Neutron Capture on the s-Process Branching Point

The neutron capture cross sections of several unstable nuclides acting as branching points in the s process are crucial for stellar nucleosynthesis studies. The unstable ^{171}Tm (t_{1/2}=1.92 yr) is part of the branching around mass A∼170 but its neutron capture cross section as a function of the neutron energy is not known to date. In this work, following the production for the first time of more than 5 mg of ^{171}Tm at the high-flux reactor Institut Laue-Langevin in France, a sample was produced at the Paul Scherrer Institute in Switzerland. Two complementary experiments were carried out at the neutron time-of-flight facility (n_TOF) at CERN in Switzerland and at the SARAF liquid lithium target facility at Soreq Nuclear Research Center in Israel by time of flight and activation, respectively. The result of the time-of-flight experiment consists of the first ever set of resonance parameters and the corresponding average resonance parameters, allowing us to make an estimation of the Maxwellian-averaged cross sections (MACS) by extrapolation. The activation measurement provides a direct and more precise measurement of the MACS at 30 keV: 384(40) mb, with which the estimation from the n_TOF data agree at the limit of 1 standard deviation. This value is 2.6 times lower than the JEFF-3.3 and ENDF/B-VIII evaluations, 25% lower than that of the Bao et al. compilation, and 1.6 times larger than the value recommended in the KADoNiS (v1) database, based on the only previous experiment. Our result affects the nucleosynthesis at the A∼170 branching, namely, the ^{171}Yb abundance increases in the material lost by asymptotic giant branch stars, providing a better match to the available pre-solar SiC grain measurements compared to the calculations based on the current JEFF-3.3 model-based evaluation.

The Role of Flaviviral Proteins in the Induction of Innate Immunity.

Flaviviruses are positive, single-stranded, enveloped cytoplasmic sense RNA viruses that cause a variety of important diseases worldwide. Among them, Zika virus, West Nile virus, Japanese encephalitis virus, and Dengue virus have the potential to cause severe disease. Extensive studies have been performed to elucidate the structure and replication strategies of flaviviruses, and current studies are aiming to unravel the complex molecular interactions between the virus and host during the very early stages of infection. The outcomes of viral infection and rapid establishment of the antiviral state, depends on viral detection by pathogen recognition receptors and rapid initiation of signalling cascades to induce an effective innate immune response. Extracellular and intracellular pathogen recognition receptors play a crucial role in detecting flavivirus infection and inducing a robust antiviral response. One of the main hallmarks of flaviviral nonstructural proteins is their multiple strategies to antagonise the interferon system. In this chapter, we summarize the molecular characteristics of flaviviral proteins and discuss how viral proteins target different components of the interferon signalling pathway by blocking phosphorylation, enhancing degradation, and downregulating the expression of major components of the Janus kinase/signal transducer and activator of transcription pathway. We also discuss how the interactions of viral proteins with host proteins facilitate viral pathogenesis. Due to the lack of antivirals or prophylactic treatments for many flaviviral infections, it is necessary to fully elucidate how these viruses disrupt cellular processes to influence pathogenesis and disease outcomes.

Stellar

The ^{36}Ar(n,γ)^{37}Ar (t_{1/2}=35 d) and ^{38}Ar(n,γ)^{39}Ar (269 yr) reactions were studied for the first time with a quasi-Maxwellian (kT∼47 keV) neutron flux for Maxwellian average cross section (MACS) measurements at stellar energies. Gas samples were irradiated at the high-intensity Soreq applied research accelerator facility-liquid-lithium target neutron source and the ^{37}Ar/^{36}Ar and ^{39}Ar/^{38}Ar ratios in the activated samples were determined by accelerator mass spectrometry at the ATLAS facility (Argonne National Laboratory). The ^{37}Ar activity was also measured by low-level counting at the University of Bern. Experimental MACS of ^{36}Ar and ^{38}Ar, corrected to the standard 30 keV thermal energy, are 1.9(3) and 1.3(2) mb, respectively, differing from the theoretical and evaluated values published to date by up to an order of magnitude. The neutron-capture cross sections of ^{36,38}Ar are relevant to the stellar nucleosynthesis of light neutron-rich nuclides; the two experimental values are shown to affect the calculated mass fraction of nuclides in the region A=36-48 during the weak s process. The new production cross sections have implications also for the use of ^{37}Ar and ^{39}Ar as environmental tracers in the atmosphere and hydrosphere.

