A Fresh Look at Huntingtin mRNA Processing in Huntington\u27s Disease

Huntington\u27s disease (HD) is an inherited neurodegenerative disorder caused by a mutation that expands the polyglutamine (CAG) repeat in exon 1 of the huntingtin (HTT) gene. Wild-type HTT protein interacts with other proteins to protect cells against toxic stimuli, mediate vesicle transport and endocytosis, and modulate synaptic activity. Mutant HTT protein disrupts autophagy, vesicle transport, neurotransmitter signaling, and mitochondrial function. Although many of the activities of wild-type HTT protein and the toxicities of mutant HTT protein are characterized, less is known about the activities of HTT mRNA. Most putative HD therapies aim to target mutant HTT mRNA before it is translated into the protein. Therefore, it is imperative to learn as much as we can about how cells handle both wild-type and mutant HTT mRNA so that effective therapies can be designed. Here, we review the structure of wild-type and mutant HTT mRNA, with emphasis on their alternatively polyadenylated or spliced isoforms. We then consider the abundance of HTT mRNA isoforms in HD and discuss the potential implications of these findings. Evidence in the review should be used to guide future research aimed at developing mRNA-lowering therapies for HD

Brain xanthophyll content and exploratory gene expression analysis: subspecies differences in rhesus macaque

BACKGROUND: The dietary xanthophylls, lutein and zeaxanthin, accumulate in primate retina and brain, and emerging evidence indicates neural lutein content may be beneficial for cognition. Neural xanthophyll content in primates varies greatly among individuals, and genetic factors are likely to be significant contributors. Subspecies of rhesus macaques originating from different geographic locations are known to differ genetically, but the effect of origin on gene expression and carotenoid status has not been determined. The study objective was to determine whether xanthophyll status and expression of carotenoid-related genes, as well as genes with known variants between subspecies, differ between the brains of adult rhesus monkeys of Indian and Chinese origin. METHODS: Samples of prefrontal cortex, cerebellum, and striatum were collected from adult monkeys (n = 9) fed a standard stock diet containing carotenoids. Serum and brain carotenoids were determined using reverse-phase high-performance liquid chromatography. For each brain region, RNA sequencing and real-time quantitative polymerase chain reaction were used to determine differentially expressed genes between the subspecies. RESULTS: Indian-origin monkeys had higher xanthophyll levels in brain tissue compared to Chinese-origin monkeys despite consuming similar amounts of dietary carotenoids. In a region-specific manner, four genes related to carotenoid and fatty acid metabolism (BCO2, RPE65, ELOVL4, FADS2) and four genes involved in the immune response (CD4, CD74, CXCL12 LTBR) were differentially expressed between Indian- and Chinese-origin monkeys. Expression of all four genes involved in carotenoid and fatty acid metabolism were correlated with brain xanthophyll concentration in a region-specific manner. CONCLUSIONS: These results indicate that origin is related to differences in both gene expression and xanthophyll content in the brain. Findings from this study may have important implications regarding genetic diversity, lutein status, and cognition in primates

Evidence of Drug–Nutrient Interactions with Chronic Use of Commonly Prescribed Medications: An Update

The long-term use of prescription and over-the-counter drugs can induce subclinical and clinically relevant micronutrient deficiencies, which may develop gradually over months or even years. Given the large number of medications currently available, the number of research studies examining potential drug–nutrient interactions is quite limited. A comprehensive, updated review of the potential drug–nutrient interactions with chronic use of the most often prescribed medications for commonly diagnosed conditions among the general U.S. adult population is presented. For the majority of the interactions described in this paper, more high-quality intervention trials are needed to better understand their clinical importance and potential consequences. A number of these studies have identified potential risk factors that may make certain populations more susceptible, but guidelines on how to best manage and/or prevent drug-induced nutrient inadequacies are lacking. Although widespread supplementation is not currently recommended, it is important to ensure at-risk patients reach their recommended intakes for vitamins and minerals. In conjunction with an overall healthy diet, appropriate dietary supplementation may be a practical and efficacious way to maintain or improve micronutrient status in patients at risk of deficiencies, such as those taking medications known to compromise nutritional status. The summary evidence presented in this review will help inform future research efforts and, ultimately, guide recommendations for patient care

Assessing US Veterans\u27 Work Role Functioning: Influences of Posttraumatic Stress, Sense of Coherence, and Vocational Identity

Veterans experience numerous psychosocial difficulties following combat including employment difficulties. This study assessed the influence of sense of coherence and vocational identity on the relationship between posttraumatic stress symptoms (PTSS) and work role functioning. Results from a sample of 131 combat Veterans found significant relationships between study variables. Sense of coherence mediated the relationship between PTSS and work role functioning. An indirect relationship between PTSS and work role functioning through vocational identity was not supported. Sense of coherence did not moderate the relationship between PTSS and vocational identity. Clinical implications, limitations, and directions for future research are addressed

Exploring Student-Athlete Grit as a Mediator in the Relationships Between Parenting, Academic Success, and Mental Health Outcomes

Due to demand for high performance inside and outside of the classroom, student-athletes are a unique subsection of college students. Researchers have focused on investigating protective factors, which may enhance student-athlete well-being and academic success in higher education and reduce athlete burnout. The current study examined grit as a mediator between parenting behaviors and academic success, mental health outcomes, and burnout in higher education among National Collegiate Athletic Association Division I and Division II student-athletes (N =202). Overparenting behaviors were negatively associated with psychological autonomy granting, mental health outcomes, and athlete burnout. Psychological autonomy granting behaviors were positively associated with grit and negatively associated with mental health outcomes and athlete burnout. Student-athlete grit mediated the relationship between overparenting behaviors and mental health outcomes. Clinical implications include improving student-athlete parent onboarding protocol; student-athlete psychoeducation; and preventative outreach and health promotion among athletes, athletic staff, and university practitioners. In summary, these findings suggest that parenting behaviors and grit are factors that require more attention in fostering student-athlete success

