Process region changes for rapidly propagating cracks

A finite element model of a plate, which contains an initial crack subjected to a rapid loading at its faces, is investigated. A cell model of the prospective process region is adopted. The cell size is assumed to represent some characteristic intrinsic material length. The size of the process region is not predetermined but depends at every time on the number of cells that have reached a state characteristic for the process region i.e. essentially instability if load control would prevail. Outside the process region the material is assumed to be linearly elastic.For low loading magnitudes the simulations show a rather long period of crack acceleration, but at higher loads this period is short or even not detectable, and a constant terminal velocity, significantly lower than the Rayleigh wave velocity, is reached. At lower loads both the energy release rate and the extension of the process region stay rather constant, but at higher loads they increase considerably with time, even though the crack tip velocity stays constant. Thus it appears that a tendency towards increased energy flow to the process region is met by increased size of this region, and thereby increased energy dissipation per unit of crack growth, rather than by increased crack edge velocity. The process region may finally occupy several cell rows, and the control of the process region by the characteristic length is thus lost. This can explain the apparent loss of the unique relation between stress intensity factor and crack edge velocity at high crack velocities.In some simulations branching was obtained. The results from the simulations showed qualitative agreement with some recent experimental results e.g. those by Ravi-Chandar.     

Wire bonding to advanced copper, low-K integrated circuits, the metal/dielectric stacks, and materials considerations

There are three areas to consider when designing/implementing wire bonding to advanced ULSI damascene-copper chips having copper metallization and low dielectric-constant polymers embedded beneath them (Cu/LoK). These are: 1) the copper-pad top-surface oxidation inhibitor coating - metal/organic/inorganic. (Current work involves evaluating the metal and inorganic options); 2) the low dielectric constant materials available; 3) under-pad metal/polymer stacks and support structures necessary for bondability and reliability. There are also various polymer/metallurgical interactions, resulting in long term packaged-device reliability problems, that can occur as the result of the wire bonding process over low modulus, LoK materials with barriers. These include cracked diffusion barriers, copper diffusion into the LoK polymers, cracking/spalling/crazing of the LoK materials, and bond pad indentation ("cupping"). Low-K polymer materials, with high expansion coefficients and low thermal conductivities, can also increase the stress and further extend any existing damage to barriers. Well designed LoK and the underpad structures should have no negative effect on bonding parameters and be invisible to the bonding process.     

Transcriptional regulation of prostaglandin-H synthase-2 gene in human trophoblasts

Abnormal PG production by placental PG-H synthase (PGHS) is associated with preeclampsia. There are two PGHS isozymes, and their regulation in trophoblasts is presently unknown. We hypothesized that the PGHS isozymes are differentially regulated in human trophoblasts. To test this hypothesis, we transfected primary trophoblasts and JEG3 cells with promoter constructs of either PGHS-1 or PGHS-2 genes. We found that in both cell systems, the basal activity of PGHS-2 promoter was 10- to 30-fold higher than the activity of PGHS-1 promoter. In response to either 12-0-tetradecanoylphorbol-13-acetate (TPA) or 8-bromo-cAMP, we observed an increase in PGHS-2 promoter activity but no change in activity of PGHS-1 promoter. Similarly, both agents enhanced PGHS-2 expression, as well as prostaglandin E2 production. The activity of PGHS-2 promoter was potentiated by coexpression of protein kinase A and inhibited by coexpression of kinase A inhibitor. Aspirin attenuated the stimulatory effect of TPA on PGHS-2 promoter. We conclude that both PGHS-1 and PGHS-2 promoters are active in trophoblasts. The activity of PGHS-2 promoter is stimulated by either TPA or cAMP, and the stimulatory effect of TPA is attenuated by aspirin. These pathways may play a role in modulation of prostanoid synthesis by trophoblasts.     

In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces genital dysmorphogenesis in the female rat

Recently, Gray and Ostby (Toxicol. Appl. Pharmacol. 133, 285-294, 1995) reported that in utero and lactational TCDD exposure causes striking abnormalities in the rat female reproductive system, including reduced fecundity and vaginal threads. The mechanism by which TCDD induces such abnormalities is unknown. Thus, we sought to determine: (1) whether TCDD reduced fecundity by destroying ovarian follicles and (2) whether the vaginal threads resulted from a TCDD-induced developmental defect during embryogenesis or abnormal vaginal opening at puberty. Pregnant Holtzman rats were treated with 1.0 microgram TCDD/kg or vehicle by a single oral dose on gestation day (GD) 11, 15, or 18. Female offspring were monitored for vaginal opening and terminated on postnatal days 2, 21, and 42. The reproductive tract was removed and evaluated for structural abnormalities. The number of primordial follicles also was determined for each ovary. TCDD exposure on GD 11, 15, or 18 did not change the day of vaginal opening, affect ovarian morphology, or reduce the number of primordial follicles. However, this exposure induced the cleft clitoris and vaginal thread originally described by Gray and Ostby (1995) in approximately 55-96% and 36-44% of the litters in our study, respectively. Histologically the thread presented as a thick cord of mesenchyme surrounded by epithelial cells. This defect was clearly visible in histological sections at birth and was noted in the closed vaginas of prepubertal animals. These data suggest that in utero and lactational exposure to TCDD does not reduce the size of the primordial follicle pool; however, it induces developmental abnormalities in the vaginal canal.     

