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Failure behavior of internally pressurized flawed and unflawed steam generator tubing at high temperatures -- Experiments and comparison with model predictions
This report summarizes experimental work performed at Argonne National Laboratory on the failure of internally pressurized steam generator tubing at high temperatures ({le} 700 C). A model was developed for predicting failure of flawed and unflawed steam generator tubes under internal pressure and temperature histories postulated to occur during severe accidents. The model was validated by failure tests on specimens with part-through-wall axial and circumferential flaws of various lengths and depths, conducted under various constant and ramped internal pressure and temperature conditions. The failure temperatures predicted by the model for two temperature and pressure histories, calculated for severe accidents initiated by a station blackout, agree very well with tests performed on both flawed and unflawed specimens
Oncogenic PIK3CA corrupts growth factor signaling specificity
Pathological activation of the PI3K/AKT pathway is among the most frequent defects in human cancer and is also the cause of rare overgrowth disorders. Yet, there is currently no systematic understanding of the quantitative flow of information within PI3K/AKT signaling and how it is perturbed by disease-causing mutations. Here, we develop scalable, single-cell approaches for systematic analyses of signal processing within the PI3K pathway, enabling precise calculations of its information transfer for different growth factors. Using genetically-engineered human cell models with allele dose-dependent expression of PIK3CAH1047R, we show that this oncogene is not a simple, constitutive pathway activator but a context-dependent modulator of extracellular signal transfer. PIK3CAH1047Rreduces information transmission downstream of IGF1 while selectively enhancing EGF-induced signaling and transcriptional responses. This leads to a gross reduction in signaling specificity, akin to “blurred” signal perception. The associated increase in signaling heterogeneity promotes phenotypic diversity in a human cervical cancer cell line model and in human induced pluripotent stem cells. Collectively, these findings and the accompanying methodological advances lay the foundations for a systematic mapping of the quantitative mechanisms of PI3K/AKT-dependent signal processing and phenotypic control in health and disease
Speed, Sensitivity, and Bistability in Auto-activating Signaling Circuits
Cells employ a myriad of signaling circuits to detect environmental signals and drive specific gene expression responses. A common motif in these circuits is inducible auto-activation: a transcription factor that activates its own transcription upon activation by a ligand or by post-transcriptional modification. Examples range from the two-component signaling systems in bacteria and plants to the genetic circuits of animal viruses such as HIV. We here present a theoretical study of such circuits, based on analytical calculations, numerical computations, and simulation. Our results reveal several surprising characteristics. They show that auto-activation can drastically enhance the sensitivity of the circuit's response to input signals: even without molecular cooperativity, an ultra-sensitive threshold response can be obtained. However, the increased sensitivity comes at a cost: auto-activation tends to severely slow down the speed of induction, a stochastic effect that was strongly underestimated by earlier deterministic models. This slow-induction effect again requires no molecular cooperativity and is intimately related to the bimodality recently observed in non-cooperative auto-activation circuits. These phenomena pose strong constraints on the use of auto-activation in signaling networks. To achieve both a high sensitivity and a rapid induction, an inducible auto-activation circuit is predicted to acquire low cooperativity and low fold-induction. Examples from Escherichia coli's two-component signaling systems support these predictions
Socioeconomic development, family income, and psychosocial risk factors: a study of families with children in public elementary school
A genome-wide identification and comparative analysis of the lentil MLO genes
Revista electrónica on linePowdery mildew is a widespread fungal plant disease that can cause significant losses in
many crops. Some MLO genes (Mildew resistance locus O) have proved to confer a durable
resistance to powdery mildew in several species. Resistance granted by the MLO gene family
members has prompted an increasing interest in characterizing these genes and implementing
their use in plant breeding. Lentil (Lens culinaris Medik.) is a widely grown food
legume almost exclusively consumed as dry seed with an average world production of 4.5
million tons. Powdery mildew causes severe losses on certain lentil cultivars under particular
environmental conditions. Data mining of the lentil CDC Redberry draft genome allowed to
identify up to 15 gene sequences with homology to known MLO genes, designated as
LcMLOs. Further characterization of these gene sequences and their deduced protein
sequences demonstrated conformity with key MLO protein characteristics such as the presence
of transmembrane and calmodulin binding domains, as well as that of other conserved
motifs. Phylogenetic and other comparative analyses revealed that LcMLO1 and LcMLO3
are the most likely gene orthologs related to powdery mildew response in other species,
sharing a high similarity with other known resistance genes of dicot species, such as pea
PsMLO1 and Medicago truncatula MtMLO1 and MtMLO3. Sets of primers were designed
as tools to PCR amplify the genomic sequences of LcMLO1 and LcMLO3, also to screen
lentil germplasm in search of resistance mutants. Primers were used to obtain the complete
sequences of these two genes in all of the six wild lentil relatives. Respective to each gene,
all Lens sequences shared a high similarity. Likewise, we used these primers to screen a
working collection of 58 cultivated and 23 wild lentil accessions in search of length polymorphisms
present in these two genes. All these data widen the insights on this gene family and
can be useful for breeding programs in lentil and close related species.S
Functional Analysis of an Acid Adaptive DNA Adenine Methyltransferase from Helicobacter pylori 26695
