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At least 1,603 records · Page 89Linked to original sources
PubMed2006

Lymphocyte apoptosis as an immune subversion strategy of microbial pathogens.

Apoptosis is a component of cellular death in several immunological reactions. Lymphocyte apoptosis is a feature of negative selection of thymic lymphocytes. Target cells die by apoptosis during their interaction with cytotoxic T cells. Antigens derived from apoptotic cells can be cross-presented by antigen presenting cells (APCs). In these examples, apoptotic death is a beneficial feature for the individual. The apoptosis of cells also occurs during infection with a variety of microorganisms, but this process can be detrimental to the handling of the infection by the host. Here, we aim to highlight some of the recent advances in understanding why apoptosis can be a detrimental event during infection. We will focus on recent research with the intracellular bacterial pathogen Listeria monocytogenes, which demonstrates how apoptosis is induced, some of the host pathways that are exploited and the immunological consequences of cell death. We propose that L. monocytogenes causes lymphocyte death by enhancing the cell-death programs of the host. The presence of apoptotic lymphocytes downregulates early innate immunity, creating a permissive environment for bacterial growth.

Animals↗
PubMed2001

Axonal outgrowth of hippocampal neurons on micro-scale networks of polylysine-conjugated laminin.

Microcontact printing was used to define an interconnected lattice network of polylysine-conjugated laminin, a protein-polypeptide ligate that is an effective promoter of neuron outgrowth on material surfaces. In the presence of serum proteins, rat hippocampal neurons selectively adhered to features of polylysine-conjugated laminin as narrow as 2.6 microm in width. Adhering neurons extended long axonal processes, which precisely followed and did not deviate from the prescribed patterns, demonstrating that neurons respond to this protein with high selectivity and that these techniques effectively provide long-range guidance of axonal outgrowth. Further examination of neuron response under serum-free cell culture conditions demonstrated that the outgrowth-promoting activity of polylysine-conjugated laminin was attributed to biologically active laminin. Together, these results demonstrate that polylysine-conjugated laminin provides for high-precision guidance of neuron attachment and axon outgrowth on material surfaces in a serum-independent manner. This ability to guide hippocampal neuron response in low-density, serum-free culture with high precision is valuable for the development of advanced, neuron-based devices.

Animals↗
PubMed2003

Selection of oligonucleotide aptamers with enhanced uptake and activation of human leukemia B cells.

The clinical use of oligonucleotide (ODN) therapeutics has been hampered by their limited ability to penetrate intact cells. To identify ODN properties that would facilitate cellular uptake, we developed a repetitive selection procedure using an ODN library containing at least 10(14) different molecules and human B lymphoma cells as a target. Natural phosphodiester single-stranded DNA ODNs (R-aptamers) were obtained after 10 rounds of selection. A common feature in the R-aptamers was guanine-rich 3' terminal sequences, and many also contained potential immunostimulatory (ISS) CpG sequence motifs. Two R-aptamers (R10-60 and D-R15-8) with the predominant shared characteristics were selected for further study on primary human chronic lymphocytic leukemia (CLL) B cells, which are well known to be difficult to transfect and activate. Flow cytometry analysis of the CLL cells demonstrated that the fluorochrome-labeled R-aptamers were internalized much more efficiently than nonselected random sequence ODN. Studies on sequence modifications indicated that efficient uptake required ODN multimerization, that was promoted by guanine-rich sequences at the 3' terminus. In addition, CLL cells that were exposed to the aggregating R-aptamers containing CpG motifs were strongly activated, as indicated by upregulation of CD40 levels as compared to cells treated with nonaggregating CpG R-aptamers. Together, these findings suggest that the sequence compositions in R-aptamers that promote multimerization and contain optimal ISS CpG motifs facilitate the delivery of ISS-ODN to CLL cells and enhance the activation of these cells.

Adjuvants, Immunologic↗
PubMed1999

The utility of mixed-form likelihoods.

