p53 activity contributes to defective interfollicular epidermal differentiation in hyperproliferative murine skin.

Background- The role of p53 in the pathogenesis of skin diseases such as plaque-type psoriasis has long been questioned but never resolved. Objectives- In this study we set out to determine the contribution of p53 activity to defective interfollicular epidermal skin differentiation in a murine hyperproliferative skin model. Methods- We used the tamoxifen-inducible K14MycER mouse model which exhibits abnormal epidermal differentiation in response to high MYC activity, crossed with p53 knock-out mice. Results- We show that genetic deletion of p53 leads to improvements in granular layer formation. Furthermore, we show that p53 activity regulates down-stream expression of Keratin 6a, Pparb/d and Pparg and is regulated upstream by retinoic acid signalling-dependent mechanisms. Conclusion- We conclude aberrant non-apoptotic p53 activity contributes, in-part, to abnormal differentiation and granular layer defects.This work was supported by the Prof. Fiona M. Watt via the MRC, Wellcome Trust, CRUK, EU FP7 programme, the University of Cambridge, Hutchison Whampoa Ltd. This work was also supported by A/ Prof. Ian M. Smyth and Monash University.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1111/bjd.1404

Acute cardiorespiratory responses to inspiratory pressure threshold loading

This is a non-final version of an article (under the working title "Acute cardiovascular and ventilatory responses to inspiratory pressure threshold loading") published in final form in Medicine & Science in Sports & Exercise, 42(9), 1696-1703, 2010 .Purpose: We tested the acute responses to differing pressure threshold inspiratory loading intensities in well-trained rowers. The purpose of this study was to evaluate 1) how the magnitude of inspiratory pressure threshold loading influences repetition maximum (RM), tidal volume (VT), and external work undertaken by the inspiratory muscle; and 2) whether the inspiratory muscle metaboreflex is activated during acute inspiratory pressure threshold loading. Methods: Eight males participated in seven trials. Baseline measurements of maximal inspiratory pressure (PImax), resting tidal volume (VT), and forced vital capacity (FVC) were made. During the remaining sessions, participants undertook a series of resistive inspiratory breathing tasks at loads corresponding to 50%, 60%, 70%, 80%, and 90% of PImax using a pressure threshold inspiratory muscle trainer. The number of repetitions completed at each load, VT, heart rate (fc), and measures of arterial blood pressure was assessed continuously during each trial. Results: A standardized cutoff of 10% FVC was used to define the RM, which decreased as loading intensity increased (P < 0.05). This response was nonlinear, with an abrupt decrease in RM occurring at loads ≥70% of PImax. The most commonly used inspiratory muscle training regimen of 30RM corresponded to 62.5% ± 4.6% of PImax and also resulted in the highest external work output. Tidal volume (VT) decreased significantly over time at 60%, 70%, and 80% of PImax (P < 0.05), as did the amount of external work completed (P<0.05). Conclusions: Although all loads elicited a sustained increase in fc, only the 60% load elicited a sustained rise in mean arterial blood pressure (P = 0.016), diastolic blood pressure (P = 0.015), and systolic blood pressure (P = 0.002), providing evidence for a metaboreflex response at this load

TRAP binding to the Bacillus subtilis trp leader region RNA causes efficient transcription termination at a weak intrinsic terminator

The Bacillus subtilis trpEDCFBA operon is regulated by a transcription attenuation mechanism controlled by the trp RNA-binding attenuation protein (TRAP). TRAP binds to 11 (G/U)AG repeats in the trp leader transcript and prevents formation of an antiterminator, which allows formation of an intrinsic terminator (attenuator). Previously, formation of the attenuator RNA structure was believed to be solely responsible for signaling RNA polymerase (RNAP) to halt transcription. However, base substitutions that prevent formation of the antiterminator, and thus allow the attenuator structure to form constitutively, do not result in efficient transcription termination. The observation that the attenuator requires the presence of TRAP bound to the nascent RNA to cause efficient transcription termination suggests TRAP has an additional role in causing termination at the attenuator. We show that the trp attenuator is a weak intrinsic terminator due to low GC content of the hairpin stem and interruptions in the U-stretch following the hairpin. We also provide evidence that termination at the trp attenuator requires forward translocation of RNA polymerase and that TRAP binding to the nascent transcript can induce this activity

Developments and challenges in dermatology: an update from the Interactive Derma Academy (IDeA) 2019

