Separate and overlapping relationships of inattention and hyperactivity/impulsivity in children and adolescents with attention-deficit/hyperactivity disorder

There is debate regarding the dimensional versus categorical nature of attention-deficit/hyperactivity disorder (ADHD). This study utilized confirmatory factor analysis to examine this issue. ADHD symptoms rated on interviews and rating scales from a large sample of individuals (ages 3–17, 74 % male, 75 % Caucasian) with ADHD were examined (n = 242). Four potential factor structures were tested to replicate prior findings in a sample with a wide age range and included only participants who met DSM-IV-TR diagnostic criteria for ADHD. Correlations with executive function measures were performed to further assess the separability and validity of the derived factors. The data support a bifactor model with a general ADHD factor and two specific factors, inattention and hyperactivity/impulsivity. Importantly, the individual factors were also differentially correlated with executive functioning measures. This study adds to a growing literature suggesting both a general component to ADHD, as well as dimensional traits of inattention and hyperactivity/impulsivity, associated with distinct executive functioning profiles. The presence of a general underlying factor contraindicates separating the inattentive and combined subtypes of ADHD into distinct disorders.     

Blood lactate loads of redthroat emperor Lethrinus miniatus associated with angling stress and exhaustive exercise

Baseline, post‐angling and maximum attainable blood lactate concentrations were measured for the fishery species redthroat emperor Lethrinus miniatus to gain insight into the condition of fish released following c. 30 s angling and <45 s air exposure. Mean ± s.d . baseline blood lactate was 1·5 ± 0·6 mmol l^?1, which increased and plateaued around 6 mmol l^?1 at 15–30 min post‐angling. These values were significantly lower than those obtained from fish maximally exhausted with a prolonged chase and air exposure protocol following capture (10·9 ± 1·8 mmol l^?1), suggesting that L. miniatus is not maximally exhausted during standard angling practices.     

A comparison of two novel alcohol dehydrogenase enzymes (ADH1 and ADH2) from the extreme halophile Haloferax volcanii

Haloarchaeal alcohol dehydrogenases are exciting biocatalysts with potential industrial applications. In this study, two alcohol dehydrogenase enzymes from the extremely halophilic archaeon Haloferax volcanii (HvADH1 and HvADH2) were homologously expressed and subsequently purified by immobilized metal-affinity chromatography. The proteins appeared to copurify with endogenous alcohol dehydrogenases, and a double Δadh2 Δadh1 gene deletion strain was constructed to prevent this occurrence. Purified HvADH1 and HvADH2 were compared in terms of stability and enzymatic activity over a range of pH values, salt concentrations, and temperatures. Both enzymes were haloalkaliphilic and thermoactive for the oxidative reaction and catalyzed the reductive reaction at a slightly acidic pH. While the NAD⁺-dependent HvADH1 showed a preference for short-chain alcohols and was inherently unstable, HvADH2 exhibited dual cofactor specificity, accepted a broad range of substrates, and, with respect to HvADH1, was remarkably stable. Furthermore, HvADH2 exhibited tolerance to organic solvents. HvADH2 therefore displays much greater potential as an industrially useful biocatalyst than HvADH1.     

The discovery of the benzazepine class of histamine H3 receptor antagonists

This Letter describes the discovery of a novel series of H₃ receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H₃ receptor antagonists based on the benzazepine core. Employing an H₃ driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties.     

Direct Measurements of Smartphone Screen-Time: Relationships with Demographics and Sleep

BackgroundSmartphones are increasingly integrated into everyday life, but frequency of use has not yet been objectively measured and compared to demographics, health information, and in particular, sleep quality.AimsThe aim of this study was to characterize smartphone use by measuring screen-time directly, determine factors that are associated with increased screen-time, and to test the hypothesis that increased screen-time is associated with poor sleep.MethodsWe performed a cross-sectional analysis in a subset of 653 participants enrolled in the Health eHeart Study, an internet-based longitudinal cohort study open to any interested adult (≥ 18 years). Smartphone screen-time (the number of minutes in each hour the screen was on) was measured continuously via smartphone application. For each participant, total and average screen-time were computed over 30-day windows. Average screen-time specifically during self-reported bedtime hours and sleeping period was also computed. Demographics, medical information, and sleep habits (Pittsburgh Sleep Quality Index–PSQI) were obtained by survey. Linear regression was used to obtain effect estimates.ResultsTotal screen-time over 30 days was a median 38.4 hours (IQR 21.4 to 61.3) and average screen-time over 30 days was a median 3.7 minutes per hour (IQR 2.2 to 5.5). Younger age, self-reported race/ethnicity of Black and "Other" were associated with longer average screen-time after adjustment for potential confounders. Longer average screen-time was associated with shorter sleep duration and worse sleep-efficiency. Longer average screen-times during bedtime and the sleeping period were associated with poor sleep quality, decreased sleep efficiency, and longer sleep onset latency.ConclusionsThese findings on actual smartphone screen-time build upon prior work based on self-report and confirm that adults spend a substantial amount of time using their smartphones. Screen-time differs across age and race, but is similar across socio-economic strata suggesting that cultural factors may drive smartphone use. Screen-time is associated with poor sleep. These findings cannot support conclusions on causation. Effect-cause remains a possibility: poor sleep may lead to increased screen-time. However, exposure to smartphone screens, particularly around bedtime, may negatively impact sleep.     

