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Results for “target of selection”

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At least 199 records · Page 11Linked to original sources

PubMed1993

Long-term effects of selective target removal on brainstem premotor neurons in the adult cat.

The electrical activity of antidromically identified abducens internuclear neurons selectively deprived of their target motoneurons was recorded in chronic alert cats. Target motoneurons were killed by the injection of the cytotoxic lectin of Ricinus communis into the medial rectus muscle. Following target removal, the discharge pattern of abducens internuclear neurons showed an overall decrease in firing rate, a significant reduction in their sensitivity to eye position and velocity, and the presence of anomalous responses such as bursts of spikes associated with off-directed saccades. The decreased excitability of abducens internuclear neurons correlated well with a marked reduction in the synaptic efficacy of their inputs. Thus, both excitatory and inhibitory synaptic potentials of vestibular origin showed a noticeable decrease in amplitude. The alterations in firing properties and synaptic transmission were only observed during an initial period of 3 weeks following ricin injection. Within 1 month the electrophysiological parameters returned to control values and remained unaltered for 1 year. Retrograde labelling of abducens internuclear neurons revealed that no cell death occurred after target loss. The anterograde axonal labelling of these neurons showed a progressive decrease in the density of their axonal terminals, and no sign of redistribution to other areas was found. These findings indicate that abducens internuclear neurons are not dependent on the presence of their natural target cells, either for the survival or for the maintenance of appropriate physiological signals.

Abducens Nerve↗

PubMed1992

Alternate neuromuscular target selection following the loss of single muscle fibers in Drosophila.

The Drosophila embryonic and larval body wall consists of a simple array of segmental muscle fibers, innervated in a precise manner by identified neurons. During development motoneurons were forced to find alternate targets following the selective deletion of a single muscle fiber, the pleural internal oblique #5. We used backfills, intracellular dyefills, and immunocytochemistry in embryos and larvae to characterize the normal motoneurons to the fiber. Deleting the fiber using either a genetic or laser lesioning method yielded essentially the same result. In nearly half the cases examined, an ectopically placed neuromuscular projection was found on either of two neighboring muscle fibers, with one favored eight times more than the other. The ectopic projection derived from the nerve branch that normally supplied the deleted muscle fiber 5. Motoneuronal endings on undeleted muscle fibers elsewhere in the body wall had normal morphology. The ectopically placed motor terminals accumulated glutamate in normally sized synaptic boutons, beneath which transmitter sensitivity was localized. The number of boutons and branches at the ectopic endings did not differ significantly from those on intact muscle fiber 5s. Also, the native motoneurons did not alter their arborization sizes in response to a supernumerary ectopically placed contact. While the orientation of the individual ectopically placed branches was variable, the ectopic endings occupied a predictable site on the surrogate muscle fibers. The results suggest that Drosophila motoneurons can project to body wall destinations in the absence of their muscle fiber targets, and that alternate muscle fibers are selected by their proximity. The muscle fibers will support apparently stable and functional supernumerary motor endings on ectopic sites, and these inputs do not significantly influence the behavior of the native motoneurons. The data suggest that Drosophila motoneurons may behave autonomously when making synapses, and that competition does not play a major role in the matching of motoneuron to muscle fiber.

Animals↗

PubMed2005

Structural genomics of human proteins--target selection and generation of a public catalogue of expression clones.

BACKGROUND: The availability of suitable recombinant protein is still a major bottleneck in protein structure analysis. The Protein Structure Factory, part of the international structural genomics initiative, targets human proteins for structure determination. It has implemented high throughput procedures for all steps from cloning to structure calculation. This article describes the selection of human target proteins for structure analysis, our high throughput cloning strategy, and the expression of human proteins in Escherichia coli host cells. RESULTS AND CONCLUSION: Protein expression and sequence data of 1414 E. coli expression clones representing 537 different proteins are presented. 139 human proteins (18%) could be expressed and purified in soluble form and with the expected size. All E. coli expression clones are publicly available to facilitate further functional characterisation of this set of human proteins.

