Twofold Mechanism Research Articles

A complete implementation of the efficient allocation of pollution

This paper presents a simple twofold mechanism that attains a complete implementation of the efficient allocation of pollution. The first component is adopted from Duggan and Roberts [Duggan, J., Roberts, J., 2002. Implementing the efficient allocation of pollution. American Economic Review 92, 1070–1078.]. The second new component takes care of the moral hazard problem.

Mitigating application-level denial of service attacks on Web servers

Recently, we have seen increasing numbers of denial of service (DoS) attacks against online services and Web applications either for extortion reasons or for impairing and even disabling the competition. These DoS attacks have increasingly targeted the application level. Application-level DoS attacks emulate the same request syntax and network-level traffic characteristics as those of legitimate clients, thereby making the attacks much harder to detect and counter. Moreover, such attacks often target bottleneck resources such as disk bandwidth, database bandwidth, and CPU resources. In this article, we propose handling DoS attacks by using a twofold mechanism. First, we perform admission control to limit the number of concurrent clients served by the online service. Admission control is based on port hiding that renders the online service invisible to unauthorized clients by hiding the port number on which the service accepts incoming requests. Second, we perform congestion control on admitted clients to allocate more resources to good clients. Congestion control is achieved by adaptively setting a client's priority level in response to the client's requests in a way that can incorporate application-level semantics. We present a detailed evaluation of the proposed solution using two sample applications: Apache HTTPD and the TPCW benchmark (running on Apache Tomcat and IBM DB2). Our experiments show that the proposed solution incurs low performance overhead and is resilient to DoS attacks.

Asthme réfractaire : évoquer une aspergillose bronchopulmonaire allergique

Allergic bronchopulmonary aspergillosis (ABPA) results from a twofold mechanism: Th2-like hypersensitivity reaction and bronchial colonization by Aspergillus fumigatus. This relatively rare disease occurs in immunocompetent patients in two very different situations: refractory asthma and cystic fibrosis. Diagnosis in asthma patients is relatively easy; it is based on the association of several criteria: clinical (recurrent exacerbations despite adequate therapy and a positive A. fumigatus skin prick-test), laboratory (inconsistent blood eosinophilia, high serum levels of total IgE, presence of A. fumigatus-specific IgE and IgG) and radiological (mainly central bronchiectasis, sometimes transitory pulmonary infiltrates). Diagnosis is more difficult in patients with cystic fibrosis because of the similarity of their various criteria. Long-term prognosis is good in the early stages of the illness, although the natural history and course of the disease are not fully understood. Early diagnosis and active screening for exacerbations are recommended to prevent bronchiectasis and progression to end-stage lung disease. Two drugs have shown their efficacy in treating ABPA: corticosteroids and itraconazole. They are recommended in acute exacerbations and should not be used as long-term therapy, except in corticosteroid-dependent asthma and in some cases of cystic fibrosis.

Two-fold mechanism of the interaction of incident light with a phase diffraction grating

It is suggested to use antireflection diffraction gratings for introducing light into the active regions of optoelectronic devices. The dependence of the diffraction efficiency on the grating groove depth, which controls the reflection from the optical surface and forms the diffraction order in the material, has been numerically modeled.

A structural and thermodynamic escape mechanism from a drug resistant mutation of the HIV-1 protease.

