BZLF1, an Epstein–Barr virus immediate–early protein, induces p65 nuclear translocation while inhibiting p65 transcriptional function

AbstractWe have previously demonstrated that the Epstein–Barr virus immediate–early BZLF1 protein interacts with, and is inhibited by, the NF-κB family member p65. However, the effects of BZLF1 on NF-κB activity have not been intensively studied. Here we show that BZLF1 inhibits p65-dependent gene expression. BZLF1 inhibited the ability of IL-1, as well as transfected p65, to activate the expression of two different NF-κB-responsive genes, ICAM-1 and IκB-α. BZLF1 also reduced the constitutive level of IκB-α protein in HeLa and A549 cells, and increased the amount of nuclear NF-κB to a similar extent as tumor necrosis factor-alpha (TNF-α) treatment. In spite of this BZLF1-associated increase in the nuclear form of NF-κB, BZLF1 did not induce binding of NF-κB to NF-κB responsive promoters (as determined by chromatin immunoprecipitation assay) in vivo, although TNF-α treatment induced NF-κB binding as expected. Overexpression of p65 dramatically inhibited the lytic replication cycle of EBV in 293-EBV cells, confirming that NF-κB also inhibits BZLF1 transcriptional function. Our results are consistent with a model in which BZLF1 inhibits the transcriptional function of p65, resulting in decreased transcription of IκB-α, decreased expression of IκB-α protein, and subsequent translocation of NF-κB to the nucleus. This nuclear translocation of NF-κB may promote viral latency by negatively regulating BZLF1 transcriptional activity. In situations where p65 activity is limiting in comparison to BZLF1, the ability of BZLF1 to inhibit p65 transcriptional function may protect the virus from the host immune system during the lytic form of infection

Effect of high parity on occurrence of anemia in pregnancy: a cohort study

<p>Abstract</p> <p>Background</p> <p>Studies that explore the controversial association between parity and anaemia-in-pregnancy (AIP) were often hampered by not distinguishing incident cases caused by pregnancy from prevalent cases complicated by pregnancy. The authors' aim in conducting this study was to overcome this methodological concern.</p> <p>Methods</p> <p>A retrospective cohort study was conducted in Oman on 1939 pregnancies among 479 parous female participants with available pregnancy records in a community trial. We collected information from participants, the community trial, and health records of each pregnancy. Throughout the follow-up period, we enumerated 684 AIP cases of which 289 (42.2%) were incident cases. High parity (HP, ≥ 5 pregnancies) accounted for 48.7% of total pregnancies. Two sets of regression analyses were conducted: the first restricted to incident cases only, and the second inclusive of all cases. The relation with parity as a dichotomy and as multiple categories was examined for each set; multi-level logistic regression (MLLR) was employed to produce adjusted models.</p> <p>Results</p> <p>In the fully adjusted MLLR models that were restricted to incident cases, women with HP pregnancies had a higher risk of AIP compared to those who had had fewer pregnancies (Risk Ratio, RR = 2.92; 95% CI 2.02, 4.59); the AIP risk increased in a dose-response fashion over multiple categories of parity. In the fully adjusted MLLR models that included all cases, the association disappeared (RR = 1.11; 95% CI 0.91, 1.18) and the dose-response pattern flattened.</p> <p>Conclusions</p> <p>This study shows the importance of specifying which cases of AIP are incident and provides supportive evidence for a causal relation between parity and occurrence of incidental AIP.</p

Design of the New Life(style) study: a randomised controlled trial to optimise maternal weight development during pregnancy. [ISRCTN85313483]

BACKGROUND: Preventing excessive weight gain during pregnancy is potentially important in the prevention of overweight and obesity among women of childbearing age. However, few intervention studies aiming at weight management during pregnancy have been performed and most of these interventions were not as successful as expected. In this paper the design of the New Life(style) study is described as well as the content of the individually tailored intervention program, which focuses on controlling weight development during pregnancy. METHODS: The effectiveness of the New Life(style) intervention program versus usual care by midwives is evaluated in a randomised controlled trial. Women who expect their first child and visit one of the participating midwifery practices are included. The intervention is standardised in a protocol and executed by trained counsellors with the women who are randomised in the intervention group. During 5 sessions – at 18, 22, 30 and 36 weeks of pregnancy and at 8 weeks postpartum – individual weight gain is discussed in relation to weight gain guidelines for pregnant women of the American Institute of Medicine. Counsellors coach the women to maintain or optimise a healthy lifestyle, in a period of drastic physical and mental changes. Data is collected at 15, 25, 35 weeks of pregnancy and at 6, 26, and 52 weeks after delivery. Primary outcome measures are body weight, BMI, and skinfold thickness. Secondary outcome measures include physical activity, nutrition and blood levels of factors that are associated with energy homeostasis. DISCUSSION: Results of the current RCT will improve the knowledge of determinants of weight gain during pregnancy, weight retention after childbirth and of the effectiveness of the intervention program that is described. Caregivers and researchers in the field of health promotion are offered more insight in specific elements of the New Life(style) intervention program

Strong HLA-DR expression in microsatellite stable carcinomas of the large bowel is associated with good prognosis

