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Little research has assessed serum 25-hydroxyvitamin D (25(OH)D) concentration and its predictors in Western-dwelling South Asians in a relatively large sample size. This observational, cross-sectional analysis assessed baseline prevalence of 25(OH)D deficiency in UK-dwelling South Asians (aged 40–69 years, 2006–2010) from the UK Biobank Cohort. Serum 25(OH)D measurements were undertaken using the DiaSorin Liaison XL assay. Of 6433 South Asians with a 25(OH)D measurement, using commonly used cut-off thresholds, 55 % (n 3538) had 25(OH)D < 25 nmol/l (severe deficiency) and 92 % (n 5918) had 25(OH)D < 50 nmol/l (insufficiency). Of the participants with a measurement, 20 % (n 1287) had 25(OH)D concentration <15 nmol/l (very severe deficiency). When 824 participants with undetectable (<10 nmol/l) 25(OH)D measurements were included (total n 7257), 29 % (n 2105) had 25(OH)D < 15 nmol/l, 60 % (n 4354) had 25(OH)D < 25 nmol/l and 93 % (n 6749) had 25(OH)D < 50 nmol/l. Logistic regression predictors of 25(OH)D < 25 nmol/l included the following characteristics: being male; Pakistani; higher BMI; 40–59 years old; never consuming oily fish; summer sun exposure <5 h/d, not using a vitamin D-containing supplement, measurement in winter or spring and vegetarianism. In terms of region, median 25(OH)D concentration was 19–20 nmol/l in Scotland, Northern England, the Midlands and Wales. Across Southern England and London, it was slightly higher at 24–25 nmol/l. Our analyses suggest the need for increased awareness of vitamin D deficiency in South Asians as well as urgent public health interventions to prevent and treat vitamin D deficiency in this group.

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of several human malignancies. Human tumour viruses such as KSHV are known to interact with the DNA damage response (DDR), the molecular pathways that recognise and repair lesions in cellular DNA. Here it is demonstrated that lytic reactivation of KSHV leads to activation of the ATM and DNA-PK DDR kinases resulting in phosphorylation of multiple downstream substrates. Inhibition of ATM results in the reduction of overall levels of viral replication while inhibition of DNA-PK increases activation of ATM and leads to earlier viral release. There is no activation of the ATR-CHK1 pathway following lytic replication and CHK1 phosphorylation is inhibited at later times during the lytic cycle. Despite evidence of double-strand breaks and phosphorylation of H2AX, 53BP1 foci are not consistently observed in cells containing lytic virus although RPA32 and MRE11 localise to sites of viral DNA synthesis. Activation of the DDR following KSHV lytic reactivation does not result in a G1 cell cycle block and cells are able to proceed to S-phase during the lytic cycle. KSHV appears then to selectively activate DDR pathways, modulate cell cycle progression and recruit DDR proteins to sites of viral replication during the lytic cycle.

Vitamin D deficiency (serum 25-hydroxyvitamin D<25nmol/L) is extremely common in western-dwelling South Asians but evidence regarding vitamin D supplement usage in this group is very limited. This work identifies demographic, dietary and lifestyle predictors associated with vitamin D supplement use. Cross-sectional analysis of baseline vitamin D supplement use data. UK Biobank cohort. In total, n 8024 South Asians (Bangladeshi, Indian, Pakistani), aged 40-69 years. Twenty-three % of men and 39% of women (P<0.001) [22% of Bangladeshis, 32% of Indians, 25% of Pakistanis (P<0.001)] took a vitamin D containing supplement. Median vitamin D intakes from diet were low at 1.0-3.0 micrograms per day, being highest in Bangladeshis and lowest in Indians (P<0.001). Logistic regression modelling showed that females had a higher odds of vitamin D supplement use than males (odds ratio (OR) = 2.02; 95% confidence interval (CI) 1.79 to 2.28). A lower supplement usage was seen in younger persons (40-60 years) (OR=0.75; 95% CI 0.65 to 0.86 reference= >60 years), and those living outside of Greater London (OR=0.53 to 0.77), with borderline trends for a lower body mass index, higher oily fish intake and higher household income associated with increased odds of vitamin D supplement use. Vitamin D supplements were not used by most South Asians and intakes from diet alone are likely to be insufficient to maintain adequate vitamin D status. Public health strategies are now urgently required to promote the use of vitamin D supplements in these specific UK South Asian subgroups.

The hTREX complex mediates cellular bulk mRNA nuclear export by recruiting the nuclear export factor, TAP, via a direct interaction with the export adaptor, Aly. Intriguingly however, depletion of Aly only leads to a modest reduction in cellular mRNA nuclear export, suggesting the existence of additional mRNA nuclear export adaptor proteins. In order to efficiently export Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs from the nucleus, the KSHV ORF57 protein recruits hTREX onto viral intronless mRNAs allowing access to the TAP-mediated export pathway. Similarly however, depletion of Aly only leads to a modest reduction in the nuclear export of KSHV intronless mRNAs. Herein, we identify a novel interaction between ORF57 and the cellular protein, UIF. We provide the first evidence that the ORF57-UIF interaction enables the recruitment of hTREX and TAP to KSHV intronless mRNAs in Aly-depleted cells. Strikingly, depletion of both Aly and UIF inhibits the formation of an ORF57-mediated nuclear export competent ribonucleoprotein particle and consequently prevents ORF57-mediated mRNA nuclear export and KSHV protein production. Importantly, these findings highlight that redundancy exists in the eukaryotic system for certain hTREX components involved in the mRNA nuclear export of intronless KSHV mRNAs.

