Miracle-dz/UniFAR-FTUs huggingface dataset:
Allosteric Modulation of Human P-glycoprotein

The human multidrug transporter P-glycoprotein (Pgp, ABCB1) contributes to the poor bioavailability of many anticancer and antimicrobial agents as well as to drug resistance at the cellular level. For rational design of effective Pgp inhibitors, a clear understanding of its mechanism of action and functional regulation is essential. In this study, we demonstrate that inhibition of Pgp-mediated drug transport bycis-(Z)-flupentixol, a thioxanthene derivative, occurs through an allosteric mechanism. Unlike competitive inhibitors, such as cyclosporin A and verapamil,cis-(Z)-flupentixol does not interfere with substrate ([125I]iodoarylazidoprazosin) recognition by Pgp, instead it prevents substrate translocation and dissociation, resulting in a stable but reversible Pgp-substrate complex.cis-(Z)-Flupentixol-induced complex formation requires involvement of the Pgp substrate site, because agents that either physically compete (cyclosporin A) for or indirectly occlude (vanadate) the substrate-binding site prevent formation of the complex. Allosteric modulation by cis-(Z)-flupentixol involves a conformational change in Pgp detectable by monoclonal antibody UIC2 binding to a conformation-sensitive external epitope of Pgp. The conformational change observed is distinct from that induced by Pgp substrates or competitive inhibitors. A single amino acid substitution (F983A) in TM12 of Pgp that impairs inhibition bycis-(Z)-flupentixol of Pgp-mediated drug transport also affects stabilization of the Pgp-substrate complex as well as the characteristic conformational change. Taken together, our results describe the molecular mechanism by which the Pgp modulatorcis-(Z)-flupentixol allosterically inhibits drug transport.
Growth Factors , Cytokines , and Cell Cycle Molecules Methotrexate Chemotherapy Promotes Osteoclast Formation in the Long Bone of Rats via Increased Pro-Inflammatory Cytokines and Enhanced NF-B Activation

Cancer chemotherapy with methotrexate (MTX) is known to cause bone loss. However, the underlying mechanisms remain unclear. This study investigated the potential role of MTX-induced pro-inflammatory cytokines and activation of NFB in the associated osteoclastogenesis in rats. MTX (0.75 mg/kg per day) was administered for 5 days, and bone and bone marrow specimens were collected on days 6, 9, and 14. Compared with a normal control, MTX increased the density of osteoclasts within the metaphyseal bone and the osteoclast formation potential of marrow cells on day 9. RT-PCR analysis of mRNA expression for pro-osteoclastogenic cytokines in the metaphysis indicated that, although the receptor activator of NFB ligand/osteoprotegerin axis was unaffected, expression of tumor necrosis factor (TNF), IL-1, and IL-6 increased on day 9. Enzyme-linked immunosorbent assay analysis of plasma showed increased levels of TNFon day 6 and of IL-6 on day 14. Plasma from treated rats induced osteoclast formation from normal bone marrow cells, which was attenuated by a TNF–neutralizing antibody. Indicative of a role for NFB signaling, plasma on day 6 increased NFB activation in RAW264.7 cells, and plasma-induced osteoclastogenesis was abolished in the presence of the NFB inhibitor, parthenolide. Our results demonstrate mechanisms for MTX-induced osteoclastogenesis and show that MTX induces osteoclast differentiation by generating a pro-osteoclastogenic environment in both bone and the circulation, specifically with increased TNFlevels and activation of NFB. (Am J Pathol 2012, 181: 121–129; http://dx.doi.org/10.1016/j.ajpath.2012.03.037)
Role of Tannins in Defending Plants Against Ruminants: Reduction in Dry Matter Digestion?