Decline in self-renewal factors contributes to aging of the stem cell niche in the Drosophila testis

Aging is characterized by compromised organ and tissue function. A decrease in stem cell number and/or activity could lead to the aging-related decline in tissue homeostasis. We have analyzed how the process of aging affects germ line stem cell (GSC) behavior in the Drosophila testis and report that significant changes within the stem cell microenvironment, or niche, occur that contribute to a decline in stem cell number over time. Specifically, somatic niche cells in testes from older males display reduced expression of the cell adhesion molecule DE-cadherin and a key self-renewal signal unpaired (upd). Loss of upd correlates with an overall decrease in stem cells residing within the niche. Conversely, forced expression of upd within niche cells maintains GSCs in older males. Therefore, our data indicate that age-related changes within stem cell niches may be a significant contributing factor to reduced tissue homeostasis and regeneration in older individuals.     

Localization and activity of multidrug resistance protein 1 in the secretory pathway of Leishmania parasites

Upregulation of the multidrug resistance protein 1 (LeMDR1) in the protozoan parasite, Leishmania enriettii, confers resistance to hydrophobic drugs such as vinblastine, but increases the sensitivity of these parasites to the mitochondrial drug, rhodamine 123. In order to investigate the mechanism of action of LeMDR1, the subcellular localization of green fluorescent protein (GFP)-tagged versions of LeMDR1 and the fate of the traceable-fluorescent LeMDR1 substrate calcein AM were examined in both Leishmania mexicana and L. enriettii LeMDR1 -/- and overexpressing cell lines. The LeMDR1-GFP chimera was localized by fluorescence microscopy to a number of secretory and endocytic compartments, including the Golgi apparatus, endoplasmic reticulum (ER) and a multivesicular tubule (MVT)-lysosome. Pulse-chase labelling experiments with calcein AM suggested that the Golgi and ER pools, but not the MVT-lysosome pool, of LeMDR1 were active in pumping calcein AM out of the cell. Cells labelled with calcein AM under conditions that slow vesicular transport (low temperature and stationary growth) inhibited export and resulted in the accumulation of fluorescent calcein in both the Golgi and the mitochondria. We propose that LeMDR1 substrates are pumped into secretory compartments and exported from the parasite by exocytosis. Accumulation of MDR substrates in the ER can result in alternative transport to the mitochondrion, explaining the reciprocal sensitivity of drug-resistant Leishmania to vinblastine and rhodamine 123.     

Ex vivo analysis of T-cell responses to Epstein-Barr virus-encoded oncogene latent membrane protein 1 reveals highly conserved epitope sequences in virus isolates from diverse geographic regions

Epstein-Barr virus (EBV)-encoded oncogene latent membrane protein (LMP) 1, which is consistently expressed in multiple EBV-associated malignancies, has been proposed as a potential target antigen for any future vaccine designed to control these malignancies. However, the high degree of genetic variation in the LMP1 sequence has been considered a major impediment for its use as a potential immunotherapeutic target for the treatment of EBV-associated malignancies. In the present study, we have employed a highly efficient strategy, based on ex vivo functional assays, to conduct an extensive sequence-wide analysis of LMP1-specific T-cell responses in a large panel of healthy virus carriers of diverse ethnic origin and nasopharyngeal carcinoma patients. By comparing the frequencies of T cells specific for overlapping peptides spanning LMP1, we mapped a number of novel HLA class I- and class II-restricted LMP1 T-cell epitopes, including an epitope with dual HLA class I restriction. More importantly, extensive sequence analysis of LMP1 revealed that the majority of the T-cell epitopes were highly conserved in EBV isolates from Caucasian, Papua New Guinean, African, and Southeast Asian populations, while unique geographically constrained genetic variation was observed within one HLA A2 supertype-restricted epitope. These findings indicate that conserved LMP1 epitopes should be considered in designing epitope-based immunotherapeutic strategies against EBV-associated malignancies in different ethnic populations.