nutritional Assessment-Short Form). Methods Sixty-nine patients (n = 44 men; n = 25 women; age 82.1 ± 7.6 y range 62â-96 y; body mass index 25.8 ± 5.4 kg/m2 range 16.6â-45.1 kg/m2) were recruited from hospital wards specializing in the care of frail older individuals from the United Kingdom. Bioelectrical impedance assessment was performed at 50 khz frequency, \{BIVA\} was performed using raw impedance data, \{PA\} was calculated, and data were compared against reference population groups. Patients were categorized by malnutrition risk by \{MUST\} and MNA-SF. Results \{BIVA\} indicated that the men and women in the study were significantly different from reference population groups (P &lt; 0.0001), with a noticeable reduced capacitive reactance (xC) component. The group mean \{PA\} was 4.6° ± 1.1° (2.4°â-9.2°). The mean \{PA\} for men was 4.7° ± 1.3° (2.4°â-9.2°), and for women it was 4.5° ± 0.7° (2.8â-6.0°). Group \{PA\} correlated with MNA-SF score (P = 0.05). \{MUST\} categorized patients predominantly at low risk for malnutrition (80%); whereas MNA-SF was at risk (46%) and malnourished (45%). Conclusions The significant reduction in xC component and \{PA\} is consistent with other studies and is indicative of a reduced body cell mass and nutritional status with aging and illness. The general trend in MNA-SF scoring was more consistent with these patterns as a group; but requires clarification in larger cohorts. Future studies are necessary with an aim to improve and optimize care of frail older people

Testing the credibility, feasibility and acceptability of an optimised behavioural intervention (OBI) for avoidant chronic low back pain patients: protocol for a randomised feasibility study

Background: Chronic back pain continues to be a costly and prevalent condition. The latest NICE guidelines issued in 2009 state that for patients with persistent back pain (of between six weeks and twelve months duration), who are highly distressed and/or disabled and for whom exercise, manual therapy and acupuncture has not been beneficial, the evidence supports a combination of around 100 hours of combined physical and psychological treatment. This is costly, and may prove unacceptable to many patients. A key recommendation of these guidelines was for further randomised controlled trials (RCTs) of psychological treatment and to target treatment to specific sub-groups of patients. Recent trials that have included psychological interventions have shown only moderate improvement at best, and results are not maintained long term. There is therefore a need to test theoretically driven interventions that focus on specific high-risk sub-groups, in which the intervention is delivered at full integrity against a credible control. Methods/design: A feasibility study of a pragmatic randomised controlled trial comparing psychologist-delivered Contextual Cognitive Behavioural Therapy (CCBT) against Treatment As Usual (TAU) physiotherapy delivered by physiotherapists for the treatment of chronic lower back pain in ‘avoidant’ patients. Ninety-two patients referred for physiotherapy will be recruited and randomised on a 1:1 basis to receive CCBT or TAU. Treatment groups will be balanced by centre and pain interference score. Primary outcomes include assessing the credibility and acceptability of the intervention, and to demonstrate proof of principle through a greater change in pain acceptance in the CCBT arm, measured by the Acceptance and Action –II and the Chronic Pain Acceptance questionnaires. In addition, the feasibility of carrying out a full trial will be explored with reference to recruitment and follow-up rates including the assessment of the burden of outcome measure completion. Secondary patient outcomes include disability, pain, fear of movement, mood, quality of life, and global recovery. Outcomes are measured at three and six months post-randomisation. Discussion: This paper details the rationale, design, therapist training system and recruitment methods to be used in a feasibility study which will inform the design and efficient implementation of a future definitive RCT

Concordant Gene Expression in Leukemia Cells and Normal Leukocytes Is Associated with Germline cis-SNPs

The degree to which gene expression covaries between different primary tissues within an individual is not well defined. We hypothesized that expression that is concordant across tissues is more likely influenced by genetic variability than gene expression which is discordant between tissues. We quantified expression of 11,873 genes in paired samples of primary leukemia cells and normal leukocytes from 92 patients with acute lymphoblastic leukemia (ALL). Genetic variation at >500,000 single nucleotide polymorphisms (SNPs) was also assessed. The expression of only 176/11,783 (1.5%) genes was correlated (p<0.008, FDR = 25%) in the two tissue types, but expression of a high proportion (20 of these 176 genes) was significantly related to cis-SNP genotypes (adjusted p<0.05). In an independent set of 134 patients with ALL, 14 of these 20 genes were validated as having expression related to cis-SNPs, as were 9 of 20 genes in a second validation set of HapMap cell lines. Genes whose expression was concordant among tissue types were more likely to be associated with germline cis-SNPs than genes with discordant expression in these tissues; genes affected were involved in housekeeping functions (GSTM2, GAPDH and NCOR1) and purine metabolism