Generation and characterization of a rat monoclonal antibody against the RNA polymerase protein from Dengue Virus-2.

Dengue virus (DENV) RNA replication requires 2 viral proteins, non-structural protein 3 (NS3) and NS5. NS5 consists of 2 functional domains: a methyltransferase (MTase) domain involved in RNA cap formation and located in the amino terminal region and a RNA-dependent RNA polymerase domain essential for virus replication and located in the carboxyl terminal region. To gain additional insight into the structural interactions between viral proteins and cellular factors involved in DENV RNA replication, we generated a panel of rat monoclonal antibodies (mAbs) against the NS5 MTase domain. Six rat mAbs were selected from 41 clones, of which clone 13G7 was further characterized. The specificity of this antibody for NS5 was demonstrated by western blot of DENV-infected cells, which revealed that this antibody recognizes all 4 DENV serotypes. Furthermore, Western blotting analysis suggested that this antibody recognizes a sequential epitope of the NS5 protein. Positive and specific staining with 13G7 was detected predominantly in nuclei of DENV-infected cells, similarly a pattern was observed in both in human and monkey cells. Furthermore, the NS5 staining co-localized with a Lamin A protein (Pierson index: 0.7). In summary, this monoclonal antibody could be used to identify and evaluate different cellular factors that may interact with NS5 during DENV replication.

Otubain 2 is a novel promoter of beta cell survival as revealed by siRNA high-throughput screens of human pancreatic islets.

AIMS/HYPOTHESIS: Pro-inflammatory cytokines induce death of beta cells and hamper engraftment of transplanted islet mass. Our aim was to reveal novel genes involved in this process, as a platform for innovative therapeutic approaches. METHODS: Small interfering RNA (siRNA) high-throughput screening (HTS) of primary human islets was employed to identify novel genes involved in cytokine-induced beta cell apoptosis. Dispersed human islets from nine human donors, treated with a combination of TNF-α, IL-1ß and IFN-γ were transfected with ∼730 different siRNAs. Caspase-3/7 activity was measured, results were analysed and potential anti- and pro-apoptotic genes were identified. RESULTS: Dispersed human pancreatic islets appeared to be suitable targets for performance of siRNA HTS. Using this methodology we found a number of potential pro- and anti-apoptotic target hits that have not been previously associated with pancreatic beta cell death. One such hit was the de-ubiquitinating enzyme otubain 2 (OTUB2). OTUB2 knockdown increased caspase-3/7 activity in MIN6 cells and primary human islets and inhibited insulin secretion and increased nuclear factor-κB (NF-κB) activity both under basal conditions and following cytokine treatment. CONCLUSIONS: Use of dispersed human islets provides a new platform for functional HTS in a highly physiological system. Employing this technique enabled the identification of OTUB2 as a novel promoter of viability and insulin secretion in human beta cells. OTUB2 acts through the inhibition of NF-κB signalling, which is deleterious to beta cell survival. siRNA screens of human islets may therefore identify new targets, such as OTUB2, for therapeutic intervention in type 1 diabetes and islet transplantation.

Periparturient dairy cows do not exhibit hepatic insulin resistance, yet adipose-specific insulin resistance occurs in cows prone to high weight loss.