The Contribution of Self-Efficacy in Assessing Interests Using the Self-Directed Search

Using the variables self-efficacy, self-estimates, and self-competencies in a hierarchical multiple regression and confirmatory factor analysis, the present study provided strong support for 3 of 6 RIASEC (Realistic, Investigative, Artistic, Social, Enterprising, and Conventional) interest domains regarding Holland\u27s (1997) assertion that it is unnecessary to administer a separate measure of self-efficacy when using the Self-Directed Search (SDS; Holland, Powell, & Fritzsche, 1994) to measure interests in career counseling. Implications for the interpretation of SDS scores in light of self-efficacy assessment are discussed

Measuring Client Perceptions of Motivational Interviewing: Factor Analysis of the Client Evaluation of Motivational Interviewing Scale

Motivational interviewing (MI) is an intervention approach that has solid evidence of efficacy with substance use disorders. Research and training have benefitted from the development of observational measures to assess MI fidelity and competence. However, one untapped area of assessment is the client perception of the clinician use of MI. Client perceptions of MI have been found through qualitative interviews to relate to motivation to change, view of the therapist and safety of therapy. The Client Evaluation of MI (CEMI) scale was developed to assess client perception of clinician MI use. This study further evaluated the CEMI through exploratory and confirmatory factor analysis with a sample of 500 individuals with dual diagnosis pre-discharge from an inpatient unit. Participants completed an MI based session prior to completing CEMIs. A two factor (relational and technical) model explained 51.1% of the cumulative variance and was supported through confirmatory factor analysis. Suggestions for revisions are provided as well as potential uses of the CEMI and future directions for research. (C) 2013 Elsevier Inc. All rights reserved

Lutein accumulates in subcellular membranes of brain regions in adult rhesus macaques: Relationship to DHA oxidation products

<div><p>Objectives</p><p>Lutein, a carotenoid with anti-oxidant functions, preferentially accumulates in primate brain and is positively related to cognition in humans. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (PUFA), is also beneficial for cognition, but is susceptible to oxidation. The present study characterized the membrane distribution of lutein in brain regions important for different domains of cognitive function and determined whether membrane lutein was associated with brain PUFA oxidation.</p><p>Methods</p><p>Adult rhesus monkeys were fed a stock diet (~2 mg/day lutein or ~0.5 μmol/kg body weight/day) (n = 9) or the stock diet plus a daily supplement of lutein (~4.5 mg/day or~1 μmol/kg body weight/day) and zeaxanthin (~0.5 mg/day or 0.1 μmol/kg body weight/day) for 6–12 months (n = 4). Nuclear, myelin, mitochondrial, and neuronal plasma membranes were isolated using a Ficoll density gradient from prefrontal cortex (PFC), cerebellum (CER), striatum (ST), and hippocampus (HC). Carotenoids, PUFAs, and PUFA oxidation products were measured using HPLC, GC, and LC-GC/MS, respectively.</p><p>Results</p><p>All-<i>trans</i>-lutein (ng/mg protein) was detected in all regions and membranes and was highly variable among monkeys. Lutein/zeaxanthin supplementation significantly increased total concentrations of lutein in serum, PFC and CER, as well as lutein in mitochondrial membranes and total DHA concentrations in PFC only (P<0.05). In PFC and ST, mitochondrial lutein was inversely related to DHA oxidation products, but not those from arachidonic acid (P <0.05).</p><p>Discussion</p><p>This study provides novel data on subcellular lutein accumulation and its relationship to DHA oxidation in primate brain. These findings support the hypothesis that lutein may be associated with antioxidant functions in the brain.</p></div

The Subcellular Distribution of Alpha-Tocopherol in the Adult Primate Brain and Its Relationship with Membrane Arachidonic Acid and Its Oxidation Products

The relationship between α-tocopherol, a known antioxidant, and polyunsaturated fatty acid (PUFA) oxidation, has not been directly investigated in the primate brain. This study characterized the membrane distribution of α-tocopherol in brain regions and investigated the association between membrane α-tocopherol and PUFA content, as well as brain PUFA oxidation products. Nuclear, myelin, mitochondrial, and neuronal membranes were isolated using a density gradient from the prefrontal cortex (PFC), cerebellum (CER), striatum (ST), and hippocampus (HC) of adult rhesus monkeys (n = 9), fed a stock diet containing vitamin E (α-, γ-tocopherol intake: ~0.7 µmol/kg body weight/day, ~5 µmol/kg body weight/day, respectively). α-tocopherol, PUFAs, and PUFA oxidation products were measured using high performance liquid chromatography (HPLC), gas chromatography (GC) and liquid chromatography-gas chromatography/mass spectrometry (LC-GC/MS) respectively. α-Tocopherol (ng/mg protein) was highest in nuclear membranes (p &lt; 0.05) for all regions except HC. In PFC and ST, arachidonic acid (AA, µg/mg protein) had a similar membrane distribution to α-tocopherol. Total α-tocopherol concentrations were inversely associated with AA oxidation products (isoprostanes) (p &lt; 0.05), but not docosahexaenoic acid oxidation products (neuroprostanes). This study reports novel data on α-tocopherol accumulation in primate brain regions and membranes and provides evidence that α-tocopherol and AA are similarly distributed in PFC and ST membranes, which may reflect a protective effect of α-tocopherol against AA oxidation

Rhesus monkey characteristics (mean ± SEM) in stock diet and L/Z supplemented treatment groups.

<p>Rhesus monkey characteristics (mean ± SEM) in stock diet and L/Z supplemented treatment groups.</p