👤 Asa Tirosh

The association between autoimmune diseases and type 1 diabetes (T1D) is mostly based on studies among people with T1D at baseline. We assessed the risk of incident T1D among adolescents with other autoimmune diseases. Included were all Israeli adolescents without a history of dysglycemia, aged 16-19 years, undergoing medical evaluation before mandatory military service between January 1996 and December 2016. Data were linked with information on adult-onset T1D from the Israeli National Diabetes Registry. The cohort was dichotomized by the presence of any autoimmune disease. Cox proportional hazards modeling was applied. A total of 1,426,362 people were included, of whom 38,766 (2.7%) had a history of autoimmunity at study entry (10,333 with autoimmune thyroid disease [AITD] and 9,603 with celiac disease). Over 15,810,751 person-years of follow-up, there were 37 and 740 incident cases of T1D among people with and without autoimmunity, respectively, and a crude incident rate of 9.6 and 4.8 cases per 105 person-years, respectively. In a multivariable model adjusted for sex, birth year, and sociodemographic variables, the hazard ratio (HR) for incident T1D among people with autoimmunity was 2.19 (95% CI 1.57-3.04) versus those without. Results persisted when islet autoantibody data were used as mandatory criteria for T1D case definition (HR 2.22, 95% CI 1.13-4.35). The HRs among people with AITD and celiac disease were 3.99 (2.5-6.4) and 2.82 (1.46-5.45), respectively. Autoimmune diseases in late adolescence were associated with an increased risk of T1D in adulthood in both sexes, especially among those with AITD and celiac disease. Show less

Proper protein targeting to organelles is crucial for maintaining eukaryotic cellular function and homeostasis. This necessity has driven the evolution of specific targeting signals on proteins and the targeting factors that recognize them. A prominent example is peroxisomal matrix proteins, most of which depend on the targeting factor Pex5 to localize and function correctly. Although most Pex5 cargoes contain a peroxisomal targeting signal type 1 (PTS1), they are not all targeted similarly. Some undergo priority targeting, facilitated either by stronger binding to specific subsets of PTS1 signals or by additional interaction interfaces. These observations highlight the extensive complexity of Pex5-mediated targeting. In this study, we reveal that the Saccharomyces cerevisiae (yeast) matrix protein Eci1 can reach peroxisomes and bind Pex5 in the absence of PTS1. By solving the structure of the yeast Pex5-Eci1 complex using cryo-electron microscopy, we identified additional binding interfaces. Our findings provide new insights into the versatile interactions between Pex5 and its cargo, Eci1. More broadly, this work highlights the intricate, dynamic nature of the interactions between cargo factors and their cargoes to meet the complex environment within eukaryotic cells. Show less

Acid-β-glucosidase (GCase, EC3.2.1.45), the lysosomal enzyme which hydrolyzes the simple glycosphingolipid, glucosylceramide (GlcCer), is encoded by the GBA1 gene. Biallelic mutations in GBA1 cause the human inherited metabolic disorder, Gaucher disease (GD), in which GlcCer accumulates, while heterozygous GBA1 mutations are the highest genetic risk factor for Parkinson's disease (PD). Recombinant GCase (e.g., Cerezyme Show less