The periparturient period in dairy cows is associated with alterations in insulin action in peripheral tissues; however, the molecular mechanism underlying this process is not completely understood. The objective was to examine the response to a glucose tolerance test (GTT) and to analyze insulin signaling in liver and adipose tissues in pre- and postpartum dairy cows. Liver and adipose tissue biopsies were taken before and after GTT, at 17d prepartum and again at 3 to 5d postpartum from 8 high-yielding Israeli Holstein dairy cows. Glucose clearance rate after GTT was similar pre- and postpartum. Basal insulin concentrations and the insulin response to GTT were approximately 4-fold higher prepartum than postpartum. In accordance, phosphorylation of the hepatic insulin receptor after GTT was higher prepartum than postpartum. Across periods, a positive correlation was observed between the basal and peak plasma insulin and phosphorylated insulin receptor after GTT in the liver. Hepatic phosphorylation of protein kinase B after GTT was elevated pre- and postpartum. Conversely, in adipose tissue, phosphorylation of protein kinase B after GTT pre- and postpartum was increased only in 4 out of 8 cows that lost less body weight postpartum. Our results demonstrate that hepatic insulin signaling is regulated by plasma insulin concentrations as part of the homeorhetic adjustments toward calving, and do not support a model of hepatic insulin resistance in periparturient cows. Nevertheless, we suggest that specific insulin resistance in adipose tissue occurs pre- and postpartum only in cows prone to high weight loss. The different responses among these cows imply that genetic background may affect insulin responsiveness in adipose tissue pre- and postpartum.

RETENTION OF 7Be IN THE LUNGS FOLLOWING INTAKE BY INHALATION.

Several workers were internally exposed to 7Be particles following their dispersion in air from a damaged electrodeposited source. A series of in vivo measurements performed with one worker up to 108 days post exposure determined that retention of 7Be in the thoracic region of the respiratory tract was best described by a two-component exponential function with half-lives of ~0.4 and ~109 days. The initial deposition in the thoracic region was estimated to be 6.8 kBq. The concentration of 7Be in single void urine samples collected from this worker up to 3 days post intake ranged from 1 to 10 Bq/l. In the absence of specific knowledge about the physical and chemical characteristics of the inhaled particles, the committed effective dose was estimated to be 0.3 µSv.

Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic ß cells.

Insulin resistance results from impaired insulin signaling in target tissues that leads to increased levels of insulin required to control plasma glucose levels. The cycle of hyperglycemia and hyperinsulinemia eventually leads to pancreatic cell deterioration and death by a mechanism that is yet unclear. Insulin induces ROS formation in several cell types. Furthermore, death of pancreatic cells induced by oxidative stress could be potentiated by insulin. Here, we investigated the mechanism underlying this phenomenon. Experiments were done on pancreatic cell lines (Min-6, RINm, INS-1), isolated mouse and human islets, and on cell lines derived from nonpancreatic sources. Insulin (100nM) for 24h selectively increased the production of ROS in pancreatic cells and isolated pancreatic islets, but only slightly affected the expression of antioxidant enzymes. This was accompanied by a time- and dose-dependent decrease in cellular reducing power of pancreatic cells induced by insulin and altered expression of several ER stress response elements including a significant increase in Trb3 and a slight increase in iNos The effect on iNos did not increase NO levels. Insulin also potentiated the decrease in cellular reducing power induced by H2O2 but not cytokines. Insulin decreased the expression of MCL-1, an antiapoptotic protein of the BCL family, and induced a modest yet significant increase in caspase 3/7 activity. In accord with these findings, inhibition of caspase activity eliminated the ability of insulin to increase cell death. We conclude that prolonged elevated levels of insulin may prime apoptosis and cell death-inducing mechanisms as a result of oxidative stress in pancreatic cells.

Demonstration of a high-intensity neutron source based on a liquid-lithium target for Accelerator based Boron Neutron Capture Therapy.

