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At least 145 records · Page 8Linked to original sources
PubMed2001

Pharmacotherapy of obesity: targets and perspectives.

The search for anti-obesity agents has become one of the most exciting areas in drug discovery. Subsequent to an enormous increase in the number of possible molecular targets, the focus has shifted from target identification to target validation. Because important biological functions such as the regulation of energy intake and expenditure are controlled by complex systems, an improved understanding of pathophysiology is a prerequisite for the selection of successful development candidates for the treatment of obesity. Although most of the information on the regulation of energy balance has been obtained from rodents, various monogenic forms of human obesity provide clinical proof of concept for some of these mechanisms. However, it is still not known which are the most promising clinical approaches to lowering body weight and subsequently reducing morbidity and mortality.

Adipose Tissue↗
PubMed1998

Human cortical-evoked fields during detection, localisation, and identification of 'pop-out' targets.

We investigated human cortical activity during four 'effortless-pop-out' visual search tasks with the use of magnetoencephalography. The search display, which was identical across all the tasks, consisted of vertical line segments, one of which was rotated abruptly 45 degrees clockwise or counterclockwise. In the passive-viewing task the observers gave no response to the search display. In the target-detection task they responded to the onset of the target motion irrespective of its location and direction. In the target-localisation task the observers reported whether the line rotation appeared above or below the fixation point while ignoring the direction of the rotation. In contrast, in the target-identification task they indicated the direction of the line rotation, and the location of the rotation in the array was irrelevant. Cortical activity was recorded with a whole-scalp magnetometer while the observers were performing each task. In addition to the expected activation of the occipital and somatomotor cortical regions, two other active cortical areas were consistently identified in both hemispheres: one in the occipito-temporal area, probably corresponding to the motion-specific V5 complex, and another in the parieto-temporal region. The activation of the right occipito-temporal source depended on the task. The maximum amplitude was smallest for the passive viewing, increased for the detection task, and was largest for the localisation and identification.

Adult↗
PubMed1984

The use of a backward masking paradigm to assess information-processing deficits among schizotypics. A re-evaluation of Steronko and Woods.

In 1978, Steronko and Woods (J. Abnorm. Psychol., 87: 481-490, 1978) failed to find significant differences in early visual information processing between "schizotypic" and "psychiatric control" college students, as identified by the MMPI; yet these authors concluded that schizotypics suffer from information-processing deficits. The present study was designed to extend and clarify these findings by modifying the methods and procedures used by these researchers. A visual backward masking task was employed to study the information processing of individuals whose MMPI-168 profiles indicated schizophrenic tendencies in the absence of an obvious thought disorder. These schizotypic individuals were identified by the MMPI 2-7-8 code type and were compared with three other groups, also identified by their MMPI profiles: an "inflation-free" control group, an "other-inflations" control group, and a group with an 8-9/9-8 MMPI code type. The 8-9/9-8 code type has been associated with psychotic features in adolescents and adults. Two dependent measures were evaluated: critical stimulus duration in a no-mask condition and mean target identification as a function of varying interstimulus intervals. The 2-7-8 group had significantly higher critical stimulus duration values than either the inflation-free group or the 8-9 groups. The 2-7-8 group and the 8-9 groups had fewer correct identifications of target stimuli than either the inflation-free group or the other-inflations group. These results suggest that both the 2-7-8 group and the 8-9 group may be more vulnerable to the effects of the masking stimulus.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

A risk assessment for lead in birds.

