Physical,Behavioural and Genetic Predictors of Adult Hypertension: The Findings of the Kaunas Cardiovascular Risk Cohort Study

Background

The roots of adult hypertension go back to childhood. This study aimed to examine the independent effects of physical, behavioural and genetic factors identified in childhood and mid-adulthood for prediction of adult hypertension.

Methods

The study subjects were participants of the Kaunas Cardiovascular Risk Cohort study started in 1977 (n = 1082, age 12–13 years). In 2012, a total of 507 individuals (63.9% of eligible sample) participated in the 35-year follow-up survey. Health examination involved measurements of blood pressure (BP), anthropometric parameters, and interview about health behaviours. Subjects were genotyped for AGT (M235T), ACE (I/D, rs4340), ADM (rs7129220), and CACNB2 (rs12258967) genes polymorphisms. A genetic risk score was calculated as the sum of the number of risk alleles at each of four single nucleotide polymorphisms.

Results

AGT TT genotype male carriers had the highest mean values of systolic BP in childhood. In females, ADM genotype AA was associated with the highest values of systolic and diastolic BP, while CACNB2 genotype CC carriers had the highest values of diastolic BP in childhood. Systolic and diastolic BP in childhood, gain in BMI from childhood to adulthood, and risky alcohol consumption predicted hypertension in middle-aged men. In women, genetic risk score together with diastolic BP in childhood and gain in BMI were significant predictors of adult hypertension. The comparison of four nested logistic regression models showed that the prediction of hypertension improved significantly after the addition of BMI gain. Genetic risk score had a relatively weak effect on the improvement of the model performance in women.

Conclusions

BP in childhood and the gain in BMI from childhood to adulthood were significant predictors of adult hypertension in both genders. Genetic risk score in women and risky alcohol consumption in men were independently related with the risk of adult hypertension.     

Electron transport across the plasmalemma of Lemna gibba G1

Lemna gibba L., grown in the presence or absence of Fe, reduced extracellular ferricyanide with a V _max of 3.09 mol · g^-1 fresh weight · h^-1 and a K _m of 115 M. However, Fe³⁺-ethylenediaminetetraacetic acid (EDTA) was reduced only after Fe-starvation. External electron acceptors such as ferricyanide, Fe³⁺-EDTA, 2,6-dichlorophenol indophenol or methylene blue induced a membrane depolarization of up to 100 mV, but electron donors such as ferrocyanide or NADH had no effect. Light or glucose enhanced ferricyanide reduction while the concomitant membrane depolarization was much smaller. Under anaerobic conditions, ferricyanide had no effect on electrical membrane potential difference (E_m). Ferricyanide reduction induced H⁺ and K⁺ release in a ratio of 1.16 H⁺+1 K⁺/2 e^- (in +Fe plants) and 1.28 H⁺+0.8 K⁺/2 e^- (in -Fe plants). Anion uptake was inhibited by ferricyanide reduction. It is concluded that the steady-state transfer of electrons and protons proceeds by separate mechanisms, by a redox system and by a H⁺-ATPase.Abbreviations E _m electrical membrane potential difference - EDTA ethylenediaminetetraacetic acid - DCPIP dichlorophenol indophenol - +Fe control plant - -Fe iron-deficient plant - FW fresh weight - H⁺ electrochemical proton gradient     

From START to FINISH: The Influence of Osmotic Stress on the Cell Cycle

The cell cycle is a sequence of biochemical events that are controlled by complex but robust molecular machinery. This enables cells to achieve accurate self-reproduction under a broad range of different conditions. Environmental changes are transmitted by molecular signalling networks, which coordinate their action with the cell cycle. The cell cycle process and its responses to environmental stresses arise from intertwined nonlinear interactions among large numbers of simpler components. Yet, understanding of how these pieces fit together into a coherent whole requires a systems biology approach. Here, we present a novel mathematical model that describes the influence of osmotic stress on the entire cell cycle of S. cerevisiae for the first time. Our model incorporates all recently known and several proposed interactions between the osmotic stress response pathway and the cell cycle. This model unveils the mechanisms that emerge as a consequence of the interaction between the cell cycle and stress response networks. Furthermore, it characterises the role of individual components. Moreover, it predicts different phenotypical responses for cells depending on the phase of cells at the onset of the stress. The key predictions of the model are: (i) exposure of cells to osmotic stress during the late S and the early G2/M phase can induce DNA re-replication before cell division occurs, (ii) cells stressed at the late G2/M phase display accelerated exit from mitosis and arrest in the next cell cycle, (iii) osmotic stress delays the G1-to-S and G2-to-M transitions in a dose dependent manner, whereas it accelerates the M-to-G1 transition independently of the stress dose and (iv) the Hog MAPK network compensates the role of the MEN network during cell division of MEN mutant cells. These model predictions are supported by independent experiments in S. cerevisiae and, moreover, have recently been observed in other eukaryotes.     

