Hypothalamic gene expression during voluntary hypophagia in the Sprague-Dawley rat on withdrawal of the palatable liquid diet, Ensure

Copyright © 2014 Elsevier Inc. All rights reserved.Peer reviewedPostprin

Sandy Feet

Sgt. Brady is a former armed forces member with a transtibial amputation. He walks on sand frequently for work and leisure, but experiences severe pain and inconvenience because his current prosthesis is not meant for use on sand. Sand Foot V2 is a prosthesis that allows Sgt. Brady to walk on sand for long periods of time without issue

Presence of the brown fat-specific mitochondrial uncoupling protein and iodothyronine 5'-deiodinase activity in subcutaneous adipose tissue of neonatal lambs

AbstractSubcutaneous adipose tissue of neonatal lambs has been examined for the presence of markers diagnostic of thermogenic brown fat. Uncoupling protein, uncoupling protein mRNA, and iodothyronine 5'-deiodinase activity were each detected in subcutaneous adipose tissue, as well as in the major internal fat depot (perirenal), of newborn lambs. These brown fat markers were not present, however, in adipose tissue of adult sheep. It is concluded that subcutaneous fat in newborn lambs is functionally ‘brown’, and similar to the internal fat; subcutaneous and internal adipose tissues follow a similar developmental path - from ‘brown’ to ‘white’

Site-Specific Inhibition of Transcription Factor Binding to DNA by a Metallointercalator

The metallointercalator Λ-1-Rh(MGP)_2phi^(5+) binds tightly and specifically to the site 5‘-CATATG-3‘ in the major groove of double helical DNA by a combination of direct readout and shape selection. To examine competitive interactions between this small metal complex and a DNA-binding transcription factor, the preferred binding site for Λ-1-Rh(MGP)_2phi^(5+) was engineered into the AP-1 recognition element (ARE) of the major-groove binding bZIP transcription factor yAP-1, the yeast analogue of mammalian AP-1. Binding experiments confirmed that the modified ARE retained normal yAP-1 binding affinity. Photocleavage experiments demonstrated that the modified ARE contained a high-affinity binding site for Λ-1-Rh(MGP)_2phi^(5+), whereas the native ARE showed no interaction. Competition experiments using gel shift mobility assays demonstrated that Λ-1-Rh(MGP)_2phi^(5+) at 120 nM competes 50% of yAP-1 binding to the 5‘-CATATG-3‘ containing oligonucleotide. In contrast, competitive disruption of protein binding to the native ARE requires 3 μM Λ-1-Rh(MGP)_2phi^(5+). Metallointercalator derivatives, including geometric isomers of Λ-1-Rh(MGP)_2phi^(5+), show no specific binding to the target site and show no inhibition of yAP-1/DNA complexes at concentrations as high as 20 μM. Thus, metallointercalators can be tuned to show selectivity for major groove sites on DNA comparable to transcription factors and indeed can inhibit transcription factor binding site selectively

Contribution of the μ-opioid receptor system to affective disorders in temporal lobe epilepsy: A bidirectional relationship?

OBJECTIVE Affective disorders are frequent comorbidities of temporal lobe epilepsy (TLE). The endogenous opioid system has been implicated in both epilepsy and affective disorders, and may play a significant role in their bidirectional relationship. In this cross-sectional study, we investigated the association between μ-opioid receptor binding and affective disorders in patients with TLE. METHODS Nine patients with TLE and depression/anxiety underwent $^{11}$ C-carfentanil positron emission tomography (CFN PET) and neuropsychiatric assessment, including the Hospital Anxiety and Depression Scale and the Positive and Negative Affect Schedule. The normalized CFN PET scans were compared with those of 26 age-matched healthy controls. Correlation analyses with affective symptoms were performed by region of interest-based analysis focusing on the limbic circuit and orbitofrontal cortex. RESULTS We observed widely reduced CFN binding potential (BP) in bilateral frontal lobes and striata in patients with TLE compared to healthy controls. In the TLE group, more severe anxiety and negative affect were associated with decreased CFN BP in the posterior cingulate gyrus. SIGNIFICANCE In patients with TLE, interictally reduced binding in the opioid system was associated with higher levels of anxiety and negative affect. We speculate that seizure-related agonist-driven desensitization and downregulation of opioid receptors could be a potential underlying pathomechanism

A personalised smartphone-delivered just-in-time adaptive intervention (JITABug) to increase physical activity in older adults: Feasibility pilot study (Preprint)