Polyphenolic allelochemicals, such as tannins, are widely thought to reduce the digestibility of plants consumed by herbivores by binding to digestive enzymes and dietary proteins. While the apparent digestibility of protein and, therefore, cell solubles is reduced in mule deer (Odocoileus hemionus) and white-tailed deer (O. virginianus) consuming tanniferous forages, digestion of the plant cell wall is not reduced beyond that predicted from its content of lignin, cutin, and silica. The lack of a tannin effect on cell wall digestion in deer is in contrast to studies with domestic sheep and numerous in vitro studies. Herbivores adapted to consume tanniferous forages may defend against such allelochemicals by producing salivary proteins that bind tannins in a highly specific manner. These tannin-salivary protein complexes would reduce apparent digestibilities of protein and cell solubles and, if completely effective, would not reduce cell wall digestion. The occurrence of such proteins in ruminants is reported here for the first time. The saliva composition of mule deer (a mixed feeder that commonly consumes browse) and domestic cattle and sheep (predominant grazers) are compared, and the higher potential of the deer saliva to neutralize tannins is related to their feeding habits. Salivary proteins that preferentially bind tannins may minimize fecal nitrogen losses by maximizing the efficiency of tannin-binding per unit of protein and may reduce the absorption of hydrolyzable tannins and the potential for tannin toxicity.
Gradients of CO2 tension in the brain.

In cat experiments measurements were made of the CO2 tensions in arterial and cerebral venous blood, in cisternal cerebrospinal fluid (CSF), and on the surface of the cerebral cortex. It was found that both the CSF CO2 tension and the CO2 tension measured on the surface of the brain exceeded the arithmetic mean of the arterial and the venous CO2 tensions by 0.5–1 mm Hg. This means that the CSF and the cortical surface CO2 tensions coincided with the mean tissue CO2 tension, which can be calculated from the diffusion equations, and they were distinctly different from the cerebral venous CO2 tension. The arterio-venous PCO2 difference was found to change linearly from 12 to 4 mm Hg when the arterial CO2 tension increased from 30 to 90 mm Hg. The arterio-venous difference was found to be very sensitive to the experimental conditions. Thus, it was influenced by the craniotomy and the other procedures connected with the tissue measurements, and also by the sampling of CSF. It is recommended that mean tissue CO2 tensions in the brain are obtained by means of direct measurements on cisternal CSF, or by means of calculation from the arterial and the cerebral venous CO2 tensions. In the latter case, a fairly exact value is obtained by adding 1 mm Hg to the arithmetic mean of the blood tensions. Tissue measurements are recommended for studies of CO2 transients, or for conditions with a disturbed local circulation. If none of these measurements are feasible, the tissue CO2 tension can be approximately calculated from the arterial CO2 tension, as described in the text.
Risk and Protective Factors for Leprosy Development Determined by Epidemiological Surveillance of Household Contacts

ABSTRACT Household contacts of leprosy patients are the group with the highest risk of developing the disease, and although many risk or prevention factors have been identified, they have not been employed in leprosy-monitoring programs. This investigation aimed to establish the relative risks or the preventive effects of the presence of BCG vaccination, the Mitsuda test, and the ML-Flow assay. Household contacts (1,396) were monitored for a 5-year period. Twenty-eight contacts (2%) developed leprosy and had their clinical and operational classifications established. All immunological tests were performed, and intradermal BCG vaccination was given after the BCG scar count. Of the affected contacts, 75% developed the disease in the first year, and 71.4% were classified as having paucibacillary forms. Contacts of lepromatous leprosy patients presented a 3.8-fold-higher risk of developing leprosy. BCG vaccination and the Mitsuda test showed a protective effect against leprosy of 0.27 (at least one scar) and 0.16 (>7 mm), respectively, and the positive ML-Flow test indicated a relative risk approximately sixfold higher for occurrence of the disease. All unfavorable combinations of two and three assays generated significant risk values that ranged from 5.76 to 24.47, with the highest risk given by the combination of no BCG scar, negative Mitsuda test, and positive ML-Flow test. We suggest that the BCG vaccination may be given to stimulate Mitsuda test positivity, reducing the patient's risk of developing multibacillary forms. The high significance of these tests may have a great impact on programs to monitor contacts and should be used to improve early detection and treatment.
Strategic Interaction between Governments and Investors under Privatization Programs