Journal Article↗

PubMed2005

Novel oncolytic adenovirus selectively targets tumor-associated polo-like kinase 1 and tumor cell viability.

PURPOSE: Polo-like kinase 1 (plk1) is a serine/threonine protein kinase essential for multiple mitotic processes. Previous observations have validated plk1 as a promising therapeutic target. Despite being conceptually attractive, the potency and specificity of current plk1-based therapies remain limited. We sought to develop a novel plk1-targeting strategy by constructing an oncolytic adenovirus to selectively silence plk1 in tumor cells. EXPERIMENTAL DESIGN: Two artificial features were engineered into one wild-type adenovirus type 5 (wt-Adv5) genome to generate a new oncolytic adenovirus (M1). First, M1 contains a 27-bp deletion in E1A region, which confers potent, oncolytic efficacy. Second, M1 is armed with a fragment of antisense plk1 cDNA that substitutes the E3 region encoding 6.7K and gp19K. In this design, tumor-selective replication of M1 would activate the native adenovirus E3 promoters to express the antisense plk1 cDNA preferentially in tumor cells and silence tumor-associated plk1 protein. RESULTS: By virtue of combining oncolysis with plk1 targeting, M1 exhibited potent antitumoral efficacy in vitro and in vivo. Systemic administration of M1 plus cisplatin induced complete tumor regression in 80% of orthotopic hepatic carcinoma model mice that were otherwise resistant to cisplatin and disseminated metastases. CONCLUSIONS: Coupling plk1 targeting with oncolysis had shown superior antitumor efficacy. Present findings would benefit the development of novel oncolytic adenoviruses generally applicable to a wide range of molecule-based therapeutics.

Adenoviridae↗

PubMed2001

Multisensory interactions in saccade target selection: curved saccade trajectories.

In a series of experiments, we examined the change in saccade trajectories observed when distractors are presented at non-target locations. The primary aim of the experiments was to examine multisensory interaction effects between the visual, auditory and somatosensory modalities in saccade generation. In each experiment observers made saccades to visual targets above and below fixation in the presence of visual, auditory or tactile stimuli to the left or right of fixation. In experiment 1 distractor location indicated which of two stimuli was the target for the saccade. Saccade trajectories showed strong leftward curvature following right-side distractors and showed rightward curvature following left-side distractors. The largest effects on trajectories were observed for visual distractors, but significant curvature was observed with auditory and somatosensory distractors. In experiment 2 saccades were made following the onset of a visual target (reflexive) or following presentation of an arrow at fixation (voluntary), and task-irrelevant crossmodal distractors were presented simultaneously with target onset. Both voluntary and reflexive saccades were found to curve away from task-irrelevant visual distractors, but auditory and somatosensory distractors did not modulate saccade trajectories. In experiment 3 task-irrelevant distractors preceded the onset of the target by 100 ms. Reflexive saccades were found to curve away from visual, auditory and somatosensory distractors, but voluntary saccades curved away from visual distractors only. The modulation of saccade trajectories by distractors from different modalities is interpreted in terms of inhibitory processes operating in neural structures involved in saccade generation. Our findings suggest that visual, auditory and somatosensory distractors can all modulate saccade trajectories. Such effects could be related to the inhibition of populations of neurons, in a common motor map, for the selection of a saccade target.

Attention↗

PubMed1993

High-affinity self-reactive human antibodies by design and selection: targeting the integrin ligand binding site.

A strategy for the design and selection of human antibodies that bind receptors is described. We have demonstrated the validity of the approach by producing semi-synthetic human antibodies that bind integrins alpha v beta 3 and alpha IIb beta 3 with high affinity (10(-10) M). The selected antibodies mimic the integrins' natural ligands as demonstrated by their ability to compete with these ligands and Arg-Gly-Asp (RGD)-containing peptides for binding to the integrins. Furthermore, the antibodies bind in a cation-dependent fashion and are functional in cell adhesion assays. Antibodies that are high-affinity inhibitors of cell adhesion receptors should be of use in assessing receptor function and dissecting mechanisms of adhesion. Semisynthetic human antibodies that target integrins are potential therapeutic agents for the treatment of a number of diseases including thrombosis and metastasis. Furthermore, antibodies that are optimized to bind by a single complementarity determining region may be important lead compounds for the design of small molecule pharmaceuticals.

