990 resultados para Positive Definite Functions


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While effector molecules produced by activated macrophages (including nitric oxide, tumor necrosis factor α, interleukin 1, etc.) help to eliminate pathogens, high levels of these molecules can be deleterious to the host itself. Despite their importance, the mechanisms modulating macrophage effector functions are poorly understood. This work introduces two key negative regulators that control the levels and duration of macrophage cytokine production. Vacuolar-type H+-ATPase (V-ATPase) and calcineurin (Cn) constitutively act in normal macrophages to suppress expression of inflammatory cytokines in the absence of specific activation and to inhibit macrophage cytokine responses induced by bacterial lipopolysaccharide (V-ATPase), interferon γ (V-ATPase and Cn), and calcium (Ca2+) flux (Cn). Cn and V-ATPase modulate effector gene expression at the mRNA level by inhibiting transcription factor NF-κB. This negative regulation by Cn is opposite to its crucial positive role in T cells, where it activates NFAT transcription factor(s) leading to expression of interleukin 2, tumor necrosis factor α, and other cytokine genes. The negative effects of V-ATPase and Cn on NF-κB-dependent gene expression are not limited to the macrophage lineage, as similar effects have been seen with a murine fibroblast cell line and with primary astrocytes.

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Many bacterial plasmids replicate by a rolling-circle mechanism that involves the generation of single-stranded DNA (ssDNA) intermediates. Replication of the lagging strand of such plasmids initiates from their single strand origin (sso). Many different types of ssos have been identified. One group of ssos, termed ssoA, which have conserved sequence and structural features, function efficiently only in their natural hosts in vivo. To study the host specificity of sso sequences, we have analyzed the functions of two closely related ssoAs belonging to the staphylococcal plasmid pE194 and the streptococcal plasmid pLS1 in Staphylococcus aureus. The pLS1 ssoA functioned poorly in vivo in S. aureus as evidenced by accumulation of high levels of ssDNA but supported efficient replication in vitro in staphylococcal extracts. These results suggest that one or more host factors that are present in sufficient quantities in S. aureus cell-free extracts may be limiting in vivo. Mapping of the initiation points of lagging strand synthesis in vivo and in vitro showed that DNA synthesis initiates from specific sites within the pLS1 ssoA. These results demonstrate that specific initiation of replication can occur from the pLS1 ssoA in S. aureus although it plays a minimal role in lagging strand synthesis in vivo. Therefore, the poor functionality of the pLS1 in vivo in a nonnative host is caused by the low efficiency rather than a lack of specificity of the initiation process. We also have identified ssDNA promoters and mapped the primer RNAs synthesized by the S. aureus and Bacillus subtilis RNA polymerases from the pE194 and pLS1 ssoAs. The S. aureus RNA polymerase bound more efficiently to the native pE194 ssoA as compared with the pLS1 ssoA, suggesting that the strength of RNA polymerase–ssoA interaction may play a major role in the functionality of the ssoA sequences in Gram-positive bacteria.

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The PTEN/MMAC1 phosphatase is a tumor suppressor gene implicated in a wide range of human cancers. Here we provide biochemical and functional evidence that PTEN/MMAC1 acts a negative regulator of the phosphoinositide 3-kinase (PI3-kinase)/Akt pathway. PTEN/MMAC1 impairs activation of endogenous Akt in cells and inhibits phosphorylation of 4E-BP1, a downstream target of the PI3-kinase/Akt pathway involved in protein translation, whereas a catalytically inactive, dominant negative PTEN/MMAC1 mutant enhances 4E-BP1 phosphorylation. In addition, PTEN/MMAC1 represses gene expression in a manner that is rescued by Akt but not PI3-kinase. Finally, higher levels of Akt activation are observed in human prostate cancer cell lines and xenografts lacking PTEN/MMAC1 expression when compared with PTEN/MMAC1-positive prostate tumors or normal prostate tissue. Because constitutive activation of either PI3-kinase or Akt is known to induce cellular transformation, an increase in the activation of this pathway caused by mutations in PTEN/MMAC1 provides a potential mechanism for its tumor suppressor function.