This article analyses the strategic moves of governments and investors under privatization programs in a game-theoretic context. In sequential-move games of both perfect information and incomplete information, the best response of the strategic investors to observing a slow pace of privatization is to have a low participation in economic activity because of concerns over public policy credibility. This is true even if the government chooses to randomize its action to send mixed signals to the investors while adopting a slow pace of privatization for budgetary reasons. However, the outcome is Pareto inferior to a situation of phased but fast implementation of privatization programs and high private-sector participation under plausible assumptions. Copyright © 2011 John Wiley & Sons, Ltd.
Carboetomidate: A Pyrrole Analog of Etomidate Designed Not to Suppress Adrenocortical Function

Background:Etomidate is a sedative hypnotic that is often used in critically ill patients because it provides superior hemodynamic stability. However, it also binds with high affinity to 11&bgr;-hydroxylase, potently suppressing the synthesis of steroids by the adrenal gland that are necessary for survival. The authors report the results of studies to define the pharmacology of (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), a pyrrole analog of etomidate specifically designed not to bind with high affinity to 11&bgr;-hydroxylase. Methods:The hypnotic potency of carboetomidate was defined in tadpoles and rats using loss of righting reflex assays. Its ability to enhance wild-type &agr;1&bgr;2&ggr;2l and etomidate-insensitive mutant &agr;1&bgr;2M286W&ggr;2l human &ggr;-aminobutyric acid type A receptor activities was assessed using electrophysiologic techniques. Its potency for inhibiting in vitro cortisol synthesis was defined using a human adrenocortical cell assay. Its effects on in vivo hemodynamic and adrenocortical function were defined in rats. Results:Carboetomidate was a potent hypnotic in tadpoles and rats. It increased currents mediated by wild-type but not etomidate-insensitive mutant &ggr;-aminobutyric acid type A receptors. Carboetomidate was a three orders of magnitude less-potent inhibitor of in vitro cortisol synthesis by adrenocortical cells than was etomidate. In rats, carboetomidate caused minimal hemodynamic changes and did not suppress adrenocortical function at hypnotic doses. Conclusions:Carboetomidate is an etomidate analog that retains many beneficial properties of etomidate, but it is dramatically less potent as an inhibitor of adrenocortical steroid synthesis. Carboetomidate is a promising new sedative hypnotic for potential use in critically ill patients in whom adrenocortical suppression is undesirable.
Loaded custom-made zirconia and titanium implants show similar osseointegration: an animal experiment.

BACKGROUND Zirconia might be an alternative material to titanium for dental implant fabrication. The aim of the present study was to investigate the histological behavior (osseointegration) of loaded zirconia implants in an animal model and to compare it with the behavior of titanium implants. METHODS Five months after extraction of the upper anterior teeth, 12 custom-made titanium implants (control group) and 12 custom-made zirconia implants (test group) were inserted in the extraction sites in six monkeys. Before insertion, the titanium implant surfaces were sandblasted with Al2O3 and subsequently acid-etched. The zirconia implants were only sandblasted. Six months following implant insertion, impressions were taken for the fabrication of single crowns. A further 3 months later, nonprecious metal crowns were inserted. Five months after insertion of the crowns, the implants with the surrounding hard and soft tissues were harvested, histologically prepared, and evaluated under the light microscope regarding the peri-implant soft tissue dimensions and mineralized bone-to-implant contact. RESULTS No implant was lost during the investigational period. The mean height of the soft peri-implant tissue cuff was 5 mm around the titanium implants and 4.5 mm around the zirconia implants. No statistically significant differences were found in the extent of the different soft tissue compartments. The mean mineralized bone-to-implant contact after 9 months of healing and 5 months of loading amounted to 72.9% (SD: 14%) for the titanium implants and to 67.4% (SD: 17%) for the zirconia implants. There was no statistically significant difference between the different implant materials. CONCLUSION Within the limits of this animal experiment, it can be concluded that the custom-made zirconia implants osseointegrated to the same extent as custom-made titanium control implants and show the same peri-implant soft tissue dimensions.
Validity of a short computerized assessment battery for moderate cognitive impairment and dementia