Ecotoxicologists and ecologists have examined the effects of pollutants on individuals and populations largely in terms of one or only a few effects. Yet the recent trend toward a holistic approach to ecological risk assessment suggests that a rigorous paradigm should be applied to toxicants, from hazard identification to risk characterization. Recent discussions have recognized that an up-front problem formulation phase is more critical in ecological risk assessment than it is for human health risk assessment. In this article a modified environmental health risk assessment paradigm is used to examine the risk of lead to birds. This risk analysis is largely conceptual, based on laboratory and field data, and incorporates information currently available. The model expands the hazard identification phase to create a target identification phase that includes the identification of receptors, endpoints, relationships, spatial and temporal scales, and indicators. The target identification phase is unique to the particular hazard, species, population, or community being examined. Lead can cause mortality, or can indirectly affect populations through effects on the food base, avian behavior, reproductive success, and recruitment. Lead can (1) decrease the abundance and availability of prey, (2) bioaccumulate in prey causing increased lead toxicosis in predators, or (3) increase prey availability by interfering with its hiding or escape behavior. Moreover, lower abundance of prey can lead to starvation or nutrient deficiencies, which amplify the absorption and retention of lead. Lead also causes decreases in clutch and egg size, mortality of embryos and nestlings, depression of growth, and deficits in behavior that affect survival. Lead decreases migratory behavior, and increases vulnerability to cold stress, hunters, and other predators. Research needs for evaluating the risk of lead in birds include obtaining data on (1) metal dynamics within various tissues as a function of dose and time since initial exposure, (2) low-level effects on embryos, (3) effects on chicks following fledging and in the period prior to recruitment, (4) effects on adult foraging skills and reproductive behavior, and (5) the relationship between effects from exposure in the laboratory and those from exposure in the wild. This latter point is extremely important, particularly if wild birds have other means of ridding the body of lead not available or less apparent to laboratory birds.

Animals↗
PubMed2002

Identification of target genes regulated by the two-component system HP166-HP165 of Helicobacter pylori.

Two-component systems are signal transduction systems which enable bacteria to regulate cellular functions in response to changing environmental conditions. In most cases regulation is accomplished on the transcriptional level by a response regulator protein, which, according to the phosphorylation state of its receiver domain, displays different affinities for its target promoters. Here we describe identification of genes regulated by the two-component system HP166-HP165 of Helicobacter pylori and characterization of the corresponding target promoters. We demonstrated that expression of the HP166-HP165 two-component system is negatively autoregulated under conditions favoring autophosphorylation of the histidine kinase. Furthermore, we found that response regulator HP166 activates transcription of genes encoding a protein family with an unknown function present in H. pylori 26695, as well as an operon composed of five H. pylori-specific genes. While open reading frame HP166 is an essential gene, the target genes of the response regulator are not required for growth under in vitro culture conditions.

Base Sequence↗
PubMed2005

Construction of lycopene-overproducing E. coli strains by combining systematic and combinatorial gene knockout targets.

Identification of genes that affect the product accumulation phenotype of recombinant strains is an important problem in industrial strain construction and a central tenet of metabolic engineering. We have used systematic (model-based) and combinatorial (transposon-based) methods to identify gene knockout targets that increase lycopene biosynthesis in strains of Escherichia coli. We show that these two search strategies yield two distinct gene sets, which affect product synthesis either through an increase in precursor availability or through (largely unknown) kinetic or regulatory mechanisms, respectively. Exhaustive exploration of all possible combinations of the above gene sets yielded a unique set of 64 knockout strains spanning the metabolic landscape of systematic and combinatorial gene knockout targets. This included a global maximum strain exhibiting an 8.5-fold product increase over recombinant K12 wild type and a twofold increase over the engineered parental strain. These results were further validated in controlled culture conditions.

Carotenoids↗
PubMed2006

From genome to phenome--RNAi library screening and hit characterization using signaling pathway analysis.

Comprehensive, high-throughput analysis of gene function using RNA interference (RNAi)-based screens is emerging as a significant step forward for preliminary drug-target identification. Until quite recently drug target identification depended heavily on the analysis of changes in gene expression, which in turn needed to be correlated with gene function. The promise of obtaining preliminary 'gene to phenotype' information using a single high-throughput platform is propelling major investment in this area by biotechnology and pharmaceutical companies. This review discusses recent developments in the use of RNAi library screens, and the various assay formats and techniques currently in use for data analysis downstream of such screens.

Animals↗
PubMed2006

Inverse drug screens: a rapid and inexpensive method for implicating molecular targets.

Identification of gene products that function in some specific process of interest is a common goal in developmental biology. Although use of drug compounds to probe biological systems has a very long history in teratology and toxicology, systematic hierarchical drug screening has not been capitalized upon by the developmental biology community. This "chemical genetics" approach can greatly benefit the study of embryonic and regenerative systems, and we have formalized a strategy for using known pharmacological compounds to implicate specific molecular candidates in any chosen biological phenomenon. Taking advantage of a hierarchical structure that can be imposed on drug reagents in a number of fields such as ion transport, neurotransmitter function, metabolism, and cytoskeleton, any assay can be carried out as a binary search algorithm. This inverse drug screen methodology is much more efficient than exhaustive testing of large numbers of drugs, and reveals the identity of a manageable number of specific molecular candidates that can then be validated and targeted using more expensive and specific molecular reagents. Here, we describe the process of this loss-of-function screen and illustrate its use in uncovering novel bioelectrical and serotonergic mechanisms in embryonic patterning. This technique is an inexpensive and rapid complement to existing molecular screening strategies. Moreover, it is applicable to maternal proteins, and model species in which traditional genetic screens are not feasible, significantly extending the opportunities to identify key endogenous players in biological processes.

