Grain boundary formation through particle detachment during coarsening of nanoporous metals.

Grain boundary formation during coarsening of nanoporous gold (NPG) is investigated wherein a nanocrystalline structure can form by particles detaching and reattaching to the structure. MicroLaue and electron backscatter diffraction measurements demonstrate that an in-grain orientation spread develops as NPG is coarsened. The volume fraction of the NPG sample is near the limit of bicontinuity, at which simulations predict that a bicontinuous structure begins to fragment into independent particles during coarsening. Phase-field simulations of coarsening using a computationally generated structure with a volume fraction near the limit of bicontinuity are used to model particle detachment rates. This model is tested by using the measured NPG structure as an initial condition in the phase-field simulations. We predict that up to ∼5% of the NPG structure detaches as a dealloyed [Formula: see text] sample is annealed at 300 °C for 420 min. The quantity of volume detached is found to be highly dependent on the volume fraction and volume fraction homogeneity of the nanostructure. As the void phase in the experiments cannot support independent particles, they must fall and reattach to the structure, a process that results in the formation of new grain boundaries. This particle reattachment process, along with other classic processes, leads to the formation of grain boundaries during coarsening in nanoporous metals. The formation of grain boundaries can impact a variety of applications, including mechanical strengthening; thus, the consideration and understanding of particle detachment phenomena are essential when studying nanoporous metals.

Pharmacogenomics of 17-alpha hydroxyprogesterone caproate for recurrent preterm birth: a case-control study.

OBJECTIVE: To compare maternal genotypes between women with and without significant prolongation of pregnancy in the setting of 17-alpha hydroxyprogesterone caproate (17-P) administration for the prevention of recurrent preterm birth (PTB). DESIGN: Case-control. SETTING: Three tertiary-care centres across the USA. POPULATION: Women (n = 99) with ≥ 1 prior singleton spontaneous PTB, receiving 17-P. METHODS: Women were classified as having successful prolongation of pregnancy during the 17-P treated pregnancy, in two ways: (1) Definition A: success/non-success based on difference in gestational age at delivery between 17-P-treated and untreated pregnancies (success: delivered ≥ 3 weeks later with 17-P) and (2) Definition B: success/non-success based on reaching term (success: delivered at term with 17-P). MAIN OUTCOME MEASURES: To assess genetic variation, all women underwent whole exome sequencing. Between-group sequence variation was analysed with the Variant Annotation, Analysis, and Search Tool (VAAST). Genes scored by VAAST with P < 0.05 were then analysed with two online tools: (1) Protein ANalysis THrough Evolutionary Relationships (PANTHER) and (2) Database for Annotation, Visualization, and Integrated Discovery (DAVID). RESULTS: Using Definition A, there were 70 women with successful prolongation and 29 without; 1375 genes scored by VAAST had P < 0.05. Using Definition B, 47 women had successful prolongation and 52 did not; 1039 genes scored by VAAST had P < 0.05. PANTHER revealed key differences in gene ontology pathways. Many genes from definition A were classified as prematurity genes (P = 0.026), and those from definition B as pharmacogenetic genes (P = 0.0018); (P, non-significant after Bonferroni correction). CONCLUSION: A novel analytic approach revealed several genetic differences among women delivering early vs later with 17-P. TWEETABLE ABSTRACT: Several key genetic differences are present in women with recurrent preterm birth despite 17-P treatment.

Diffusion of Handwashing Knowledge and Water Treatment Practices From Mothers in an Antenatal Hygiene Promotion Program to Nonpregnant Friends and Relatives, Machinga District, Malawi.

Access to safe drinking water and improved hygiene are essential for preventing diarrheal diseases in low- and middle-income countries. Integrating water treatment and hygiene products into antenatal clinic care can motivate water treatment and handwashing among pregnant women. Free water hygiene kits (water storage containers, sodium hypochlorite water treatment solution, and soap) and refills of water treatment solution and soap were integrated into antenatal care and delivery services in Machinga District, Malawi, resulting in improved water treatment and hygiene practices in the home and increased maternal health service use. To determine whether water treatment and hygiene practices diffused from maternal health program participants to friends and relatives households in the same communities, we assessed the practices of 106 nonpregnant friends and relatives of these new mothers at baseline and 1-year follow-up. At follow-up, friends and relatives were more likely than at baseline to have water treatment products observable in the home (33.3% vs. 1.2%, p < 0.00001) and detectable free chlorine residual in their water, confirming water treatment (35.7% vs. 1.4%; p < 0.00001). Qualitative data from in-depth interviews also suggested that program participants helped motivate adoption of water treatment and hygiene behaviors among their friends and relatives.

Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT.

The maintenance of chromosome termini, or telomeres, requires the action of the enzyme telomerase, as conventional DNA polymerases cannot fully replicate the ends of linear molecules. Telomerase is expressed and telomere length is maintained in human germ cells and the great majority of primary human tumours. However, telomerase is not detectable in most normal somatic cells; this corresponds to the gradual telomere loss observed with each cell division. It has been proposed that telomere erosion eventually signals entry into senescence or cell crisis and that activation of telomerase is usually required for immortal cell proliferation. In addition to the human telomerase RNA component (hTR; ref. 11), TR1/TLP1 (refs 12, 13), a protein that is homologous to the p80 protein associated with the Tetrahymena enzyme, has been identified in humans. More recently, the human telomerase reverse transcriptase (hTRT; refs 15, 16), which is homologous to the reverse transcriptase (RT)-like proteins associated with the Euplotes aediculatus (Ea_p123), Saccharomyces cerevisiae (Est2p) and Schizosaccharomyces pombe (5pTrt1) telomerases, has been reported to be a telomerase protein subunit. A catalytic function has been demonstrated for Est2p in the RT-like class but not for p80 or its homologues. We now report that in vitro transcription and translation of hTRT when co-synthesized or mixed with hTR reconstitutes telomerase activity that exhibits enzymatic properties like those of the native enzyme. Single amino-acid changes in conserved telomerase-specific and RT motifs reduce or abolish activity, providing direct evidence that hTRT is the catalytic protein component of telomerase. Normal human diploid cells transiently expressing hTRT possessed telomerase activity, demonstrating that hTRT is the limiting component necessary for restoration of telomerase activity in these cells. The ability to reconstitute telomerase permits further analysis of its biochemical and biological roles in cell aging and carcinogenesis.

Reducing pediatric liver transplant complications: a potential roadmap for transplant quality improvement initiatives within North America.

Though robust clinical data are available within transplantation, these data are not used for broad-based, multicentered quality improvement initiates. This article describes a targeted quality improvement initiative within the Studies of Pediatric Liver Transplantation (SPLIT) Registry. Using standard statistical techniques and clinical expertise to adjust for data and statistical reliability, we identified the pediatric liver transplant centers in North America with the lowest hepatic artery thrombosis rate and biliary complication rates. A survey was completed to establish current practices within the entire SPLIT group. Surgeons from the highest performing centers presented a detailed, technically oriented overview of their current practices. The presentations and discussion that followed were recorded and form the basis of the best practices described herein. We frame this work as a unique six-step approach roadmap that may serve as an efficient and cost effective model for novel broad-based quality improvement initiatives within transplantation.

William Horner Andrews (1887-1953)- first professor of physiology at Onderstepoort.

W H Andrews qualified as a veterinarian in London in 1908 and was recruited soon after, in 1909, by Sir Arnold Theiler to join the staff of the newly established veterinary laboratory at Onderstepoort. After initial studies on the treatment of trypanosomosis and on snake venoms he was deployed by Theiler in 1911 to start research on lamsiekte (botulism)at a field station on the farm Kaffraria near Christiana, where he met and married his wife Doris. After a stint as Captain in the SA Veterinary Corps during World War I he succeeded D T Mitchell as head of the Allerton Laboratory in 1918, where he excelled in research on toxic plants, inter alia identifying Matricaria nigellaefolia as the cause of staggers in cattle. When the Faculty of Veterinary Science was established in 1920 he was appointed as the first Professor of Physiology. After the graduation of the first class in 1924, and due to health problems, he returned to the UK, first to the Royal Veterinary College and then to the Weybridge Veterinary Laboratories of which he became Director in 1927. After his retirement in 1947 he returned to South Africa as a guest worker at Onderstepoort where he again became involved in teaching physiology when Prof. Quin unexpectedly died in 1950. Andrews died in Pretoria in 1953 and was buried in the Rebecca Street Cemetery.

Telomerase catalytic subunit homologs from fission yeast and human.

Catalytic protein subunits of telomerase from the ciliate Euplotes aediculatus and the yeast Saccharomyces cerevisiae contain reverse transcriptase motifs. Here the homologous genes from the fission yeast Schizosaccharomyces pombe and human are identified. Disruption of the S. pombe gene resulted in telomere shortening and senescence, and expression of mRNA from the human gene correlated with telomerase activity in cell lines. Sequence comparisons placed the telomerase proteins in the reverse transcriptase family but revealed hallmarks that distinguish them from retroviral and retrotransposon relatives. Thus, the proposed telomerase catalytic subunits are phylogenetically conserved and represent a deep branch in the evolution of reverse transcriptases.

