An investigation of gill and blood carbonic anhydrase characteristics in three basal actinopterygian species: alligator gar (Atractosteus spatula), white sturgeon (Acipenser transmontanus) and Senegal bichir (Polypterus senegalus).

Many teleosts possess a unique set of respiratory characteristics allowing enhanced oxygen unloading to the tissues during stress. This system comprises three major components: highly pH sensitive haemoglobins (large Bohr and Root effects), rapid red blood cell (RBC) intracellular pH (pHi) protection, and a heterogeneous distribution of membrane-bound plasma-accessible carbonic anhydrase (paCA; absence in the gills). The first two components have received considerable research effort; however, the evolutionary loss of branchial paCA has received little attention. In the current study, we investigated the availability of branchial membrane-bound CA, along with several other CA-related characteristics in species belonging to three basal actinopterygian groups: the Lepisosteiformes, Acipenseriformes and Polypteriformes to assess the earlier hypothesis that Root effect haemoglobins constrain branchial paCA availability. We present the first evidence suggesting branchial membrane-bound CA presence in a basal actinopterygian species: the Senegal bichir (Polypterus senegalus) and show that like the teleosts, white sturgeon (Acipenser transmontanus) and alligator gar (Atractosteus spatula) do not possess branchial membrane-bound CA. We discuss the varying respiratory strategies for these species and propose that branchial paCA may have been lost much earlier than previously thought, likely in relation to the changes in haemoglobin buffer capacity associated with the increasing magnitude of the Bohr effect. The findings described here represent an important advancement in our understanding of the evolution of the unique system of enhanced oxygen unloading thought to be present in most teleosts, a group that encompasses half of all vertebrates.

Exposure to Solar UV During Outdoor Construction Work in Britain.

Excessive exposure to ultraviolet (UV) radiation from the sun in summer can cause skin cancer and in Britain there are around 1500 new cases of non-melanoma skin cancer (NMSC) each year, caused by exposure to solar UV at work. Little is known about the magnitude of UV exposure amongst outdoor construction workers in Britain, although this is one of the main groups at risk. The aim of this paper is to summarise measurements of erythema-weighted UVB radiation amongst construction workers in Scotland and the Southeast of England and interpret the data in terms of the risk of NMSC. The measurements were made as part of an intervention study using short mobile phone text messages to alter worker behaviour to either reduce UV exposure in summer or increase serum vitamin D in winter; the intervention is only briefly reported here. Data were collected from 67 workers from 9 worksites, of whom 41 provided measures of UV exposure for 758 working days. Daily exposure ranged from 0 to 13.47 standard erythema dose (SED), with the mean exposure for outdoor workers being 2.0 SED and the corresponding value for indoor workers being 0.7 SED. These data were obtained from a sensor located on the back of the workers hard hat; others have measured exposure on the wrist or upper arm and these locations probably, on average, have higher levels of UV exposure. It is likely that an outdoor construction worker in Britain could accumulate sufficient solar UV exposure over 30-40 years of work to more than double their risk of NMSC. We argue that employers in Britain should take a more proactive approach to manage sun safety and they should take responsibility for skin health surveillance for their workers.

Sun protection education for adolescents: a feasibility study of a wait-list controlled trial of an intervention involving a presentation, action planning, and SMS messages and using objective measurement of sun exposure.

BACKGROUND: People increase their risk of melanoma unless they are protected from the harmful effects of sun exposure during childhood and adolescence. We aimed to assess the feasibility of a three-component sun protection intervention- presentation, action planning, and SMS messages - and trial parameters. METHODS: This feasibility wait-list trial was conducted in the United Kingdom in 2018. Students aged 13-15 years were eligible. Feasibility outcomes were collected for recruitment rates; data availability rates for objective measurements of melanin and erythema using a Mexameter and self-reported sunburn occurrences, severity and body location, tanning, sun protection behaviours and Skin Self-Examination (SSE) collected before (baseline) and after the school summer holidays (follow-up); intervention reach, adherence, perceived impact and acceptability. Quantitative data were analysed using descriptive statistics; qualitative data were analysed thematically. RESULTS: Five out of eight schools expressing an interest in participating with four allocated to act as intervention and one control. Four parents/carers opted their child out of the study. Four hundred and eighty-seven out of 724 students on the school register consented to the study at baseline (67%). Three hundred and eighty-five were in intervention group schools. Objective skin measurements were available for 255 (66%) of the intervention group at baseline and 237 (61%) of the group at follow up. Melanin increased; erythema decreased. Complete self-report data were available for 247 (64%) students in the intervention group. The number of students on the school register who attended the presentation and given the booklet was 379 (98%) and gave their mobile phone number was 155 (40%). No intervention component was perceived as more impactful on sun protection behaviours. Adolescents did not see the relevance of sun protection in the UK or for their age group. CONCLUSIONS: This is the first study to use a Mexameter to measure skin colour in adolescents. Erythema (visible redness) lasts no more than three days and its measurement before and after a six week summer holiday may not yield relevant or meaningful data. A major challenge is that adolescents do not see the relevance of sun protection and SSE. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN11141528. Date registered 0/2/03/2018; last edited 31/05/2018. Retrospectively registered.