The vitamin D status of the United Kingdom (UK) African-Caribbean (AC) population remains under-researched, despite an increased risk of vitamin D deficiency due to darker skin phenotypes and living at a high latitude. This cross-sectional study explored the vitamin D status and intake of AC individuals (n = 4046 with a valid serum 25(OH)D measurement) from the UK Biobank Cohort, aged ≥40 years at baseline (2006–2010). Over one third of the population were deficient (<25 nmol/L), 41.1% were insufficient (25–50 nmol/L) and 15.9% were sufficient (>50 nmol/L). Median (IQR) 25(OH)D was 30.0 (20.9) nmol/L. Logistic regression showed that brown/black skin phenotype, winter blood draw, not consuming oily fish and not using vitamin D supplements predicted increased odds of vitamin D deficiency, whilst older age and a summer or autumn blood draw were significantly associated with reduced odds of vitamin D deficiency. Vitamin D deficiency and insufficiency were prevalent in this AC population and is of considerable concern given the individual and societal implications of increased morbidity. Public health messaging for this group should focus on year-round vitamin D supplementation and increasing intakes of culturally appropriate vitamin D-rich foods. These data also support the urgent requirement for a revised vitamin D RNI for ethnic groups.

These essays do not assume the primacy of national allegiance. Instead, by using the ?sense of place? as a prism to look at German identity in new ways, they examine a sense of ?Germanness? that was neither self-evident nor unchanging.

Background Aflatoxin B 1 (AFB 1 ) contamination of food is very high in most sub-Saharan African countries. AFB 1 is known to cause hepatocellular carcinoma (HCC) by inducing mutation in the tumour suppressor gene TP53. The number of new HCC cases is high in West Africa with an accompanying high mortality. The type I interferon (IFN) pathway of the innate immune system limits viral infections and exerts its anti-cancer property by up-regulating tumour suppressor activities and pro-apoptotic pathways. Indeed, IFN-α is reported to show significant protective effects against hepatic fibrogenesis and carcinogenesis. However, the mechanism behind AFB 1 deregulation of the type I interferon (IFN) signalling pathway, with consequent HCC is largely unknown. This current study seeks to test the hypothesis that AFB 1 inhibits the type I IFN response by directly interfering with key signalling proteins and thus increase the risk of HCC in humans. Methods We evaluated the effects of AFB 1 on the type I IFN signalling pathway using IFN stimulated response element (ISRE)-based luciferase reporter gene assay. In addition, the effects of AFB 1 on the transcript levels of JAK1 , STAT1 and OAS3 were assessed by real-time quantitative polymerase chain reaction (RT-qPCR) and confirmed by immunoblot assay. Results Our results indicated that AFB 1 inhibited the type I IFN signalling pathway in human hepatoma cell line HepG2 cells by suppressing the transcript levels of JAK1 , STAT1 and OAS3 . AFB 1 also decreased the accumulation of STAT1 protein. Conclusion The inhibition of the type I IFN anti-cancer response pathway by AFB 1 suggest a novel mechanism by which AFB 1 may induce hepatocellular carcinoma in humans.

Merkel cell carcinoma (MCC) is an aggressive poorly differentiated neuroendocrine cutaneous carcinoma associated with older age, immunodeficiency and Merkel cell polyomavirus (MCPyV) integrated within malignant cells. The presence of intra-tumoural CD8+ lymphocytes reportedly predicts better MCC-specific survival. In this study, the distribution of inflammatory cells and properties of CD8+ T lymphocytes within 20 primary MCC specimens were characterised using immunohistochemistry and multicolour immunofluorescent staining coupled to confocal microscopy. CD8+ cells and CD68+ macrophages were identified in 19/20 primary MCC. CD20+ B cells were present in 5/10, CD4+ cells in 10/10 and FoxP3+ cells in 7/10 specimens. Only two specimens had almost no inflammatory cells. Within specimens, inflammatory cells followed the same patchy distribution, focused at the edge of sheets and nodules and, in some cases, more intense in trabecular areas. CD8+ cells were outside vessels on the edge of tumour. Those few within malignant sheets typically lined up in fine septa not contacting MCC cells expressing MCPyV large T antigen. The homeostatic chemokine CXCL12 was expressed outside malignant nodules whereas its receptor CXCR4 was identified within tumour but not on CD8+ cells. CD8+ cells lacked CXCR3 and granzyme B expression irrespective of location within stroma versus malignant nodules or of the intensity of the intra-tumoural infiltrate. In summary, diverse inflammatory cells were organised around the margin of malignant deposits suggesting response to aberrant signaling, but were unable to penetrate the tumour microenvironment itself to enable an immune response against malignant cells or their polyomavirus.

Much of the evidence that human herpesvirus type 8 (HHV-8) is associated with Kaposi's sarcoma (KS) has come from molecular studies of HHV-8 DNA. Seroepidemiological studies have been hampered by the lack of a reliable assay. The serological data reported here were obtained by means of a mouse monoclonal antibody-enhanced immunofluorescence assay for antibodies to lytic and latent HHV-8 antigens. 1435 single samples of serum (or plasma) from many different disease groups and parts of the world were assayed. All patients with African endemic KS and 96% of American patients with AIDS-associated KS were seropositive for lytic antigen, as were 90% of American HIV-infected homosexual men; by contrast only 23% of HIV-seropositive drug users and 21% of HIV-seropositive women were positive for HHV-8 antibody. Factor VIII treatment before 1983 did not increase the risk of HHV-8 infection in patients with haemophilia. In the American general population, about 25% of adults (including volunteer blood donors) and 2–8% of children had antibodies to HHV-8. Our data are consistent with HHV-8 being primarily associated with sexual transmission, but the HHV-8 seropositivity rate in American children suggests that there is a non-sexual route of HHV-8 infection also. On the evidence available so far, the risk of parenteral transmission is low.