Amino Acid Sequence↗

PubMed1991

Anti-MY9-blocked-ricin: an immunotoxin for selective targeting of acute myeloid leukemia cells.

The use of immunotoxins (IT) to selectively destroy acute myeloid leukemia (AML) cells in vivo or in vitro is complicated by both the antigenic similarity of AML cells to normal progenitor cells and the difficulty of producing a sufficiently toxic conjugate. The monoclonal antibody (MoAb) anti-MY9 is potentially ideal for selective recognition of AML cells because it reacts with an antigen (CD33) found on clonogenic AML cells from greater than 80% of cases and does not react with normal pluripotent stem cells. In this study, we describe an immunotoxin that is selectively active against CD33+ AML cells: Anti-MY9-blocked-Ricin (Anti-MY9-bR), comprised of anti-MY9 conjugated to a modified whole ricin that has its nonspecific binding eliminated by chemical blockage of the galactose binding domains of the B-chain. A limiting dilution assay was used to measure elimination of HL-60 leukemic cells from a 20-fold excess of normal bone marrow cells. Depletion of CD33+ HL-60 cells was found to be dependent on the concentration of Anti-MY9-bR and on the duration of incubation with IT at 37 degrees C. More than 4 logs of these leukemic cells were specifically depleted following short exposure to high concentrations (10(-8) mol/L) of Anti-MY9-bR. Incubation with much lower concentrations of Anti-MY9-bR (10(-10) mol/L), as compatible with in vivo administration, resulted in 2 logs of depletion of HL-60 cells, but 48 to 72 hours of continuous exposure were required. Anti-MY9-bR was also shown to be toxic to primary AML cells, with depletion of greater than 2 logs of clonogenic cells following incubation with Anti-MY9-bR 10(-8) mol/L at 37 degrees C for 5 hours. Activity of Anti-MY9-bR could be blocked by unconjugated Anti-MY9 but not by galactose. As expected, Anti-MY9-bR was toxic to normal colony-forming unit granulocyte-monocyte (CFU-GM), which expresses CD33, in a concentration- and time-dependent manner, and also to burst-forming unit-erythroid and CFU-granulocyte, erythroid, monocyte, megakaryocyte, although to a lesser extent. When compared with anti-MY9 and complement (C'), Anti-MY9-bR could be used in conditions that provided more effective depletion of AML cells with substantially less depletion of normal CFU-GM. Therefore, Anti-MY9-bR may have clinical utility for in vitro purging of AML cells from autologous marrow when used at high IT concentrations for short incubation periods. Much lower concentrations of Anti-MY9-bR that can be maintained for longer periods may be useful for elimination of AML cells in vivo.

Acute Disease↗

PubMed2026

Cell type-selective targeting by heterobifunctional protein binders via in-cell enrichment.

Non-catalytic heterobifunctional protein binders promise to expand the range of therapeutic options by establishing complexes between key target proteins and accessory presenter proteins equipped with additional properties. Here, we systematically investigate the rational design of such molecules, explore the biochemical basis of complex formation and determine how they achieve cellular efficacy using the endogenously expressed immunophilin FKBP12 as presenter protein and the transcriptional regulator BRD4 as target protein. We present classes of bifunctional molecules that enable selective, FKBP12-dependent killing of specific cell types at subnanomolar concentrations and allow to differentiate between closely related bromodomains of the BET family. We propose that the strongly potentiated efficacy of these bifunctional compounds is based on cellular enrichment through binding to the highly abundant presenter protein FKBP12, a mechanism we term "CellTrap". Our findings substantiate the concept that highly expressed, non-essential proteins can be repurposed as selective recruiters to expand therapeutic windows of existing small-molecule inhibitors, opening new avenues for designing targeted drugs with improved cell-type specificity.