ABSTRACT Background: Computerized cognitive assessment tools have been developed to make precise neuropsychological assessment readily available to clinicians. Mindstreams batteries for mild impairment have been validated previously. We examined the validity of a Mindstreams battery designed specifically for evaluating those with moderate cognitive impairment. Methods: 170 participants over the age of 60 years performed the computerized battery in addition to standard clinical evaluation. The battery consists of six technician-administered tests and one patient-administered interactive test sampling the cognitive domains of orientation (to time and place), memory, executive function, visual spatial processing, and verbal function. Staging was according to the Clinical Dementia Rating Scale (CDR) on the basis of clinical data but independent of computerized cognitive testing results, thus serving as the gold standard for evaluating the discriminant validity of the computerized measures. Results: Seven participants received a global CDR score of 0 (not impaired), 76 were staged as CDR 0.5 (very mildly impaired), 58 as CDR 1 (mildly impaired), 26 as CDR 2 (moderately impaired), and 3 as CDR 3 (severely impaired). Mindstreams Global Score performance was significantly different across CDR groups (p < 0.001), reflecting poorer overall battery performance for those with greater impairment. This was also true for the domain summary scores, with Executive Function (d = 0.67) and Memory (d = 0.65) distinguishing best between CDR 0.5 and 1, and Orientation best differentiating among CDR 1 and 2 (d = 1.20). Conclusions: The Mindstreams battery for moderate impairment differentiates among varying degrees of cognitive impairment in older adults, providing detailed and distinct cognitive profiles.
The expression of focus in Basque

There are two theories which have tried to account for focus assignment in transformational grammar: the deep structure theory and the surface structure theory. According to the deep structure theory, focus is assigned at the deep structure level. Akmajian (1970) thinks focus is identical to a predicate of the higher clause in deep structure. Chomsky in the standard theory discusses the notion of focus as a predicate of the dominant proposition of the deep structure. The first phrase-structure rule of grammar would introduce two arbitrary structures, F and P, for focus and presupposition, and S' would be the initial symbol of the categorial component of the base;
Advanced Oxidation Protein Products Accelerate Atherosclerosis Through Promoting Oxidative Stress and Inflammation

Objective—Increased level of plasma advanced oxidation protein products (AOPPs) has been found in patients with uremia and nonuremic subjects with coronary artery disease. This study was conducted to test the hypothesis that AOPPs play a causal role in atherosclerosis. Methods and Results—Hypercholesterolemic (0.5% wt/wt diet) or normal rabbits received either repeated intravenous injections of AOPPs modified rabbit serum albumin (AOPPs-RSA) or unmodified RSA for 8 weeks. Compared with RSA- or vehicle-treated hypercholesterolemic rabbits, AOPPs-RSA–treated animals displayed increased atherosclerotic plaque area oxidized low-density lipoprotein (oxLDL) deposition, macrophage infiltration, and smooth muscle cell proliferation. Aortic sections from AOPPs-RSA–treated normal rabbits showed significant focal intima proliferation and mild Oil-Red-O staining lipid deposition in the affected areas, a phenomenon not observed in the RSA- or vehicle-treated controls. Plasma AOPPs levels in AOPPs-treated groups significantly increased in both hypercholesterolemic and normal rabbits compared with their relevant controls. Close correlations were found between plasma levels of AOPPs and the parameters of oxidative stress, eg, oxLDL and thiobarbituric acid reactive substances levels, or glutathione peroxidase activity. A highly significant correlation was also observed between plasma AOPPs and tumor necrosis factor (TNF)-α levels. Conclusions—This study provides in vivo evidence for a causal relationship between chronic AOPPs accumulation and atherosclerosis.
Optical transfer function (OTF) of a Rotman lens antenna for imaging applications

This paper presents a new approach to analyzing a Rotman lens for imaging applications. The optical transfer function (OTF) is used to analyze the imaging capability of a Rotman lens. The variations in optical transfer function and the image pattern were calculated with variations in the design parameters due to beam-port spacing, antenna spacing, array size, and so on. As a result, it was found that the cutoff frequency corresponds to the array size in λ , and the resolution is the inverse of the cutoff frequency. The beam-port spacing should be narrow enough to avoid aliasing. For a typical design in which the antenna spacing is λ/2 and the scanning angle is from -45° to 45°, the number of beam ports should be π/2 times greater than the number of array ports to avoid aliasing, and the antenna spacing should be less than 0. 707λ to avoid grating lobes. For the first time, a Rotman lens has been analyzed in terms of the optical transfer function. As a result, important criteria for designing a Rotman lens are presented for imaging applications. This analysis will provide guidance to the design and estimation of a focal-plane antenna array, as well as a Rotman lens for imaging and sensing applications.
MicroRNA‐dependent regulation of DNA methyltransferase‐1 and tumor suppressor gene expression by interleukin‐6 in human malignant cholangiocytes