Self-Similarity and the Dynamics of Coarsening in Materials.

Two-phase mixtures, from metallic alloys to islands on surfaces, undergo coarsening wherein the total interfacial area of the system decreases with time. Theory predicts that during coarsening the average size-scale of a two-phase mixture increases with time as t1/3 when the two-phase mixture is self-similar, or time independent when scaled by a time-dependent length. Here, we explain why this temporal power law is so robustly observed even when the microstructure is not self-similar. We show that there exists an upper limit to the length scales in the system that are kinetically active during coarsening, which we term the self-similar length scale. Length scales smaller than the self-similar length scale evolve, leading to the classical temporal power law for the coarsening dynamics of the system. Longer length scales are largely inactive, leading to a non-self-similar structure. This result holds for any two-phase mixture with a large distribution of morphological length scales.

Oxidation of a specific methionine in thrombomodulin by activated neutrophil products blocks cofactor activity. A potential rapid mechanism for modulation of coagulation.

Endothelial thrombomodulin (TM) plays a critical role in hemostasis as a cofactor for thrombin-dependent formation of activated protein C, a potent anticoagulant. Chloramine T, H2O2, or hypochlorous acid generated from H2O2 by myeloperoxidase rapidly destroy 75-90% of TM cofactor activity. Activated PMN, the primary in vivo source of biological oxidants, also rapidly inactivate TM. Oxidation of TM by PMN is inhibited by diphenylene iodonium, an inhibitor of NADPH oxidase. Both Met291 and Met388 in the six epidermal growth factor-like repeat domain are oxidized; however, only substitutions of Met388 lead to TM analogues that resist oxidative inactivation. We suggest that in inflamed tissues activated PMN may inactivate TM and demonstrate further evidence of the interaction between the inflammatory process and induction of thrombotic potential.

Determination of natural and depleted uranium in urine at the ppt level: an interlaboratory analytical exercise.

An analytical exercise was initiated in order to determine those procedures with the capability to measure total uranium and uranium (238U/235U) isotopic ratios in urine samples containing >0.02 microg U kg-1 urine. A host laboratory prepared six identical sets of twelve synthetic urine samples containing total uranium in the range of 25 to 770 ng U kg-1 urine and with 238U/235U isotopic ratios ranging from 138 (100% NU) to 215 (51% DU). Sets of samples were shipped to five testing laboratories (four based in Canada and one based in Europe). Each laboratory utilized one of the following analytical techniques: sector field inductively coupled plasma mass spectrometry (ICP-SF-MS), quadrupole inductively coupled plasma mass spectrometry (ICP-Q-MS), thermal ionization mass spectrometry (TIMS), and instrumental/delayed neutron activation analysis (I/DNAA), in their analyses.

Elevated in vivo insulin clearance in pima indians with non-insulin-dependent diabetes mellitus.

In vivo insulin clearance in 10 subjects with non-insulin-dependent diabetes mellitus (NIDDM) has been compared with clearance in eight equally obese nondiabetic control subjects by two different methods. The first approach consisted of determining the metabolic clearance rates of exogenously infused insulin (MCRI) during hyperinsulinemic (100 mU/m2/min) glucose clamp studies. The results indicated that mean (+/- SEM) MCRI was 1.4-fold greater in the diabetic subjects (436 +/- 22 ml/m2/min) than in the controls (325 +/- 24 ml/m2/min, P less than 0.005), resulting in a lower steady-state plasma insulin concentration in the diabetic (255 +/- 8 microU/ml) compared with the nondiabetic subjects (329 +/- 29 microU/ml, P less than 0.001). The impact of NIDDM on insulin removal rates was also estimated by a second method in which extraction of endogenously secreted insulin (EXTI) in response to an oral glucose load was calculated from the integrated area above basal of plasma insulin (IRI) and of plasma C-peptide (CPR), an estimate of beta-cell secretion. The results demonstrated that fractional extraction of endogenously secreted insulin (EXTI = 100 [(CPR - IRI)/CPR]) was also 1.2-fold greater for diabetic subjects (88.9 +/- 2.5%) than for nondiabetic controls (72.0 +/- 2.8%, P less than 0.001). Finally, these two independent measurements of in vivo insulin removal rates (MCRI and EXTI) were significantly correlated with each other (r = 0.71, P less than 0.002). These observations are consistent with the view that elevated insulin clearance may contribute to the postchallenge hypoinsulinemia of NIDDM in Pima Indians.