Biological Assay↗
PubMed2004

Identification and validation of novel drug targets in tuberculosis.

There is an urgent need for new antimycobacterial drugs, and in particular for novel agents that will shorten the duration of tuberculosis chemotherapy, or overcome drug-resistant strains of the causative organism, Mycobacterium tuberculosis. Our knowledge of the tubercle bacillus and its complex interaction with the human host has improved dramatically in recent years, particularly with the determination of its complete genome sequence. New genome-scale tools are being applied to aid in drug target identification, alongside traditional approaches aimed at understanding the basic biology of M. tuberculosis. Many potential drug targets have been identified, but very few have been validated by showing that they are essential for growth or survival of the bacterium. In this review, the landscape of potential drug targets is surveyed.Structural Bioinformatic Approaches to the Discovery of New Antimycobacterial Drugs.

Animals↗
PubMed2005

Finding the target after screening the phenotype.

Although most screening for new drug leads is being directed at known or emerging molecular targets, there has been a renaissance in screening based on changes in cell or organismal phenotypes. Phenotype-based screening is accompanied by the challenge of identifying the molecular target or targets bound by the drug leads and responsible for their pharmacological activity. A variety of technologies and approaches are being explored for target identification after phenotypic screening. Direct approaches employing affinity chromatography, expression cloning and protein microarrays analyze the compound bound to its target. Indirect approaches are based on comparison of the genome-wide activity profile of the compound with databases of the activity profiles of other compounds with known targets or activity profiles following specific genetic changes. This review will use case studies of target identification efforts and highlight the advantages and disadvantages of the various approaches to target identification after phenotypic screening.

Animals↗
PubMed2002

A rapid and cost-effective screening method for identification of targeted embryonic stem cells.

Generation and characterization of knockout mice from targeted embryonic stem (ES) cells have become one of the most powerful approaches to study gene function in vivo. However, experiments to identify targeted ES clones can be both labor-intensive and expensive when the targeting efficiency is low. Using the steroid receptor coactivator-3 (SRC-3) gene as a model, we have developed a rapid and cost-effective method for identification of targeted ES clones. Specifically, a promoterless LacZ sequence was fused to the 5'-coding sequence of SRC-3 in the targeting vector. After homologous recombination in ES cells, LacZ expression was regulated by the endogenous gene promoter. In cases of random insertions the beta-galactosidase would more likely not be produced due to lacking promoter or missing amino acid-reading frame. Accordingly, targeted ES clones were enriched more than 30 times in the population of blue clones positive to X-gal staining. Therefore, targeted ES clones can be selected quickly and economically by X-gal staining in large scale followed by Southern blot analysis on small number of blue clones if the gene of interest is expressed in ES cells. This strategy is particularly useful when the targeting efficiency is low and a reporter such as LacZ or GFP for mouse gene expression is desired.

Animals↗
PubMed2006

Atlas-based identification of targets for functional radiosurgery.