The efficacy of HIV-1 protease inhibition therapies is often compromised by the appearance of mutations in the protease molecule that lower the binding affinity of inhibitors while maintaining viable catalytic activity and substrate affinity. The V82F/I84V double mutation is located within the binding site cavity and affects all protease inhibitors in clinical use. KNI-764, a second-generation inhibitor currently under development, maintains significant potency against this mutation by entropically compensating for enthalpic losses, thus minimizing the loss in binding affinity. KNI-577 differs from KNI-764 by a single functional group critical to the inhibitor response to the protease mutation. This single difference changes the response of the two inhibitors to the mutation by one order of magnitude. Accordingly, a structural understanding of the inhibitor response will provide important guidelines for the design of inhibitors that are less susceptible to mutations conveying drug resistance. The structures of the two compounds bound to the wild type and V82F/I84V HIV-1 protease have been determined by X-ray crystallography at 2.0 A resolution. The presence of two asymmetric functional groups, linked by rotatable bonds to the inhibitor scaffold, allows KNI-764 to adapt to the mutated binding site cavity more readily than KNI-577, with a single asymmetric group. Both inhibitors lose about 2.5 kcal/mol in binding enthalpy when facing the drug-resistant mutant protease; however KNI-764 gains binding entropy while KNI-577 loses binding entropy. The gain in binding entropy by KNI-764 accounts for its low susceptibility to the drug-resistant mutation. The heat capacity change associated with binding becomes more negative when KNI-764 binds to the mutant protease, consistent with increased desolvation. With KNI-577, the opposite effect is observed. Structurally, the crystallographic B factors increase for KNI-764 when it is bound to the drug-resistant mutant. The opposite is observed for KNI-577. Consistent with these observations, it appears that KNI-764 is able to gain binding entropy by a two-fold mechanism: it gains solvation entropy by burying itself deeper within the binding pocket and gains conformational entropy by losing interaction with the protease.

Preclinical mechanisms of action of docetaxel and docetaxel combinations in prostate cancer

Docetaxel, a semisynthetic taxane, has exhibited significant single-agent activity against prostatic tumors. In phase I/II studies, single-agent docetaxel and the combination of docetaxel plus estramustine were effective in inducing prostate-specific antigen reductions of ≥50% in men with androgen-independent prostate cancer (AIPC). The underlying reason for docetaxel's clinical activity against prostate cancer has been a focus of ongoing research. Docetaxel is believed to have a two-fold mechanism of antineoplastic activity: (1) inhibition of microtubular depolymerization, and (2) attenuation of the effects of bcl-2 and bcl-xL gene expression. Taxane-induced microtubule stabilization arrests cells in the G 2M phase of the cell cycle and induces bcl-2 phosphorylation, thereby promoting a cascade of events that ultimately leads to apoptotic cell death. In preclinical studies, docetaxel had a higher affinity for tubulin and was shown to be a more potent inducer of bcl-2 phosphorylation than paclitaxel. Laboratory evidence also supports the clinical evaluation of docetaxel-based combinations that include agents such as trastuzumab and/or estramustine. The pathways for docetaxel-induced apoptosis appear to differ in androgen-dependent and androgen-independent prostate cancer cells. Further elucidation of these differences will be instrumental in designing targeted regimens for the treatment of localized and advanced prostate cancer.

Proton-Electron Reactions as Precursors of Anomalous Nuclear Events

In some experiments, intense electron fluxes were made to encounter high proton concentrations to achieve p + e fusions. Anomalies were observed: The electron energies were often below the threshold energy, and the cross-section results were unexpectedly high. A twofold mechanism consisting of hydrogen squeezed atom formation and of virtual neutron absorption is suggested to justify the observed anomalous nuclear events. The hypothesis is extended to the d + e reaction.

Transcriptional activation of p21WAF1 by PTEN/MMAC1 tumor suppressor.

The recently discovered tumor suppressor gene PTEN has been found mutated in many types of advanced tumors. When introduced into tumor cells that lack the wild-type allele of the gene, PTEN was able to suppress the growth of these cells. Here, we have analyzed how PTEN might alter cell cycle-regulatory controls to achieve this growth-inhibitory effect. We found that overexpression of PTEN stimulates the synthesis of three inhibitors of cyclin-dependent kinases, p21WAF1, p27KIP1, and p57KIP2. This effect is very specific, as the expression of other components of the cell cycle engine, various cyclins and cyclin-dependent kinases, is not affected. For p21WAF1 we show that this induction is due to the p53-independent transcriptional activation of its promoter. In addition, increased expression of PTEN rendered the cells more sensitive to apoptotic cell death. Therefore, our data suggest a two-fold mechanism of growth inhibition by PTEN: one that acts via the increased expression of CKIs such as p21WAF1, and another that augments the cellular propensity for apoptotic cell death.

Mechanisms and receptor subtypes involved in the stimulatory action of endothelin-1 on rat adrenal zona glomerulosa.