We highlight a feature of likelihood-based methods that provides flexibility in model formulation and inference. In particular, overall likelihoods that consist of likelihood contributions with different forms are considered. The particular forms may be predetermined by design criteria or may be selected based on features of the data. Inferences based on such mixed-form likelihoods are valid provided standard regularity conditions hold and the parameters of interest have the same interpretation in the various forms. The advantages of constructing overall likelihoods in this way are illustrated by applications involving the analysis of 2 x 2 x K tables and left-censored water quality data.

Biometry↗
PubMedDate not supplied

[Selection of behavioral test parameters for estimation of typological features of rat behavior].

Behavior of 86 rats was examined in three behavioral tests, i.e., open field, forced swimming and emotionality by F. King. The results of statistical analysis of all the indices obtained with application of factor analysis suggest that the three tests characterize four relatively independent behavioral components: emotionality, locomotor-exploratory activity, olfactory performance, and resistance to adverse emotional factors. A contribution of each measured parameter to the above components was estimated. Such an approach makes it possible to reasonably select most important behavioral features when estimating locomotor activity and emotionality of animals.

Animals↗
PubMed1992

Crystal structure of a berenil-d(CGCAAATTTGCG) complex. An example of drug-DNA recognition based on sequence-dependent structural features.

The AT-selective drug berenil has been co-crystallized with the dodecanucleotide sequence d(CGCAAATTTGCG)2. The crystal structure has been solved to a resolution of 2.0 A and an R factor of 18.3%, with the location of 65 water molecules. The drug is symmetrically bound in the 5'-AATT region of the minor groove, with its amidinium groups hydrogen-bonding to O-2 atoms of the thymine base at each end of the binding site. This arrangement is distinct from that previously found for berenil with the sequence d(CGCGAATTCGCG)2, which has the drug bound to the sequencing 5'-ATT via hydrogen bonds to adenine N-3 atoms with the involvement of a bridging water molecule at one end of the binding site. The reasons for these differences are discussed in terms of changes in helical parameters; in particular propeller twist and base-pair roll are considered to be important. The conformational and base-pair geometry of the dodecanucleotide in the structure reported here, is closely similar to that for the native structure, suggesting that the 5'-AAATTT sequence does not significantly alter during drug binding, either because of its inflexibility or because its geometry is nearly ideal for berenil binding.

Base Sequence↗
PubMed2006

2-Aza-1,3-butadiene derivatives featuring an anthracene or pyrene unit: highly selective colorimetric and fluorescent signaling of Cu2+ cation.

[Structure: see text] A new probe based on an anthryl derivative bearing an azadiene side chain selectively senses Cu2+ in acetonitrile through two different channels: the yellow-to-orange color change and a remarkable enhancement of the fluorescence, whereas the pyrenyl analogous behaves as a fluorescent sensor for Cu2+ and Hg2+ in aqueous environment.

Journal Article↗
PubMed1992

Distinctive features of rilmenidine possibly related to its selectivity for imidazoline receptors.

Rilmenidine is an oxazoline derivative with antihypertensive activity which was developed to enhance the dissociation between the hypotensive and adverse effect profile of centrally acting agents. Experimental studies have indicated that rilmenidine is selective for both alpha 2-adrenoceptors (v alpha 1) and newly discovered nonadrenergic imidazoline receptors in the brain and in the periphery. In experimental studies, rilmenidine differs from clonidine in that it is more selective for imidazoline receptors than for alpha 2-adrenoceptors; at equihypotensive doses, rilmenidine causes less bradycardia and reduction in cardiac output, less sedation, and little or no antinociceptive action compared to clonidine. The hypotensive effects of rilmenidine are antagonised by idazoxan and yohimbine, but idazoxan (imidazoline structure) is six times more potent than yohimbine (a selective alpha 2-antagonist). In isolated renal proximal tubule cells, where imidazoline binding has also been shown, rilmenidine inhibits reabsorption of sodium. Clinical studies comparing 1 mg rilmenidine with placebo demonstrated significant reductions in blood pressure (BP) (61% rilmenidine v 23% placebo normalized to 160/90 mm Hg). The reduction in BP was not associated with classical alpha 2 side effects such as dry mouth or daytime drowsiness. Compared with clonidine (0.15 to 0.3 mg), equihypotensive doses of rilmenidine (1 to 2 mg) induced two to three times less dry mouth, daytime drowsiness, and constipation; no orthostatic hypotension was reported. Methyldopa (0.5 to 1 mg) v rilmenidine (1 to 2 mg) indicated a comparable reduction of BP with significantly less weakness, drowsiness, orthostatic dizziness, and dry mouth on rilmenidine; there was no evidence of the "clonidine withdrawal syndrome" on drug withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed2007