Insulin therapy in obese, non-insulin-dependent diabetes induces improvements in insulin action and secretion that are maintained for two weeks after insulin withdrawal.

The effects of rigorous insulin treatment on insulin action (insulin clamp) and secretion (plasma insulin response to glucose) were studied in 13 obese patients with non-insulin-dependent diabetes mellitus (NIDDM). Improvements were documented in fasting (P less than 0.0001) and postprandial (P less than 0.0001) plasma glucose concentrations, insulin secretion after oral glucose (P less than 0.001), and insulin action (P less than 0.005) after 30 days of therapy. Mean integrated plasma insulin response to glucose increased 2.5-fold after insulin therapy, but this improvement varied considerably from patient to patient. Insulin action also increased with insulin treatment and the resulting values were no longer significantly different from a weight- and age-matched group of subjects with normal glucose tolerance. However, there was considerable patient-to-patient variation in the degree to which insulin action was enhanced. The insulin-induced improvements in glucose tolerance persisted for at least 2 wk after insulin withdrawal, and were associated with continued increased insulin secretion and insulin action. In conclusion, control of hyperglycemia for 1 mo led to improvements in both insulin secretion and action in a series of obese patients with NIDDM that persisted for at least 2 wk after cessation of therapy.

Gonadotropin-releasing hormone stimulates mass changes in phosphoinositides and diacylglycerol accumulation in purified gonadotrope cell cultures.

GnRH stimulates rapid and specific hydrolysis of the phosphoinositides and their conversion to diacylglycerols (DAGs) in enriched gonadotrope cultures. In short term labeling studies, we observed stimulation of 32P incorporation into inositol phospholipids; no corresponding change was seen in other major phospholipids. The observation that this response continues in the presence of the Ca2+ channel antagonist D600 suggests that, unlike LH release, stimulation of phosphatidylinositol (PI) production is independent of mobilization of extracellular Ca2+. Agents that substitute for endogenous DAGs (phorbol myristate acetate) or mobilize Ca2+ directly (ionophore A23187) did not stimulate 32P incorporation into PI. Relative mass changes in PIs in response to GnRH were measured in a 32P/33P protocol. These showed a fall (40%) in the level of the inositol phospholipids within 45 sec, with a new steady state achieved at a lower level by 5 min. Phosphatidic acid formation was stimulated by GnRH within 2 min, with a 150% increase above control values at the highest dose of GnRH tested (10(-7) M). In cells prelabeled with [3H]arachidonic acid, GnRH caused a transient increase in DAG formation (twice the control value) within 1 min (with or without D600) which declined thereafter. This effect of GnRH was not seen in cells stimulated to release LH with ionophore A23187 or phorbol myristate acetate, suggesting that these may act distally to inositol phospholipid turnover. The data suggest that GnRH stimulates the hydrolysis of newly synthesized PIs, leading to the formation of DAGs. This pathway appears to be regulated independently of mobilization of extracellular Ca2+.

A quantitative analysis of the maturation of steroid negative feedbacks controlling gonadotropin release in the female rat: the infantile-juvenile periods, transition from an androgenic to a predominantly estrogenic control.

To determine what ovarian or adrenal steroid(s) are involved in restraining gonadotropin secretion in infantile female rats, several experiments were performed. Adrenalectomy of 10-day-old rats markedly decreased serum progesterone (P) and, to a lesser extent, serum estradiol (E2) levels. Androgen (A) levels were only transiently reduced, and serum dihydrotestosterone was not affected. Serum LH and FSH, on the other hand, increased only transiently after adrenalectomy. Ovariectomy (OVX) failed to decrease serum P and partially depressed serum E2, but resulted in a marked fall of both testosterone (T) and dihydrotestosterone. Serum LH and FSH were increased in these animals. Replacement of pre-OVX serum T levels via Silastic capsules prevented the postcastration rise in both LH and FSH, suggesting that the increase in gonadotropins that follows OVX of 10-day-old rats is, to a large extent, a consequence of the loss of ovarian T. OVX of juvenile (27 days old) rats increased serum FSH and LH 48 h later and reduced both serum T and E2 levels, with no significant change in serum P. Replacement of pre-OVX serum T levels depressed post-OVX serum FSH and LH titers only partially. In contrast, replacement of pre-OVX serum E2 levels, effectively suppressed the postcastration rise in serum gonadotropins. The results suggest that 1) during the infantile period, gonadotropin release is predominantly under ovarian androgenic inhibitory control, but this mechanism is not very effective, because basal serum gonadotropin levels, particularly FSH, are elevated; 2) the effectiveness of the A negative feedback on FSH remains unchanged during prepubertal development; and 3) the previously reported increase in E2 negative feedback effectiveness that occurs after day 15 results in an E2 inhibitory signal that surpasses that of As, so that during juvenile days, most of the ovarian steroidal inhibitory control on gonadotropin release is mediated by E2.