Tacrolimus Binding Protein 1A↗

PubMed2002

An ephrin mimetic peptide that selectively targets the EphA2 receptor.

Eph receptor tyrosine kinases represent promising disease targets because they are differentially expressed in pathologic versus normal tissues. The EphA2 receptor is up-regulated in transformed cells and tumor vasculature where it likely contributes to cancer pathogenesis. To exploit EphA2 as a therapeutic target, we used phage display to identify two related peptides that bind selectively to EphA2 with high affinity (submicromolar K(D) values). The peptides target the ligand-binding domain of EphA2 and compete with ephrin ligands for binding. Remarkably, one of the peptides has ephrin-like activity in that it stimulates EphA2 tyrosine phosphorylation and signaling. Furthermore, this peptide can deliver phage particles to endothelial and tumor cells expressing EphA2. In contrast, peptides corresponding to receptor-interacting portions of ephrin ligands bind weakly and promiscuously to many Eph receptors. Bioactive ephrin mimetic peptides could be used to selectively deliver agents to Eph receptor-expressing tissues and modify Eph signaling in therapies for cancer, pathological angiogenesis, and nerve regeneration.

Amino Acid Sequence↗

PubMed2006

HIV integration site selection: targeting in macrophages and the effects of different routes of viral entry.

We have studied the selection of HIV DNA integration sites in primary macrophages to investigate two questions. First, mature macrophages do not divide, allowing us to investigate whether HIV integration targeting differs between dividing cells and nondividing cells. We sequenced and analyzed 754 unique integration sites and found that integration in macrophages is favored in active transcription units (TUs), as was observed previously for other cell types. However, HIV integration in genes was slightly less favored in macrophages than in dividing PBMC or T cell lines. Second, we compared integration targeting by HIV-vector particles bearing either of two different envelope proteins (HIV R5 Env or VSV-G) to determine whether the mechanism of entry influenced subsequent integration targeting. Integration sites generated by HIV R5- or VSV-G-bearing particles showed no significant differences in their distributions in the human genome. Analysis of additional published integration site sequences also indicated that the route of entry did not affect integration site selection for other viral envelopes as well.

Base Sequence↗

PubMed1996

Saccade target selection and object recognition: evidence for a common attentional mechanism.

The spatial interaction of visual attention and saccadic eye movements was investigated in a dual-task paradigm that required a target-directed saccade in combination with a letter discrimination task. Subjects had to saccade to locations within horizontal letter strings left and right of a central fixation cross. The performance in discriminating between the symbols "E" and "E", presented tachistoscopically before the saccade within the surrounding distractors was taken as a measure of visual attention. The data show that visual discrimination is best when discrimination stimulus and saccade target refer to the same object; discrimination at neighboring items is close to chance level. Also, it is not possible, in spite of prior knowledge of discrimination target position, to direct attention to the discrimination target while saccading to a spatially close saccade target. The data strongly argue for an obligatory and selective coupling of saccade programming and visual attention to one common target object. The results favor a model in which a single attentional mechanism selects objects for perceptual processing and recognition, and also provides the information necessary for motor action.

Adult↗

PubMed1984

Oviposition by African malaria vector mosquitoes. II. Effects of site tone, water type and conspecific immatures on target selection by freshwater Anopheles gambiae Giles, sensu lato.

Females of Anopheles gambiae s. lat., most of which would have been A. gambiae s. str., were collected from houses in coastal Kenya and tested for their oviposition preferences using Petri dishes in large laboratory cages with lighting equivalent to weak moonlight. Significantly more eggs were laid overnight in water over black than over paler tones, and this difference increased as contrast with the surrounding floor was increased. Direct observation revealed that over white targets, females oviposited from a settled posture, whereas over black targets they did so from flight. The influence on this behaviour of target darkness (tone) overrode that of cage size or target size. In tests which yielded markedly fewer eggs in sea water than in tap water, no significant difference was detected when cage floors were either black or white, although a black floor might have resulted in significantly greater discrimination against sea water had more tests been conducted. All further testing was done over black cage floors. Turbid water from a natural development site received more eggs than distilled, tap or swamp water, even though the turbid water appeared paler than the others. The females did not discriminate between rearing water and tap water, or tap water with and without pupae, but the presence of larvae was repellent. Turbid water from a development site thus seemed to possess an arrestant property which overrode selection favouring darker targets, and which was not derived from prior presence of conspecific immatures. It is suggested that for A. gambiae, oviposition from a settled posture is a response to sub-optimal stimuli, possibly indicating conditions under which oviposition would not occur in nature, and hence why cage experiments using white targets have in the past yielded confusing results.

Africa↗

PubMedDate not supplied

L-nucleoside analogues as potential antimalarials that selectively target Plasmodium falciparum adenosine deaminase.

The L-stereoisomer analogues of D-coformycin selectively inhibited P. falciparum adenosine deaminase (ADA) in the picomolar range (L-isocoformycin, Ki 7 pM; L-coformycin, Ki 250 pM). While the L-nucleoside analogues, L-adenosine, 2,6-diamino-9-(L-ribofuranosyl)purine and 4-amino-1-(L-ribofuranosyl)pyrazolo[3,4-d]-pyrimidine were selectively deaminated by P. falciparum ADA, L-thioinosine and L-thioguanosine were not. This is the first example of 'non-physiological' L-nucleosides that serve as either substrates or inhibitors of malarial ADA and are not utilised by mammalian ADA.

Adenosine Deaminase Inhibitors↗

PubMed1990

Latex nanosphere delivery system (LNDS): novel nanometer-sized carriers of fluorescent dyes and active agents selectively target neuronal subpopulations via uptake and retrograde transport.

A wide range of latex particles are described which are capable of carrying high concentrations of fluorescent dyes, drugs, and photoactive agents selectively to subpopulations of neurons in vitro and in vivo. Particle size, charge, and concentration were all found to influence uptake into cultured neurons or retrograde transport in vivo. Chromophore loadings of greater than 14% (w/w) were obtained. Incorporation of a photoactivated dye (chlorin e6) into the polymer did not compromise the ability of the dye to produce singlet oxygen following light exposure. We refer to this unique family of latex particles as the latex nanosphere delivery system (LNDS). The LNDS will be usefull for studies of neuroanatomy and nervous system development, as well as more general areas of biomedical research where it is desirable to selectively label subpopulations of cells. The LNDS also offers a means of providing targeted delivery of drugs or photoactive agents to selected subpopulations of cells; this will allow experimentation not currently possible using any existent methodology.

Animals↗

PubMed1990

Phototoxic liposomes coupled to an antibody that alone cannot modulate its cell-surface antigen kill selected target cells.

Molecules such as antibodies that bind to cell surfaces can be used to deliver cytotoxic drugs to selected cells. To be effective the drug must usually be taken into the cells by endocytosis. In this study a T-cell line (CCRF-CEM) was effectively killed by liposomes carrying a photosensitizer and bearing the antibody OKT4 (anti-CD4). The unconjugated antibody does not induce antigenic modulation in the target cells, an indication of the absence of endocytosis, and would therefore not normally have been selected as an agent for drug delivery. It cannot, however, be concluded with certainty that the conjugates act at the cell surface and several alternative explanations of their efficacy are offered.

Animals↗

PubMed2005

Epidermal growth factor-induced signaling in breast cancer cells results in selective target gene activation by orphan nuclear receptor estrogen-related receptor alpha.