Endothelin (ET)-1 is the prototype of a family of 21-amino acid residue hypertensive peptides, acting through two subtypes of receptors, named ETA and ETB. ETs and their receptors are expressed in the adrenal cortex and medulla, and ET-1 enhances both corticosteroid and catecholamine release. ET-1 concentration-dependently (from 10(-11) to 10(-8) M) increased aldosterone secretion of both dispersed rat zona glomerulosa (ZG) cells and adrenal slices containing a core of medullary chromaffin tissue, but the response of the latter preparations was significantly more intense than that of the formers. The stimulatory effect of 10(-8) M ET-1 on dispersed ZG cells was blocked by the ETB-receptor antagonist BQ-788 (10(-7) M), but not by the ETA-receptor antagonist BQ-123 (10(-7) M); conversely, both ET-receptors antagonists counteracted aldosterone response of adrenal slices to ET-1. The -adrenoceptor antagonist l-alprenolol (10(-6) M) did not affect aldosterone response of dispersed ZG cells to ET-1 (10(-8) M), but it significantly lowered that of adrenal slices. l-Alprenolol also counteracted the aldosterone response of adrenal slices to the pure activation of ETB or ETA receptors, as obtained by using the selective ETB-receptor agonist BQ-3020 (10(-8) M) or ET-1 (10(-8) M) plus BQ-788 (10(-7) M). ET-1 concentration-dependently (from 10(-9) to 10(-8)/10(-7) M) stimulated catecholamine release by adrenal slices, and the effect was counteracted by both BQ-123 and BQ-788 (10(-7) M). Collectively, our findings suggest that, when the integrity of adrenal tissue is preserved, a two-fold mechanism underlies the aldosterone secretagogue action of ET-1 in the rat: i) a direct mechanism mediated by ETB receptors located on ZG cells; and ii) an indirect mechanism involving the ETA and ETB receptor-mediated local release of catecholamines, which in turn stimulate ZG cells in a paracrine manner.

Cluster formation by direct laser vaporization: evidence for the twofold mechanism

In this Letter we report experimental evidence relevant to the mechanism of cluster formation by direct laser vaporization of chemical compounds. The mechanism is different due to the type of samples and the type of clusters produced. While the clusters are formed generally through gas-phase recombination reactions, some clusters possess similar stoichiometry to the precursor sample, which, together with the velocity distribution, suggests a direct surface ejection mechanism.

CERAMIC FOAMS FROM A PRECERAMIC POLYMER AND POLYURETHANES : PREPARATION AND MORPHOLOGICAL INVESTIGATIONS

Open-cell ceramic foams were obtained from a preceramic polymer (silicone resin) and blown polyurethanes. The preceramic polymer, which is crosslinked by condensation of silanol groups, was dissolved in CH2Cl2 and added to a liquid polyol containing the surfactant and the amine catalyst. Isocyanate was then added to the mixture and the foam was obtained through a twofold blowing mechanism (physical and chemical blowing). The morphology of the expanded polyurethane, which can be flexible or semirigid, characterized the final structure of the ceramic foam. The materials obtained were pyrolyzed in a nitrogen flux at temperatures of 1000–1200°C, thus allowing for the polymer-to-ceramic transformation to occur in the preceramic polymer. The ceramic foams produced in this way consisted of an amorphous silicon oxycarbide ceramic (SiOC). They presented a density ranging from 0.1 to 0.3 g/cm3. The average pore diameter ranged from 200 to 400 μm and they possessed 80 to 90% open porosity.

Evidence of a two-fold mechanism responsible for the inhibition by allopurinol of the hypersensitive response induced in tobacco by tobacco necrosis virus

