Children with Type 1 Diabetes of Early Age at Onset - Immune and Metabolic Phenotypes

Objectives We aimed to evaluate children with type 1 diabetes (T1D) with early age at onset (EAO) for clinical, immune and metabolic features in order to identify age-related disease phenotypes. Methods Comparative study of two groups of T1D children: EAO (≤5 years) and later age at onset (LAO; >5 years), regarding the presence of other autoimmune (AI) diseases, diabetes ketoacidosis and immunologic profile at onset and metabolic data 1 year after diagnosis. Statistical analysis was performed with significance set for p < 0.05. Results The study included 137 children (EAO = 52, mean age 3.6 ± 1.5 [mean ± standard deviation (SD)] and LAO = 85, mean age 10.4 ± 2.9). EAO was more associated with concomitant AI diseases (p = 0.032). Despite no differences in disease onset, EAO presented with lower C-peptide levels (p = 0.01) and higher absolute lymphocyte number (p < 0.0001), with an inverse correlation between these two variables (p = 0.028). Additionally, the EAO group had a higher frequency of serum detection of three antibodies (Abs) (p = 0.0008), specifically insulin Abs (p = 0.0001). One year after diagnosis, EAO had higher total daily insulin (TDI) dose (p = 0.008), despite similar hemoglobin A1c (HbA1c). Conclusions Our data show an association of EAO T1D with more AI diseases, higher number of Abs, lower initial insulin reservoir and higher insulin requirements 1 year after diagnosis. In this group, immune imbalance seems more evident and disease progression faster, probably reflecting distinct "immune environment" with different ages at disease onset. Further studies in the field of immunogenetics and immune tolerance are required, to improve patient stratification and find novel targets for therapeutic intervention.info:eu-repo/semantics/publishedVersio

Otimização de cascas reforçadas assegurando fiabilidade de nível I e II = Level I and II reliability-based optimum design of stiffened shells

Sign.: a-e>8886<Apostillas marginales en latínPort. a dos tinta

E-Cadherin Destabilization Accounts for the Pathogenicity of Missense Mutations in Hereditary Diffuse Gastric Cancer

E-cadherin is critical for the maintenance of tissue architecture due to its role in cell-cell adhesion. E-cadherin mutations are the genetic cause of Hereditary Diffuse Gastric Cancer (HDGC) and missense mutations represent a clinical burden, due to the uncertainty of their pathogenic role. In vitro and in vivo, most mutations lead to loss-of-function, although the causal factor is unknown for the majority. We hypothesized that destabilization could account for the pathogenicity of E-cadherin missense mutations in HDGC, and tested our hypothesis using in silico and in vitro tools. FoldX algorithm was used to calculate the impact of each mutation in E-cadherin native-state stability, and the analysis was complemented with evolutionary conservation, by SIFT. Interestingly, HDGC patients harbouring germline E-cadherin destabilizing mutants present a younger age at diagnosis or death, suggesting that the loss of native-state stability of E-cadherin accounts for the disease phenotype. To elucidate the biological relevance of E-cadherin destabilization in HDGC, we investigated a group of newly identified HDGC-associated mutations (E185V, S232C and L583R), of which L583R is predicted to be destabilizing. We show that this mutation is not functional in vitro, exhibits shorter half-life and is unable to mature, due to premature proteasome-dependent degradation, a phenotype reverted by stabilization with the artificial mutation L583I (structurally tolerated). Herein we report E-cadherin structural models suitable to predict the impact of the majority of cancer-associated missense mutations and we show that E-cadherin destabilization leads to loss-of-function in vitro and increased pathogenicity in vivo

Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences

The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemésio 2007; Donegan 2008, 2009; Nemésio 2009a–b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016