Onecut is a direct neural-specific transcriptional activator of Rx in Ciona intestinalis

AbstractRetinal homeobox (Rx) genes play a crucial and conserved role in the development of the anterior neural plate of metazoans. During chordate evolution, they have also acquired a novel function in the control of eye formation and neurogenesis. To characterize the Rx genetic cascade and shed light on the mechanisms that led to the acquisition of this new role in eye development, we studied Rx transcriptional regulation using the ascidian, Ciona intestinalis. Through deletion analysis of the Ci-Rx promoter, we have identified two distinct enhancer elements able to induce Ci-Rx specific expression in the anterior part of the CNS and in the photosensory organ at tailbud and larva stages. Bioinformatic analysis highlighted the presence of two Onecut binding sites contained in these enhancers, so we explored the role of this transcription factor in the regulation of Ci-Rx. By in situ hybridization, we first confirmed that these genes are co-expressed in the same cells. Through a series of in vivo and in vitro experiments, we then demonstrated that the two Onecut sites are responsible for enhancer activation in Ci-Rx endogenous territories. We also demonstrated in vivo that Onecut misexpression is able to induce ectopic activation of the Rx promoter. Finally, we demonstrated that Ci-Onecut is able to promote Ci-Rx expression in the sensory vesicle. Together, these results support the conclusion that in Ciona embryogenesis, Ci-Rx expression is under the control of the Onecut transcription factor and that this factor is necessary and sufficient to specifically activate Ci-Rx through two enhancer elements

The Mitochondrial A10398G Polymorphism, Interaction with Alcohol Consumption, and Breast Cancer Risk

Polymorphisms in the mitochondrial genome are hypothesized to be associated with risk of various diseases, including cancer. However, there has been conflicting evidence for associations between a common polymorphism in the mitochondrial genome (A10398G, G10398A in some prior reports) and breast cancer risk. Reactive oxygen species, a by-product of mitochondrial energy production, can lead to oxidative stress and DNA damage in both the mitochondria and their cells. Alcohol consumption, which may also lead to oxidative stress, is associated with breast cancer risk. Therefore, we hypothesized that polymorphisms in the mitochondrial genome interact with alcohol consumption to alter breast cancer risk. We genotyped the A10398G polymorphism in a case-control study nested within the Nurses' Health Study (NHS, 1,561 cases, 2,209 controls). We observed an interaction between alcohol consumption (yes/no) and A10398G on breast cancer risk (p-int = 0.03). The risk associated with alcohol consumption was limited to carriers of the 10398G allele (Odds Ratio 1.52, 95% Confidence Interval 1.10–2.08 comparing drinkers to non-drinkers). However, we were unable to replicate these findings in the Women's Health Study (WHS, 678 cases, 669 controls), although the power to detect this interaction in the WHS was low (power = 0.57). Further examination of this interaction, such as sufficiently powered epidemiological studies of cancer risk or associations with biomarkers of oxidative stress, may provide further evidence for GxE interactions between the A10398G mitochondrial polymorphism and alcohol consumption on breast cancer risk

Baseline Characteristics of Study Participants from the Nurses' Health Study and Women's Health Study

<p>Baseline Characteristics of Study Participants from the Nurses' Health Study and Women's Health Study</p

Interaction between A10398G, Alcohol Consumption, and Breast Cancer Risk in the Nurses' Health Study (NHS) and the Women's Health Study (WHS)

*<p>Unconditional logistic regression controlling for fasting status, date and time of blood draw, age, body mass index (at blood draw and age 18), menopausal status, family history of breast cancer and history of benign breast disease. P-interaction = 0.03</p>**<p>Unconditional logistic regression controlling for age, history of benign breast disease and family history of breast cancer. P-interaction = 0.95</p

People living with undiagnosed HIV infection and a low CD4 count: Estimates from surveillance data, Italy, 2012 to 2014

Background and aims: Late HIV diagnosis is associated with onward HIV transmission, higher morbidity, mortality and healthcare costs. In Italy, more than half of people living with HIV were diagnosed late during the last decade, with a CD4 count < 350 cells/mm3 at diagnosis. We aimed to determine the number and characteristics of people living with undiagnosed HIV infection and low CD4 counts in Italy. Methods: Data on newly reported HIV diagnoses from 2012 \u20132014 were obtained from the national HIV surveillance system. We used the European Centre for Disease Prevention and Control HIV modelling tool to calculate the undiagnosed prevalence and yearly diagnosed fraction (YDF) in people with low CD4 count. Results: The estimated annual number undiagnosed HIV infections with low CD4 count was on average 6,028 (95% confidence interval (CI): 4,954\u20138,043) from 2012\u20132014. In 2014, most of the undiagnosed people with low CD4 count were men (82.8%), a third acquired HIV through sex between men (MSM) (35.0%), and heterosexual transmission (33.4%), respectively. The prevalence of undiagnosed HIV infection was 11.3 (95% CI: 9.3\u201314.9) per 100,000 residents ranging from 0.7 to 20.8 between Italian regions. Nationally the prevalence rate was 280.4 (95% CI: 173.3\u2013450.2) per 100,000 MSM, 8.3 (95% CI: 4.9\u201313.6) per 100,000 heterosexual men, and 3.0 (95% CI: 1.4\u20135.6) per 100,000 women. The YDF was highest among heterosexual women (27.1%; 95% CI: 16.9\u201345.2%). Conclusions: These findings highlight the importance of improving efforts to identify undiagnosed HIV infections primarily among men, both MSM and heterosexual men