Is psychosis in DSM-IV mania due to severity? The relevance of selected demographic and comorbid social-phobic features.

OBJECTIVE: We tested whether factors other than episode severity contributed to psychosis in mania. METHOD: Psychiatrists collected systematic clinical data on 1090 hospitalized DSM-IV manic patients in France, and completed the Mania Rating Scale (MRS) and the Scale for the Assessment of Positive Symptoms (SAPS). RESULTS: Using DSM-IV specifiers, 21.9% were non-severe, 28.2% severe without psychosis, and 49.9% severe with psychosis. On the MRS, patients with psychosis scored significantly higher (P < 0.0001) than non-severe, but did not differ from the severe without psychosis. We found significant correlations between both the Hallucination and the Delusion subscores of the SAPS and the MRS, as well as correlations between age, single marital status, comorbid social phobia and psychotic mania. CONCLUSION: Apart from episode severity, social isolation - associated with younger age, single marital status and social phobia - seems to make a contribution to the origin of manic psychosis largely independent from such severity.

Adult↗
PubMed1998

Attentional control within 3-D space.

Four experiments investigated whether directing attention to a particular plane in depth enables observers to filter out information from another depth plane. Observers viewed stereoscopic displays and searched for a red line segment among green line segments. The results showed that directing attention to a particular depth plane cannot prevent attentional capture from another depth plane when the colors of the target and distractor are identical. However, it can prevent attentional capture by a singleton from another depth plane when the colors of the target and distractor are different. These results indicate that only when both color and depth information are selective in guiding attention to the target singleton can attentional capture by irrelevant singletons be prevented. The results also suggest that retinal disparity does not have the same special status as location information in two dimensions and should be considered as just another feature along which selection may occur.

Adolescent↗
PubMed1979

The transfer of selected image data to a computer using a conductive tablet.

The processing and analysis of images in a computer often requires the selection of particular features of a complex image for more detailed study. Sometimes such decisions are empirical, in which case it would be extremely difficult to describe a rigorous algorithm for detecting these features automatically in a computer. In this situation graphic tablets can be very useful as they allow an operator to use experience in deciding which features are to be transferred into a computer. A tablet is described which uses a conductive glass plate and pencil probe. A number of subroutines are available in a general purpose program for conventional processing, calculation and displays to be effected by simple option selection on the tablet for specific applications in cell growth, modeling and three dimensional reconstruction of serial sections, special programs were developed which could include appropriate subroutines. The categorisation of subsections by an operator was particularly useful in allowing different methods of analysis and display to be applied to each. For example they could be displayed separately or given different dentisy levels by choosing the appropriate option in the program.

Analog-Digital Conversion↗
PubMed1998

New DNA sequence rules for high affinity binding to histone octamer and sequence-directed nucleosome positioning.

DNA sequences that position nucleosomes are of increasing interest because of their relationship to gene regulation in vivo and because of their utility in studies of nucleosome structure and function in vitro. However, at present our understanding of the rules for DNA sequence-directed nucleosome positioning is fragmentary, and existing positioning sequences have many limitations. We carried out a SELEX experiment starting with a large pool of chemically synthetic random. DNA molecules to identify those individuals having the highest affinity for histone octamer. A set of highest-affinity molecules were selected, cloned, and sequenced, their affinities (free energies) for histone octamer in nucleosome reconstitution measured, and their ability to position nucleosomes in vitro assessed by native gel electrophoresis. The selected sequences have higher affinity than previously known natural or non-natural sequences, and have a correspondingly strong nucleosome positioning ability. A variety of analyses including Fourier transform, real-space correlation, and direct counting computations were carried out to assess non-random features in the selected sequences. The results reveal sequence rules that were already identified in earlier studies of natural nucleosomal DNA, together with a large set of new rules having even stronger statistical significance. Possible physical origins of the selected molecules' high affinities are discussed. The sequences isolated in this study should prove valuable for studies of chromatin structure and function in vitro and, potentially, for studies in vivo.

