Case report : De novo pathogenic variant in WFS1 causes Wolfram-like syndrome debuting with congenital bilateral deafness

Background: Congenital deafness could be the first manifestation of a syndrome such as in Usher, Pendred, and Wolfram syndromes. Therefore, a genetic study is crucial in this deficiency to significantly improve its diagnostic efficiency, to predict the prognosis, to select the most adequate treatment required, and to anticipate the development of other associated clinical manifestations. Case presentation: We describe a young girl with bilateral congenital profound deafness, who initially received a single cochlear implant. The genetic study of her DNA using a custom-designed next-generation sequencing (NGS) panel detected a de novo pathogenic heterozygous variant in the WFS1 gene related to Wolfram-like syndrome, which is characterized by the presence of other symptoms such as optic atrophy. Due to this diagnosis, a second implant was placed after the optic atrophy onset. The speech audiometric results obtained with both implants indicate that this work successfully allows the patient to develop normal speech. Deterioration of the auditory nerves has not been observed. Conclusion: The next-generation sequencing technique allows a precise molecular diagnosis of diseases with high genetic heterogeneity, such as hereditary deafness, while this was the only symptom presented by the patient at the time of analysis. The NGS panel, in which genes responsible for both syndromic and non-syndromic hereditary deafness were included, was essential to reach the diagnosis in such a young patient. Early detection of the pathogenic variant in the WFS1 gene allowed us to anticipate the natural evolution of the disease and offer the most appropriate management to the patient

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Poly(n-alkylsilsesquioxane)s: Synthesis, Characterization, and Modification with Poly(dimethylsiloxane)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Self-supported translucent films constituted of poly(n-octylsilsesquioxane) or poly(n-dodecylsilsesquioxane) were obtained from the hydrolysis and condensation of n-octyltriethoxysilane (OTES) or n-dodecyltriethoxysi lane (DTES), respectively. Dense films were obtained in the absence of organic solvents, with dibutyltin diacetate as catalyst. These films exhibited good optical transparency and thermal stability. The incorporation of oligomeric dimethylsiloxane units (D(Me,Me)) in these materials, derived from silanol-terminated poly(dimethylsiloxane) (PDMS) or 1,1,3,3-tetramethyl-1,3-diethoxydisiloxane (TMDES), was carried out during the hydrolysis and condensation of OTES and DTES and was confirmed by solid-state (29)Si NMR. Poly(n-octylsilsesquioxane) showed a glass-transition temperature at -65 degrees C, due to the increase in the free volume, promoted by the bulky n-octyl groups. The differential scanning calorimetric (DSC) curves of the polymer derived from DTES were characterized by first-order transitions at temperatures ranging from -15.8 to -0.7 degrees C. Further studies of these networks by low-temperature XRD evidenced narrowing of the diffraction halos suggesting a partial order-disorder transition for these materials at lower temperatures. Good thermal stability up to 350 degrees C and the solvent-free production process make these polymers potential candidates for the development of self-supported hydrophobic protective coatings. (C) 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 1220-1229, 201048512201229Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP [03/09, 962-1]CNPq [305916/2006-8

Poly(dimethylsiloxane) networks modified with poly (phenylsilsesquioxane)s: Synthesis, structural characterisation and evaluation of the thermal stability and gas permeability

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Self-supported translucent films constituted of semi-inorganic polymeric materials were prepared by sol-gel process from poly(phenylsilsesquioxane) (PPSQ) and poly(dimethylsiloxane) (PDMS), modified by diphenylsilanediol (DPS), phenyltriethoxysilane (PTES) and/or tetraethoxysilane (TEOS). These materials were characterized by infrared spectroscopy (FTIR), X-ray diffraction (XRD) and thermo-gravimetric analysis (TGA). Permeability to N-2, O-2, CH4 and CO2 and selectivity for a specific gas pair were investigated using the time-lag method. In the gas separation process high permeability and selectivity coefficients were observed, particularly for the membrane containing DPS and PTES as additives, which presented potential applications in the separation of CO2/CH4 and CO2/N-2. The materials also showed good thermal stability, which could be correlated to the relative amounts between di-functional (D), tri-functional (T) and tetra-functional (Q) silicon units. (c) 2008 Elsevier Ltd. All rights reserved.441030803086Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP [03/09962-1]CNPq [305916/2006-8

Effect of filler functionalization on thermo-mechanical properties of polyamide-12/carbon nanofibers composites: a study of filler-matrix molecular interactions

The effect of carbon nanofiber (CNF) functionalization on the thermo-mechanical properties of polyamide-12/CNF nanocomposites was investigated. Three main different surface treatments were performed to obtain CNF-OH (OH rich), CNF-Silane (C6H5Si-O-), and CNF-peroxide. CNF modified with poly-(tert-butyl acrylate) chains grown from the surface via ATRP (atom transfer radical polymerization) were also prepared and tested. The modified CNFs and neat CNFs were used as fillers in polyamide-12 nanocomposites and the properties of the ensuing materials were characterized and compared. Universal tensile tests demonstrated a substantial increase (up to 20 %) of the yield strength, without reduction of the final elongation, for all functionalized samples tested within 1 wt% filler content. Further evidences of mechanical properties improvement were given by dynamic mechanical thermal analyses. CNFs functionalized with poly-(tert-butyl acrylate) and silane exhibited the best performance with stiffening and strengthening at low (a parts per thousand currency sign1 wt%) filler loadings, via a partial decrease of the intensity of beta-transitions attributed to favorable interactions between the functional groups on the surface of functionalized CNFs and polyamide-12. CNFs treated with peroxide proved to be the most simple preparation technique and the ensuing nanocomposites exhibited the highest storage modulus at high (5 wt%) filler content. Theoretical simulations using the micro-mechanics model were used to predict the Young modulus of the composites and compare them with experimental data. The results obtained suggest a synergistic effect between the matrix and the filler enhanced by surface functionalization