Adult height and risk of breast cancer: a possible effect of early nutrition

The relationship of breast cancer to early reproductive development and height suggests that fetal and childhood nutrition may be important in its aetiology. Caloric restriction sufficient to reduce adult height may reduce breast cancer risk. During World War II (WWII) there was a marked reduction in average caloric intake in Norway that resulted in greater nutritional diversity. We hypothesized that a positive association between height and risk of breast cancer would be stronger among women who were born during this period than among women born before or after the war. A total of 25 204 Norwegian women were followed up for approximately 11 years, and 215 incident cases of breast cancer were registered. We found the strongest positive association between height and breast cancer among women born during WWII: women in the tallest tertile (>167 cm) had a relative risk of 2.5 (95% confidence interval = 1.2–5.5) compared with the shortest (≤ 162 cm). Among women born before or after the war we found no clear association with height. The association with height in the WWII cohort may imply a role for early nutrition in breast cancer aetiology. © 2001 Cancer Research Campaignhttp://www.bjcancer.co

Crimean-Congo hemorrhagic fever: epidemiological trends and controversies in treatment

Crimean-Congo hemorrhagic fever (CCHF) virus has the widest geographic range of all tick-borne viruses and is endemic in more than 30 countries in Eurasia and Africa. Over the past decade, new foci have emerged or re-emerged in the Balkans and neighboring areas. Here we discuss the factors influencing CCHF incidence and focus on the main issue of the use of ribavirin for treating this infection. Given the dynamics of CCHF emergence in the past decade, development of new anti-viral drugs and a vaccine is urgently needed to treat and prevent this acute, life-threatening disease

Comparative Structural Analysis of Human DEAD-Box RNA Helicases

DEAD-box RNA helicases play various, often critical, roles in all processes where RNAs are involved. Members of this family of proteins are linked to human disease, including cancer and viral infections. DEAD-box proteins contain two conserved domains that both contribute to RNA and ATP binding. Despite recent advances the molecular details of how these enzymes convert chemical energy into RNA remodeling is unknown. We present crystal structures of the isolated DEAD-domains of human DDX2A/eIF4A1, DDX2B/eIF4A2, DDX5, DDX10/DBP4, DDX18/myc-regulated DEAD-box protein, DDX20, DDX47, DDX52/ROK1, and DDX53/CAGE, and of the helicase domains of DDX25 and DDX41. Together with prior knowledge this enables a family-wide comparative structural analysis. We propose a general mechanism for opening of the RNA binding site. This analysis also provides insights into the diversity of DExD/H- proteins, with implications for understanding the functions of individual family members

Social-ecological outcomes of agricultural intensification

Land-use intensification in agrarian landscapes is seen as a key strategy to simultaneously feed humanity and use ecosystems sustainably, but the conditions that support positive social-ecological outcomes remain poorly documented. We address this knowledge gap by synthesizing research that analyses how agricultural intensification affects both ecosystem services and human well-being in low- and middle-income countries. Overall, we find that agricultural intensification is rarely found to lead to simultaneous positive ecosystem service and well-being outcomes. This is particularly the case when ecosystem services other than food provisioning are taken into consideration

Vasodilator factors in the systemic and local adaptations to pregnancy

We postulate that an orchestrated network composed of various vasodilatory systems participates in the systemic and local hemodynamic adaptations in pregnancy. The temporal patterns of increase in the circulating and urinary levels of five vasodilator factors/systems, prostacyclin, nitric oxide, kallikrein, angiotensin-(1–7) and VEGF, in normal pregnant women and animals, as well as the changes observed in preeclamptic pregnancies support their functional role in maintaining normotension by opposing the vasoconstrictor systems. In addition, the expression of these vasodilators in the different trophoblastic subtypes in various species supports their role in the transformation of the uterine arteries. Moreover, their expression in the fetal endothelium and in the syncytiotrophoblast in humans, rats and guinea-pigs, favour their participation in maintaining the uteroplacental circulation. The findings that sustain the functional associations of the various vasodilators, and their participation by endocrine, paracrine and autocrine regulation of the systemic and local vasoactive changes of pregnancy are abundant and compelling. However, further elucidation of the role of the various players is hampered by methodological problems. Among these difficulties is the complexity of the interactions between the different factors, the likelihood that experimental alterations induced in one system may be compensated by the other players of the network, and the possibility that data obtained by manipulating single factors in vitro or in animal studies may be difficult to translate to the human. In addition, the impossibility of sampling the uteroplacental interface along normal pregnancy precludes obtaining longitudinal profiles of the various players. Nevertheless, the possibility of improving maternal blood pressure regulation, trophoblast invasion and uteroplacental flow by enhancing vasodilation (e.g. L-arginine, NO donors, VEGF transfection) deserves unravelling the intricate association of vasoactive factors and the systemic and local adaptations to pregnancy

Targeting poly(ADP-ribose) polymerase activity for cancer therapy

Poly(ADP-ribosyl)ation is a ubiquitous protein modification found in mammalian cells that modulates many cellular responses, including DNA repair. The poly(ADP-ribose) polymerase (PARP) family catalyze the formation and addition onto proteins of negatively charged ADP-ribose polymers synthesized from NAD+. The absence of PARP-1 and PARP-2, both of which are activated by DNA damage, results in hypersensitivity to ionizing radiation and alkylating agents. PARP inhibitors that compete with NAD+ at the enzyme’s activity site are effective chemo- and radiopotentiation agents and, in BRCA-deficient tumors, can be used as single-agent therapies acting through the principle of synthetic lethality. Through extensive drug-development programs, third-generation inhibitors have now entered clinical trials and are showing great promise. However, both PARP-1 and PARP-2 are not only involved in DNA repair but also in transcription regulation, chromatin modification, and cellular homeostasis. The impact on these processes of PARP inhibition on long-term therapeutic responses needs to be investigated

Mapping Protein Interactions between Dengue Virus and Its Human and Insect Hosts

Dengue virus (DENV) represents a major disease burden in tropical and subtropical regions of the world, and has shown an increase in the number of cases in recent years. DENV is transmitted to humans through the bite of an infected mosquito, typically Aedes aegypti, after which it begins the infection and replication lifecycle within human cells. To perform the molecular functions required for invasion, replication, and spread of the virus, proteins encoded by DENV must interact with and alter the behavior of protein networks in both of these hosts. In this work, we used a computational method based on protein structures to predict interactions between DENV and its human and insect hosts. We predict numerous interactions, with many involved in known cell death, stress, and immune system pathways. Further investigation of these predicted protein-protein interactions should provide targets to combat the clinical manifestations of this disease in humans as well as points of intervention focused within the mosquito vector

Measurement of the angular coefficients in Z-boson events using electron and muon pairs from data taken at √s=8 TeV with the ATLAS detector

The angular distributions of Drell-Yan charged lepton pairs in the vicinity of the Z-boson mass peak probe the underlying QCD dynamics of Z-boson production. This paper presents a measurement of the complete set of angular coefficients A0−7 describing these distributions in the Z-boson Collins-Soper frame. The data analysed correspond to 20.3 fb−1 of pp collisions at s√=8s=8 TeV, collected by the ATLAS detector at the CERN LHC. The measurements are compared to the most precise fixed-order calculations currently available (O(α2s))(O(αs2)) and with theoretical predictions embedded in Monte Carlo generators. The measurements are precise enough to probe QCD corrections beyond the formal accuracy of these calculations and to provide discrimination between different parton-shower models. A significant deviation from the (O(α2s))(O(αs2)) predictions is observed for A0 − A2. Evidence is found for non-zero A5,6,7, consistent with expectations