HP0593 DNA-(N6-adenine)-methyltransferase (HP0593 MTase) is a member of a Type III restriction-modification system in Helicobacter pylori strain 26695. HP0593 MTase has been cloned, overexpressed and purified heterologously in Escherichia coli. The recognition sequence of the purified MTase was determined as 5′-GCAG-3′and the site of methylation was found to be adenine. The activity of HP0593 MTase was found to be optimal at pH 5.5. This is a unique property in context of natural adaptation of H. pylori in its acidic niche. Dot-blot assay using antibodies that react specifically with DNA containing m6A modification confirmed that HP0593 MTase is an adenine-specific MTase. HP0593 MTase occurred as both monomer and dimer in solution as determined by gel-filtration chromatography and chemical-crosslinking studies. The nonlinear dependence of methylation activity on enzyme concentration indicated that more than one molecule of enzyme was required for its activity. Analysis of initial velocity with AdoMet as a substrate showed that two molecules of AdoMet bind to HP0593 MTase, which is the first example in case of Type III MTases. Interestingly, metal ion cofactors such as Co2+, Mn2+, and also Mg2+ stimulated the HP0593 MTase activity. Preincubation and isotope partitioning analyses clearly indicated that HP0593 MTase-DNA complex is catalytically competent, and suggested that DNA binds to the MTase first followed by AdoMet. HP0593 MTase shows a distributive mechanism of methylation on DNA having more than one recognition site. Considering the occurrence of GCAG sequence in the potential promoter regions of physiologically important genes in H. pylori, our results provide impetus for exploring the role of this DNA MTase in the cellular processes of H. pylori
Attitudes towards the male contraceptive pill:Psychosocial and cultural explanations for delaying a marketable product
The role of metacognition in self-critical rumination: an investigation in individuals presenting with low self-esteem
Background: No research, to date, has directly investigated the role of metacognition in self-critical rumination and low self-esteem. Aim: To investigate the presence of metacognitive beliefs about self-critical rumination; the goal of self-critical rumination and its stop signal; and the degree of detachment from intrusive self-critical thoughts. Method: Ten individuals reporting both a self-acknowledged tendency to judge themselves critically and having low self-esteem were assessed using metacognitive profiling, a semi-structured interview. Results: All participants endorsed both positive and negative metacognitive beliefs about self-critical rumination. Positive metacognitive beliefs concerned the usefulness of self-critical rumination as a means of improving cognitive performance and enhancing motivation. Negative metacognitive beliefs concerned the uncontrollability of self-critical rumination and its negative impact on mood, motivation and perception of self-worth. The primary goal of engaging in self-critical rumination was to achieve a better or clearer understanding of a given trigger situation or to feel more motivated to resolve it. However, only four participants were able to identify when this goal had been achieved, which was if the trigger situation were not to occur again. Participants unanimously stated that they were either unable to detach from their self-critical thoughts or could do so some of the time with varying degrees of success. More often than not, though, self-critical thoughts were viewed as facts, would rarely be seen as distorted or biased, and could take hours or days to dissipate. Conclusions: These findings provide preliminary evidence that specific facets of metacognition play a role in the escalation and perseveration of self-critical rumination
Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells
Cellular functions accompanying establishment of premature senescence in methotrexate-treated human colon cancer C85 cells are deciphered in the present study from validated competitive expression microarray data, analyzed with the use of Ingenuity Pathways Analysis (IPA) software. The nitrosative/oxidative stress, inferred from upregulated expression of inducible nitric oxide synthase (iNOS) and mitochondrial dysfunction-associated genes, including monoamine oxidases MAOA and MAOB, β-amyloid precursor protein (APP) and presenilin 1 (PSEN1), is identified as the main determinant of signaling pathways operating during senescence establishment. Activation of p53-signaling pathway is found associated with both apoptotic and autophagic components contributing to this process. Activation of nuclear factor κB (NF-κB), resulting from interferon γ (IFNγ), integrin, interleukin 1β (IL-1β), IL-4, IL-13, IL-22, Toll-like receptors (TLRs) 1, 2 and 3, growth factors and tumor necrosis factor (TNF) superfamily members signaling, is found to underpin inflammatory properties of senescent C85 cells. Upregulation of p21-activated kinases (PAK2 and PAK6), several Rho molecules and myosin regulatory light chains MYL12A and MYL12B, indicates acquisition of motility by those cells. Mitogen-activated protein kinase p38 MAPK β, extracellular signal-regulated kinases ERK2 and ERK5, protein kinase B AKT1, as well as calcium, are identified as factors coordinating signaling pathways in senescent C85 cells
Role of β-Catenin in Post-Meiotic Male Germ Cell Differentiation
Though roles of β-catenin signaling during testis development have been well established, relatively little is known about its role in postnatal testicular physiology. Even less is known about its role in post-meiotic germ cell development and differentiation. Here, we report that β-catenin is highly expressed in post-meiotic germ cells and plays an important role during spermiogenesis in mice. Spermatid-specific deletion of β-catenin resulted in significantly reduced sperm count, increased germ cell apoptosis and impaired fertility. In addition, ultrastructural studies show that the loss of β-catenin in post-meiotic germ cells led to acrosomal defects, anomalous release of immature spermatids and disruption of adherens junctions between Sertoli cells and elongating spermatids (apical ectoplasmic specialization; ES). These defects are likely due to altered expression of several genes reportedly involved in Sertoli cell-germ cell adhesion and germ cell differentiation, as revealed by gene expression analysis. Taken together, our results suggest that β-catenin is an important molecular link that integrates Sertoli cell-germ cell adhesion with the signaling events essential for post-meiotic germ cell development and maturation. Since β-catenin is also highly expressed in the Sertoli cells, we propose that binding of germ cell β-catenin complex to β-catenin complex on Sertoli cell at the apical ES surface triggers a signaling cascade that regulates post-meiotic germ cell differentiation
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