Lysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization

Differentiation is critical for cell fate decisions, but the signals involved remain unclear. The kidney proximal tubule (PT) cells reabsorb disulphide-rich proteins through endocytosis, generating cystine via lysosomal proteolysis. Here we report that defective cystine mobilization from lysosomes through cystinosin (CTNS), which is mutated in cystinosis, diverts PT cells towards growth and proliferation, disrupting their functions. Mechanistically, cystine storage stimulates Ragulator-Rag GTPase-dependent recruitment of mechanistic target of rapamycin complex 1 (mTORC1) and its constitutive activation. Re-introduction of CTNS restores nutrient-dependent regulation of mTORC1 in knockout cells, whereas cell-permeant analogues of L-cystine, accumulating within lysosomes, render wild-type cells resistant to nutrient withdrawal. Therapeutic mTORC1 inhibition corrects lysosome and differentiation downstream of cystine storage, and phenotypes in preclinical models of cystinosis. Thus, cystine serves as a lysosomal signal that tailors mTORC1 and metabolism to direct epithelial cell fate decisions. These results identify mechanisms and therapeutic targets for dysregulated homeostasis in cystinosis

Ancient Migratory Events in the Middle East: New Clues from the Y-Chromosome Variation of Modern Iranians

Knowledge of high resolution Y-chromosome haplogroup diversification within Iran provides important geographic context regarding the spread and compartmentalization of male lineages in the Middle East and southwestern Asia. At present, the Iranian population is characterized by an extraordinary mix of different ethnic groups speaking a variety of Indo-Iranian, Semitic and Turkic languages. Despite these features, only few studies have investigated the multiethnic components of the Iranian gene pool. In this survey 938 Iranian male DNAs belonging to 15 ethnic groups from 14 Iranian provinces were analyzed for 84 Y-chromosome biallelic markers and 10 STRs. The results show an autochthonous but non-homogeneous ancient background mainly composed by J2a sub-clades with different external contributions. The phylogeography of the main haplogroups allowed identifying post-glacial and Neolithic expansions toward western Eurasia but also recent movements towards the Iranian region from western Eurasia (R1b-L23), Central Asia (Q-M25), Asia Minor (J2a-M92) and southern Mesopotamia (J1-Page08). In spite of the presence of important geographic barriers (Zagros and Alborz mountain ranges, and the Dasht-e Kavir and Dash-e Lut deserts) which may have limited gene flow, AMOVA analysis revealed that language, in addition to geography, has played an important role in shaping the nowadays Iranian gene pool. Overall, this study provides a portrait of the Y-chromosomal variation in Iran, useful for depicting a more comprehensive history of the peoples of this area as well as for reconstructing ancient migration routes. In addition, our results evidence the important role of the Iranian plateau as source and recipient of gene flow between culturally and genetically distinct population

Quality of Life in European Patients with Addison’s Disease: Validity of the Disease-Specific Questionnaire AddiQoL

Context: Patients with Addison’s disease (AD) self-report impairment in specific dimensions on well-being questionnaires. An AD-specific quality-of-life questionnaire (AddiQoL) was developed to aid evaluation of patients. Objective: We aimed to translate and determine construct validity, reliability, and concurrent validity of the AddiQoL questionnaire. Methods: After translation, the final versions were tested in AD patients from Norway (n = 107), Sweden (n = 101), Italy (n = 165), Germany (n = 200), and Poland (n = 50). Construct validity was examined by exploratory factor analysis and Rasch analysis, aiming at unidimensionality and fit to the Rasch model. Reliability was determined by Cronbach’s coefficient- and Person separation index. Longitudinal reliability was tested by differential item functioning in stable patient subgroups. Concurrent validity was examined in Norwegian (n = 101) and Swedish (n = 107) patients. Results: Exploratory factor analysis and Rasch analysis identified six items with poor psychometric properties. The 30 remaining items fitted the Rasch model and proved unidimensional, supported by appropriate item and person fit residuals and a nonsignificant X² probability. Crohnbach’s α-coefficient 0.93 and Person separation index 0.86 indicate high reliability. Longitudinal reliability was excellent. Correlation with Short Form-36 and Psychological General Well-Being Index scores was high. A shorter subscale comprising eight items also proved valid and reliable. Testing of AddiQoL-30 in this large patient cohort showed significantly worse scores with increasing age and inwomencompared withmenbutnodifference between patients with isolatedADand those with concomitant diseases. Conclusion: The validation process resulted in a revised 30-item AddiQoL questionnaire and an eight-item AddiQoL short version with good psychometric properties and high reliability

Characterization of the biological processes shaping the genetic structure of the Italian population

BACKGROUND: The genetic structure of human populations is the outcome of the combined action of different processes such as demographic dynamics and natural selection. Several efforts toward the characterization of population genetic architectures and the identification of adaptation signatures were recently made. In this study, we provide a genome-wide depiction of the Italian population structure and the analysis of the major determinants of the current existing genetic variation. RESULTS: We defined and characterized 210 genomic loci associated with the first Principal Component calculated on the Italian genotypic data and correlated to the North–south genetic gradient. Using a gene-enrichment approach we identified the immune function as primarily involved in the Italian population differentiation and we described a locus on chromosome 13 showing combined evidence of North–south diversification in allele frequencies and signs of recent positive selection. In this region our bioinformatics analysis pinpointed an uncharacterized long intergenic non-coding (lincRNA), whose expression appeared specific for immune-related tissues suggesting its relevance for the immune function. CONCLUSIONS: Our study, combining population genetic analyses with biological insights provides a description of the Italian genetic structure that in future could contribute to the evaluation of complex diseases risk in the population context. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12863-015-0293-x) contains supplementary material, which is available to authorized users

The use of surname and Y-chromocome analyses for reconstructing past population structures: the test case of Sardinia

The male specific region of the Y chromosome is uniparentally transmitted. It escapes recombination and its evolution is only due to the sequential accumulation of new mutations along radiating paternal lineages. Due to this process, which occurred mainly during and after the process of human colonization and diffusion into the different geographic region, the present Y-chromosome sequence variation represents a unique record of the biological history of our species and modern populations. Its analysis allows the identification of ancestral and founder haplotypes, the detection of ancient migration routes and the estimation of migration times. However, this analysis is sometimes undermined by recent migrations which became more and more important also for “isolated” populations, weakening the boundaries of genetic isolates by making uniform the distribution of genetic markers. A solution for this problem is represented by the reconstruction of the ancient isolates starting from the present data by using the information obtained from the surname analysis. With the aim of investigating the peopling of Sardinia and the aspects of its human Y-chromosome contemporary variation that can be ascribed to primary colonization, Neolithic dispersals or more recent events of gene flow, we have analyzed in detail the Y chromosome haplogroup distributions in a wide sample (more than 500 Y chromosomes) whose surname origin could be attributed specifically to one of the different Sardinian linguistic zones (Contini et al., 1989, Piazza et al. 1987). In addition, in order to evaluate the divergence of the different haplogroups observed in the island, and therefore their coalescent time, a set of 12 STR loci was examined. On the whole, by the comparison of 11 regions representative of ancient Sardinian isolates, a significant differentiation has been confirmed for the central eastern area of the island, in agreement with historical and linguistic data that indicate this region as the “archaic”zone. This is due to a lower incidence of haplogroups arrived in Europe during the Neolithic and post Neolithic times (Cruciani et al. 2004, Semino et et al. 2004), but mainly to a significative higher frequency of the Paleolithic haplogroup I-M26