Relationships of beverage consumption and actigraphy-assessed sleep parameters among urban-dwelling youth from Mexico.

OBJECTIVE: To examine whether usual beverage intake was associated with sleep timing, duration and fragmentation among adolescents. DESIGN: Usual beverage intake was assessed with a FFQ. Outcomes included sleep duration, midpoint (median of bed and wake times) and fragmentation, assessed with 7-d actigraphy. Sex-stratified linear regression was conducted with sleep characteristics as separate outcomes and quantiles of energy-adjusted beverage intake as exposures, accounting for age, maternal education, physical activity and smoking. SETTING: Mexico City. PARTICIPANTS: 528 adolescents residing in Mexico City enrolled in a longitudinal cohort. RESULTS: The mean age (sd) was 14·4 (2·1) years; 48 % were male. Among males, milk and water consumption were associated with longer weekday sleep duration (25 (95 % CI 1, 48) and 26 (95 % CI 4, 47) more minutes, in the 4th compared to the 1st quartile); and higher 100 % fruit juice consumption was related to earlier weekday sleep timing (-22 (95 % CI -28, 1) minutes in the 1st compared to the last quantile; P = 0·03). Among females, soda was associated with higher sleep fragmentation (1·6 (95 % CI 0·4, 2·8) % in the 4th compared to the 1st), and coffee/tea consumption was related to shorter weekend sleep duration (-23 (95 % CI -44, 2) minutes in the 4th compared to the 1st). CONCLUSIONS: Among females, adverse associations with sleep were observed for caffeinated drinks, while males with higher consumption of healthier beverage options (water, milk and 100 % juice) had evidence of longer and earlier-timed sleep. Potential mechanisms involving melatonin and tryptophan should be further investigated.

Novel modulators of p53-signaling encoded by unknown genes of emerging viruses.

The p53 transcription factor plays a key role both in cancer and in the cell-intrinsic response to infections. The ORFEOME project hypothesized that novel p53-virus interactions reside in hitherto uncharacterized, unknown, or hypothetical open reading frames (orfs) of human viruses. Hence, 172 orfs of unknown function from the emerging viruses SARS-Coronavirus, MERS-Coronavirus, influenza, Ebola, Zika (ZIKV), Chikungunya and Kaposi Sarcoma-associated herpesvirus (KSHV) were de novo synthesized, validated and tested in a functional screen of p53 signaling. This screen revealed novel mechanisms of p53 virus interactions and two viral proteins KSHV orf10 and ZIKV NS2A binding to p53. Originally identified as the target of small DNA tumor viruses, these experiments reinforce the notion that all viruses, including RNA viruses, interfere with p53 functions. These results validate this resource for analogous systems biology approaches to identify functional properties of uncharacterized viral proteins, long non-coding RNAs and micro RNAs.

Genome Sequences of Diverse Human Cytomegalovirus Strains with Utility in Drug Screening and Vaccine Evaluation.

Cytomegalovirus displays genetic heterogeneity, which has implications for antiviral and vaccine development. Many studies have focused on laboratory isolates that have been extensively adapted for growth on fibroblasts. Here, we report whole-genome sequences for 10 human cytomegalovirus (HCMV) strains that readily grow on ARPE-19 human retinal pigment epithelial cells.

Expression of the Antisense-to-Latency Transcript Long Noncoding RNA in Kaposi's Sarcoma-Associated Herpesvirus.