A free surface liquid-lithium jet target is operating routinely at Soreq Applied Research Accelerator Facility (SARAF), bombarded with a ~1.91 MeV, ~1.2 mA continuous-wave narrow proton beam. The experiments demonstrate the liquid lithium target (LiLiT) capability to constitute an intense source of epithermal neutrons, for Accelerator based Boron Neutron Capture Therapy (BNCT). The target dissipates extremely high ion beam power densities (>3 kW/cm(2), >0.5 MW/cm(3)) for long periods of time, while maintaining stable conditions and localized residual activity. LiLiT generates ~3×10(10) n/s, which is more than one order of magnitude larger than conventional (7)Li(p,n)-based near threshold neutron sources. A shield and moderator assembly for BNCT, with LiLiT irradiated with protons at 1.91 MeV, was designed based on Monte Carlo (MCNP) simulations of BNCT-doses produced in a phantom. According to these simulations it was found that a ~15 mA near threshold proton current will apply the therapeutic doses in ~1h treatment duration. According to our present results, such high current beams can be dissipated in a liquid-lithium target, hence the target design is readily applicable for accelerator-based BNCT.

Autocatalytic activation of human legumain at aspartic acid residues.

Human legumain was characterized following overexpression in a murine cell line as the C-terminal Ig-fusion protein. Upon acid treatment, the prolegumain autoproteolyzed distal to two aspartic acid residues to yield a highly active form. The ability of mature legumain to cleave after aspartic acid residues was confirmed with a small peptide substrate. Substitution of alanine for the putative catalytic cysteine, or for either of two strictly conserved histidine residues, partly or wholly eliminated autoactivation but not the ability of wild-type legumain to correctly process the variants to the properly sized proteins.

The juxtamembrane but not the carboxyl-terminal domain of the insulin receptor mediates insulin's metabolic functions in primary adipocytes and cultured hepatoma cells.

Insulin-stimulated signaling pathways are activated upon interactions between the intracellular domains of the receptor and its downstream effectors. Insulin receptor substrate proteins (IRS-1, -2, -3 and -4) are the best-studied substrates for the insulin receptor kinase (IRK). We have previously shown that IRS-1 and IRS-2 interact with the juxtamembrane (JM) but not with the carboxyl-terminal (CT) region of the insulin receptor (IR) in vitro. However, the precise role of these IR regions in mediating insulin's bioeffects is still unresolved. In the present work we made use of vaccinia virus as a vector for quantitative expression of the JM and CT domains within the cytoplasm of physiologically insulin-responsive primary rat adipocytes and rat hepatoma Fao cells. We could demonstrate that overexpression of either the JM or the CT domains did not inhibit either insulin binding or insulin-stimulated receptor autophosphorylation. In contrast, metabolic effects such as insulin-induced glucose utilization in adipocytes, and insulin-induced amino acid utilization in Fao hepatoma cells were inhibited (70-80%) in cells overexpressing the JM but not the CT domains of IR. The inhibitory effects of the overexpressed JM domain were accompanied by inhibition of insulin-stimulated IRS-1 phosphorylation, decreased IRS-1-associated PI3K activity, and decreased phosphorylation of the downstream effectors of PI3K, PKB and p70 S6K. Insulin-stimulated thymidine incorporation in Fao cells was also inhibited (40%) upon overexpression of the JM but not the CT region of IR. Our findings suggest that interactions between the JM region of IR and its downstream effectors are obligatory for insulin-stimulated metabolic functions in physiologically relevant insulin responsive cells. They also rule out the possibility that interaction of proteins, including PI3K, with the CT domain can provide an alternative pathway.

Smoking status and lipid levels in adults of different ethnic origins: the Jerusalem Lipid Research Clinic Program.

Jerusalem Lipid Research Clinic Program. International Journal of Epidermiology 1984; 13: 177-183. The relationship between cigarette smoking and plasma lipids and lipoproteins was examined in a random sample of 1115 male and 563 female adult participants in the Jerusalem Lipid Research Clinics Program. Differences in plasma lipids and lipoproteins, cigarette smoking, alcohol consumption, and body mass index were demonstrated between the four country of origin groups in both sexes. Using multiple linear regression analysis, an inverse association was shown between smoking and HDL cholesterol, significant only in females (p less than 0.001). Potential confounding variables-Quetelet's index of body mass, alcohol consumption, age, and country of origin groups-revealed only a weak effect on the smoking-HDL-cholesterol association. Examination of an interaction between origin group and smoking showed the same smoking-lipid level association in each of the four country of origin groups, and in both sexes. A strong association was found between smoking and LDL-cholesterol only in females (p less than 0.01). Triglycerides and VLDL-cholesterol showed a weak association with smoking in this study.