Synthesis and biological evaluation of novel mono- and bivalent ASGP-R-targeted drug-conjugates

Asialoglycoprotein receptor (ASGP-R) is a promising biological target for drug delivery into hepatoma cells. Nevertheless, there are only few examples of small-molecule conjugates of ASGP-R selective ligand equipped by a therapeutic agent for the treatment of hepatocellular carcinoma (HCC). In the present work, we describe a convenient and versatile synthetic approach to novel mono- and multivalent drug-conjugates containing N-acetyl-2-deoxy-2-aminogalactopyranose and anticancer drug – paclitaxel (PTX). Several molecules have demonstrated high affinity towards ASGP-R and good stability under physiological conditions, significant in vitro anticancer activity comparable to PTX, as well as good internalization via ASGP-R-mediated endocytosis. Therefore, the conjugates with the highest potency can be regarded as a promising therapeutic option against HCC.     

Life cycle assessment of lightweight and end-of-life scenarios for generic compact class passenger vehicles

Goal, Scope and Background  The automotive industry has a long history in improving the environmental performance of vehicles - fuel economy and emission improvements, introduction of recycled and renewable materials, etc. The European Union also aims at improving the environmental performance of products by reducing, in particular, waste resulting from End-of-Life Vehicles (ELVs) for example. The European Commission estimates that ELVs contribute to approximately 1 % of the total waste in Europe [9]. Other European Union strategies are considering more life cycle aspects, as well as other impacts including resource or climate change. This article is summarizing the results of a European Commission funded project (LIRECAR) that aims at identifying the environmental impacts and relevance for combinations of recycling / recovery and lightweight vehicle design options over the whole life cycle of a vehicle - i.e. manufacturing, use and recycling/recovery. Three, independent and scientific LCA experts reviewed the study according to ISO 14040. From the beginning, representatives of all Life Cycle Stakeholders have been involved (European materials & supplier associations, an environmental Non-Governmental Organization, recycler’s association). Model and System Definition  The study compared 3 sets of theoretical vehicle weight scenarios: 1000 kg reference (material range of today’s end-of-life, mid-sized vehicles produced in the early 1990’s) and 2 lightweight scenarios for 100 kg and 250 kg less weight based on reference functions (in terms of comfort, safety, etc.) and a vehicle concept. The scenarios are represented by their material range of a broad range of lightweight strategies of most European car manufacturers. In parallel, three End-of-Life (EOL) scenarios are considered: EOL today and two theoretical extreme scenarios (100% recycling, respectively, 100% recovery of shredder residue fractions that are disposed of today). The technical and economical feasibility of the studied scenarios is not taken into consideration (e.g. 100% recycling is not possible). Results and Discussion  Significant differences between the various, studied weight scenarios were determined in several scenarios for the environmental categories of global warming, ozone depletion, photochemical oxidant creation (summer smog), abiotic resource depletion, and hazardous waste. However, these improvement potentials can be only realized under well defined conditions (e.g. material compositions, specific fuel reduction values and EOL credits) based on case-by-case assessments for improvements over the course of the life cycle. Looking at the studied scenarios, the relative contribution of the EOL phase represents 5% or less of the total life cycle impact for most selected impact categories and scenarios. The EOL technology variations studied do not impact significantly the considered environmental impacts. Exceptions include total waste, as long as stockpile goods (overburden, tailings and ore/coal processing residues) and EOL credits are considered. Conclusions and Recommendations  LIRECAR focuses only on lightweight/recycling, questions whereas other measures (changes in safety or comfort standards, propulsion improvements for CO₂, user behavior) are beyond the scope of the study. The conclusions are also not necessarily transferable to other vehicle concepts. However, for the question of end-of-life options, it can be concluded that LIRECAR cannot support any general recommendation and/or mandatory actions to improve recycling if lightweight is affected. Also, looking at each vehicle, no justification could be found for the general assumption that lightweight and recycling greatly influence the affected environmental dimension (Global Warming Potential or resource depletion and waste, respectively). LIRECAR showed that this general assumption is not true under all analyzed circumstances and not as significant as suggested. Further discussions and product development targets shall not focus on generic targets that define the approach/technology concerned with how to achieve environmental improvement (weight reduction [kg], recycling quota [%]), but on overall life cycle improvement). To enable this case-by-case assessment, exchanges of necessary information with suppliers are especially relevant.     