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The pir gene of plasmid R6K encodes the protein, π, a replication and transcription factor. Two translational options for the pir gene give rise to two forms of π protein: a 35.0-kDa form (π35.0) and a shortened 30.5-kDa form (π30.5). Although both proteins bind to a series of 22-bp direct repeats essential for plasmid R6K replication, only π35.0 can bind to a site in the (A⋅T)-rich segment of its γ ori and activate the γ ori in vivo and in vitro. However, unlike π35.0, π30.5can inhibit in vivo and in vitro replication (activated by π35.0). We propose that the two forms of π might have distinct functions in replication. We show that although both forms of π produce dimers, the nature of these dimers is not identical. The N-terminal 37 amino acid residues appear to control the formation of the more stable π35.0 dimers, whereas another, apparently weaker interface holds together dimers of π30.5. We speculate that the leucine zipper-like motif, absent in π30.5, controls very specific functions of π protein.

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We construct an Euler product from the Hecke eigenvalues of an automorphic form on a classical group and prove its analytic continuation to the whole complex plane when the group is a unitary group over a CM field and the eigenform is holomorphic. We also prove analytic continuation of an Eisenstein series on another unitary group, containing the group just mentioned defined with such an eigenform. As an application of our methods, we prove an explicit class number formula for a totally definite hermitian form over a CM field.

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General transcription factor SIII, a heterotrimer composed of 110-kDa (p110), 18-kDa (p18), and 15-kDa (p15) subunits, increases the catalytic rate of transcribing RNA polymerase II by suppressing transient pausing by polymerase at multiple sites on DNA templates. Here we report molecular cloning and biochemical characterization of the SIII p18 subunit, which is found to be a member of the ubiquitin homology (UbH) gene family and functions as a positive regulatory subunit of SIII. p18 is a 118-amino acid protein composed of an 84-residue N-terminal UbH domain fused to a 34-residue C-terminal tail. Mechanistic studies indicate that p18 activates SIII transcriptional activity above a basal level inherent in the SIII p110 and p15 subunits. Taken together, these findings establish a role for p18 in regulating the activity of the RNA polymerase II elongation complex, and they bring to light a function for a UbH domain protein in transcriptional regulation.

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The indefinite determiner yi 'one'+ classifier' is the most approximate to an indefinite article, like the English a, in Chinese. It serves all the functions characteristic of representative stages of grammaticalization from a numeral to a generalized indefinite determiner as elaborated in the literature. It is established in this paper that the Chinese indefinite determiner has developed a special use with definite expressions, serving as a backgrounding device marking entities as of low thematic importance and unlikely to receive subsequent mentions in ensuing discourse. 'yi+ classifier' in the special use with definite expressions displays striking similarities in terms of semantic bleaching and phonological reduction with the same determiner at the advanced stage of grammaticalization characterized by uses with generics, nonspecifics and nonreferentials. An explanation is offered in terms of an implicational relation between nonreferentiality and low thematic importance which characterize the two uses of the indefinite determiner. While providing another piece of evidence in support of the claim that semantically nonreferentials and entities of low thematic importance tend to be encoded in terms of same linguistic devices in language, findings in this paper have shown how an indefinite determiner can undergo a higher degree of grammaticalization than has been reported in the literature-it expands its scope to mark not only indefinite but also definite expressions as semantically nonreferential and/or thematically unimportant. (C) 2003 Elsevier B.V. All rights reserved.

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E. L. DeLosh, J. R. Busemeyer, and M. A. McDaniel (1997) found that when learning a positive, linear relationship between a continuous predictor (x) and a continuous criterion (y), trainees tend to underestimate y on items that ask the trainee to extrapolate. In 3 experiments, the authors examined the phenomenon and found that the tendency to underestimate y is reliable only in the so-called lower extrapolation region-that is, new values of x that lie between zero and the edge of the training region. Existing models of function learning, such as the extrapolation-association model (DeLosh et al., 1997) and the population of linear experts model (M. L. Kalish, S. Lewandowsky, & J. Kruschke, 2004), cannot account for these results. The authors show that with minor changes, both models can predict the correct pattern of results.