Base Composition↗
PubMed2004

Characteristics of attention and visual short-term memory: implications for visual interface design.

Although the human retina can code many object images simultaneously, observers are often aware of only a tiny fraction of this information. These processing limitations of the visual brain have evolved to prioritize particularly relevant features of a scene while ignoring other irrelevant features. However, such selectivity has its drawbacks. In information-rich environments, such as driving a car or landing an aircraft, vision can fail to cope, and accidents can result. Accordingly, much recent research in psychophysics and ergonomics has examined how display characteristics affect our ability to process multiple features of the visual environment simultaneously. The majority of these experiments has found that performance can be optimized by combining several features into one visual 'object'. In contrast, several recent studies from my own laboratory have found the opposite pattern, indicating that information sources can often be more efficiently processed when they belong to separate objects. Indeed, these data suggest that the number of objects has no general effect on our perceptual performance. Instead, I argue for a two-pathway approach to understanding human visual capacities, and suggest that this approach may have important implications for a diverse range of display technologies, including cockpit displays.

Attention↗
PubMedDate not supplied

Enhancing specificity and sensitivity of pharmacophore-based virtual screening by incorporating chemical and shape features--a case study of HIV protease inhibitors.

Virtual screening (VS), if applied appropriately, could significantly shorten the hit identification and hit-to-lead processes in drug discovery. Recently, the version of VS that is based upon similarity to a pharmacophore has received increased attention. This is due to two major factors: first, the public availability of the ZINC1 conformational database has provided a large selection pool with high-quality and purchasable small molecules; second, new technology has enabled a more accurate and flexible definition of pharmacophore models coupled with an efficient search speed. The major goal of this study was to achieve improved specificity and sensitivity of pharmacophore-based VS by optimizing the variables used to generate conformations of small molecules and those used to construct pharmacophore models from known inhibitors or from inhibitor-protein complex structures. By using human immunodeficiency virus protease and its inhibitors (PIs) as a case study, the impact of the key variables, including the selection of chemical features, involvement of excluded volumes (EV), the tolerance radius of excluded volumes, energy windows, and the maximum number of conformers in conformation generation, was explored. Protein flexibility was simulated by adjusting the sizes of EV. Our best pharmacophore model, combining both chemical features and excluded volumes, was able to correctly identify 60 out of 75 structurally diverse known PIs, while misclassifying only 5 out of 75 similar compounds that are not inhibitors. To evaluate the specificity of the model, 1193 oral drugs on the market were screened, and 25 original hits were identified, including 5 out of 6 known PI drugs.

Drug Design↗
PubMed1999

A new algorithm to align three-dimensional maps of helical structures.

By subtracting one three-dimensional (3-D) map from another, one can calculate a difference map that can reveal structural changes, such as conformational changes, not detectable by eye. Furthermore, statistical significances can be assigned to such differences. The validity of the features in the difference map, however, depends on the alignment of the two maps; that is, one needs to align the two 3-D maps so that densities corresponding to equivalent parts of the structures are at the same coordinates. An existing method using the Fourier-Bessel coefficients Gn,1(R) is commonly used for the alignment of maps of helical structures. This procedure works well if the two maps have most features in common. But if they do not, it is difficult to control which features are used in the alignment procedure since the contributions from different features in the map are not easy to separate. We devised a procedure using the radial transform of Gn,1(R) (i.e., g(n),1(r)), which retains the powerful mathematical advantage of the Fourier-Bessel representation of the data and which provides the ability to select the radial features used in the alignment procedure. We applied the new method to 3-D maps of F-actin and F-actin decorated with various myosin motor constructs. Whereas the procedure using G(n),1(R) failed to align myosin-S1 decorated actin to undecorated actin, the new procedure accurately aligned maps.