Progression of colorectal cancer may follow either of two main genetic routes: the chromosome- or microsatellite-instability pathways. Association between the patients' prognosis and microsatellite instability has been questioned. Improved survival has previously been found in patients with expression of HLA-DR antigens on their tumour cells. In this study, the expression of HLA-DR antigen was investigated by immunohistochemistry in 357 large bowel carcinomas stratified by microsatellite instability status. Sixteen per cent of the tumours showed strong HLA-DR expression and 35% had weak DR expression. We confirmed that patients with strong positive HLA-DR staining had improved survival (P<0.001) compared to patients with no HLA-DR expression. Strong epithelial HLA-DR staining was significantly associated with high level of microsatellite instability (P<0.001). In the subgroup of tumours with characteristics typical of the chromosomal instability phenotype, i.e. in microsatellite-stable tumours, the patients positive for the HLA-DR determinants showed better survival than those without HLA-DR expression. The protective effect of HLA-DR expression on survival was confirmed by multivariate analysis, both in the whole patient group and in the microsatellite-stable/microsatellite instability-low group. This might be explained by enhanced T-cell mediated anti-tumour immune responses against tumour cells in the HLA-DR positive tumours. The finding of better patient survival in the subgroup of strong HLA-DR positive microsatellite-stable tumours may have clinical implications for these patients

An effector from the Huanglongbing-associated pathogen targets citrus proteases

The citrus industry is facing an unprecedented challenge from Huanglongbing (HLB). All cultivars can be affected by the HLB-associated bacterium ‘Candidatus Liberibacter asiaticus’ (CLas) and there is no known resistance. Insight into HLB pathogenesis is urgently needed in order to develop effective management strategies. Here, we use Sec-delivered effector 1 (SDE1), which is conserved in all CLas isolates, as a molecular probe to understand CLas virulence. We show that SDE1 directly interacts with citrus papain-like cysteine proteases (PLCPs) and inhibits protease activity. PLCPs are defense-inducible and exhibit increased protein accumulation in CLas-infected trees, suggesting a role in citrus defense responses. We analyzed PLCP activity in field samples, revealing specific members that increase in abundance but remain unchanged in activity during infection. SDE1-expressing transgenic citrus also exhibit reduced PLCP activity. These data demonstrate that SDE1 inhibits citrus PLCPs, which are immune-related proteases that enhance defense responses in plants

Continental flood basalts derived from the hydrous mantle transition zone

It has previously been postulated that the Earth's hydrous mantle transition zone may play a key role in intraplate magmatism, but no confirmatory evidence has been reported. Here we demonstrate that hydrothermally altered subducted oceanic crust was involved in generating the late Cenozoic Chifeng continental flood basalts of East Asia. This study combines oxygen isotopes with conventional geochemistry to provide evidence for an origin in the hydrous mantle transition zone. These observations lead us to propose an alternative thermochemical model, whereby slab-triggered wet upwelling produces large volumes of melt that may rise from the hydrous mantle transition zone. This model explains the lack of pre-magmatic lithospheric extension or a hotspot track and also the arc-like signatures observed in some large-scale intracontinental magmas. Deep-Earth water cycling, linked to cold subduction, slab stagnation, wet mantle upwelling and assembly/breakup of supercontinents, can potentially account for the chemical diversity of many continental flood basalts

The XMM Cluster Survey: Exploring scaling relations and completeness of the Dark Energy Survey Year 3 redMaPPer cluster catalogue

We cross-match and compare characteristics of galaxy clusters identified in observations from two sky surveys using two completely different techniques. One sample is optically selected from the analysis of three years of Dark Energy Survey observations using the redMaPPer cluster detection algorithm. The second is X-ray selected from XMM observations analysed by the XMM Cluster Survey. The samples comprise a total area of 57.4 deg$^2$, bounded by the area of 4 contiguous XMM survey regions that overlap the DES footprint. We find that the X-ray selected sample is fully matched with entries in the redMaPPer catalogue, above $\lambda>$20 and within 0.1$< z <$0.9. Conversely, only 38\% of the redMaPPer catalogue is matched to an X-ray extended source. Next, using 120 optically clusters and 184 X-ray selected clusters, we investigate the form of the X-ray luminosity-temperature ($L_{X}-T_{X}$), luminosity-richness ($L_{X}-\lambda$) and temperature-richness ($T_{X}-\lambda$) scaling relations. We find that the fitted forms of the $L_{X}-T_{X}$ relations are consistent between the two selection methods and also with other studies in the literature. However, we find tentative evidence for a steepening of the slope of the relation for low richness systems in the X-ray selected sample. When considering the scaling of richness with X-ray properties, we again find consistency in the relations (i.e., $L_{X}-\lambda$ and $T_{X}-\lambda$) between the optical and X-ray selected samples. This is contrary to previous similar works that find a significant increase in the scatter of the luminosity scaling relation for X-ray selected samples compared to optically selected samples.Comment: Accepted for publication to MNRA

Dark Energy Survey year 1 results: cosmological constraints from cluster abundances and weak lensing

We perform a joint analysis of the counts and weak lensing signal of redMaPPer clusters selected from the Dark Energy Survey (DES) Year 1 dataset. Our analysis uses the same shear and source photometric redshifts estimates as were used in the DES combined probes analysis. Our analysis results in surprisingly low values for S8=σ8(Ωm/0.3)0.5=0.65±0.04, driven by a low matter density parameter, Ωm=0.179+0.031−0.038, with σ8−Ωm posteriors in 2.4σ tension with the DES Y1 3x2pt results, and in 5.6σ with the Planck CMB analysis. These results include the impact of post-unblinding changes to the analysis, which did not improve the level of consistency with other data sets compared to the results obtained at the unblinding. The fact that multiple cosmological probes (supernovae, baryon acoustic oscillations, cosmic shear, galaxy clustering and CMB anisotropies), and other galaxy cluster analyses all favor significantly higher matter densities suggests the presence of systematic errors in the data or an incomplete modeling of the relevant physics. Cross checks with x-ray and microwave data, as well as independent constraints on the observable-mass relation from Sunyaev-Zeldovich selected clusters, suggest that the discrepancy resides in our modeling of the weak lensing signal rather than the cluster abundance. Repeating our analysis using a higher richness threshold (λ≥30) significantly reduces the tension with other probes, and points to one or more richness-dependent effects not captured by our model