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At least 1,225 records · Page 68Linked to original sources
PubMed2006

Toward a rational design of selective multi-trypanosomatid inhibitors: a computational docking study.

Compound V7, a benzothiazole which was recently found as selective inhibitor of trypanosomal TIMs, was docked into TIMs from Trypanosoma cruzi, Trypanosoma brucei, Entamoeba histolytica, Plasmodium falciparum, yeast, and human. Structural analyses revealed the importance of the accessibility to the two aromatic clusters located at the dimer's interface for the selective inhibition of trypanosomal TIMs. Thus, it was found that different accessibilities of the protein interface of TIMs plays an important role in the inhibitory activity of benzothiazoles. These findings will contribute to the rational development and improvement of benzothiazoles to be used as multi-trypanosomatid inhibitors.

Animals↗
PubMed2005

Reasoning or reacting to others? How consumers use the rationality of other consumers.

Consumers adapt their behavior to the structure of the information available in the environment where they form expectations. One factor in people's environments is other people. "Others" are a significant source of information and means of orientating oneself. In conditions such as uncertainty, insecurity, anxiety but also euphoria, it is "the others" who provide market participants with coordinates. The purpose of this paper is to pass forward an approach that relates to consumers' other-directedness and to demonstrate in what ways consumers use the rationality of other consumers.

Adaptation, Psychological↗
PubMed2004

NO suppresses while peroxynitrite sustains NF-kappaB: a paradigm to rationalize cytoprotective and cytotoxic actions attributed to NO.

OBJECTIVE: NO has both cytoprotective and cytotoxic effects. A key cytoprotective action of NO is attributed to inhibition of nuclear factor-kappaB (NF-kappaB)-mediated gene expression; this potentially endows NO with ubiquitous anti-inflammatory activity. Since immunostimulant-induced iNOS gene expression is itself dependent on NF-kappaB, NO is expected to limit its own synthesis. On the other hand, many cytotoxic actions of NO have been attributed to the chemical reactivity of peroxynitrite (ONOO-) formed from NO by near diffusion-limited reaction with O2-. To assess whether ONOO- shares the ability of NO to inhibit NF-kappaB activation and consequent iNOS gene expression, we compared effects of NO donors (NOR3 and SNAP), an ONOO- donor (SIN-1), and pure ONOO- on LPS-induced responses in vascular smooth muscle cells (VSMC). METHODS AND RESULTS: NO donors, but not ONOO-, suppressed LPS-induced NF-kappaB activation and expression of a murine iNOS promoter/reporter construct. An NO donor also suppressed NF-kappaB activation when induced by IL-1beta or TNFalpha. Northern blot and RT-PCR analyses showed that NO, but not ONOO- or 8-bromo-cGMP, decreases LPS-induced expression of iNOS mRNA. Electrophoretic mobility shift assays (EMSA) and immunocytochemical analyses confirmed that NO but not ONOO- inhibits nuclear translocation of NF-kappaB. Although ONOO- generation from SIN-1 did not inhibit NF-kappaB activation, conversion of SIN-1 to a pure NO donor (by addition of excess superoxide dismutase) resulted in potent inhibition of NF-kappaB activation. Dose-response analyses suggest that the inhibitory effect of NO on iNOS gene transcription results specifically from inhibition of NF-kappaB activation, and is mediated by a G-cyclase-independent mechanism that is unavailable to ONOO-. LPS stimulates IkappaB-alpha phosphorylation by inducing IkappaB kinase (IKK) activity, and NO, but not ONOO-, inhibits LPS-induced IkappaB-alpha phosphorylation and IKK activity. CONCLUSION: We demonstrate that only NO inhibits the activation of NF-kappaB and suppresses iNOS gene expression. This distinction provides a novel paradigm to rationalize cytoprotective and cytotoxic actions attributed to NO.

Animals↗
PubMed2006

The rational design of an AIDS vaccine.

The extraordinary genetic diversity and immune evasion of human immunodeficiency virus (HIV) pose significant challenges for vaccine development. AIDS vaccine design requires a scientifically driven, rational approach that encompasses the latest advances in viral molecular genetics, structural biology, and immunology.

AIDS Vaccines↗
PubMed2026

RNA structures regulate norovirus life cycle and enable rational attenuation in vivo.

Viral genomes encode regulatory RNA structures that orchestrate key steps of viral replication and gene expression. Although these structures are increasingly recognized as critical regulators of viral function, their systematic characterization in an infection context and roles in regulating viral fitness and immune recognition in vivo remain limited. Here, we systematically map and functionally interrogate structured RNA elements across the murine norovirus genome using orthogonal in-cell chemical probing, revealing conserved motifs that regulate viral function. Targeted disruption of specific structural elements reduces viral replication in cell culture, modulates translation in cis, and decreases viral RNA levels in animal infection models. These findings enabled the rational design of a genetically stable, attenuated virus that elicits protective immunity and limits viral replication upon secondary challenge. Together, this work uncovers essential roles for RNA structure in norovirus biology and establishes a generalizable framework for RNA structure-guided design of antiviral vaccines and therapeutics.

