Upregulation of Id1 by Epstein-Barr Virus-encoded LMP1 confers resistance to TGFβ-mediated growth inhibition

BACKGROUND: Epstein-Barr virus (EBV)-encoded LMP1 protein is commonly expressed in nasopharyngeal carcinoma (NPC). LMP1 is a prime candidate for driving tumourigenesis given its ability to activate multiple signalling pathways and to alter the expression and activity of variety of downstream targets. Resistance to TGFβ-mediated cytostasis is one of the growth transforming effects of LMP1. Of the downstream targets manipulated by LMP1, the induction of Id1 and inactivation of Foxo3a appear particularly relevant to LMP1-mediated effects. Id1, a HLH protein is implicated in cell transformation and plays a role in cell proliferation, whilst Foxo3a, a transcription factor controls cell integrity and homeostasis by regulating apoptosis. The mechanism(s) by which LMP1 induces these effects have not been fully characterised. RESULTS: In this study, we demonstrate that the ability of LMP1 to induce the phosphorylation and inactivation of Foxo3a is linked to the upregulation of Id1. Furthermore, we show that the induction of Id1 is essential for the transforming function of LMP1 as over-expression of Id1 increases cell proliferation, attenuates TGFβ-SMAD-mediated transcription and renders cells refractory to TGFβ-mediated cytostasis. Id1 silencing in LMP1-expressing epithelial cells abolishes the inhibitory effect of LMP1 on TGFβ-mediated cell growth arrest and reduces the ability of LMP1 to attenuate SMAD transcriptional activity. In response to TGFβ stimulation, LMP1 does not abolish SMAD phosphorylation but inhibits p21 protein expression. In addition, we found the induction of Id1 in LMP1-expressing cells upon stimulation by TGFβ. We provide evidence that LMP1 suppresses the transcriptional repressor ATF3, possibly leading to the TGFβ-induced Id1 upregulation. CONCLUSION: The current data provide novel information regarding the mechanisms by which LMP1 suppresses TGFβ-induced cytostasis, highlighting the importance of Id1 in LMP1 mediated cell transformatio

Barriers and facilitators to human papillomavirus vaccination among Chinese adolescent girls in Hong Kong: A qualitative-quantitative study

Objectives: To explore perceptions towards cervical cancer, human papillomavirus (HPV) infection and HPV vaccination and to identify factors affecting the acceptability of HPV vaccination among Chinese adolescent girls in Hong Kong. Methods: Six focus groups were conducted with Chinese adolescent girls (median age 16 years, age range 13-20, n = 64) in Hong Kong in April 2007. Thematic analysis was employed to identify major themes related to cervical cancer and HPV vaccination. A supplementary questionnaire was administered to all participants before and after group discussion to assess their knowledge, attitudes and intention to be vaccinated and to collect demographic information. Results: Participants' knowledge on cervical cancer was limited and HPV was largely unheard of. They had difficulty understanding the mechanism linking cervical cancer with HPV infection. Participants held a favourable attitude towards HPV vaccination but the perceived timing of vaccination varied. Barriers to vaccination include high monetary cost, uncertain length of vaccine effectiveness, low perceived risk of HPV infection, no immediate perceived need of vaccination, anticipated family disapproval and fear of the pain of injection. Factors conducive to vaccination include perceived family and peer support and medical reassurance on safety and efficacy of vaccine. The differences on knowledge, attitudes, intention to be vaccinated now and willingness to conform to significant others before and after the discussion were statistically significant, with an increased tendency towards favouring vaccination after the focus group. Conclusions: Participants favoured HPV vaccination despite not feeling an immediate need to be vaccinated. Interventions could focus on providing professional information on HPV vaccination and raising adolescents' perceived need to take preventive measures against HPV infection.published_or_final_versio

Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and cerine residues in the Epstein-Barr Virus lytic switch protein