ATP-induced reversed thermal sensitivity of O2 binding in both major haemoglobin polymorphs of the non-endothermic Atlantic cod, Gadus morhua.

Atlantic cod is a species that is affected by climate change, with some populations being exposed to higher temperatures than others. The two polymorphs of its major haemoglobin type (HbI) show an inverse change in frequency along a latitudinal temperature cline in the North East Atlantic, which has been associated with differences in population performance and behavioural traits. An earlier study at the northern distribution limit of the species reported differential temperature sensitivities of red blood cell oxygen (O2) affinity between the northern cold-water HbI-2 polymorph and its southern, warm-water HbI-1 counter-part, which has since widely been held as adaptive for the species across its distributional range. The present study critically re-examined this hypothesis by comparing the thermal sensitivity of O2 binding in both purified HbI polymorphs from the southern, high-temperature distribution limit of the species under controlled conditions of allosteric modifiers of Hb function. Contrary to the prevailing view, the O2 affinity of the major HbI polymorphs did not differ from each other under any of the tested conditions. Depending on pH and ATP concentration, the temperature-sensitive and temperature-insensitive Hb-O2 affinity phenotypes - previously exclusively ascribed to HbI-1 and HbI-2, respectively - could be induced in both HbI polymorphs. These results are the first to establish a molecular mechanism behind a reversed temperature dependence of red blood cell O2 affinity in a non-endotherm fish and lay the basis for future studies on alternative mechanisms behind the differences in distribution, performance and behavioural traits associated with the different HbI polymorphs of Atlantic cod.

A randomised control crossover trial of a theory based intervention to improve sun-safe and healthy behaviours in construction workers: study protocol.

BACKGROUND: Exposure to sunlight can have both positive and negative health impacts. Excessive exposure to ultra-violet (UV) radiation from the sun can cause skin cancer, however insufficient exposure to sunlight has a detrimental effect on production of Vitamin D. In the construction industry there are onsite proactive behaviours for safety, but sun-safety remains a low priority. There is limited research on understanding the barriers to adopting sun-safe behaviours and the association this may have with Vitamin D production. This paper reports a protocol for an intervention study, using text messaging in combination with a supportive smartphone App. The intervention aims to both reduce UV exposure during months with higher UV levels and promote appropriate dietary changes to boost Vitamin D levels during months with low UV levels. METHOD/DESIGN: Approximately 60 construction workers will be recruited across the United Kingdom. A randomised control crossover trial (RCCT) will be used to test the intervention, with randomisation at site level - i.e. participants will receive both the control (no text messages or supportive App support) and intervention (daily text messages and supportive App). Using the Theory of Planned Behaviour (TPB) the intervention focuses on supporting sun-safety and healthy dietary decisions in relation to Vitamin D intake. The intervention emphasises cultivating the perception of normative support in the workplace, increasing awareness of control and self-efficacy in taking sun-protective behaviours, making healthier eating choices to boost Vitamin D, and tackling stigmas attached to image and group norms. Each study epoch will last 21 days with intervention text messages delivered on workdays only. The supportive App will provide supplementary information about sun protective behaviours and healthy dietary choices. The primary outcome measure is 25-hydroxy-Vitamin D [25(OH)D] level (obtained using blood spot sampling), which will be taken pre and post control and intervention periods. Secondary outcome measures are two-fold, (1) using the TPB to detect changes in behaviour, and (2) quantifying UV exposure during the UK peak radiation season (April-September) using body-mounted UV sensors. DISCUSSION: This study will provide important information about the effectiveness of a technology-based intervention to promote sun-safety and healthy behaviours in outdoor construction workers. TRIAL REGISTRATION: ISRCTN15888934 retrospectively registered 15.01.2018.