Knowing your habitat: linking patch-encounter rate and patch exploitation in parasitoids

According to optimal foraging theory, animals should decidewhether or not to leave a resource patch by comparing the currentprofitability of the patch with the expected profitability ofsearching elsewhere in the habitat. Although there is abundantevidence in the literature that foragers in general are wellable to estimate the value of a single resource patch, theirdecision making has rarely been investigated with respect tohabitat quality. This is especially true for invertebrates.We have conducted experiments to test whether parasitic waspsadjust patch residence time and exploitation in relation tothe abundance of patches within the environment. We used thebraconid Asobara tabida, a parasitoid of Drosophila larvae,as our model species. Our experiments show that these waspsreduce both the residence time and the degree of patch exploitationwhen patches become abundant in their environment, as predictedby optimal foraging models. Based upon a detailed analysis ofwasp foraging behavior, we discuss proximate mechanisms thatmight lead to the observed response. We suggest that parasitoidsuse a mechanism of sensitization and desensitization to chemicalsassociated with hosts and patches, in order to respond adaptivelyto the abundance of patches within their environment.     

Molecular dynamics simulations of photoactive yellow protein (PYP) in three states of its photocycle: a comparison with X-ray and NMR data and analysis of the effects of Glu46 deprotonation and mutation

Photoactive yellow protein (PYP) is a prototype of the PAS domain superfamily of signaling proteins. The signaling process is coupled to a three-state photocycle. After the photoinduced trans-cis isomerization of the chromophore, 4-hydroxycinnamic acid (pCA), an early intermediate (pR) is formed, which proceeds to a second intermediate state (pB) on a sub-millisecond time scale. The signaling process is thought to be connected to the conformational changes upon the formation of pB and its recovery to the ground state (pG), but the exact signaling mechanism is not known. Experimental studies of PYP by solution NMR and X-ray crystallography suggest a very flexible protein backbone in the ground as well as in the signaling state. The relaxation from the pR to the pB state is accompanied by the protonation of the chromophore's phenoxyl group. This was found to be of crucial importance for the relaxation process. With the goal of gaining a better understanding of these experimental observations on an atomistic level, we performed five MD simulations on the three different states of PYP: a 1 ns simulation of PYP in its ground state [pG(MD)], a 1 ns simulation of the pR state [pR(MD)], a 2 ns simulation of the pR state with the chromophore protonated (pRprot), a 2 ns simulation of the pR state with Glu46 exchanged by Gln (pRGln) and a 2 ns simulation of PYP in its signaling state [pB(MD)]. Comparison of the pG simulation results with X-ray and NMR data, and with the results obtained for the pB simulation, confirmed the experimental observations of a rather flexible protein backbone and conformational changes during the recovery of the pG from the pB state. The conformational changes in the region around the chromophore pocket in the pR state were found to be crucially dependent on the strength of the Glu46-pCA hydrogen bond, which restricts the mobility of the chromophore in its unprotonated form considerably. Both the mutation of Glu46 with Gln and the protonation of the chromophore weaken this hydrogen bond, leading to an increased mobility of pCA and large structural changes in its surroundings. These changes, however, differ considerably during the pRGln and pRprot simulations, providing an atomistic explanation for the enhancement of the rate constant in the Gln46 mutant. Electronic supplementary material to this article is available at and is accessible for athorized users. Electronic Publication