Cell division genes promote asymmetric interaction between Numb and Notch in the Drosophila CNS.

Cell intrinsic and cell extrinsic factors mediate asymmetric cell divisions during neurogenesis in the Drosophila embryo. In the NB4-2->GMC-1->RP2/sib lineage, one of the well-studied neuronal lineages in the ventral nerve cord, the Notch (N) signaling interacts with the asymmetrically localized Numb (Nb) to specify sibling neuronal fates to daughter cells of GMC-1. In this current study, we have investigated asymmetric cell fate specifications by N and Nb in the context of cell cycle. We have used loss-of-function mutations in N and nb, cell division mutants cyclinA (cycA), regulator of cyclin A1 (rca1) and string/cdc25 phosphatase (stg), and the microtubule destabilizing agent, nocodazole, to investigate this issue. We report that the loss of cycA, rca1 or stg leads to a block in the division of GMC-1, however, this GMC-1 exclusively adopts an RP2 identity. While the loss of N leads to the specification of RP2 fates to both progeny of GMC-1 and loss of nb results in the specification of sib fates to these daughter cells, the GMC-1 in the double mutant between nb and cycA assumes a sib fate. These epistasis results indicate that both N and nb function downstream of cell division genes and that progression through cell cycle is required for the asymmetric localization of Nb. In the absence of entry to metaphase, the Nb protein prevents the N signaling from specifying sib fate to the RP2/sib precursor. These results are also consistent with our finding that the sib cell is specified as RP2 in N; nb double mutants. Finally, our results show that nocodazole-arrested GMC-1 in wild-type embryos randomly assumes either an RP2 fate or a sib fate. This suggests that microtubules are involved in mediating the antagonistic interaction between Nb and N during RP2 and sib fate specification.     

Mutation of Dcdc2 in mice leads to impairments in auditory processing and memory ability

Dyslexia is a complex neurodevelopmental disorder characterized by impaired reading ability despite normal intellect, and is associated with specific difficulties in phonological and rapid auditory processing (RAP), visual attention and working memory. Genetic variants in Doublecortin domain‐containing protein 2 (DCDC2) have been associated with dyslexia, impairments in phonological processing and in short‐term/working memory. The purpose of this study was to determine whether sensory and behavioral impairments can result directly from mutation of the Dcdc2 gene in mice. Several behavioral tasks, including a modified pre‐pulse inhibition paradigm (to examine auditory processing), a 4/8 radial arm maze (to assess/dissociate working vs. reference memory) and rotarod (to examine sensorimotor ability and motor learning), were used to assess the effects of Dcdc2 mutation. Behavioral results revealed deficits in RAP, working memory and reference memory in Dcdc2^del2/del2 mice when compared with matched wild types. Current findings parallel clinical research linking genetic variants of DCDC2 with specific impairments of phonological processing and memory ability.     

The Rap GTPases regulate integrin-mediated adhesion, cell spreading, actin polymerization, and Pyk2 tyrosine phosphorylation in B lymphocytes

Integrin-mediated adhesion plays an important role in B cell development and activation. Signaling initiated by antigens, chemokines, or phorbol esters can rapidly convert integrins to an activated adhesion-competent state. The binding of integrins to their ligands can then induce actin-dependent cell spreading, which can facilitate cell-cell adhesion or cell migration on extracellular matrices. The signaling pathways involved in integrin activation and post-adhesion events in B cells are not completely understood. We have previously shown that anti-Ig antibodies, the chemokine stromal cell-derived factor-1 (SDF-1; CXCL12), and phorbol esters activate the Rap1 and Rap2 GTPases in B cells and that Rap activation is essential for SDF-1-induced B cell migration (McLeod, S. J., Li, A. H. Y., Lee, R. L., Burgess, A. E., and Gold, M. R. (2002) J. Immunol. 169, 1365-1371; Christian, S. L., Lee, R. L., McLeod, S. J., Burgess, A. E., Li, A. H. Y., Dang-Lawson, M., Lin, K. B. L., and Gold, M. R. (2003) J. Biol. Chem. 278, 41756-41767). We show here that preventing Rap activation by expressing Rap-specific GTPase-activating protein II (RapGAPII) significantly decreased lymphocyte function-associated antigen-1- and alpha(4) integrin-dependent binding of murine B cell lines to purified adhesion molecules and to other cells. Conversely, augmenting Rap activation by expressing a constitutively active form of Rap2 enhanced B cell adhesion, showing for the first time that Rap2 can promote integrin activation. We also show that blocking Rap activation inhibited anti-Ig-induced cell spreading and phorbol ester-induced actin polymerization as well as anti-Ig- and SDF-1-induced phosphorylation of Pyk2, a tyrosine kinase involved in morphological changes and chemokine-induced B cell migration. Thus, the Rap GTPases regulate integrin-mediated B cell adhesion as well as processes that control B cell morphology and migration.     

Risk of Breast Cancer by Type of Menopausal Hormone Therapy: a Case-Control Study among Post-Menopausal Women in France

Background

There is extensive epidemiological evidence that menopausal hormone therapy (MHT) increases breast cancer risk, particularly combinations of estrogen and progestagen (EP). We investigated the effects of the specific formulations and types of therapies used by French women. Progestagen constituents, regimen (continuous or sequential treatment by the progestagen), and time interval between onset of menopause and start of MHT were examined.

Methods

We conducted a population-based case-control study in France in 1555 menopausal women (739 cases and 816 controls). Detailed information on MHT use was obtained during in-person interviews. Odds ratios and 95% confidence interval adjusted for breast cancer risk factors were calculated.