The histone demethylase JMJD1A induces cell migration and invasion by up-regulating the expression of the long noncoding RNA MALAT1.

Patients with neuroblastoma due to N-Myc oncogene amplification have a high frequency of tumor metastasis. However, it is not clear how N-Myc induces cell migration, invasion and metastasis. The histone demethylase JMJD1A activates gene transcription by demethylating the lysine 9 residue of histone H3 (H3K9) at target gene promoters. The long noncoding RNA MALAT1 induces lung cancer cell migration and plays a pivotal role in lung cancer metastasis. Here we demonstrated that N-Myc up-regulated the expression of JMJD1A in N-Myc oncogene-amplified human neuroblastoma cells by directly binding to the JMJD1A gene promoter. Affymetrix microarray studies revealed that the gene second most significantly up-regulated by JMJD1A was MALAT1. Consistent with this finding, RT-PCR and chromatin immunoprecipitation assays showed that JMJD1A bound to the MALAT1 gene promoter and demethylated histone H3K9 at the MALAT1 gene promoter. Moreover, JMJD1A and MALAT1 induced, while the small molecule JMJD1A inhibitor DMOG suppressed, neuroblastoma cell migration and invasion. Taken together, our data identify a novel pathway through which N-Myc causes neuroblastoma cell migration and invasion, and provide important evidence for further development of more potent JMJD1A/MALAT1 inhibitors for the prevention of tumor metastasis.

Enhancing the anticancer effect of the histone deacetylase inhibitor by activating transglutaminase.

Histone deacetylase (HDAC) inhibitors have shown promising anticancer effects in clinical trials. However, a proportion of patients do not respond to HDAC inhibitor therapy. We have previously demonstrated that tissue transglutaminase (TG2) is one of the genes commonly up-regulated by HDAC inhibitors in vitro and in vivo, and that two structurally distinct TG2 protein isoforms, the full-length (TG2-L) and the short form (TG2-S), exert opposing effects on cell differentiation due to difference in transamidation activity. Here we show that the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) transcriptionally activates the expression of both TG2-L and TG2-S, and that up-regulation of TG2-L renders neuroblastoma cells less sensitive to SAHA-induced cytotoxicity. Combination therapy with SAHA and the transamidation activator Naringenin, a natural product found in citrus fruits, synergistically enhanced transamidation activity and SAHA-induced cytotoxicity in neuroblastoma cells, but not in normal non-malignant cells. In tumour-bearing N-Myc transgenic mice, SAHA and Naringenin synergistically suppressed tumour progression. Taken together, our data demonstrate that SAHA-induced TG2-L over-expression renders cancer cells less sensitive to SAHA therapy, and suggest the addition of Naringenin to SAHA and probably also other HDAC inhibitors in future clinical trials in cancer patients.

The prognostic importance of comorbidity for mortality in patients with stable coronary artery disease.

OBJECTIVES: To identify the prevalent and prognostically important coexisting illnesses among single coronary artery disease (CAD) patients. BACKGROUND: As the population ages, physicians are increasingly required to make decisions concerning patients with multiple co-existing illnesses (comorbidity). Many trials of CAD therapy have excluded patients with significant comorbidity, such that there are limited data to guide the management of those patients. METHODS: To consider the long-term prognostic importance of comorbid illness, we examined a cohort of 1471 patients with CAD who underwent cardiac catheterization between 1985 and 1989 and were followed up through 2000 in the Duke Databank for Cardiovascular Diseases. Weights were assigned to individual diseases according to their prognostic significance in Cox proportional hazards models, thus creating a new CAD-specific index. The new index was compared with the widely used Charlson index, according to prevalence of conditions, individual and overall associations with survival, and agreement. RESULTS: The Charlson index and the CAD-specific index were highly associated with long-term survival and almost equivalent to left ventricular ejection fraction. When considering the components of the Charlson index, diabetes, renal insufficiency, chronic obstructive pulmonary disease, and peripheral vascular disease had greater prognostic significance among CAD patients, whereas peptic ulcer disease, connective tissue disease, and lymphoma were less significant. Hemiplegia, leukemia, lymphoma, severe liver disease, and acquired immunodeficiency syndrome were rarely identified among patients undergoing coronary angiography. CONCLUSIONS: Comorbid disease is strongly associated with long-term survival in patients with CAD. These data suggest co-existing illnesses should be measured and considered in clinical trials, disease registries, quality comparisons, and counseling of individual patients.