The regulation of latency is central to herpesvirus biology. Recent transcriptome-wide surveys have uncovered evidence for promiscuous transcription across the entirety of the Kaposi's sarcoma-associated herpesvirus (KSHV) genome and postulated the existence of multiple viral long noncoding RNAs (lncRNAs). Next-generation sequencing studies are highly dependent on the specific experimental approach and particular algorithms of analysis and therefore benefit from independent confirmation of the results. The antisense-to-latency transcript (ALT) lncRNA was discovered by genome-tiling microarray (Chandriani et al., J Virol 86:7934-7942, 2010, https://doi.org/10.1128/JVI.00645-10). To characterize ALT in detail, we physically isolated this lncRNA by a strand-specific hybrid capture assay and then employed transcriptome sequencing and novel reverse transcription-PCR (RT-PCR) assays to distinguish all RNA species in the KSHV latency region. These methods confirm that ALT initiates at positions 120739/121012 and encodes a single splice site, which is shared with the 3'-coterminal K14-vGPCR/ORF74 mRNA, terminating at 130873 (GenBank accession number GQ994935), resulting in an ∼10,000-nucleotide transcript. No shorter ALT isoforms were identified. This study also identified a novel intron within the LANA 5' untranslated region using a splice acceptor at 127888. In summary, ALT joins PAN/nut1/T1.1 as a bona fide lncRNA of KSHV with potentially important roles in viral gene regulation and pathogenesis. IMPORTANCE: Increasing data support the importance of noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and lncRNAs, which have been shown to exert critical regulatory functions without coding for recognizable proteins. Defining the sequences of these ncRNAs is essential for future studies aiming to functionally characterize a specific ncRNA. Most lncRNA studies are highly dependent on high-throughput sequencing and bioinformatic analyses, few studies follow up on the initial predictions, and analyses are at times discordant. The manuscript characterizes one key viral lncRNA, ALT, by physically isolating ALT and by a sequencing-independent assay. It provides for a simple assay to monitor lncRNA expression in experimental and clinical samples. ALT is expressed antisense to the major viral latency transcripts encoding LANA as well as the viral miRNAs and thus has the potential to regulate this key part of the viral life cycle.

Comprehensive functional characterization of cancer-testis antigens defines obligate participation in multiple hallmarks of cancer.

Tumours frequently activate genes whose expression is otherwise biased to the testis, collectively known as cancer-testis antigens (CTAs). The extent to which CTA expression represents epiphenomena or confers tumorigenic traits is unknown. In this study, to address this, we implemented a multidimensional functional genomics approach that incorporates 7 different phenotypic assays in 11 distinct disease settings. We identify 26 CTAs that are essential for tumor cell viability and/or are pathological drivers of HIF, WNT or TGFß signalling. In particular, we discover that Foetal and Adult Testis Expressed 1 (FATE1) is a key survival factor in multiple oncogenic backgrounds. FATE1 prevents the accumulation of the stress-sensing BH3-only protein, BCL-2-Interacting Killer (BIK), thereby permitting viability in the presence of toxic stimuli. Furthermore, ZNF165 promotes TGFß signalling by directly suppressing the expression of negative feedback regulatory pathways. This action is essential for the survival of triple negative breast cancer cells in vitro and in vivo. Thus, CTAs make significant direct contributions to tumour biology.

Treatment-specific changes in decentering following mindfulness-based cognitive therapy versus antidepressant medication or placebo for prevention of depressive relapse.

OBJECTIVE: To examine whether metacognitive psychological skills, acquired in mindfulness-based cognitive therapy (MBCT), are also present in patients receiving medication treatments for prevention of depressive relapse and whether these skills mediate MBCT's effectiveness. METHOD: This study, embedded within a randomized efficacy trial of MBCT, was the first to examine changes in mindfulness and decentering during 6-8 months of antidepressant treatment and then during an 18-month maintenance phase in which patients discontinued medication and received MBCT, continued on antidepressants, or were switched to a placebo. In total, 84 patients (mean age = 44 years, 58% female) were randomized to 1 of these 3 prevention conditions. In addition to symptom variables, changes in mindfulness, rumination, and decentering were assessed during the phases of the study. RESULTS: Pharmacological treatment of acute depression was associated with reductions in scores for rumination and increased wider experiences. During the maintenance phase, only patients receiving MBCT showed significant increases in the ability to monitor and observe thoughts and feelings as measured by the Wider Experiences (p < .01) and Decentering (p < .01) subscales of the Experiences Questionnaire and by the Toronto Mindfulness Scale. In addition, changes in Wider Experiences (p < .05) and Curiosity (p < .01) predicted lower Hamilton Rating Scale for Depression scores at 6-month follow-up. CONCLUSIONS: An increased capacity for decentering and curiosity may be fostered during MBCT and may underlie its effectiveness. With practice, patients can learn to counter habitual avoidance tendencies and to regulate dysphoric affect in ways that support recovery.

