Less efficient pattern separation may contribute to age-related spatial memory deficits

Spatial memory deficits have been well-documented in older adults and may serve as an early indicator of mild cognitive impairment (MCI) or Alzheimer's disease (AD) in some individuals. Pattern separation is a critical mechanism for reducing potential interference among similar memory representations to enhance memory accuracy. A small but growing literature indicates that spatial pattern separation may become less efficient as a result of normal aging, possibly due to age-related changes in subregions of the hippocampus. This decreased efficiency in spatial pattern separation may be a critical processing deficit that could be a contributing factor to spatial memory deficits and episodic memory impairment associated with aging. The present paper will review recently published studies in humans, non-human primates, and rodents that have examined age-related changes in spatial pattern separation. The potential basic science, translational, and clinical implications from these studies are discussed to illustrate the need for future research to further examine the relationship between spatial pattern separation and brain changes associated with aging and neurodegenerative disease

Myc Oncogene-Induced Genomic Instability: DNA Palindromes in Bursal Lymphomagenesis

Genetic instability plays a key role in the formation of naturally occurring cancer. The formation of long DNA palindromes is a rate-limiting step in gene amplification, a common form of tumor-associated genetic instability. Genome-wide analysis of palindrome formation (GAPF) has detected both extensive palindrome formation and gene amplification, beginning early in tumorigenesis, in an experimental Myc-induced model tumor system in the chicken bursa of Fabricius. We determined that GAPF-detected palindromes are abundant and distributed nonrandomly throughout the genome of bursal lymphoma cells, frequently at preexisting short inverted repeats. By combining GAPF with chromatin immunoprecipitation (ChIP), we found a significant association between occupancy of gene-proximal Myc binding sites and the formation of palindromes. Numbers of palindromic loci correlate with increases in both levels of Myc over-expression and ChIP-detected occupancy of Myc binding sites in bursal cells. However, clonal analysis of chick DF-1 fibroblasts suggests that palindrome formation is a stochastic process occurring in individual cells at a small number of loci relative to much larger numbers of susceptible loci in the cell population and that the induction of palindromes is not involved in Myc-induced acute fibroblast transformation. GAPF-detected palindromes at the highly oncogenic bic/miR-155 locus in all of our preneoplastic and neoplastic bursal samples, but not in DNA from normal and other transformed cell types. This finding indicates very strong selection during bursal lymphomagenesis. Therefore, in addition to providing a platform for gene copy number change, palindromes may alter microRNA genes in a fashion that can contribute to cancer development

Why do people not attend for treatment for trachomatous trichiasis in Ethiopia? A study of barriers to surgery.

BACKGROUND: Trachomatous trichiasis (TT) surgery is provided free or subsidised in most trachoma endemic settings. However, only 18-66% of TT patients attend for surgery. This study analyses barriers to attendance among TT patients in Ethiopia, the country with the highest prevalence of TT in the world. METHODOLOGY/PRINCIPAL FINDINGS: Participants with previously un-operated TT were recruited at 17 surgical outreach campaigns in Amhara Region, Ethiopia. An interview was conducted to ascertain why they had not attended for surgery previously. A trachoma eye examination was performed by an ophthalmologist. 2591 consecutive individuals were interviewed. The most frequently cited barriers to previous attendance for surgery were lack of time (45.3%), financial constraints (42.9%) and lack of an escort (35.5% in females, 19.6% in males). Women were more likely to report a fear of surgery (7.7% vs 3.2%, p<0.001) or be unaware of how to access services (4.5% vs 1.0% p<0.001); men were more frequently asymptomatic (19.6% vs 10.1%, p<0.001). Women were also less likely to have been previously offered TT surgery than men (OR = 0.70, 95%CI 0.53-0.94). CONCLUSIONS/SIGNIFICANCE: The major barriers to accessing surgery from the patients' perspective are the direct and indirect costs of surgery. These can to a large extent be reduced or overcome through the provision of free or low cost surgery at the community level. TRIAL REGISTRATION: ClinicalTrials.gov NCT00522860 and NCT00522912

Brain serotonin synthesis capacity in obsessive-compulsive disorder: effects of cognitive behavioral therapy and sertraline.

Cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) are both effective treatments for some patients with obsessive-compulsive disorder (OCD), yet little is known about the neurochemical changes related to these treatment modalities. Here, we used positron emission tomography and the α-[11C]methyl-L-tryptophan tracer to examine the changes in brain regional serotonin synthesis capacity in OCD patients following treatment with CBT or SSRI treatment. Sixteen medication-free OCD patients were randomly assigned to 12 weeks of either CBT or sertraline treatment. Pre-to-post treatment changes in the α-[11C]methyl-L-tryptophan brain trapping constant, K* (ml/g/min), were assessed as a function of symptom response, and correlations with symptom improvement were examined. Responders/partial responders to treatment did not show significant changes in relative regional tracer uptake; rather, in responders/partial responders, 12 weeks of treatment led to serotonin synthesis capacity increases that were brain-wide. Irrespective of treatment modality, baseline serotonin synthesis capacity in the raphe nuclei correlated positively with clinical improvement. These observations suggest that, for some patients, successful remediation of OCD symptoms might be associated with greater serotonergic tone

Fitting parametric random effects models in very large data sets with application to VHA national data