RNA structure↗
PubMed2004

Hydroxylated polychlorinated biphenyls selectively bind transthyretin in blood and inhibit amyloidogenesis: rationalizing rodent PCB toxicity.

Polychlorinated biphenyls (PCBs) and their hydroxylated metabolites (OH-PCBs) are known to bind to transthyretin (TTR) in vitro, possibly explaining their bioaccumulation, rodent toxicity, and presumed human toxicity. Herein, we show that several OH-PCBs bind selectively to TTR in blood plasma; however, only one of the PCBs tested binds TTR in plasma. Some of the OH-PCBs displace thyroid hormone (T4) from TTR, rationalizing the toxicity observed in rodents, where TTR is the major T4 transporter. Thyroid binding globulin and albumin are the major T4 carriers in humans, making it unlikely that enough T4 could be displaced from TTR to be toxic. OH-PCBs are excellent TTR amyloidogenesis inhibitors in vitro because they bind to the TTR tetramer, imparting kinetic stability under amyloidogenic denaturing conditions. Four OH-PCB/TTR cocrystal structures provide further insight into inhibitor binding interactions.

Amyloid↗
PubMed2006

Chromatographic fingerprint analysis--a rational approach for quality assessment of traditional Chinese herbal medicine.

Traditional Chinese Herbal Medicine (TCHM) contain multiple botanicals, each of which contains many compounds that may be relevant to the medicine's putative activity. Therefore, analytical techniques that look at a suite of compounds, including their respective ratios, provide a more rational approach to the authentication and quality assessment of TCHM. In this paper we present several examples of applying chromatographic fingerprint analysis for determining the identity, stability, and consistency of TCHM as well as the identification of adulterants as follows: (1) species authentication of various species of ginseng (Panax ginseng, Panax quinquefolium, Panax noto-ginseng) and stability of ginseng preparations using high performance thin-layer chromatography (HPTLC) fingerprint analysis; (2) batch-to-batch consistency of extracts of Total Glycosides of Peony (TGP), to be used as a raw material and in finished products (TGP powdered extract products), using high performance liquid chromatography (HPLC) fingerprint analysis with a pattern recognition software interface (CASE); (3) documenting the representative HPLC fingerprints of Immature Fruits of Terminalia chebula (IFTC) through the assessment of raw material, in-process assay of the extracts, and the analysis of the finished product (tablets); (4) HPLC fingerprint study demonstrating the consistent quality of total flavonoids of commercial extracts of ginkgo (Ginkgo biloba) leaves (EGb) along with detection of adulterations. The experimental conditions as well as general comments on the application of chromatographic fingerprint analysis are discussed.

Chromatography, High Pressure Liquid↗
PubMed2004

Rational use of the laboratory for childhood and adult growth hormone deficiency.

No laboratory test has sufficient diagnostic sensitivity and specificity to serve as a gold standard for the diagnosis for GHD: therefore, test results must be interpreted after assessment of risk for GHD is determined on clinical grounds. Growth data are particularly crucial for diagnosis of childhood GHD;history of known pituitary damage and presence or absence of other pituitary hormone deficiencies are the critical elements for the diagnosis of adult GHD. New reference preparations are available for GH and IGF-I and should greatly aid interassay comparisons when the preparations are universally adopted.GH stimulation testing remains a key part of the diagnosis of adult GHD, but is currently being de-emphasized for the diagnosis of pediatric GHD. Better interassay comparative data and organized clinical collaboration between clinicians and test manufacturers/laboratories to set rational clinical diagnostic cutoffs would improve greatly the clinical usefulness of GH stimulation testing. The availability of statistically sound age- and sex-related normative data for IGF-I and IGFBP3 make these key tests for the diagnosis of childhood GHD. Although IGF-I may not be a perfect test for the diagnosis of adult GHD, it may be sufficiently informative in many cases to warrant using it ona routine basis. IGF-I also has a role in monitoring the safety of adult patients who are on GH treatment; studies are underway to determine if IGF-I may be useful in the future for optimization of GH dosaging.

Adult↗
PubMed2006

Neural basis of quasi-rational decision making.

Standard economic theories conceive homo economicus as a rational decision maker capable of maximizing utility. In reality, however, people tend to approximate optimal decision-making strategies through a collection of heuristic routines. Some of these routines are driven by emotional processes, and others are adjusted iteratively through experience. In addition, routines specialized for social decision making, such as inference about the mental states of other decision makers, might share their origins and neural mechanisms with the ability to simulate or imagine outcomes expected from alternative actions that an individual can take. A recent surge of collaborations across economics, psychology and neuroscience has provided new insights into how such multiple elements of decision making interact in the brain.