Ubiquitin-mediated regulation of CD86 protein expression by the ubiquitin ligase membrane-associated RING-CH-1 (MARCH1).

The activation of naïve T cells requires antigen presentation by dendritic cells (DCs), and the process of antigen presentation is regulated over the course of DC maturation. One key aspect of this regulation is the cell surface up-regulation upon DC maturation of peptide·MHC-II complexes and the costimulatory molecule CD86. It is now clear that these critical induction events involve changes in ubiquitin-dependent trafficking of MHC-II and CD86 by the E3 ligase membrane-associated RING-CH-1 (MARCH1). Although ubiquitin-dependent trafficking of MHC-II has been well characterized, much less is known regarding the post-transcriptional regulation of CD86 expression. Here, we examined the physical and functional interaction between CD86 and MARCH1. We observed that CD86 is rapidly endocytosed in the presence of MARCH1 followed by lysosome-dependent degradation. Furthermore, we found that the association between CD86 and MARCH1 was conferred primarily by the transmembrane domains of the respective proteins. In contrast to MHC-II, which has a single, conserved ubiquitin acceptor site in the cytosolic domain, we found that multiple lysine residues in the cytosolic tail of CD86 could support ubiquitination consistent with the relative lack of sequence conservation across species within the CD86 cytosolic domain. These findings suggest that MARCH1 recruits multiple substrates via transmembrane domain-mediated interactions to permit substrate ubiquitination in the face of diverse cytosolic domain sequences.

Effects of suppression and appraisals on thought frequency and distress.

Cognitive theories of obsessions highlight appraisals of personal significance and thought suppression in the development and maintenance of intrusive thoughts. The current study examined the role of personal significance within the context of a thought suppression paradigm. The primary aim was to examine whether suppression would have differential effects for target thoughts appraised as personally meaningful versus relatively unimportant. A blasphemous thought served as the target thought, and highly religious and nonreligious participants were recruited. Participants completed a two-interval thought suppression task; during interval 1 they were randomly assigned to suppress or not suppress the target thought and during interval 2, all participants were given "do not suppress" instructions. Suppression resulted in sustained frequency of thoughts in contrast to the decline in thought frequency observed for non-suppression. Differential effects of suppression were found across the two groups. Moreover, suppression was associated with increased negative mood and anxiety. Results suggest that suppression of personally meaningful thoughts is a counterproductive strategy.

Adapter-mediated substrate selection for endoplasmic reticulum-associated degradation.

During endoplasmic reticulum (ER)-associated degradation (ERAD), a relatively small number of ubiquitin ligases (E3) must be capable of ubiquitinating an assortment of substrates diverse in both structure and location (ER lumen, membrane, and/or cytosol). Therefore, mechanisms that operate independently of primary sequence determinants must exist to ensure specificity during this process. Here we provide direct evidence for adapter-mediated substrate recruitment for a virus-encoded ERAD E3 ligase, mK3. Members of an ER membrane protein complex that normally functions during major histocompatibility complex class I biogenesis in the immune system are required for mK3 substrate selection. We demonstrate that heterologous substrates could be ubiquitinated by mK3 if they were recruited by these ER accessory molecules to the proper position relative to the ligase domain of mK3. This mechanism of substrate recruitment by adapter proteins may explain the ability of some E3 ligases, including cellular ERAD E3 ligases, to specifically target the ubiquitination of multiple substrates that are unrelated in sequence.

Appraisals of obsessional thoughts in normal samples.