Although the inflammation‐associated cytokine interleukin‐6 (IL‐6) has been implicated in cholangiocarcinoma growth, the relationship between IL‐6 and oncogenic changes is unknown. IL‐6 can increase expression of DNA methyltransferase‐1 (DNMT‐1) and epigenetically regulate the expression of several genes, including microRNAs (miRNAs). DNMT‐1 up‐regulation occurs in hepatobiliary cancers and is associated with a poor prognosis. To understand the potential regulation of DNMT‐1 by IL‐6–dependent miRNAs, we examined the expression of a group of miRNAs which have sequence complementarity to the 3'‐untranslated region of DNMT‐1, namely miR‐148a, miR‐152, and miR‐301. The expression of these miRNAs was decreased in cholangiocarcinoma cells. Moreover, the expression of all three miRNAs was decreased in IL‐6–overexpressing malignant cholangiocytes in vitro and in tumor cell xenografts. There was a concomitant decrease in expression of the methylation‐sensitive tumor suppressor genes Rassf1a and p16INK4a. Using luciferase reporter constructs, DNMT‐1 was verified as a target for miR‐148a and miR‐152. Precursors to miR‐148a and miR‐152 decreased DNMT‐1 protein expression, increased Rassf1a and p16INK4a expression, and reduced cell proliferation. Conclusion: These data indicate that IL‐6 can regulate the activity of DNMT‐1 and expression of methylation‐dependent tumor suppressor genes by modulation of miR‐148a and miR‐152, and provide a link between this inflammation‐associated cytokine and oncogenesis in cholangiocarcinoma. (HEPATOLOGY 2010.)
Factors Influencing the Decision to Drive or Walk Short Distances to Public Transport Facilities

ABSTRACT Samples of drivers and walkers are examined to understand factors influencing the decision to walk. The driver sample was limited to those who lived within 1 km of the park-and-ride facility to avoid confounds such as car dependency and travel distance. These drivers exhibit a break in car dependency because they use public transport. A 62-item survey examines ten main factors: fear of crime; trip-chaining; weather; distance/time; social pressure; fatigue and fitness; parking charges; enjoyment of walking; inconvenience; and geography. Results show the convenience of a car park induces park-and-ride demand. Weather influences decisions to walk. However, walking is not impeded by factors such as distance, fear of crime, carriage of goods or concern for time.
The Square-Root Law of Precautionary Reserves

This article presents a generalization of the square-root theorems formulated by various authors with regard to special kinds of safety reserves. Some of the results established in the paper are the following: (1) the validity of the square-root law does not require that the actual components of net demand be stochastically independent and identically distributed; (2) in particular, such a law is compatible with the existence of serial correlation among reserve changes; and (3) if expected net demand differs from zero, the elasticity of the total reserve with respect to expected demand is between 0.5 and 1.
Workers, Unions and the High Performance Workplace

he high performance workplace (HPW) is the latest derivative of the lean production model that, like such predecessors as the ‘high commitment’ organization or ‘world class manufacturing’, is supposed to encapsulate current shifts in the organization of the labour process and employment relations. Whether it is a term that will stay with us or fade away as a result of the ever mutating business and management discourse remains to be seen. For the moment it has become a salient topic for public policy debates on the competitiveness of British industry. Like human resource management the concept, if not the practice, of the HPW arrived on these shores from the USA and so it is no coincidence that both books in this review have been written by researchers based mostly in North America. Although the different authors have contrasting theoretical positions they share similar definitions of the HPW concept itself. At its core is the notion of a more systematic mobilization of tacit knowledge and worker discretion by managerial practices (high performance work systems) that permit workers to participate in decisions that affect their organizational routines. In the interests of organizational flexibility and efficiency, workers in the HPW should experience more autonomy over job tasks and working methods and enjoy a greater input into managerial decision-making processes through extensive systems of organizational communications. Appelbaum et