Animals↗
PubMed2005

Rational design of dental materials using computational chemistry.

One of our primary research emphases is the rational design of biomaterials. In this effort we apply a combination of theoretical and experimental approaches, both of which contribute directly to the completion of such a project. Computational chemistry has achieved routine status in modern chemical investigations, and the state-of-the-art is briefly summarized. In such a difficult endeavor as the systematic development of biomaterials, computational chemistry is a natural partner for traditional chemists. Herein, we describe several successful applications of this synergy to the design of dental biomaterials. These include reactivity modeling, sensitization, and density. We also report preliminary progress of polymerization volume change experiments on epoxides that have been specifically designed to provide standardized results for computational analysis.

Combinatorial Chemistry Techniques↗
PubMed2004

Design, synthesis and biological evaluation of new potent 5-nitrofuryl derivatives as anti-Trypanosoma cruzi agents. Studies of trypanothione binding site of trypanothione reductase as target for rational design.

Design, using force-field calculations on the catalytic site of trypanothione reductase from Trypanosoma cruzi, has led to the development of new 5-nitrofuryl derivatives as potential anti-trypanosomal agents. The synthesized compounds were tested in vitro against T. cruzi and more than 75% of the prepared derivatives showed higher activity than nifurtimox. Compounds 5 and 11, hexyl 4-(5-nitrofurfurylidene)carbazate and N-hexyl 3-(5-nitrofuryl)propenamide, showed the highest in vitro trypanocidal effect reported to date for members of the nitrofuran family. Partition coefficients and energies for the single-electron reduction of compounds were theoretically determined. These properties could be not the major cause of the activities' differences. The physicochemical environment around E19, W22, C53 and Y111 residues within the trypanothione binding site of trypanothione reductase resulted a valuable target for the rational design of anti-trypanosomal drugs.

Animals↗
PubMed2003

Lipid drug delivery and rational formulation design for lipophilic drugs with low oral bioavailability, applied to cyclosporine.

By using a rational formulation approach, we have tried to find the general characteristics for promising self-emulsifying drug delivery systems (SEDDS) based on natural lipid components, for the oral delivery of lipophilic drugs. Galactolipids, which are polar lipids commonly found in the chloroplast membranes of green plants, and a natural part of the human diet, were the main surfactants in these formulations. This was done in three clinical studies: a screening study, followed by a prediction study and, finally, a confirmatory study; in all 17 experimental formulations were investigated. The clinical trials were performed in healthy volunteers. Cyclosporine, a well-known lipophilic peptide, was incorporated in different SEDDS, and administered orally, followed by the measurement of the blood concentration of the drug over time. The pharmacokinetic parameters, which describe the rate and extent of absorption, were estimated. We found that fractionated oat oil (FOO) and medium chain monoglycerides (60:30:10 mono-, di- and tri-glycerides) promoted absorption, and resulted in a formulation with absorption characteristics nearly equal to the commercial formulation of cyclosporine, Sandimmun Neoral.

Adult↗
PubMed2006

Rationalization and regionalization of treatment for ductal carcinoma in situ of the breast.

PURPOSE: In ductal carcinoma in situ (DCIS) of the breast, conservative surgery plus radiotherapy (CS+RT) decreases risk of recurrence compared with CS alone. Although nearly one third of patients are reported as treated with CS alone, it is unclear whether this potentially "undertreated" group represents high- or low-risk patients. We evaluated national patterns of DCIS treatment from 1996 to 2001 by patient risk profile. METHODS AND MATERIALS: In a retrospective cohort of DCIS patients from the Surveillance, Epidemiology, and End Results data, patients were risk stratified on the basis of age at diagnosis, tumor grade, tumor size, and comedo histology. Treatment included CS alone, CS+RT, or mastectomy. Patients were followed for the development of ipsilateral invasive or in situ event. RESULTS: Of 14,202 patients, 19% were low-risk, 46% moderate-risk, and 35% high-risk. A total of 28% received CS alone, 40% CS+RT, and 31% mastectomy. Overall, only 17% of high-risk patients but 44% of low-risk patients received CS alone (p < 0.001). In multivariable analysis, older age, smaller tumor size, and treatment in San Francisco/Los Angeles predicted treatment with CS alone (p < 0.01). Yet despite the tendency to receive CS alone, patients in San Francisco/Los Angeles did not experience an increased risk of ipsilateral event (hazard ratio = 0.79; 95% confidence interval, 0.55-1.12). CONCLUSION: Patient risk profiles rationally affect treatment choice in DCIS patients, and the vast majority of high-risk patients do not receive CS alone. Additional follow up is needed to determine whether geographic variation in care influences long-term outcomes.