Diagnosing neurofibromatosis type I in children

Neurofibromatosis is the single most common genetic disease of the neurologic system. Because neurofibromatosis type 1 (NF-1) is often diagnosed early in life, it is essential that health care providers deepen their understanding of this common genetic disorder. Children who meet particular criteria, as formulated by the National Institutes of Health, must be worked-up for NF-1 in order to initiate appropriate treatment implementation and evaluation. This article provides a review of the literature regarding the pathophysiology, clinical manifestations, and plan of treatment related to NF-1, specifically as it affects children. Clear guidelines for health care providers in primary care are outlined.     

Ceramide selectively decreases tau levels in differentiated PC12 cells through modulation of calpain I

Ceramide has been recently proposed to be a signal mediator in several important physiological processes including apoptosis, cellular growth, and differentiation. Because the microtubule-associated protein tau plays an important role in the establishment and maintenance of neuronal morphology, the effects of ceramide on tau were examined. Treatment of differentiated PC12 cells with the cell-permeable ceramide derivative N-acetylsphingosine (C2) resulted in a significant reduction in tau levels. Significant decreases in tau levels were also observed when the cells were treated with another ceramide derivative, N-hexanoylsphingosine (C6). In addition, C2 treatment increased the levels of a calpain-derived spectrin breakdown product but did not alter the levels of two cytoskeletal proteins, alpha-actin and alpha-tubulin. Because both tau and spectrin are proteolyzed in vitro by the calcium-activated cysteine protease calpain, the effects of ceramide analogues on the activity of this protease were examined. Treatment of PC12 cells with C2 enhanced calcium-stimulated proteolytic activity significantly, as revealed by monitoring the hydrolysis of the membrane-permeable calpain-selective fluorescence probe N-succinyl-L-leucyl-L-leucyl-L-valyl-L-tyrosine-7-amido-4-methylcoumarin . This activity increase was not due to a direct effect of C2 on calpains, because C2 did not alter the activities of purified calpain I or II. In addition, C2 treatment of PC12 cells resulted in a significant increase in the levels of calpain I and, to a lesser extent, the levels of calpastatin (an endogenous calpain inhibitor protein), whereas the levels of calpain II were not changed. Moreover, treatment of the cells with the synthetic calpain-specific inhibitor N-carbobenzoxy-L-leucyl-L-leucyl-L-tyrosine diazomethyl ketone blocked the C2-induced decreases in tau levels. These results indicate that tau levels are regulated in response to a physiological factor and, thus, have implications for ceramide-mediated changes in normal and pathological neuronal processes.     

C2 region-derived peptides of beta-protein kinase C regulate cardiac Ca2+ channels

We have previously shown that alpha1-adrenergic activation inhibited beta-adrenergic-stimulated L-type Ca2+ current (I(Ca)). To determine the role of protein kinase C (PKC) in this regulation, the inositol trisphosphate pathway was bypassed by direct activation of PKC with 4beta-phorbol 12-myristate 13-acetate (PMA). To minimize Ca2+-induced Ca2+ inactivation, Ba2+ current (I(Ba)) was recorded through Ca2+ channels in adult rat ventricular myocytes. We found that PMA (0.1 micromol/L) consistently inhibited basal I(Ba) by 40.5+/-7.4% and isoproterenol (ISO, 0.1 micromol/L)-stimulated I(Ba) by 48.9+/-7.8%. These inhibitory effects were not observed with the inactive phorbol ester analogue alpha-phorbol 12,13-didecanoate (0.1 micromol/L). To identify the PKC isozymes that mediate these PMA effects, we intracellularly applied peptide inhibitors of a subclass of PKC isozymes, the C2-containing cPKCs. These peptides (betaC2-2 and betaC2-4) specifically inhibit the translocation and function of C2-containing isozymes (alpha-PKC, betaI-PKC, and betaII-PKC), but not the C2-less isozymes (delta-PKC and epsilon-PKC). We first used the pseudosubstrate peptide (0.1 micromol/L in the pipette), which inhibits the catalytic activity of all the PKC isozymes, and found that PMA-induced inhibition of ISO-stimulated I(Ba) was reduced to 16.8+/-7.4% but was not affected by the scrambled pseudosubstrate peptide. The effects of PMA on basal and ISO-stimulated I(Ba) were then determined in the presence of C2-derived peptides or control peptides. When the pipette contained 0.1 micromol/L of betaC2-2 or betaC2-4, PMA-induced inhibition of basal I(Ba) was 26.1+/-4.5% and 23.6+/-2.2%, respectively. Similarly, ISO-stimulated I(Ba) was inhibited by 29.9+/-6.6% and 29.3+/-7.8% in the presence of betaC2-2 and betaC2-4, respectively. In contrast, there was no significant change in the effect of PMA in the presence of control peptides, scrambled betaC2-4, or pentalysine. Finally, PMA-induced inhibition of basal and ISO-stimulated I(Ba) was almost completely abolished in cells dialyzed with both betaC2-2 and betaC2-4. Together, these data suggest a role for C2-containing isozymes in mediating PMA-induced inhibition of L-type Ca2+ channel activity.