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with various malignancies, including Burkitt's lymphoma and nasopharyngeal carcinoma. Like all herpesviruses, the EBV life cycle alternates between latency and lytic replication. During latency, the viral genome is largely silenced by host-driven methylation of CpG motifs and, in the switch to the lytic cycle, this epigenetic silencing is overturned. A key event is the activation of the viral BRLF1 gene by the immediate-early protein Zta. Zta is a bZIP transcription factor that preferentially binds to specific response elements (ZREs) in the BRLF1 promoter (Rp) when these elements are methylated. Zta's ability to trigger lytic cycle activation is severely compromised when a cysteine residue in its bZIP domain is mutated to serine (C189S), but the molecular basis for this effect is unknown. Here we show that the C189S mutant is defective for activating Rp in a Burkitt's lymphoma cell line. The mutant is compromised both in vitro and in vivo for binding two methylated ZREs in Rp (ZRE2 and ZRE3), although the effect is striking only for ZRE3. Molecular modeling of Zta bound to methylated ZRE3, together with biochemical data, indicate that C189 directly contacts one of the two methyl cytosines within a specific CpG motif. The motif's second methyl cytosine (on the complementary DNA strand) is predicted to contact S186, a residue known to regulate methyl-ZRE recognition. Our results suggest that C189 regulates the enhanced interaction of Zta with methylated DNA in overturning the epigenetic control of viral latency. As C189 is conserved in many bZIP proteins, the selectivity of Zta for methylated DNA may be a paradigm for a more general phenomenon

A randomized controlled trial reporting functional outcomes of cognitive-behavioural therapy in medication‑treated adults with ADHD and comorbid psychopathology

Studies assessing psychological treatment of attention deficit hyperactivity disorder (ADHD) in adults are increasingly reported. However, functional outcomes are often neglected in favour of symptom outcomes. We investigated functional outcomes in 95 adults with ADHD who were already treated with medication and randomized to receive treatment as usual (TAU/MED) or psychological treatment (CBT/MED) using a cognitive–behavioural programme, R&R2ADHD, which employs both group and individual modalities. RATE-S functional outcomes associated with ADHD symptoms, social functioning, emotional control and antisocial behaviour were given at baseline, end of treatment and three-month follow-up. The Total composite score of these scales is associated with life satisfaction. In addition, independent evaluator ratings of clinicians who were blind to treatment arm were obtained on the Clinical Global Impression scale at each time point. CBT/MED showed overall (combined outcome at end of treatment and 3-month follow-up) significantly greater functional improvement on all scales. Post-group treatment effects were maintained at follow-up with the exception of emotional control and the Total composite scales, which continued to improve. The largest treatment effect was for the RATE-S Total composite scale, associated with life satisfaction. CGI significantly correlated with all outcomes except for social functioning scale at follow-up. The study provides further evidence for the effectiveness of R&R2ADHD and demonstrates the importance of measuring functional outcomes. The key mechanism associated with improved functional outcomes is likely to be behavioural control

The stroke oxygen pilot study: a randomized control trial of the effects of routine oxygen supplementation early after acute stroke--effect on key outcomes at six months

Introduction: Post-stroke hypoxia is common, and may adversely affect outcome. We have recently shown that oxygen supplementation may improve early neurological recovery. Here, we report the six-month outcomes of this pilot study. Methods: Patients with a clinical diagnosis of acute stroke were randomized within 24 h of admission to oxygen supplementation at 2 or 3 L/min for 72 h or to control treatment (room air). Outcomes (see below) were assessed by postal questionnaire at 6 months. Analysis was by intention-to-treat, and statistical significance was set at p#0.05. Results: Out of 301 patients randomized two refused/withdrew consent and 289 (148 in the oxygen and 141 in the control group) were included in the analysis: males 44%, 51%; mean (SD) age 73 (12), 71 (12); median (IQR) National Institutes of Health Stroke Scale score 6 (3, 10), 5 (3, 10) for the two groups respectively. At six months 22 (15%) patients in the oxygen group and 20 (14%) in the control group had died; mean survival in both groups was 162 days (p= 0.99). Median (IQR) scores for the primary outcome, the modified Rankin Scale, were 3 (1, 5) and 3 (1, 4) for the oxygen and control groups respectively. The covariate-adjusted odds ratio was 1.04 (95% CI 0.67, 1.60), indicating that the odds of a lower (i.e. better) score were non-significantly higher in the oxygen group (p= 0.86). The mean differences in the ability to perform basic (Barthel Index) and extended activities of daily living (NEADL), and quality of life (EuroQol) were also non-significant. Conclusions: None of the key outcomes differed at 6 months between the groups. Although not statistically significant and generally of small magnitude, the effects were predominantly in favour of the oxygen group; a larger trial, powered to show differences in longer-term functional outcomes, is now on-going. Trial Registration: Controlled-Trials.com ISRCTN12362720; Eudract.ema.europa.eu 2004-001866-4