Breast Neoplasms↗
PubMed2004

Exact and global rational approximate expressions for resistance coefficients for a colloidal solid sphere moving in a quiescent liquid parallel to a slip gas-liquid interface.

In this paper mathematical expressions have been developed to describe the hydrodynamic resistance force on a colloidal particle as it slides along a slip surface of a gas bubble held stationary in a quiescent liquid. The particle size was considered to be sufficiently small relative to the bubble size so that the bubble surface could be locally approximated to a planar interface. The modeling incorporated a bispherical coordinate transformation to solve the equations governing the liquid creeping flow disturbed by the particle. Exact numerical solutions for the resistance coefficients of the particle-shearing motion parallel to the slip bubble surface were obtained as a function of the separation distance from the bubble surface. Finally, simplified analytical rational approximations for the whole range of the separation distance were presented, which were in good agreement with the exact numerical result. Importantly, the approximations for the modeling and simulation of the bubble-particle interactions are mathematically tractable.

Journal Article↗
PubMed2005

Emergency medical services in Japan: an opportunity for the rational development of pre-hospital care and research.

Japan is at a crossroads in the development of its Emergency Medical Services (EMS). At present, Japan has an essentially pure scoop-and-run, defibrillation system. However, there is a strong movement toward expanding the scope of paramedic practice to include more complex, Advanced Life Support (ALS) and trauma protocols to its nationally standardized pre-hospital protocols. The implications of introducing complex pre-hospital protocols guided by the use of existing scientific evidence to support such action is discussed in the context of Japan's unique opportunity to test many fundamental questions in pre-hospital medical care and the public's understanding and acceptance of these practices. Japan, a technologically advanced country that is not encumbered by entrenched "standards of care," has the opportunity to develop an efficient and rational EMS system.

Ambulances↗
PubMed2004

Rational design of inhibitors of HIV-1 TAR RNA through the stabilisation of electrostatic "hot spots".

The targeting of RNA for the design of novel anti-viral compounds has until now proceeded largely without incorporating direct input from structure-based design methodology, partly because of lack of structural data, and complications arising from substrate flexibility. We propose a paradigm to explain the physical mechanism for ligand-induced refolding of trans-activation response element (TAR RNA) from human immunodeficiency virus 1 (HIV-1). Based upon Poisson-Boltzmann analysis of the TAR structure, as bound by a peptide derived from the transcriptional activator protein, Tat, our hypothesis shows that two specific electrostatic interactions are necessary to stabilise the conformation. This result contradicts the belief that a single argininamide residue is responsible for stabilising the TAR fold, as well as the conventional wisdom that electrostatic interactions with RNA are non-specific or dominated by phosphates. We test this hypothesis by using NMR and computational methods to model the interaction of a series of novel inhibitors of the in vitro RNA-binding activities for a peptide derived from Tat. A subset of inhibitors, including the bis-guanidine compound rbt203 and its analogues, induce a conformation in TAR similar to that brought about by the protein. Comparison of the interactions of two of these ligands with the RNA and structure-activity relationships observed within the compound series, confirm the importance of the two specific electrostatic interactions in the stabilisation of the Tat-bound RNA conformation. This work illustrates how the use of medicinal chemistry and structural analysis can provide a rational basis for prediction of ligand-induced conformational change, a necessary step towards the application of structure-based methods in the design of novel RNA or protein-binding drugs.

Anti-HIV Agents↗
PubMed2004

Rational reduction of periodic propagators for off-period observations.

Many common solid-state nuclear magnetic resonance problems take advantage of the periodicity of the underlying Hamiltonian to simplify the computation of an observation. Most of the time-domain methods used, however, require the time step between observations to be some integer or reciprocal-integer multiple of the period, thereby restricting the observation bandwidth. Calculations of off-period observations are usually reduced to brute force direct methods resulting in many demanding matrix multiplications. For large spin systems, the matrix multiplication becomes the limiting step. A simple method that can dramatically reduce the number of matrix multiplications required to calculate the time evolution when the observation time step is some rational fraction of the period of the Hamiltonian is presented. The algorithm implements two different optimization routines. One uses pattern matching and additional memory storage, while the other recursively generates the propagators via time shifting. The net result is a significant speed improvement for some types of time-domain calculations.

Algorithms↗
PubMed2005

Severe pruritus of cholestasis in disseminated cancer: developing a rational treatment strategy. A case report.

Severe pruritus is a frequent complication of cholestasis. Both serotonin and opioids play an important role in the development of this symptom. Guidelines to provide rational management of pruritus of cholestasis do not exist. We describe a patient with complex and malignant course of pruritus. She responded to several measures proposed (among other naltrexone), but rapidly became tolerant to them. Buprenorphine with an ultra low dose of naloxone was able to control her symptoms without development of tolerance until her death.

Aged↗