The 2019 Interactive Derma Academy (IDeA) meeting was held in Lisbon, Portugal, 10–12 May, bringing together leading dermatology experts from across Europe, the Middle East and Asia. Over three days, the latest developments and challenges in relation to the pathophysiology, diagnosis, evaluation and management of dermatological conditions were presented, with a particular focus on acne, atopic dermatitis (AD) and actinic keratosis (AK). Interesting clinical case studies relating to these key topics were discussed with attendees to establish current evidence-based best practices. Presentations reviewed current treatments, potential therapeutic approaches and key considerations in the management of acne, AK and AD, and discussed the importance of the microbiome in these conditions, as well as the provision of patient education/support. It was highlighted that active treatment is not always required for AK, depending on patient preferences and clinical circumstances. In addition to presentations, two interactive workshops on the diagnosis and treatment of sexually transmitted infections/diseases (STIs/STDs) presenting to the dermatology clinic, and current and future dermocosmetics were conducted. The potential for misdiagnosis of STIs/STDs was discussed, with dermoscopy and/or reflectance confocal microscopy suggested as useful diagnostic techniques. In addition, botulinum toxin was introduced as a potential dermocosmetic, and the possibility of microbiome alteration in the treatment of dermatological conditions emphasized. Furthermore, several challenges in dermatology, including the use of lasers, the complexity of atopic dermatitis, wound care, use of biosimilars and application of non-invasive techniques in skin cancer diagnosis were reviewed. In this supplement, we provide an overview of the presentations and discussions from the fourth successful IDeA meeting, summarizing the key insights shared by dermatologists from across the globe

A New Method for Non-Invasive Estimation of Human Muscle Fiber Type Composition

Background: It has been established that excellence in sports with short and long exercise duration requires a high proportion of fast-twitch (FT) or type-II fibers and slow-twitch (ST) or type-I fibers, respectively. Until today, the muscle biopsy method is still accepted as gold standard to measure muscle fiber type composition. Because of its invasive nature and high sampling variance, it would be useful to develop a non-invasive alternative.status: publishe

CD8+ T cell-mediated control of distant tumours following local photodynamic therapy is independent of CD4+ T cells and dependent on natural killer cells

Cancer survival rates decrease in the presence of disseminated disease. However, there are few therapies that are effective at eliminating the primary tumour while providing control of distant stage disease. Photodynamic therapy (PDT) is an FDA-approved modality that rapidly eliminates local tumours, resulting in cure of early disease and palliation of advanced disease. Numerous pre-clinical studies have shown that local PDT treatment of tumours enhances anti-tumour immunity. We hypothesised that enhancement of a systemic anti-tumour immune response might control the growth of tumours present outside the treatment field. To test this hypothesis we delivered PDT to subcutaneous (s.c.) tumours of mice bearing both s.c. and lung tumours and monitored the growth of the untreated lung tumours. Our results demonstrate that PDT of murine tumours provided durable inhibition of the growth of untreated lung tumours. The inhibition of the growth of tumours outside the treatment field was tumour-specific and dependent on the presence of CD8+ T cells. This inhibition was accompanied by an increase in splenic anti-tumour cytolytic activity and by an increase in CD8+ T cell infiltration into untreated tumours. Local PDT treatment led to enhanced anti-tumour immune memory that was evident 40 days after tumour treatment and was independent of CD4+ T cells. CD8+ T cell control of the growth of lung tumours present outside the treatment field following PDT was dependent upon the presence of natural killer (NK) cells. These results suggest that local PDT treatment of tumours lead to induction of an anti-tumour immune response capable of controlling the growth of tumours outside the treatment field and indicate that this modality has potential in the treatment of distant stage disease

Carbohydrate supplementation during prolonged cycling exercise spares muscle glycogen but does not affect intramyocellular lipid use

Using contemporary stable-isotope methodology and fluorescence microscopy, we assessed the impact of carbohydrate supplementation on whole-body and fiber-type-specific intramyocellular triacylglycerol (IMTG) and glycogen use during prolonged endurance exercise. Ten endurance-trained male subjects were studied twice during 3 h of cycling at 63 ± 4% of maximal O2 uptake with either glucose ingestion (CHO trial; 0.7 g CHO kg−1 h−1) or without (CON placebo trial; water only). Continuous infusions with [U-13C] palmitate and [6,6-2H2] glucose were applied to quantify plasma free fatty acids (FFA) and glucose oxidation rates and to estimate intramyocellular lipid and glycogen use. Before and after exercise, muscle biopsy samples were taken to quantify fiber-type-specific IMTG and glycogen content. Plasma glucose rate of appearance (Ra) and carbohydrate oxidation rates were substantially greater in the CHO vs CON trial. Carbohydrate supplementation resulted in a lower muscle glycogen use during the first hour of exercise in the CHO vs CON trial, resulting in a 38 ± 19 and 57 ± 22% decreased utilization in type I and II muscle-fiber glycogen content, respectively. In the CHO trial, both plasma FFA Ra and subsequent plasma FFA concentrations were lower, resulting in a 34 ± 12% reduction in plasma FFA oxidation rates during exercise (P < 0.05). Carbohydrate intake did not augment IMTG utilization, as fluorescence microscopy revealed a 76 ± 21 and 78 ± 22% reduction in type I muscle-fiber lipid content in the CHO and CON trial, respectively. We conclude that carbohydrate supplementation during prolonged cycling exercise does not modulate IMTG use but spares muscle glycogen use during the initial stages of exercise in endurance-trained men