Functional disorders of the brain, such as Parkinson's disease, dystonia, epilepsy, and neuropathic pain, may exhibit poor response to medical therapy. In such cases, surgical intervention may become necessary. Modern surgical approaches to such disorders include radio-frequency lesioning and deep brain stimulation (DBS). The subthalamic nucleus (STN) is one of the most useful stereotactic targets available: STN DBS is known to induce substantial improvement in patients with end-stage Parkinson's disease. Other targets include the Globus Pallidus pars interna (GPi) for dystonia and Parkinson's disease, and the centromedian nucleus of the thalamus (CMN) for neuropathic pain. Radiosurgery is an attractive noninvasive alternative to treat some functional brain disorders. The main technical limitation to radiosurgery is that the target can be selected only on the basis of magnetic resonance anatomy without electrophysiological confirmation. The aim of this work is to provide a method for the correct atlas-based identification of the target to be used in functional neurosurgery treatment planning. The coordinates of STN, CMN, and GPi were identified in the Talairach and Tournoux atlas and transformed to the corresponding regions of the Montreal Neurological Institute (MNI) electronic atlas. Binary masks describing the target nuclei were created. The MNI electronic atlas was deformed onto the patient magnetic resonance imaging-T1 scan by applying an affine transformation followed by a local nonrigid registration. The first transformation was based on normalized cross correlation and the second on optimization of a two-part objective function consisting of similarity criteria and weighted regularization. The obtained deformation field was then applied to the target masks. The minimum distance between the surface of an implanted electrode and the surface of the deformed mask was calculated. The validation of the method consisted of comparing the electrode-mask distance to the clinical outcome of the treatments in ten cases of bilateral DBS implants. Electrode placement may have an effect within a radius of stimulation equal to 2 mm, therefore the registration process is considered successful if error is less than 2 mm. The registrations of the MNI atlas onto the patient space succeeded in all cases. The comparison of the distance to the clinical outcome revealed good agreement: where the distance was high (at least in one implant), the clinical outcome was poor; where there was a close correlation between the structures, clinical outcome revealed an improvement of the pathological condition. In conclusion, the proposed method seems to provide a useful tool for the identification of the target nuclei for functional radiosurgery. Also, the method is applicable to other types of functional treatment.

Journal Article↗
PubMed2006

An array of Escherichia coli clones over-expressing essential proteins: a new strategy of identifying cellular targets of potent antibacterial compounds.

With the advancement of high throughput screening, it has become easier and faster to discover hit compounds that inhibit proliferation of bacterial cells. However, development in technologies used to identify cellular targets of potent antibacterial inhibitors has lagged behind. Here, we describe a novel strategy of target identification for antibacterial inhibitors using an array of Escherichia coli clones each over-expressing one essential protein. In a proof-of-concept study, eight essential genes were cloned into pLex5BA vector under the control of an inducible promoter. Over-expression of target proteins was confirmed. For two clones, one over-expressing FabI and the other over-expressing MurA enzymes, the host cells became 17- and 139-fold more resistant to the specific inhibitors triclosan and phosphomycin, respectively, while the susceptibility of other clones towards these inhibitors remained unchanged after induction of gene expression. Target identification via target protein over-expression was demonstrated using both mixed clone and individual clone assay formats.

Anti-Bacterial Agents↗
PubMed2002

Development of a computerized assessment for visual masking.

Visual masking provides a highly informative means of assessing the earliest stages of visual processing. This procedure is frequently used in psychopathology research, most commonly in the study of schizophrenia. Deficits in visual masking tasks appear to reflect vulnerability factors in schizophrenia, as opposed to the symptoms of the illness. Visual masking procedures are typically conducted on a tachistoscope, which limits standardization across sites, as well as the number of variables that can be examined in a testing session. Although visual masking can be administered on a computer, most methods used so far have had poor temporal resolution and yielded a limited range of variables. We describe the development of a computerized visual masking battery. This battery includes a staircase procedure to establish an individual's threshold for target detection, and a relatively dense sampling of masking intervals. It includes both forward and backward masking trials for three different masking conditions that have been used previously in experimental psychopathology (target location, target identification with high-energy mask, and target identification with low-energy mask).

Adult↗
PubMed1998

Pancreatic polypeptide: identification of target tissues using an in vivo radioreceptor assay.

The definitive function of pancreatic polypeptide in mammalian physiology remains unknown. The identification of specific PP target tissues should be helpful to further investigations into the possible regulatory actions of this peptide. An in vivo radioreceptor assay was used in the rat to locate potential binding sites of I(125) bovine PP. In vitro, high concentrations of unlabeled hormone competitively inhibit binding to receptors by low concentrations of labeled hormone. In vivo studies showed that, in the presence of concentrated unlabeled pancreatic polypeptide, labeled PP distributes between the plasma and interstitial fluid. When excess unlabeled PP is replaced with saline in the companion animals, the labeled peptide appears to distribute in a volume that exceeds the combined plasma volume and interstitial fluid volume of the tissue. Using this in vivo receptor assay, the distribution volume that exceeds the anatomic extracellular volume has been identified as the receptor compartment. With this assay we demonstrated in the rat specific and displaceable PP binding to the ductus choledochus, duodenum, ileum, and adrenal gland. The NVV determined in the adrenal gland of experimental animals was 3.9 times greater than that found in the control group. Binding was rapid and was displaced only by excess unlabeled pancreatic polypeptide. Neither excess insulin nor excess neuropeptide Y significantly reduced this binding.