The orphan nuclear hormone receptor estrogen-related receptor alpha (ERRalpha, NR3B1) is a constitutive transcription factor that is structurally and functionally related to the classic estrogen receptors. ERRalpha can recognize both the estrogen response element and its own binding site (ERRE) in either dimeric or monomeric forms. ERRalpha is also a phosphoprotein whose expression in human breast tumors correlates with that of the receptor tyrosine kinase ErbB2, suggesting that its transcriptional activity could be regulated by signaling cascades. Here, we investigated growth factor regulation of ERRalpha function and found that it is phosphorylated in MCF-7 breast cancer cells in response to epidermal growth factor (EGF), an event that enhances its DNA binding. Interestingly, treatment with alkaline phosphatase shifts ERRalpha from a dimeric to a monomeric DNA-binding factor, and only the dimeric form interacts with the coactivator PGC-1alpha. In vitro, the DNA-binding domain of ERRalpha is selectively phosphorylated by protein kinase Cdelta (PKCdelta), which increases its DNA-binding activity, whereas expression of constitutively active PKCdelta enhances TFF1 promoter activity via the ERRE. However, whereas treatment of MCF-7 cells with the phorbol ester phorbol-12-myristate 13-acetate also enhances ERRalpha activation of the TFF1 promoter reporter, it does not affect ERRalpha activity on its own promoter. In agreement, chromatin immunoprecipitation analysis shows that ERRalpha and RNA polymerase II are preferentially recruited to the TFF1 promoter after EGF treatment, whereas recruitment of these factors to its own promoter is not affected. These results reveal a mechanism through which growth factor signaling can selectively activate ERRalpha target genes in breast cancer cells.

Animals↗

PubMed1994

CT target selection in stereotactic anterior capsulotomy: anatomical considerations.

The first communications concerning stereotactic bilateral anterior capsulotomies were reported by Talairach and Leksell. This procedure has become established for the management of otherwise intractable anxiety neuroses and obsessive compulsive disorders, with a reported success rate of 70% in different series. It has been stressed that results are closely related to the extent of the lesion. The desirable lesion has a tubular shape with a length of 15-18 mm in the coronal axis. This shape is achieved by step withdrawal of a 4- to 5-mm electrode tip along a proper trajectory. A precise angulation of the trajectory is crucial to proceed without lesioning of the adjacent bordering caudate nucleus or putamen in the coronal plane. In the sagittal plane, it has to remain within the limits of the anterior capsula interna and avoid an excessive posteroanterior obliquity to ensure that the entry point through the cortex remains in the prefrontal noneloquent area. To achieve this trajectory, a target 5 mm posterior to the anterior border of the frontal horn, as seen on CT, at the level of the foramen of Monro has been suggested, along with a precoronal burr hole placed 20 degrees from the midline. Following these guidelines we have found the resulting lesions to be excessively anterior, with exclusion of their first 4- to 5-mm deep component. If the same target point is selected at two different axial levels to fix a trajectory, it usually results in an anteriorward trajectory that might require an entry point too close to the motor cortex, because the anterior horn reaches more rostrally as it deepens.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain Mapping↗

PubMed2005

Global changes in STAT target selection and transcription regulation upon interferon treatments.

The STAT (signal transducer and activator of transcription) proteins play a crucial role in the regulation of gene expression, but their targets and the manner in which they select them remain largely unknown. Using chromatin immunoprecipitation and DNA microarray analysis (ChIP-chip), we have identified the regions of human chromosome 22 bound by STAT1 and STAT2 in interferon-treated cells. Analysis of the genomic loci proximal to these binding sites introduced new candidate STAT1 and STAT2 target genes, several of which are affiliated with proliferation and apoptosis. The genes on chromosome 22 that exhibited interferon-induced up- or down-regulated expression were determined and correlated with the STAT-binding site information, revealing the potential regulatory effects of STAT1 and STAT2 on their target genes. Importantly, the comparison of STAT1-binding sites upon interferon (IFN)-gamma and IFN-alpha treatments revealed dramatic changes in binding locations between the two treatments. The IFN-alpha induction revealed nonconserved STAT1 occupancy at IFN-gamma-induced sites, as well as novel sites of STAT1 binding not evident in IFN-gamma-treated cells. Many of these correlated with binding by STAT2, but others were STAT2 independent, suggesting that multiple mechanisms direct STAT1 binding to its targets under different activation conditions. Overall, our results reveal a wealth of new information regarding IFN/STAT-binding targets and also fundamental insights into mechanisms of regulation of gene expression in different cell states.

Antineoplastic Agents↗