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If ξ is a countable ordinal and (fk) a sequence of real-valued functions we define the repeated averages of order ξ of (fk). By using a partition theorem of Nash-Williams for families of finite subsets of positive integers it is proved that if ξ is a countable ordinal then every sequence (fk) of real-valued functions has a subsequence (f'k) such that either every sequence of repeated averages of order ξ of (f'k) converges uniformly to zero or no sequence of repeated averages of order ξ of (f'k) converges uniformly to zero. By the aid of this result we obtain some results stronger than Mazur’s theorem.

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The concept of the distinguished sets is applied to the investigation of the functionally countable spaces. It is proved that every Baire function on a functionally countable space has a countable image. This is a positive answer to a question of R. Levy and W. D. Rice.

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Recent epidemiological evidences indicate that arsenic exposure increases risk of atherosclerosis, cardio vascular diseases (CVD) such as hypertension, atherosclerosis, coronary artery disease (CAD) and microangiopathies in addition to the serious global health concern related to its carcinogenic effects. In experiments on animals, acute and chronic exposure to arsenic directly correlates with cardiac tachyarrhythmia, and atherogenesis in a concentration and duration dependent manner. Moreover, the other effects of long-term arsenic exposure include induction of non-insulin dependent diabetes by mechanisms yet to be understood. On the other hand, there are controversial issues, gaps in knowledge, and future research priorities in accelerated incidences of CVD and mortalities in patients with HIV who are under long-termanti-retroviral therapy (ART). Although, both HIV infection itself and various components of ART initiate significant pathological alterations in the myocardium and the vasculature, simultaneous environmental exposure to arsenic which is more convincingly being recognized as a facilitator of HIV viral cycling in the infected immune cells, may contribute an additional layer of adversity in these patients. A high degree of suspicion and early screening may allow appropriate interventional guidelines to improve the quality of lives of those affected. In this mini-review which have been fortified with our own preliminary data, we will discuss some of the key current understating of chronic arsenic exposure, and its possible impact on the accelerated HIV/ART induced CVD. The review will conclude with notes on recent developments in mathematical modeling in this field that probabilistically forecast incidence prevalence as functions of aging and life style parameters, most of which vary with time themselves; this interdisciplinary approach provides a complementary kernel to conventional biology.

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It was recently shown [Phys. Rev. Lett. 110, 227201 (2013)] that the critical behavior of the random-field Ising model in three dimensions is ruled by a single universality class. This conclusion was reached only after a proper taming of the large scaling corrections of the model by applying a combined approach of various techniques, coming from the zero-and positive-temperature toolboxes of statistical physics. In the present contribution we provide a detailed description of this combined scheme, explaining in detail the zero-temperature numerical scheme and developing the generalized fluctuation-dissipation formula that allowed us to compute connected and disconnected correlation functions of the model. We discuss the error evolution of our method and we illustrate the infinite limit-size extrapolation of several observables within phenomenological renormalization. We present an extension of the quotients method that allows us to obtain estimates of the critical exponent a of the specific heat of the model via the scaling of the bond energy and we discuss the self-averaging properties of the system and the algorithmic aspects of the maximum-flow algorithm used.