Cognitive theories of obsessive-compulsive disorder (OCD) posit that appraisals about the significance of thoughts are critical in the development and persistence of obsessions. Rachman [(1997). A cognitive theory of obsessions. Behaviour Research and Therapy, 35, 793-802.] proposes that appraisals of unwanted thoughts distinguish clinical obsessions from normal intrusive thoughts; thoughts appraised as important and personally significant are expected to be upsetting and recur. Appraisals are also expected to be related to symptoms of OCD. To explore the features of normal appraisals of obsession-like thoughts, nonclinical participants in two studies rated the personal significance of intrusive thoughts portrayed in vignettes containing prototypical themes associated with primary obsessions: aggressive, sexual, and blasphemous thoughts. Unwanted intrusive thoughts that were described as occurring more frequently were appraised as more personally significant, but participants appraised these socially unacceptable thoughts similarly whether they imagined having personally experienced them or a friend confiding about having experienced them. Appraisals in both studies were related to subclinical OC symptoms and OC beliefs.

Recognition of facial expressions in obsessive-compulsive disorder.

Sprengelmeyer et al. [Sprengelmeyer, R., Young, A. W., Pundt, I., Sprengelmeyer, A., Calder, A. J., Berrios, G., et al. (1997). Disgust implicated in obsessive-compulsive disorder. Proceedings of the Royal Society of London, 264, 1767-1773] found that patients with OCD showed severely impaired recognition of facial expressions of disgust. This result has potential to provide a unique window into the psychopathology of OCD, but several published attempts to replicate this finding have failed. The current study compared OCD patients to normal controls and panic disorder patients on ability to recognize facial expressions of negative emotions. Overall, the OCD patients were impaired in their ability to recognize disgust expressions, but only 33% of patients showed this deficit. These deficits were related to OCD symptom severity and general functioning, factors that may account for the inconsistent findings observed in different laboratories.

Telephone-administered cognitive behavior therapy for obsessive-compulsive disorder.

Exposure with response prevention and cognitive behavior therapy are widely recognized as effective treatments for obsessive-compulsive disorder. Unfortunately, many people with obsessive-compulsive disorder--particularly those living in rural areas--do not have access to therapists providing these treatments. Accordingly, we investigated the efficacy of telephone-administered cognitive behavior therapy for obsessive-compulsive disorder. Two open trials are reported, for a total of 33 people with obsessive-compulsive disorder (without major depression). The first trial consisted of 12 weeks on a waiting list followed by 12 weeks of treatment (delayed treatment). The second trial consisted of 12 weeks of immediate treatment. Obsessive-compulsive symptoms did not change during the waiting period. Symptoms declined from pre- to post-treatment, with gains maintained at 12-week follow-up. For the pooled sample our pre-to-post-treatment effect size was as large or larger than those obtained in other studies of reduced contact treatment, and similar to those of face-to-face exposure with response prevention. Our proportion of treatment dropouts tended to be lower than those of other reduced contact interventions. The results suggest that telephone-administered cognitive behavior therapy is effective and well-tolerated, at least for people with obsessive-compulsive disorder without major depression. It remains to be seen whether this treatment is safe and effective when comorbid major depression is present.

Efficacy of telephone-administered cognitive behaviour therapy for obsessive-compulsive spectrum disorders: case studies.

Cognitive behaviour therapy is effective for obsessive-compulsive disorder and for obsessive-compulsive spectrum disorders such as trichotillomania. Unfortunately, many people with these disorders, especially those living in rural areas, have limited access to treatment. Telephone-administered cognitive behaviour therapy may help address this problem. In a recent study of telephone treatment for obsessive-compulsive disorder, we found that such treatment was often effective (42% in remission at post-treatment, and 47% in remission at 12-week follow-up). This article presents 2 case reports of the same treatment, applied to obsessive-compulsive spectrum disorders (trichotillomania and compulsive skin picking). Treatment was associated with symptom reduction for both participants, although one subsequently relapsed. Possible reasons for relapse are discussed. The findings encourage further studies to identify the characteristics of people most likely to benefit from telephone treatment for spectrum disorders.