A New Type of Metal Recognition by Human T Cells: Contact Residues for Peptide-independent Bridging of T Cell Receptor and Major Histocompatibility Complex by Nickel

In spite of high frequencies of metal allergies, the structural basis for major histocompatibility complex (MHC)-restricted metal recognition is among the unanswered questions in the field of T cell activation. For the human T cell clone SE9, we have identified potential Ni contact sites in the T cell receptor (TCR) and the restricting human histocompatibility leukocyte antigen (HLA)-DR structure. The specificity of this HLA-DR–promiscuous VA22/VB17+ TCR is primarily harbored in its α chain. Ni reactivity is neither dependent on protein processing in antigen-presenting cells nor affected by the nature of HLA-DR–associated peptides. However, SE9 activation by Ni crucially depends on Tyr29 in CDR1α, an N-nucleotide–encoded Tyr94 in CDR3α, and a conserved His81 in the HLA-DR β chain. These data indicate that labile, nonactivating complexes between the SE9 TCR and most HLA-DR/peptide conjugates might supply sterically optimized coordination sites for Ni ions, three of which were identified in this study. In such complexes Ni may effectively bridge the TCR α chain to His81 of most DR molecules. Thus, in analogy to superantigens, Ni may directly link TCR and MHC in a peptide-independent manner. However, unlike superantigens, Ni requires idiotypic, i.e., CDR3α-determined TCR amino acids. This new type of TCR–MHC linkage might explain the high frequency of Ni-reactive T cells in the human population

Технологическая подготовка производства изготовления детали "Вал выходящий" на станках с ЧПУ

В результате работы был проведен конструкторский анализ детали, разработан технологический процесс, выбрано оборудование для производства детали, составлены управляющие программы для станков с ЧПУ и разработаны карты наладки к ним. Рассчитаны припуски и допуски на технологические размеры,режимы резания и нормы времени. Предложены пути решения вопроса об экологической безопасности. Рассчитана экономическая эффективность.As a result of the work, a design analysis of the part was carried out, a technological process was developed, equipment for the production of parts was selected, control programs for CNC machine tools were compiled, and adjustment maps were developed for them. The allowances and tolerances for technological dimensions, cutting modes and time norms are calculated. Suggested ways to address the issue of environmental safety. Economic efficiency has been calculated

First report of a partial trisomy 3q12-q23 de novo—FISH breakpoint determination and phenotypic characterization

We present a 1-year-old boy with mild mental retardation, postnatal growth retardation, and facial dysmorphisms such as frontal bossing, laterally accentuated bushy eyebrows, deep set eyes with long lashes, hypertelorism, and a broad nasal bridge. Except for hip dysplasia, no congenital malformations were detected. By conventional cytogenetics a derivative chromosome 3 de novo was diagnosed which was identified as tandem dup(3)(q12q23) by fluorescence in situ hybridization (FISH) applying arm specific paints and eight different YAC-probes. The duplicated segment lies proximally from the reported dup(3q) syndrome critical region, thus explaining the absence of characteristic phenotypic features of dup(3q) syndrome. To our knowledge this is the first report of a patient with pure trisomy of this proximal region of the long arm of chromosome 3

Genetic alterations in human papillomavirus-associated oropharyngeal squamous cell carcinoma of patients with treatment failure

Objectives: Despite improved survival rates of patients with HPV-associated OPSCC, a subset has distant metastasis or develops local recurrence during follow-up. To investigate potential underlying genetic alterations, we analyzed patients with HPV-driven OPSCC who suffered from recurrence in comparison to matching pairs with successful tumor control. Materials and methods: We performed chromosomal copy number analyses and targeted next generation sequencing using a custom panel comprising genes that are frequently mutated in HPV-associated OPSCC. Results: Specific differences regarding chromosomal aberrations were not observed between both groups. In HPV-driven OPSCC from patients with recurrence we found higher mutation rates compared to patients with successful tumor control. Especially mutation rates of HRAS (p <= 0.05) PIK3R1, STK11 and TP63 (p <= 0.1 each) were statistically significant or trending towards significance. The respective genes can be linked to transcription factors and signaling pathways involved in cell cycle regulation, proliferation and survival. Additionally, combinations of alterations were observed on chromosomes 16 and 19, which might also influence outcome. Conclusion: Patients with HPV-driven OPSCC who develop recurrence or have metastasis may be defined by genetic alterations that might be responsible for poor outcome after standard therapy. This might be of importance for stratification in future de-escalation and targeted therapy