Functional Genetic Variants in DC-SIGNR Are Associated with Mother-to-Child Transmission of HIV-1

BACKGROUND: Mother-to-child transmission (MTCT) is the main cause of HIV-1 infection in children worldwide. Given that the C-type lectin receptor, dendritic cell-specific ICAM-grabbing non-integrin-related (DC-SIGNR, also known as CD209L or liver/lymph node-specific ICAM-grabbing non-integrin (L-SIGN)), can interact with pathogens including HIV-1 and is expressed at the maternal-fetal interface, we hypothesized that it could influence MTCT of HIV-1. METHODS AND FINDINGS: To investigate the potential role of DC-SIGNR in MTCT of HIV-1, we carried out a genetic association study of DC-SIGNR in a well-characterized cohort of 197 HIV-infected mothers and their infants recruited in Harare, Zimbabwe. Infants harbouring two copies of DC-SIGNR H1 and/or H3 haplotypes (H1-H1, H1-H3, H3-H3) had a 3.6-fold increased risk of in utero (IU) (P = 0.013) HIV-1 infection and a 5.7-fold increased risk of intrapartum (IP) (P = 0.025) HIV-1 infection after adjusting for a number of maternal factors. The implicated H1 and H3 haplotypes share two single nucleotide polymorphisms (SNPs) in promoter region (p-198A) and intron 2 (int2-180A) that were associated with increased risk of both IU (P = 0.045 and P = 0.003, respectively) and IP (P = 0.025, for int2-180A) HIV-1 infection. The promoter variant reduced transcriptional activity in vitro. In homozygous H1 infants bearing both the p-198A and int2-180A mutations, we observed a 4-fold decrease in the level of placental DC-SIGNR transcripts, disproportionately affecting the expression of membrane-bound isoforms compared to infant noncarriers (P = 0.011). CONCLUSION: These results suggest that DC-SIGNR plays a crucial role in MTCT of HIV-1 and that impaired placental DC-SIGNR expression increases risk of transmission

Defects in tRNA Modification Associated with Neurological and Developmental Dysfunctions in Caenorhabditis elegans Elongator Mutants

Elongator is a six subunit protein complex, conserved from yeast to humans. Mutations in the human Elongator homologue, hELP1, are associated with the neurological disease familial dysautonomia. However, how Elongator functions in metazoans, and how the human mutations affect neural functions is incompletely understood. Here we show that in Caenorhabditis elegans, ELPC-1 and ELPC-3, components of the Elongator complex, are required for the formation of the 5-carbamoylmethyl and 5-methylcarboxymethyl side chains of wobble uridines in tRNA. The lack of these modifications leads to defects in translation in C. elegans. ELPC-1::GFP and ELPC-3::GFP reporters are strongly expressed in a subset of chemosensory neurons required for salt chemotaxis learning. elpc-1 or elpc-3 gene inactivation causes a defect in this process, associated with a posttranscriptional reduction of neuropeptide and a decreased accumulation of acetylcholine in the synaptic cleft. elpc-1 and elpc-3 mutations are synthetic lethal together with those in tuc-1, which is required for thiolation of tRNAs having the 5′methylcarboxymethyl side chain. elpc-1; tuc-1 and elpc-3; tuc-1 double mutants display developmental defects. Our results suggest that, by its effect on tRNA modification, Elongator promotes both neural function and development

Spectrophotometric evaluation of the optical influence of different metal alloys and porcelains in the metal-ceramic complex

Statement of the problem. Color matching between natural teeth, shade guides, and metal-ceramic restorations is a common clinical problem. Difficulties related to color matching arise from structural differences that exist between metal-ceramic crowns and natural teeth, the limited range of available ceramic shades, inadequate shade guides, different types of metal alloys, and varying compositions of ceramic materials. Purpose. The aim of this Study was to investigate the influence of various metal alloys and 2 porcelains on the final color of metal-ceramic complex. Material and methods. Four commercial alloys for metal-ceramic restorations, a Ni-Cr (Thermobond), a Co-Cr (Wirobond), a Pd-rich noble (Cerapal-2), and a high noble Au-alloy (V-Delta) were combined with 2 porcelains (Vita Omega and Ceramco Silver) in metal-ceramic specimens with a standardized thickness of layers. Five disc-shaped (10 x 1 mm) specimens were prepared for each alloy/porcelain combination. Only opaque and dentin layers were applied (shade A3). The specimens were analyzed with a spectrophotometer, and data were obtained in the CIE Lab color system. The recorded data were analyzed with a 2-way multiple analysis of variance, a pair-wise comparison of group means (Student’s t test), and finally, a categorical regression analysis of variance (CATREG) (alpha = .01). Results. The types of alloy substrate and overlying porcelain significantly affected the color (P < .01). Au and Co-Cr alloys were found to be brighter (higher L* values) than the Ni-Cr and the Pd alloys (P < .01, SE 0.239). Cerainco porcelain was found to be most red (higher a* values) of all tested alloys (P < .01). Gold and Pd alloys caused a yellow shift to the metal-ceramic color compared to the Ni-Cr and the Co-Cr alloys with both porcelains (P < .01, SE 0.165). The detected color differences were visually perceptible for some alloy-porcclain combinations. Conclusions. The final color of metal ceramic specimens was influenced both from the type of alloy substructure and from the type of overlying porcelain