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Purpose. To determine the mechanisms predisposing penile fracture as well as the rate of long-term penile deformity and erectile and voiding functions. Methods. All fractures were repaired on an emergency basis via subcoronal incision and absorbable suture with simultaneous repair of eventual urethral lesion. Patients' status before fracture and voiding and erectile functions at long term were assessed by periodic follow-up and phone call. Detailed history included cause, symptoms, and single-question self-report of erectile and voiding functions. Results. Among the 44 suspicious cases, 42 (95.4%) were confirmed, mean age was 34.5 years (range: 18-60), mean follow-up 59.3 months (range 9-155). Half presented the classical triad of audible crack, detumescence, and pain. Heterosexual intercourse was the most common cause (28 patients, 66.7%), followed by penile manipulation (6 patients, 14.3%), and homosexual intercourse (4 patients, 9.5%). Woman on top was the most common heterosexual position (n = 14, 50%), followed by doggy style (n = 8, 28.6%). Four patients (9.5%) maintained the cause unclear. Six (14.3%) patients had urethral injury and two (4.8%) had erectile dysfunction, treated by penile prosthesis and PDE-5i. No patient showed urethral fistula, voiding deterioration, penile nodule/curve or pain. Conclusions. Woman on top was the potentially riskiest sexual position (50%). Immediate surgical treatment warrants long-term very low morbidity.

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Islet neogenesis-associated protein (INGAP) is a peptide found in pancreatic exocrine-, duct- and islet- non-β-cells from normal hamsters. Its increase induced by either its exogenous administration or by the overexpression of its gene enhances β-cell secretory function and increases β-cell mass by a combination of stimulation of cell replication and islet neogenesis and reduction of β-cell apoptosis. We studied the potential modulatory role of endogenous INGAP in insulin secretion using two different experimental approaches. Hamster islets transfected with INGAP-small interfering RNA (INGAP-siRNA) were used to study glucose-stimulated insulin secretion (GSIS). In parallel, freshly isolated islets were incubated with high glucose and the same concentration of either a specific anti-INGAP rabbit serum or normal rabbit serum. INGAP-siRNA transfected islets reduced their INGAP mRNA and protein content by 35.1% and 47.2%, respectively whereas GSIS decreased by 25.8%. GSIS by transfected islets attained levels comparable to those recorded in control islets when INGAP pentadecapeptide (INGAP-PP) was added to the culture medium. INGAP antibody in the medium decreased significantly GSIS in a dose-dependent manner. These results indicate that endogenous INGAP plays a physiological positive modulatory role in insulin secretion, supporting its possible use in the treatment of prediabetes and Type 2 diabetes.

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Streptococcus sanguinis is a commensal pioneer colonizer of teeth and an opportunistic pathogen of infectious endocarditis. The establishment of S. sanguinis in host sites likely requires dynamic fitting of the cell wall in response to local stimuli. In this study, we investigated the two-component system (TCS) VicRK in S. sanguinis (VicRKSs), which regulates genes of cell wall biogenesis, biofilm formation, and virulence in opportunistic pathogens. A vicK knockout mutant obtained from strain SK36 (SKvic) showed slight reductions in aerobic growth and resistance to oxidative stress but an impaired ability to form biofilms, a phenotype restored in the complemented mutant. The biofilm-defective phenotype was associated with reduced amounts of extracellular DNA during aerobic growth, with reduced production of H2O2, a metabolic product associated with DNA release, and with inhibitory capacity of S. sanguinis competitor species. No changes in autolysis or cell surface hydrophobicity were detected in SKvic. Reverse transcription-quantitative PCR (RT-qPCR), electrophoretic mobility shift assays (EMSA), and promoter sequence analyses revealed that VicR directly regulates genes encoding murein hydrolases (SSA_0094, cwdP, and gbpB) and spxB, which encodes pyruvate oxidase for H2O2 production. Genes previously associated with spxB expression (spxR, ccpA, ackA, and tpK) were not transcriptionally affected in SKvic. RT-qPCR analyses of S. sanguinis biofilm cells further showed upregulation of VicRK targets (spxB, gbpB, and SSA_0094) and other genes for biofilm formation (gtfP and comE) compared to expression in planktonic cells. This study provides evidence that VicRKSs regulates functions crucial for S. sanguinis establishment in biofilms and identifies novel VicRK targets potentially involved in hydrolytic activities of the cell wall required for these functions.