Association between corneal arcus and some of the risk factors for coronary artery disease.

The relationships between coronary artery disease risk factors and corneal arcus were examined in 150 adults aged 55 years and above of both sexes and from different ethnic origins. The width of the corneal arcus was measured accurately by a digitiser, and the risk factors for coronary artery disease were examined according to the standard procedure used by the Lipid Research Clinics. The results show that the corneal arcus is more frequent in males; the frequency and size of corneal arcus are positively associated with age; there is a positive correlation between the size of corneal arcus and the levels of cholesterol and low-density lipoprotein in males; and that there is negative correlation between corneal arcus and diastolic blood pressure in both sexes. No associations were found between corneal arcus and other coronary artery disease risk factors such as triglyceride, high-density lipoprotein, very low-density lipoprotein, weight, Quetelet's ratio, glucose, and smoking.

Effect of anticoagulants and antiplatelet agents on platelet-mediated thrombin generation.

The present study was designed to determine the mechanism by which and extent to which antagonists of glycoprotein IIbIIIa (GPIIbIIIa or alpha beta ) or activated factor X (FXa) activity block tissue factor-initiated thrombin generation by prothrombinase complexes assembled on the surface of activated platelets. In the presence of high concentrations of GPIIbIIIa antagonists, which eliminate platelet aggregation but not activation, there is still a substantial amount of thrombin produced. In contrast, specific antagonists of the coagulation cascade lead to abolition of both thrombin generation and platelet aggregation. In addition, inhibitors with similar inhibitory activity (Ki) against purified human FXa require a much broader range of concentrations (a variation of 10 000-fold or more) to reduce the amount of thrombin produced in a platelet-rich plasma assay. At the doses tested, inhibitors with greater potency in prevention of thrombin production in the platelet-rich plasma assay were effective in vivo antithrombotics in an animal model system, whereas a lower potency compound did not reduce thrombus mass. Therefore, inhibition of FXa within platelet bound prothrombinase rather than inhibition of purified FXa in solution may be a better predictor of antithrombotic efficacy. In addition, all the studied anticoagulants fared better than the antiplatelet agents in reducing thrombin generation.

The influence of a physical ability intervention program on improved running time and increased sport motivation among Jerusalem schoolchildren.

Several studies have demonstrated an inverse relationship between physical activity and coronary heart disease (CHD). Other studies have reported a negative correlation between aerobic capacity and obesity and CHD risk factors among adolescents. In this study, the possibility of modifying physical ability in adolescents aged 13 has been examined through a physical ability intervention program. During 1984-1985, all eligible eighth graders from five Jerusalem public schools participated in the program. Physical ability was defined in the biological dimension by the running time for 1000 meters, and in the psychological dimension by sport motivation. The intervention program involved a periodic and progressive increase of physical effort of children in 16 gym lessons during the regular curriculum. The major findings were that the test group improved their running time and had better sport motivation than did the control group, and there were differences between boys and girls and an influence of sexual maturation on running time in girls.

An epidemiologic study on differences in health status between employed men and women in Hawaii.

Differences in health status between employed men and employed women were examined. 56,203 participants in a stratified random sample of Hawaii's adult population were interviewed during 1981-1986 in the Hawaii Health Surveillance Program. Multiple regression analysis controlling for sociodemographic and occupational variables showed that although the differences were small, employed women reported more health problems than employed men, especially acute conditions and those requiring more hospital services. The findings of this study indicate a need for further study to understand the nature of the observed differences and to develop relevant preventive programs.

The health status of working women in Hawaii.