Allopurinol applied to tobacco plant roots interferes strongly with tobacco necrosis virus (TNV) induced hypersensitive response and the TNV infection process. The first detectable effect of allopurinol treatment was a great reduction in the hypersensitive response seen as reduced collapse and extent of necrosis than in untreated controls. This was evaluated as reduction in electrolyte leakage from lesions in the leaves. Only 4–6 days of allopurinol treatment were needed to achieve this effect. With prolonged treatment (6–8 days), there was a second effect consisting of a strong reduction in the number of necrotic lesions produced with a basipetal (tip-to-base) intensity pattern. This second aspect was related to a lack of TNV antigen production and therefore to the inhibition of the TNV infection process. To explain the metabolic basis for these phenomena, a study was pursued to establish the metabolic fate of allopurinol in leaves in different positions on the stem. The results obtained demonstrate that: (i) allopurinol which accumulated in leaves was oxidized to oxypurinol by host xanthine oxidase which was in turn inhibited, and consequently increasing amounts of xanthine accumulated in leaves; (ii) both allopurinol and oxypurinol were converted to their respective ribonucleosides. All these metabolic aspects connected with allopurinol metabolism in leaves, analogous with the reduced production of necrotic lesion had a basipetal (tip-to-base) intensity pattern. The present results are discussed considering that these two phenomena, i.e. inhibition of TNV-induced hypersensitive response and inhibition of the TNV infection process, are related to two metabolic mechanisms triggered by allopurinol treatment. The first depends on the inhibition of xanthine oxidase mediated superoxide production and the consequent general attenuation of the necrotic process. The second depends on the synthesis of both allopurinol and oxypurinol ribonucleosides which might directly or indirectly interfere with the process of TNV infection, and therefore be responsible for the reduction of the number of lesions in treated leaves.

Velocity saturation in the extrinsic device: a fundamental limit in HFET's

We have carried out an experimental study revealing that velocity saturation (/spl upsi//sub sat/) occurring in both the extrinsic source and drain sets a fundamental limit on maximum drain current and useful gate swing in HFET's. Using AlGaAs/n/sup +/-InGaAs HFET's as a vehicle, we find that first g/sub m/ and eventually f/sub T/ decline at high currents in two stages. Initially, the approach of /spl upsi//sub sat/ in the extrinsic device causes the small-signal source and drain resistances (r/sub s/ and r/sub d/) to rise dramatically, primarily degrading g/sub m/. As the current increases further, the large-signal source and drain resistances (R/sub s/ and R/sub d/) grow significantly as well, pushing the intrinsic HFET toward the linear regime. Combined with the rapid rise of r/sub s/ and r/sub d/, the accompanying increase in gate-drain capacitance forces f/sub T/ to decline through a strongly enhanced Miller effect. We associate this two-fold mechanism with a new regime of HFET operation, which we call the parasitic-resistance blow-up regime.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

Conflict and social marking in the acquisition of operational thinking

From its very beginnings social psychology of individual development had recourse to a twofold mechanism for explaining cognitive development. This duality is presently reflected in the studies on sociocognitive conflict and social marking. An experiment is reported ( N: 160 children from about six years and a half) which shows that combining social marking and sociocognitive conflict is a very efficient way of generating cognitive progress.

The effect of tissue and cellular pH on the selective biodistribution of porphyrin-type photochemotherapeutic agents: A volumetric titration study

Volumetric titration of aqueous solutions of haematoporphyrin IX (HP) yields two inflexion points, whereas four p K values can be obtained via mathematical fitting of the experimental data. Assignment of all p K protonation sites is made. A zwitterion is proposed as the neutral species of HP. Evaluation of the p K values of HP in the presence of sodium dodecyl sulphate (SDS) leads to a drastically altered ionic species distribution. On the basis of the distribution diagrams obtained, a pH-sensitive twofold mechanism is proposed for the selective biodistribution of porphyrin-type photochemotherapeutic agents, one involving tissue distribution and the other involving cell membrane penetration by the neutral zwitterion.

Intrahippocampal injection of kainic acid produces significant pyramidal cell loss in neonatal rats

Previous reports 655 have indicated that pyramidal cells in the developing rat hippocampal formation are not destroyed by intraventricular or inlraperitoneal administration of kainic acid. We examined the neurotoxic properties of kainic acid and ibotenic aeid following intrahippocampal injection in neonatal rats and found significant pyramidal cell death following injection of 1.0 μg kainic acid in 6, 7 and 9-day-old pups. At doses 2.5 or live times this amount, significant pyramidal cell loss was obtained in 5-day-old rats as well. The susceptibility of pyramidal neurons to kainic acid increased as a function of age. The developing hippocampus was considerably more vulnerable to ibotenic acid compared with kainic acid, in contrast to the order of potency reported in adult rats. The increased sensitivity of CA3 pyramidal cells parallels the development of the mossy fiber innervation to the dendrites of these cells supporting the twofold mechanism suggested by Coyle for kainic acid neurotoxicity; that is, a direct cytotoxic action via postsynaptic receptors as well as increased sensitivity due to the presence of excitatory inputs.

