UNC45A deficiency causes microvillus inclusion disease–like phenotype by impairing myosin VB–dependent apical trafficking

International audienceVariants in the UNC45A cochaperone have been recently associated with a syndrome combining diarrhea, cholestasis, deafness, and bone fragility. Yet the mechanism underlying intestinal failure in UNC45A deficiency remains unclear. Here, biallelic variants in UNC45A were identified by next-generation sequencing in 6 patients with congenital diarrhea. Corroborating in silico prediction, variants either abolished UNC45A expression or altered protein conformation. Myosin VB was identified by mass spectrometry as client of the UNC45A chaperone and was found misfolded in UNC45A(KO) Caco-2 cells. In keeping with impaired myosin VB function, UNC45A(KO) Caco-2 cells showed abnormal epithelial morphogenesis that was restored by full-length UNC45A, but not by mutant alleles. Patients and UNC45A(KO) 3D organoids displayed altered luminal development and microvillus inclusions, while 2D cultures revealed Rab11 and apical transporter mislocalization as well as sparse and disorganized microvilli. All those features resembled the subcellular abnormalities observed in duodenal biopsies from patients with microvillus inclusion disease. Finally, microvillus inclusions and shortened microvilli were evidenced in enterocytes from unc45a-deficient zebrafish. Taken together, our results provide evidence that UNC45A plays an essential role in epithelial morphogenesis through its cochaperone function of myosin VB and that UNC45A loss causes a variant of microvillus inclusion disease

Extra-auditory effects of noise exposure in school workers and preventive measures. A systematic review

OBJECTIVE: Noise is still today one of the main causes of occupational diseas- es; in fact, in Italy in the three-year period 2019- 2022, hearing loss represented 15% of all occu- pational diseases recognized by the National Institute for Insurance against Accidents at Work. The extra-auditory effects related to noise expo- sure also require particular attention, because they can interfere with mental activities that re- quire concentration, memory and ability to deal with complex problems, causing sleep and learn- ing disorders. For this reason, acoustic comfort is considered a fundamental requirement for ob- taining an optimal degree of well-being in closed environments. In schools, a high degree of noise pollution not only makes it difficult for students to listen and learn, but also affects school workers. The aim of this study was to perform a systemat- ic review of international literature and analysis of the preventive measures of extra-auditory effects among school workers. MATERIALS AND METHODS: The presenta- tion of this systematic review is in accordance with the PRISMA statement. The methodologi- cal quality of the selected studies was assessed with specific rating tools (INSA, Newcastle Otta- wa Scale, JADAD, JBI scale and AMSTAR). On- ly publications in English were selected. No re- strictions were applied for the publication type. We excluded articles not concerned with the ex- tra-auditory effects of noise exposure in school workers and preventive measures, findings of less academic significance, editorial articles, in- dividual contributions, and purely descriptive studies published in scientific conferences. RESULTS: Online research indicated 4,363 references: PubMed (2,319), Scopus (1,615) and Cochrane Library (429) have been consulted; 30 studies were included in this review (5 narrative or systematic reviews and 25 original articles). Regarding the scores of narrative reviews, the INSA score showed an average and a median value of 6.5, thus indicating an intermediate/high quality of the studies. Regarding the scores of systematic reviews, the AMSTAR score showed an average of 6.7 and a median and a modal val- ue of 6, thus indicating a high quality of the stud- ies. The scores assigned to the original articles have an average and median value of 7 and a modal value of 6 and this demonstrates an inter- mediate/high quality of the studies. CONCLUSIONS: We can assume that, as it is highlighted by this study, to date these con- sequences are not considered at the legisla- tive level for the protection of exposed workers. The extra-auditory effects impacting health af- terward environmental noise exposure are ma- ny and widespread. Therefore, there is a need for interventions to be carried out by institutions and that the physician of the schools, during health surveillance, investigates the effects and clinical manifestations, in order to prevent disor- ders and deficits highlighted by our study

Extra-auditory effects of noise exposure in school workers and preventive measures: a systematic review

OBJECTIVE: Noise is still today one of the main causes of occupational diseases; in fact, in Italy in the three-year period 2019-2022, hearing loss represented 15% of all occupational diseases recognized by the National Institute for Insurance against Accidents at Work. The extra-auditory effects related to noise exposure also require particular attention, because they can interfere with mental activities that require concentration, memory and ability to deal with complex problems, causing sleep and learning disorders. For this reason, acoustic comfort is considered a fundamental requirement for obtaining an optimal degree of well-being in closed environments. In schools, a high degree of noise pollution not only makes it difficult for students to listen and learn, but also affects school workers. The aim of this study was to perform a systematic review of international literature and analysis of the preventive measures of extra-auditory effects among school workers. MATERIALS AND METHODS: The presentation of this systematic review is in accordance with the PRISMA statement. The methodological quality of the selected studies was assessed with specific rating tools (INSA, Newcastle Ottawa Scale, JADAD, JBI scale and AMSTAR). Only publications in English were selected. No restrictions were applied for the publication type. We excluded articles not concerned with the extra-auditory effects of noise exposure in school workers and preventive measures, findings of less academic significance, editorial articles, individual contributions, and purely descriptive studies published in scientific conferences. RESULTS: Online research indicated 4,363 references: PubMed (2,319), Scopus (1,615) and Cochrane Library (429) have been consulted; 30 studies were included in this review (5 narrative or systematic reviews and 25 original articles). Regarding the scores of narrative reviews, the INSA score showed an average and a median value of 6.5, thus indicating an intermediate/high quality of the studies. Regarding the scores of systematic reviews, the AMSTAR score showed an average of 6.7 and a median and a modal value of 6, thus indicating a high quality of the studies. The scores assigned to the original articles have an average and median value of 7 and a modal value of 6 and this demonstrates an intermediate/high quality of the studies. CONCLUSIONS: We can assume that, as it is highlighted by this study, to date these consequences are not considered at the legislative level for the protection of exposed workers. The extra-auditory effects impacting health afterward environmental noise exposure are many and widespread. Therefore, there is a need for interventions to be carried out by institutions and that the physician of the schools, during health surveillance, investigates the effects and clinical manifestations, in order to prevent disorders and deficits highlighted by our study

The effects of age and environment on the expression of inbreeding depression in Eucalyptus globulus

Inbreeding adversely affects fitness traits in many plant and animal species, and the magnitude, stability and genetic basis of inbreeding depression (ID) will have short- and long-term evolutionary consequences. The effects of four degrees of inbreeding (selfing, f=50% full- and half-sib matings, f=25 and 12.5% and unrelated outcrosses, f=0%) on survival and growth of an island population of Eucalyptus globulus were studied at two sites for over 14 years. For selfs, ID in survival increased over time, reaching a maximum of 49% by age 14 years. However, their inbreeding depression for stem diameter remained relatively stable with age, and ranged from 28 to 36% across years and sites. ID for survival was markedly greater on the more productive site, possibly due to greater and earlier onset of inter-tree competition, but was similar on both sites for the diameter of survivors. The deleterious trait response to increasing inbreeding coefficients was linear for survival and diameter. Non-significant quadratic effects suggested that epistasis did not contribute considerably to the observed ID at the population level. Among- and within-family coefficients of variation for diameter increased with inbreeding degree, and the variance among the outcrossed families was significant only on the more productive site. The performance of self-families for diameter was highly stable between sites. This suggests that, for species with mixed mating systems, environmentally stable inbreeding effects in open-pollinated progenies may tend to mask the additive genotype-by-environment interaction for fitness traits and the adaptive response to the environment

ANCA-associated vasculitis - clinical utility of using ANCA specificity to classify patients.

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