The maturation of estradiol-negative feedback in female rats: evidence that the resetting of the hypothalamic "gonadostat" does not precede the first preovulatory surge of gonadotropins.

Several experiments were performed to study the changes in the negative feedback of estradiol on gonadotropin secretion around the time of puberty in the female rat. Ovariectomy of juvenile, first diestrus, or adult animals elevated FSH and LH levels 2 and/or 4 days later. Estradiol administered via Silastic capsules, at several dose levels, was much more effective in preventing the postcastration rise of gonadotropins in juvenile than in the older animals. A dose of estradiol that inhibited gonadotropin levels in juvenile rats, but not in adult animals, maintained preovariectomy serum estradiol levels more efficiently in the adult rats. Therefore, a more rapid removal of estradiol from the blood stream cannot explain its lower effectiveness in suppressing gonadotropin release in adult rats. Estradiol-negative feedback effectiveness remained maximal until the day of first proestrus and decreased markedly on the next day (first estrus), remaining low thereafter. "Resetting" of the gonadostat to estradiol negative feedback was advanced by inducing precocious puberty by means of hyperprolactinemia, but not by mimicking the periovulatory changes in serum estradiol and progesterone in the absence of an LH surge. Serum progesterone levels were much higher in postpubertal rats than in juvenile animals. Ovariectomy of juvenile rats slightly decreased the already low levels of serum progesterone, but it produced a striking progesterone decrease in postpubertal animals. Quantitative replacement of preovariectomy serum progesterone levels in adult rats, treated with an ineffective dose of estradiol, almost completely restored the prepubertal effectiveness of estradiol in inhibiting LH release and, to a lesser extent, release of FSH...

Development of estradiol-positive feedback on luteinizing hormone release in the female rat: a quantitative study.

Experiments were conducted to study, in a quantitative manner, the development of estradiol (E2)-positive feedback on LH release in the female rat. A Silastic capsule (20 mm in length/100 g BW) containing E2 dissolved in corn oil (400 micrograms/ml) reproduced first proestrous levels of serum E2 when implanted sc in juvenile rats of different ages (days 20-32). When similar capsules were implanted in infantile rats (days 10-18), serum E2, measured 2 days later, was found to be extremely elevated in 12- and 14-day-old rats (4-6 times higher than first proestrous levels), declining thereafter so that in 16- to 20-day-old rats the levels were only 2-fold greater than proestrous values. Serum levels of alpha-fetoprotein decreased markedly between days 12-28, and both normal and implant-produced serum E2 levels paralleled the decline in the protein titers. However, calculation of the total E2 binding capacity of alpha-fetoprotein indicated that in addition to binding to this protein, there are additional factors responsible for the persistence of E2 in the serum of infantile rats. A LH surge could not be induced in 12- or 14-day-old rats by a 48-h E2 pulse, despite the presence of substantial amounts of free E2, which exerted profound negative feedback effects. Between days 16-20, only E2 levels that were at least 2-fold higher than first proestrous values were effective in inducing a LH surge. Between days 22-34, a LH surge was elicited by serum E2 levels very similar to those seen during the first proestrus. By days 26-28, the profile of the LH surge was indistinguishable from that of the first preovulatory surge. Starting on day 26, and in addition to the LH surge elicited by the 48-h E2 pulse, an earlier surge occurred on the next day after E2 implantation. By day 30, the early LH surge became firmly established, and the late surge was no longer apparent. It is suggested that in the female rat, the development of E2-positive feedback comprises four phases: phase I, before day 16, in which the surge mechanism of the LH-releasing system is not developed; phase II, between days 16-20, in which E2 levels twice as high as those of first proestrus are necessary to activate the LH surge mechanism; phase III, which is initiated at the beginning of the juvenile period (approximately days 20-22) and in which the LH surge mechanism responds to E2 levels of preovulatory magnitude; and mechanism responds to E2 levels of preovulatory magnitude; and phase IV, which begins around days 26-28 and in which a 24-h exposure to E2 levels of preovulatory magnitude is sufficient to elicit a LH surge.