Actins↗
PubMed2006

The population dynamics of cancer: a Darwinian perspective.

Carcinogenesis, at least for some types of cancer, can be interpreted as the consequence of selection of mutated cells similar to what, in the theory of evolution, occurs at the population level. Instead of considering a population of organisms, we can refer to a population of cells belonging to multicellular organisms. Many carcinogens are mutagens, and the observed geographic distribution of cancer is, at least in part, attributable to environmental mutagens. However, the rapid change in risk for some cancers after migration suggests that carcinogenesis involves--in addition to mutations--some late event that most probably consists of the selection of cells already carrying mutations. We review a few examples of such selective pressures: finasteride in prostate cancer, vitamin supplementation in smokers, acquired resistance to chemotherapy, peripheral resistance to insulin, and sunlight and mutations in melanoma. A disease model for such a hypothesis is represented by Paroxysmal Nocturnal Hemoglobinuria (PNH). Mutations can be present at birth, as in the case of PNH, and can have a frequency much higher than the occurrence of the corresponding disease (PNH or lymphocytic leukaemia in children). However, PNH does not require a mutator phenotype, only a mutant phenotype followed by selection. A characteristic feature of cancer, instead, is likely to be the development of the mutator phenotype. We propose a 'Darwinian' model of carcinogenesis. If the model is correct, it suggests that prevention is more complex than avoiding exposure to mutagens. Mutations and genetic instability can be already present at birth. Mutations can be selected in the course of life if they increase survival advantage of the cell under certain environmental circumstances. In addition, gene-environment interactions cannot be interpreted according to a simplified linear model (based on the 'analysis of variance' concept); experimental work suggests that a more comprehensive non-linear interpretation based on the idea of 'norm of reaction' is needed.

Cell Transformation, Neoplastic↗
PubMed2002

Twistophane macrocyles with integrated 6,6'-connected-2,2'-bipyridine units: a new lead class of fluorescence sensors for metal ions.

The new twistophane macrocycles 2 and 3 have been synthesised; these compounds are composed of a cyclically conjugated dehydrobenzoannulene framework that incorporates 6,6'-connected-2,2'-bipyridine moieties for the purpose of coordinating metal ions. The cyclophanes were characterised by spectroscopic techniques, and shown by molecular mechanics calculations to be helically twisted and chiral molecules that may exist in several possible ground state conformations. UV/vis spectroscopic studies revealed that 2, 3 and precursor 9 bind with different selectivities to particular members of the following small group of metal analytes: CuII, AgI, HgII, Tl1 and PdII. Significantly, 2, 3 and 9 signal the presence of CuII ions through fluorescence emission quenching output responses. Furthermore, cyclophane 3 exhibited a particularly sensitive protontriggered chromogenic fluorescence response. With respect to their unique structural features, high analyte selectivity coupled with their enhanced and characteristic fluorescence emission responses, these molecules are among the first examples representing a new lead class of chemosensory materials. Compounds 2, 3 and 9 and derivatives thereof may, therefore, be expected to find many future applications in the detection of metal-based environmental pollutants, biologically important trace elements and monitoring proton fluxes.

Journal Article↗
PubMed1989

Calibration of ion-selective microelectrodes: flow-system and analysis program for the IBM PC.

A menu-driven program--written in C and Assembly language--has been developed for use with an IBM PC or compatible computer for calibration of ion-selective microelectrodes. Available features include (i) user-logical commands, (ii) rapid, accurate construction and display of calibration curves (fitted by least squares non-linear regression), (iii) analysis of data (stored either on- or off-line), with correction for drift and conversion from voltage or length to ion concentration or activity, (iv) calculation of selectivity coefficients, (v) optional storage and use of activity coefficients, and (vi) output of data, calculations and graphics to printer and plotter. A simple chamber and valve-activated flow-system for rapid change of solutions with either manual selection or computer control is also described.

Microelectrodes↗