Results

We found that breast cancer risk differed by type of progestagen among current users of EP therapies. No increased risk was apparent among EP therapy users treated with natural micronized progesterone. Among users of EP therapy containing a synthetic progestin, the odds ratio was 1.57 (0.99-2.49) for progesterone-derived and 3.35 (1.07-10.4) for testosterone-derived progestagen. Women with continuous regimen were at greater risk than women treated sequentially, but regimen and type of progestagen could not be investigated independently, as almost all EP combinations containing a testosterone-derivative were administered continuously and vice-versa. Tibolone was also associated with an increased risk of breast cancer. Early users of MHT after onset of menopause were at greater risk than users who delayed treatment.

Conclusion

This study confirms differential effects on breast cancer risk of progestagens and regimens specifically used in France. Formulation of EP therapies containing natural progesterone, frequently prescribed in France, was not associated with increased risk of breast cancer but may poorly protect against endometrial cancer.     

Persistent adult zebrafish behavioral deficits results from acute embryonic exposure to gold nanoparticles

As the number of products containing nanomaterials increase, human exposure to nanoparticles (NPs) is unavoidable. Presently, few studies focus on the potential long-term consequences of developmental NP exposure. In this study, zebrafish embryos were acutely exposed to three gold NPs that possess functional groups with differing surface charge. Embryos were exposed to 50 μg/mL of 1.5 nm gold nanoparticles (AuNPs) possessing negatively charged 2-mercaptoethanesulfonic acid (MES) or neutral 2-(2-(2-mercaptoethoxy)ethoxy)ethanol (MEEE) ligands or 10 μg/mL of the AuNPs possessing positively charged trimethylammoniumethanethiol (TMAT). Both MES- and TMAT-AuNP exposed embryos exhibited hypo-locomotor activity, while those exposed to MEEE-AuNPs did not. A subset of embryos that were exposed to 1.5 nm MES- and TMAT-AuNPs during development from 6 to 120 h post fertilization was raised to adulthood. Behavioral abnormalities and the number of survivors into adulthood were evaluated at 122 days post fertilization. We found that both treatments induced abnormal startle behavior following a tap stimulus. However, the MES-AuNPs exposed group also exhibited abnormal adult behavior in the light and had a lower survivorship into adulthood. This study demonstrates that acute, developmental exposure to 1.5 nm MES- and TMAT-AuNPs, two NPs differing only in the functional group, affects larval behavior, with behavioral effects persisting into adulthood.     

Economic incentive for applying vetiver grass to remediate lead, copper and zinc contaminated soils

The application of vetiver grass (Chrysopogon zizaniodes) for phytoremediation of heavy metal contaminated soils can be promoted by economic return through essential oil production. Four levels of lead (0, 500, 2000, and 8000 mg kg(-1) dry soil), copper (0, 100, 400, and 1600 mg kg(-1) dry soil) and zinc (0, 400, 1600, and 6400 mg kg(-1) dry soil) were used to study their effects on vetiver growth, essential oil composition and yield. This study also investigated the effect of nitrogen concentrations on vetiver oil yield. Vetiver accumulated high concentrations of Pb, Cu and Zn in roots (3246, 754 and 2666 mg kg(-1), respectively) and small amounts of contaminants in shoots (327, 55, and 642 mg kg(-1), respectively). Oil content and yield were not affected at low and moderate concentrations of Cu and Zn. Only the application of Pb had a significant detrimental effect on oil composition. Extraction of vetiver essential oils by hydrodistillation produced heavy metal free products. High level of nitrogen reduced oil yields. Results show that phytoremediation of Cu and Zn contaminated soils by vetiver can generate revenue from the commercialization of oil extracts.     

Structural Characteristics of Allomyrina Dichotoma Beetle＇s Hind Wings for Flapping Wing Micro Air Vehicle

In this study, we present a complete structural analysis ofAllomyrina dichotoma beetle＇s hind wings by investigating their static and dynamic characteristics. The wing was subjected to the static loading to determine its overall flexural stiffness. Dy- namic characteristics such as natural frequency, mode shape, and damping ratio of vibration modes in the operating frequency range were determined using a Bruel ＆ Kjaer fast Fourier transform analyzer along with a laser sensor. The static and dynamic characteristics of natural Allomyrina dichotoma beetle＇s hind wings were compared to those of a fabricated artificial wing. The results indicate that natural frequencies of the natural wing were significantly correlated to the wing surface area density that was defined as the wing mass divided by the hind wing surface area. Moreover, the bending behaviors of the natural wing and artificial wing were similar to that of a cantilever beam. Furthermore, the flexural stiffness of the artificial wing was a little higher than that of the natural one whereas the natural frequency of the natural wing was close to that of the artificial wing. These results provide important information for the biomimetic design of insect-scale artificial wings, with which highly ma- neuverable and efficient micro air vehicles can be designed.     

The relative risks and etiologic fractions of different causes of death and disease attributable to alcohol,tobacco and illicit drug use in Canada

BACKGROUND: In 1996 the number of deaths and admissions to hospital in Canada that could be attributed to the use of alcohol, tobacco and illicit drugs were estimated from 1992 data. In this paper we update these estimates to the year 1995. METHODS: On the basis of pooled estimates of relative risk, etiologic fractions were calculated by age, sex and province for 90 causes of disease or death attributable to alcohol, tobacco or illicit drugs; the etiologic fractions were then applied to national mortality and morbidity data for 1995 to estimate the number of deaths and admissions to hospital attributable to substance abuse. RESULTS: In 1995, 6507 deaths and 82,014 admissions to hospital were attributed to alcohol, 34,728 deaths and 194,072 admissions to hospital were attributed to tobacco, and 805 deaths and 6940 admissions to hospital were due to illicit drugs. INTERPRETATION: The use and misuse of alcohol, tobacco and illicit drugs accounted for 20.0% of deaths, 22.2% of years of potential life lost and 9.4% of admissions to hospital in Canada in 1995.