Background: Just-in-time adaptive interventions (JITAIs) provide real time in-the-moment behavior change support to people when they need it most. JITAIs could be a viable way to provide personalized physical activity (PA) support to older adults in the community. However, it is unclear how feasible it is to remotely deliver a PA intervention through a smartphone to older adults or how acceptable they would find a JITAI targeting PA in everyday life. Objective: The aims of this study are to describe the development of JitaBug, a personalized smartphone-delivered JITAI designed to support older adults to increase or maintain their PA level, assess the feasibility of conducting an effectiveness trial of the JitaBug intervention, and explore the acceptability of JitaBug among older adults in a free-living setting. Methods: The intervention was developed using the Behavior Change Wheel and consisted of a wearable activity tracker (Fitbit) and a companion smartphone app (JitaBug) that delivered goal-setting, planning, reminders, and JITAI messages to encourage achievement of personalized PA goals. Message delivery was tailored based on time of day, real time PA tracker data, and weather conditions. We tested the feasibility of remotely delivering the intervention with older adults in a 6-week trial. Data collection involved assessment of PA through accelerometery and activity tracker, self-reported mood and mental well-being through ecological momentary assessment, and contextual information on PA through voice memos. Feasibility outcomes included recruitment capability and adherence to the intervention, intervention delivery in the wild, appropriateness of data collection methodology, adverse events, and participant satisfaction. Results: Of the 46 recruited older adults (aged 56-72 years), 31 (67%) completed the intervention. The intervention was successfully delivered as intended; 87% (27/31) of the participants completed the intervention independently; 94% (2247/2390) of the PA messages were successfully delivered; 99% (2239/2261) of the Fitbit and 100% (2261/2261) of the weather data calls were successful. Valid and usable wrist-worn accelerometer data were obtained from 90% (28/31) of the participants at baseline and follow-up. On average, the participants recorded 50% (7.9/16, SD 7.3) of the voice memos, 38% (3.3/8, SD 4.2) of the mood assessments, and 50% (2.1/4, SD 1.6) of the well-being assessments through the app. Overall acceptability of the intervention was very good (23/30, 77% expressed satisfaction). Participant feedback suggested that more diverse and tailored PA messages, app use reminders, technical refinements, and an improved user interface could improve the intervention and make it more appealing. Conclusions: This study suggests that a smartphone-delivered JITAI is an acceptable way to support PA in older adults in the community. Overall, the intervention is feasible; however, based on user feedback, the JitaBug app requires further technical refinements that may enhance use, engagement, and user satisfaction before moving to effectiveness trials

“Do you think your main partner has other sex partners?” A simple question provides insight into sexual risk in Jamaica

To estimate the association between a simple measure of sexual partner concurrency and sexually transmitted infection (STI) we conducted a cross-sectional population-based household survey (n=1795) and targeted surveys of people at venues where people meet sexual partners (n=1580) to ask about sexual behavior. Persons interviewed at venues were tested for HIV, gonorrhoea, chlamydia, gonorrhea, and trichomoniasis. We compared the association between STI and reporting a partner had other partners. More women than men reported their main partner had other partners. Thirteen percent of all women in the population-based survey and 14.4% in the targeted survey reported having one partner in the past 12 months and that partner had additional partners. STI prevalence was significantly associated with reporting a partner had other partners (36.8% vs 30.2%; prevalence ratio [PR]1.2; 95% CI 1.1,1.4). Construction of complete sexual networks is costly and not routinely feasible. We recommend adding a question to cross-sectional surveys used to monitor sexual behavior about whether the respondent believes his or her partner has other sexual partners. Although subject to bias, the question was useful in Jamaica to identify a group of women with only one sexual partner at increased risk of infection

A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q- syndrome.

The identification of the genes associated with chromosomal translocation breakpoints has fundamentally changed understanding of the molecular basis of hematological malignancies. By contrast, the study of chromosomal deletions has been hampered by the large number of genes deleted and the complexity of their analysis. We report the generation of a mouse model for human 5q- syndrome using large-scale chromosomal engineering. Haploinsufficiency of the Cd74-Nid67 interval (containing Rps14, encoding the ribosomal protein S14) caused macrocytic anemia, prominent erythroid dysplasia and monolobulated megakaryocytes in the bone marrow. These effects were associated with defective bone marrow progenitor development, the appearance of bone marrow cells expressing high amounts of the tumor suppressor p53 and increased bone marrow cell apoptosis. Notably, intercrossing with p53-deficient mice completely rescued the progenitor cell defect, restoring common myeloid progenitor and megakaryocytic-erythroid progenitor, granulocyte-monocyte progenitor and hematopoietic stem cell bone marrow populations. This mouse model suggests that a p53-dependent mechanism underlies the pathophysiology of the 5q- syndrome

Development of a mouse test for repetitive, restricted behaviors: Relevance to autism

Repetitive behavior, a core symptom of autism, encompasses stereotyped responses, restricted interests, and resistance to change. These studies investigated whether different components of the repetitive behavior domain could be modeled in the exploratory hole-board task in mice. Four inbred mouse strains, C57BL/6J, BALB/cByJ, BTBR T+tf/J, and FVB/NJ, and mice with reduced expression of Grin1, leading to NMDA receptor hypofunction (NR1neo/neo mice), were tested for exploration and preference for olfactory stimuli in an activity chamber with a 16-hole floor-board. Reduced exploration and high preference for holes located in the corners of the chamber were observed in BALB/cByJ and BTBR T+tf/J mice. All inbred strains had initial high preference for a familiar olfactory stimulus (clean cage bedding). BTBR T+tf/J was the only strain that did not demonstrate a shift in hole preference towards an appetitive olfactory stimulus (cereal or a chocolate chip), following home cage exposure to the food. The NR1neo/neo mice showed lower hole selectivity and aberrant olfactory stimulus preference, in comparison to wildtype controls. The results indicate that NR1neo/neo mice have repetitive nose poke responses that are less modified by environmental contingencies than responses in wildtype mice. 25-30% of NMDA-receptor hypomorphic mice also show self-injurious responses. Findings from the olfactory studies suggest that resistance to change and restricted interests might be modeled in mice by a failure to alter patterns of hole preference following familiarization with an appetitive stimulus, and by high preference persistently demonstrated for one particular olfactory stimulus. Further work is required to determine the characteristics of optimal mouse social stimuli in the olfactory hole-board test

Accelerating functional gene discovery in osteoarthritis.

Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease