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1.
Slit proteins steer the migration of many cell types through their binding to Robo receptors, but how Robo controls cell motility is not clear. We describe the functional analysis of vilse, a Drosophila gene required for Robo repulsion in epithelial cells and axons. Vilse defines a conserved family of RhoGAPs (Rho GTPase-activating proteins), with representatives in flies and vertebrates. The phenotypes of vilse mutants resemble the tracheal and axonal phenotypes of Slit and Robo mutants at the CNS midline. Dosage-sensitive genetic interactions between vilse, slit, and robo mutants suggest that vilse is a component of robo signaling. Moreover, overexpression of Vilse in the trachea of robo mutants ameliorates the phenotypes of robo, indicating that Vilse acts downstream of Robo to mediate midline repulsion. Vilse and its human homolog bind directly to the intracellular domains of the corresponding Robo receptors and promote the hydrolysis of RacGTP and, less efficiently, of Cdc42GTP. These results together with genetic interaction experiments with robo, vilse, and rac mutants suggest a mechanism whereby Robo repulsion is mediated by the localized inactivation of Rac through Vilse.  相似文献   
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Cell culture-based transdominant genetic techniques provide new methods for discovering peptide/RNA modulators of cellular pathways. We applied this technology to isolate a peptide inhibitor of human rhinovirus. A green fluorescent protein (GFP)-scaffolded library of cDNA fragments was expressed in HeLa cells from a retroviral vector and screened for inhibitors of rhinovirus-mediated cell killing. A DNA clone, I421, increased cell survival in an HRV14 challenge assay from less than 0.5% to greater than 60%. It encodes a 53-amino-acid C-terminal extension of the GFP scaffold. Particular subclones of Hela cells expressing I421 (exemplified by I421dp3) show a delay in virus production and a 50-fold decrease in viral RNA levels at 6-8 h postinfection. HRV2, HRV14, and HRV16 show a dramatic decrease in plaque-forming ability on I421dp3 while Coxsackievirus B3 showed a small reduction. Levels of ICAM-1, the receptor for the main rhinovirus serotype, are not altered in I421dp3.  相似文献   
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Introduction: Interpretation of results from mutation screening of tumour suppressor genes known to harbour high risk susceptibility mutations, such as APC, BRCA1, BRCA2, MLH1, MSH2, TP53, and PTEN, is becoming an increasingly important part of clinical practice. Interpretation of truncating mutations, gene rearrangements, and obvious splice junction mutations, is generally straightforward. However, classification of missense variants often presents a difficult problem. From a series of 20 000 full sequence tests of BRCA1 carried out at Myriad Genetic Laboratories, a total of 314 different missense changes and eight in-frame deletions were observed. Before this study, only 21 of these missense changes were classified as deleterious or suspected deleterious and 14 as neutral or of little clinical significance. Methods: We have used a combination of a multiple sequence alignment of orthologous BRCA1 sequences and a measure of the chemical difference between the amino acids present at individual residues in the sequence alignment to classify missense variants and in-frame deletions detected during mutation screening of BRCA1. Results: In the present analysis we were able to classify an additional 50 missense variants and two in-frame deletions as probably deleterious and 92 missense variants as probably neutral. Thus we have tentatively classified about 50% of the unclassified missense variants observed during clinical testing of BRCA1. Discussion: An internal test of the analysis is consistent with our classification of the variants designated probably deleterious; however, we must stress that this classification is tentative and does not have sufficient independent confirmation to serve as a clinically applicable stand alone method.  相似文献   
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BACKGROUND: Detailed assessment of antibody responses to allergens reveals clinically relevant information about both host response and antigen structure. Microarray technology offers advantages of scale and parallel design over previous methods of epitope mapping. OBJECTIVE: We designed a redundant peptide microarray for IgE and IgG4 epitope mapping of the previously characterized peanut allergen, Ara h 2. METHODS: Six complete sets of overlapping peptides were commercially synthesized and site-specifically bound to epoxy-derivatized glass slides in triplicate. Peptides were 10, 15, or 20 amino acids in length with an offset of either 2 or 3 amino acids. A total of 10 control and 45 peanut-allergic sera were assayed. Specific IgE and IgG4 were detected by using fluorochrome-labeled monoclonal secondary antibodies. RESULTS: By using 15-mer and 20-mer peptides, we could define 11 antigenic regions, whereas only 5 were identifiable using 10-mers. Controls and patients produced IgG4 recognizing a comparable number of Ara h 2 peptides, although the dominant epitopes were distinct. As expected, patient IgE bound a larger number of Ara h 2 peptides (9.4% vs 0.9%). IgE and IgG4 epitopes recognized by patients were largely the same, and there was a positive association between IgE and IgG(4) signal, suggesting coordinate regulation. Cluster analysis of peptide binding patterns confirmed the specificity of antibody-peptide interactions and was used to define 9 core epitopes ranging from 6 to 16 residues in length-7 of which (78%) agreed with previous mapping. CONCLUSION: Epitope mapping by microarray peptide immunoassay and cluster analysis reveals interpatient heterogeneity and a more detailed map.  相似文献   
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This study analyzed serum thyroglobulin (Tg) during hypothyroidism in 207 patients with differentiated thyroid carcinoma treated with total thyroidectomy and radioiodine ablation and undetectable anti-Tg antibodies. Disease staging was defined by clinical examination, stimulated Tg, pre- and post-ablative radioiodine scanning, and other imaging methods (X-Ray, US, CT and MIBI-scan). The average interval from initial therapy was 2.3 years. 153 patients (74%) had no evident disease, 34 (16.4%) presented neck/mediastinal disease, and 20 (9.6%) had distant metastases (Mt). The best cut-off for Tg was 1 ng/ml, showing 100% sensitivity for distant Mt and 88.2% for local recurrence or lymph node Mt, and 88.8% specificity for any Mt and 74.8% for distant Mt. In patients with Tg <1 ng/ml, 2.8% showed cervical lymph nodes Mt. Cervical or mediastinal disease were 26% of cases with Tg between 1 and 5 ng/ml. Tg from 5 to 10 ng/ml was associated to distant Mt in 14.2% of the cases and others showed lymph nodes Mt. In patients with Tg >10 ng/ml, 51.3% presented distant Mt. We suggest the need for neck US even in cases with Tg <1 ng/ml. In addition, patients with Tg levels <5 ng/ml should be investigated by neck US and mediastinal CT only, and empirical therapy should be limited to patients with a minimum Tg level >5 ng/ml.  相似文献   
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Purpose