The effect of work on women's health was examined in this study by comparing selected health indicators and specific chronic conditions among employed men, employed women and housewives. The study analyzed data from the Hawaii Health Surveillance Program. The study group was comprised of 56,203 subjects and represented a randomly stratified sample of the population interviewed during the period 1981-1986. Housewives as a group were older, less educated and reported the lowest family income compared to employed men or employed women. The prevalence of several specific chronic conditions were higher among housewives than in employed men and employed women. Multiple regression analysis tested the difference in several health indicators (chronic conditions, hospital episodes and restricted activity days) between employed men, employed women and housewives, controlled for sociodemographic variables. The health status of housewives was clearly worse than that of employed men and employed women by all health indicators; employed women had more hospital episodes than employed men. The results suggest that mostly healthy women are selected for the labor force. Among employed women, those in poor health and needing hospital services more frequently, are probably at high risk of dropping out of work. Our study projects the importance of promoting occupational good health for employed women during their working life.

[Physical activity program during working hours among industrial workers in Israel].

During 1984-1985, 540 employees of 2 pharmaceutical factories of the Teva concern participated in a physical activity program. To evaluate its effects on employees' health, the participants were randomly divided into 2 groups of equal size. The test group participated in regular physical exercise before lunch for 15 minutes, 5 days a week. The controls played social games for the same time periods while seated. The physical activity program included stretching, relaxing, and aerobic exercises. The program was carried out by employees who had been trained to be instructors by the researchers and were supervised by a professional teacher. During the 7 months of the study, adherence was about 90%. The results in test and control groups were determined by questionnaires. After 7 months, the test group clearly showed increased interest in sports activities, increased job satisfaction and work efficiency, and decreased fatigue during work.

[Segev health promotion project in Jerusalem elementary schools].

The health-promotion and education project, Segev, is an Israeli version of the American Health Foundation's Know Your Body project. The aim of this cohort study was to change knowledge, attitudes, health behavior and risk factors for cardiovascular disease in elementary school children. We present the results of questionnaires about knowledge of, and attitudes to health in 656 Jewish children who started first grade in 1983-4 and completed 4 questionnaires in the first and third grades. The results indicate a statistically significant increase in knowledge and attitude scores in the experimental group after 1 and 3 years of intervention. They indicate that changes in knowledge of, and attitudes to health are possible after even a relatively short school health education program.

High-power electron beam tests of a liquid-lithium target and characterization study of (7)Li(p,n) near-threshold neutrons for accelerator-based boron neutron capture therapy.

A compact Liquid-Lithium Target (LiLiT) was built and tested with a high-power electron gun at Soreq Nuclear Research Center (SNRC). The target is intended to demonstrate liquid-lithium target capabilities to constitute an accelerator-based intense neutron source for Boron Neutron Capture Therapy (BNCT) in hospitals. The lithium target will produce neutrons through the (7)Li(p,n)(7)Be reaction and it will overcome the major problem of removing the thermal power >5kW generated by high-intensity proton beams, necessary for sufficient therapeutic neutron flux. In preliminary experiments liquid lithium was flown through the target loop and generated a stable jet on the concave supporting wall. Electron beam irradiation demonstrated that the liquid-lithium target can dissipate electron power densities of more than 4kW/cm(2) and volumetric power density around 2MW/cm(3) at a lithium flow of ~4m/s, while maintaining stable temperature and vacuum conditions. These power densities correspond to a narrow (σ=~2mm) 1.91MeV, 3mA proton beam. A high-intensity proton beam irradiation (1.91-2.5MeV, 2mA) is being commissioned at the SARAF (Soreq Applied Research Accelerator Facility) superconducting linear accelerator. In order to determine the conditions of LiLiT proton irradiation for BNCT and to tailor the neutron energy spectrum, a characterization of near threshold (~1.91MeV) (7)Li(p,n) neutrons is in progress based on Monte-Carlo (MCNP and Geant4) simulation and on low-intensity experiments with solid LiF targets. In-phantom dosimetry measurements are performed using special designed dosimeters based on CR-39 track detectors.