In vivo fluorescence microscopy of blood flow in mouse pancreatic islets: Adrenergic effects in lean and obese-hyperglycemic mice

The microcirculation in the islets of Langerhans was examined by fluorescence microscopy in living mice injected with fluorescent dextran. The islet capillary network was denser and more tortuously arranged in obese-hyperglycemic ( ob ob ) mice than in lean controls. Injection of norepinephrine (0.5–4.0 μg/kg body wt) immediately led to a pronounced inhibition of islet blood flow in ob ob mice. In experiments with lean mice less striking effects were seen. With as high a dose as 20 μg norepinephrine/kg body wt only a slight retardation and very brief stop of the flow occurred. The inhibition in ob ob mice was blocked by phentolamine, indicating that the norepinephrine-induced inhibition was mediated by α-adrenoceptors. The α-2-adrenoceptor agonist, clonidine, had no effect on islet blood flow, suggesting that the effect of norepinephrine was due to α-1-adrenoceptor stimulation. It is concluded that in the living animal norepinephrine inhibits insulin secretion from the pancreas by a twofold mechanism involving inhibition of exocytosis (α-2-receptors on the β-cells) as well as retardation of blood flow (α-1-receptors on blood vessels).

Size, shape, and hydration of a self-associating human IgG myeloma protein: Axial asymmetry as a contributing factor in serum hyperviscosity

Studies of sedimentation, diffusion, viscosity, and buoyant density have been carried out on a human IgG1-λ myeloma protein (IgG-MIT) isolated from the serum of a patient with multiple myeloma and the hyperviscosity syndrome. In comparison with pooled normal IgG, IgG-MIT exhibits smaller sedimentation and diffusion coefficients, a larger intrinsic viscosity, and a larger frictional ratio. The preferential hydration of IgG-MIT in cesium chloride was found to be within the range of values typically observed for globular proteins. The data are consistent with prolate ellipsoid geometry, and suggest that the axial ratio of the IgG-MIT monomer is approximately 50% greater than that typically observed for IgG. The concentration dependencies of the hydrodynamic data for IgG-MIT confirm the previous finding of reversible, concentration-dependent self-association for this protein. IgG-MIT thus represents the first reported instance of an IgG paraprotein for which in vivo hyperviscosity effects appear attributable to a twofold mechanism involving geometric asymmetry and concentration-dependent polymerization. The results are discussed in terms of the significant heterogeneity in molecular dimensions which may exist among normal IgG proteins.

Ventilatory and occlusion pressure responses to hypercapnia in patients with chronic renal failure.

Little is known of the effect of chronic renal failure (CRF) on ventilatory regulation. In 38 subjects (19 healthy, 19 with CRF before and after dialysis), we performed measurements of ventilation (VE) and occlusion pressure (P0.1) while the subjects were breathing air and hypercapnic gas mixtures. The results have shown that (1) during air ventilation, CRF patients exhibited lower values of VE and P0.1, which returned to normal after dialysis; (2) during hypercapnic ventilation, CRF patients had the same response as healthy subjects for VE but higher P0.1; hemodialysis induced an upward shift of the CO2 response curve in CRF patients. A twofold mechanism is probably involved: pulmonary edema, which reduces lung elasticity, and neuromuscular hypoexcitability, both implying a stronger central command.

Autoradiography of technetium-labelled diphosphonate in rat bone

The passage of technetium-labelled methylene diphosphonate (99mTc-MDP) across rat bone was examined by autoradiography. The autoradiographs showed that shortly after an injection of the bone-seeking agent there was activity outside the bone, within the bone marrow and also adjacent to the highly vascular epiphysial plate; the distribution of the isotope in the incubated bone appeared to be non-uniform, a high concentration being seen adjacent to the epiphysial plate and also on the surfaces of the bone. The evidence suggested that a two-fold mechanism resulted in the uneven distribution of 99mTc-MDP. The first factor probably represented the regional distribution of blood flow with a transcapillary movement of the tracer from the capillary bed to the extravascular space; the subsequent incorporation of the tracer into bone appeared to depend on the nature of the bone matrix.