Patients undergoing hemodialysis (HD) present persistent inflammation and protein-energy wasting (PEW), which contributes to high rates of mortality. This study aimed to assess the effects of a resistance exercise training program (RETP) on inflammation and PEW in HD patients.

Methods

Thirty-seven patients (56.7 % men, 45.9 ± 14.1 years, 23.5 ± 3.9 kg/m2) performed 6 months of intradialytic RETP. Plasma adhesion molecules levels (ICAM-1 and VCAM-1) were measured using the enzyme immunometric assay, and interleukin-6 (IL-6), C-reactive protein, and tumor necrosis factor-alpha by ELISA. Anthropometric, physical capacity, and PEW (simultaneously presence of: BMI <23 kg/m2, serum albumin <3.8 g/dL, and reduced arm muscle area) were analyzed.

Results

There was a reduction of ICAM-1 [(1,934.1 pg/mL (1,031.8–2,875.0) vs. 1,571.1 pg/mL (447.1–2,985.5), p < 0.05], VCAM-1 [5,259.51 pg/mL (3,967.4–6,682.4) vs. 3,062.11 pg/mL (2,034.0–5,034.4), p < 0.05], and CRP levels (2.3 ± 0.9 to 1.6 ± 0.6 pg/mL, p < 0.001) after 6 months of RETP. Body composition improved, albumin increased (3.7 ± 0.3 to 3.9 ± 0.2, p < 0.05), and the number of patients presenting PEW was decreased (p = 0.005).

Conclusions

Resistance exercise program for 6 months seems to be effective in reducing inflammation and PEW of HD patients. The universal trial number of this study is U1111-1139-1326.  相似文献   
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Transthoracic parametric Doppler (TPD), unlike conventional ultrasonography, measures signals originating from movements of pulmonary blood vessel walls. In this pilot study, we tested TPD in 15 patients diagnosed with pulmonary embolism on computed tomography pulmonary angiography. Results were mapped to the upper, middle, and lower thirds of the right lung. In the lower third, TPD yielded 100% specificity and positive predictive value for acute pulmonary embolism. If validated in a larger series, this rapid bedside technique might obviate the need for computed tomography in specific cases. This could be advantageous in patients who are unstable, in intensive care, or have allergies to iodinated contrast material.  相似文献   
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