Bright excitons in monolayer transition metal dichalcogenides: from Dirac cones to Dirac saddle points

In monolayer transition metal dichalcogenides, tightly bound excitons have been discovered with a valley pseudospin that can be optically addressed through polarization selection rules. Here, we show that this valley pseudospin is strongly coupled to the exciton center-of-mass motion through electron-hole exchange. This coupling realizes a massless Dirac cone with chirality index I=2 for excitons inside the light cone, i.e. bright excitons. Under moderate strain, the I=2 Dirac cone splits into two degenerate I=1 Dirac cones, and saddle points with a linear Dirac spectrum emerge in the bright exciton dispersion. Interestingly, after binding an extra electron, the charged exciton becomes a massive Dirac particle associated with a large valley Hall effect protected from intervalley scattering. Our results point to unique opportunities to study Dirac physics, with exciton's optical addressability at specifiable momentum, energy and pseudospin. The strain-tunable valley-orbit coupling also implies new structures of exciton condensates, new functionalities of excitonic circuits, and possibilities for mechanical control of valley pseudospin

Characteristics of fine and ultrafine aerosols in the London underground.

Underground railway systems are recognised spaces of increased personal pollution exposure. We studied the number-size distribution and physico-chemical characteristics of ultrafine (PM0.1), fine (PM0.1-2.5) and coarse (PM2.5-10) particles collected on a London underground platform. Particle number concentrations gradually increased throughout the day, with a maximum concentration between 18:00 h and 21:00 h (local time). There was a maximum decrease in mass for the PM2.5, PM2.5-10 and black carbon of 3.9, 4.5 and ~ 21-times, respectively, between operable (OpHrs) and non-operable (N-OpHrs) hours. Average PM10 (52 μg m-3) and PM2.5 (34 μg m-3) concentrations over the full data showed levels above the World Health Organization Air Quality Guidelines. Respiratory deposition doses of particle number and mass concentrations were calculated and found to be two- and four-times higher during OpHrs compared with N-OpHrs, reflecting events such as train arrival/departure during OpHrs. Organic compounds were composed of aromatic hydrocarbons and polycyclic aromatic hydrocarbons (PAHs) which are known to be harmful to health. Specific ratios of PAHs were identified for underground transport that may reflect an interaction between PAHs and fine particles. Scanning transmission electron microscopy (STEM) chemical maps of fine and ultrafine fractions show they are composed of Fe and O in the form of magnetite and nanosized mixtures of metals including Cr, Al, Ni and Mn. These findings, and the low air change rate (0.17 to 0.46 h-1), highlight the need to improve the ventilation conditions

Characteristics of fine and ultrafine aerosols in the London underground

\ua9 2022 The Authors. Underground railway systems are recognised spaces of increased personal pollution exposure. We studied the number-size distribution and physico-chemical characteristics of ultrafine (PM0.1), fine (PM0.1–2.5) and coarse (PM2.5–10) particles collected on a London underground platform. Particle number concentrations gradually increased throughout the day, with a maximum concentration between 18:00 h and 21:00 h (local time). There was a maximum decrease in mass for the PM2.5, PM2.5–10 and black carbon of 3.9, 4.5 and ~ 21-times, respectively, between operable (OpHrs) and non-operable (N-OpHrs) hours. Average PM10 (52 μg m−3) and PM2.5 (34 μg m−3) concentrations over the full data showed levels above the World Health Organization Air Quality Guidelines. Respiratory deposition doses of particle number and mass concentrations were calculated and found to be two- and four-times higher during OpHrs compared with N-OpHrs, reflecting events such as train arrival/departure during OpHrs. Organic compounds were composed of aromatic hydrocarbons and polycyclic aromatic hydrocarbons (PAHs) which are known to be harmful to health. Specific ratios of PAHs were identified for underground transport that may reflect an interaction between PAHs and fine particles. Scanning transmission electron microscopy (STEM) chemical maps of fine and ultrafine fractions show they are composed of Fe and O in the form of magnetite and nanosized mixtures of metals including Cr, Al, Ni and Mn. These findings, and the low air change rate (0.17 to 0.46 h−1), highlight the need to improve the ventilation conditions