Adrenal Glands↗
PubMed1982

Similarity-related channel interactions in visual processing.

Lateral interference between letters in the visual field is a joint function of their similarity and physical separation. Data needed to evaluate hypothesis about the processes implicated in these effects were obtained from two experiments in which the task was identification of a target letter always presented in the center of a three-letter display. Variation of target-flanker similarity, the primary variable, was combined factorially with spacing of target and flanker, location of the display in the visual field, delay of patterned postmasks, and exposure duration. The effect of target-flanker similarity on target identification yielded a nonmonotonic function with a minimum at an intermediate degree of similarity. Data from same-different judgments regarding target-flanker similarity indicate that some information about similarity is available even at levels of visibility that do not permit identification of individual letters. All of the findings could be accommodated by a model assuming that only variables determining visibility--exposure duration, mask properties, location in the visual field, separation of letters--influence extraction of featural information pertaining to letter identification. In contrast, visual similarity influences performance by way of sometimes subtle effects on subjects' criteria or response biases and by effects on the encoding and retention of information regarding relative positions of characters in the visual field. The varying effects of similarity reported in the literature on letter identification all appear to be interpretable in these terms.

Adult↗
PubMed1999

Functional genomics in cancer research: identification of target genes of the Epstein-Barr virus nuclear antigen 2 by subtractive cDNA cloning and high-throughput differential screening using high-density agarose gels.

In the past, the identification and isolation of phenotype-associated genes was a difficult and time-consuming task. However, recent improvements of methods that are designed to isolate differentially expressed genes have remarkably speeded up the process of target gene isolation. The ultimate goal of functional genomics is to apply these technologies to clone phenotype-associated genes irrespective of the availability of probes (e.g., antibodies) and an intimate knowledge of biological background. We demonstrate the use of a novel subtractive cDNA cloning approach for the isolation and characterization of target genes of the Epstein-Barr virus nuclear antigen 2 (EBNA2). Two different subtractive cDNA libraries specific for two different time periods following activation of a conditional estrogen receptor/EBNA2 (ER/EBNA2) fusion protein were generated. Comparison of the two libraries by cross-hybridization experiments allowed the differentiation between direct and indirect target genes of EBNA2 and led to the identification of a novel direct target gene of EBNA2.

Cloning, Molecular↗
PubMedDate not supplied

Drug localization and targeting with receptor microscopic autoradiography.

This review is an argument in favor of better drug target identification. It presents the many merits and feasibilities of drug localization and target identification through the use of a suitable technique: receptor microautoradiography. Studies of drug targets and target bioavailability require methods with high resolution and sensitivity to gain information for understanding mechanisms of action, sound modeling, prediction of effects, and toxicity. For in vivo localization of drugs in tissues and cells, receptor microautoradiography was specifically designed to preserve both tissue structure and deposition of noncovalently bound diffusible compounds and to enable microscopic viewing, quantitative analysis, and characterization of target sites. This method and its applications are explained here. Pictorial and quantitative data are provided together with a discussion of identified targets that document the utility of receptor microautoradiography. For example, when applied to quantitative studies of vitamin D compounds, pharmacokinetic data of blood differed from those of target tissues and even among target tissues. Many of the target tissues discovered and characterized with receptor microautoradiography remained unrecognized with common ADME procedures, radioassay-HPLC, and whole-body autoradiography. For a visual overview of the multiple vitamin D targets, a drug homunculus has been composed. Such a drug or target homunculus may be created for any drug, dose, and time to aid in documenting and fingerprinting. Receptor microautoradiography also is a sensitive method. It can be used for the study of low-dose stimulatory actions of toxic substances to show relationships of receptor binding to dose-dependent reversal of effects, known as hormesis. In addition, a combination of autoradiography and immunocytochemistry with radiolabeled drug and antibodies to receptor or other cellular product permits further target characterization. In its own league, receptor microautoradiography provides unique information. Through greater detail and certainty, it can validate and complement less-sensitive approaches, decrease the failure rates of current ADMET predictions, and serve as a diagnostic tool and guide for biochemical, functional, and clinical follow-up in drug research and development.

Animals↗