<p>Abstract</p> <p>Background</p> <p>With the current focus on personalized medicine, patient/subject level inference is often of key interest in translational research. As a result, random effects models (REM) are becoming popular for patient level inference. However, for very large data sets that are characterized by large sample size, it can be difficult to fit REM using commonly available statistical software such as SAS since they require inordinate amounts of computer time and memory allocations beyond what are available preventing model convergence. For example, in a retrospective cohort study of over 800,000 Veterans with type 2 diabetes with longitudinal data over 5 years, fitting REM via generalized linear mixed modeling using currently available standard procedures in SAS (e.g. PROC GLIMMIX) was very difficult and same problems exist in Stata’s gllamm or R’s lme packages. Thus, this study proposes and assesses the performance of a meta regression approach and makes comparison with methods based on sampling of the full data.</p> <p>Data</p> <p>We use both simulated and real data from a national cohort of Veterans with type 2 diabetes (n=890,394) which was created by linking multiple patient and administrative files resulting in a cohort with longitudinal data collected over 5 years.</p> <p>Methods and results</p> <p>The outcome of interest was mean annual HbA1c measured over a 5 years period. Using this outcome, we compared parameter estimates from the proposed random effects meta regression (REMR) with estimates based on simple random sampling and VISN (Veterans Integrated Service Networks) based stratified sampling of the full data. Our results indicate that REMR provides parameter estimates that are less likely to be biased with tighter confidence intervals when the VISN level estimates are homogenous.</p> <p>Conclusion</p> <p>When the interest is to fit REM in repeated measures data with very large sample size, REMR can be used as a good alternative. It leads to reasonable inference for both Gaussian and non-Gaussian responses if parameter estimates are homogeneous across VISNs.</p

Magneto-optical Kerr Effect Studies of Square Artificial Spin Ice

We report a magneto-optical Kerr effect study of the collective magnetic response of artificial square spin ice, a lithographically-defined array of single-domain ferromagnetic islands. We find that the anisotropic inter-island interactions lead to a non-monotonic angular dependence of the array coercive field. Comparisons with micromagnetic simulations indicate that the two perpendicular sublattices exhibit distinct responses to island edge roughness, which clearly influence the magnetization reversal process. Furthermore, such comparisons demonstrate that disorder associated with roughness in the island edges plays a hitherto unrecognized but essential role in the collective behavior of these systems.Comment: Physical Review B, Rapid Communications (in press

Viper

A Viper aircraft was redesigned with a new airfoil and engine to verify if improvements can be made to the baseline configuration. The two major redesigning processes were: replacing the baseline aircraft's NACA 652-415 airfoil with an NLF 0414 Natural Laminar Flow airfoil, and the baseline aircraft's Lycoming 0-235 engine with a Teledyne Continental GR-36 rotary combustion engine. As a result of these changes: (1) the Viper aircraft becomes smaller in most respects (gross weight, wing platform area, and horizontal tail area); (2) overall drag of the aircraft decreased (due to reduction in area and the reduced drug of the new airfoil); (3) cruise velocity, the maximum rate of climb at sea level, and takeoff distance (but not landing distance) decreased; and (4) cost increased. Although the overall drag decreased, the performance remained about the same due to the reduced horsepower available from the Teledyne Continental engine

The HABP2 G534E polymorphism does not increase nonmedullary thyroid cancer risk in Hispanics.

Familial nonmedullary thyroid cancer (NMTC) has not been clearly linked to causal germline variants, despite the large role that genetic factors play in risk. Recently, HABP2 G534E (rs7080536A) has been implicated as a causal variant in NMTC. We have previously shown that the HABP2 G534E variant is not associated with TC risk in patients from the British Isles. Hispanics are the largest and the youngest minority in the United States and NMTC is now the second most common malignancy in women from this population. In order to determine if the HABP2 G534E variant played a role in NMTC risk among Hispanic populations, we analyzed 281 cases and 1105 population-matched controls from a multicenter study in Colombia, evaluating the association through logistic regression. We found that the HABP2 G534E variant was not significantly associated with NMTC risk (P=0.843) in this Hispanic group. We also stratified available clinical data by multiple available clinicopathological variables and further analyzed the effect of HABP2 on NMTC presentation. However, we failed to detect associations between HABP2 G534E and NMTC risk, regardless of disease presentation (P≥0.273 for all cases). Therefore, without any significant associations between the HABP2 G534E variant and NMTC risk, we conclude that the variant is not causal of NMTC in this Hispanic population

An immortalised mesenchymal stem cell line maintains mechano-responsive behaviour and can be used as a reporter of substrate stiffness

The mechanical environment can influence cell behaviour, including changes to transcriptional and proteomic regulation, morphology and, in the case of stem cells, commitment to lineage. However, current tools for characterizing substrates’ mechanical properties, such as atomic force microscopy (AFM), often do not fully recapitulate the length and time scales over which cells ‘feel’ substrates. Here, we show that an immortalised, clonal line of human mesenchymal stem cells (MSCs) maintains the responsiveness to substrate mechanics observed in primary cells, and can be used as a reporter of stiffness. MSCs were cultured on soft and stiff polyacrylamide hydrogels. In both primary and immortalised MSCs, stiffer substrates promoted increased cell spreading, expression of lamin-A/C and translocation of mechano-sensitive proteins YAP1 and MKL1 to the nucleus. Stiffness was also found to regulate transcriptional markers of lineage. A GFP-YAP/RFP-H2B reporter construct was designed and virally delivered to the immortalised MSCs for in situ detection of substrate stiffness. MSCs with stable expression of the reporter showed GFP-YAP to be colocalised with nuclear RFP-H2B on stiff substrates, enabling development of a cellular reporter of substrate stiffness. This will facilitate mechanical characterisation of new materials developed for applications in tissue engineering and regenerative medicine