DNAJC17 is localized in nuclear speckles and interacts with splicing machinery components.

DNAJC17 is a heat shock protein (HSP40) family member, identified in mouse as susceptibility gene for congenital hypothyroidism. DNAJC17 knockout mouse embryos die prior to implantation. In humans, germline homozygous mutations in DNAJC17 have been found in syndromic retinal dystrophy patients, while heterozygous mutations represent candidate pathogenic events for myeloproliferative disorders. Despite widespread expression and involvement in human diseases, DNAJC17 function is still poorly understood. Herein, we have investigated its function through high-throughput transcriptomic and proteomic approaches. DNAJC17-depleted cells transcriptome highlighted genes involved in general functional categories, mainly related to gene expression. Conversely, DNAJC17 interactome can be classified in very specific functional networks, with the most enriched one including proteins involved in splicing. Furthermore, several splicing-related interactors, were independently validated by co-immunoprecipitation and in vivo co-localization. Accordingly, co-localization of DNAJC17 with SC35, a marker of nuclear speckles, further supported its interaction with spliceosomal components. Lastly, DNAJC17 up-regulation enhanced splicing efficiency of minigene reporter in live cells, while its knockdown induced perturbations of splicing efficiency at whole genome level, as demonstrated by specific analysis of RNAseq data. In conclusion, our study strongly suggests a role of DNAJC17 in splicing-related processes and provides support to its recognized essential function in early development.

Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition.

Cadherin-13 (CDH13), a unique glycosylphosphatidylinositol-anchored member of the cadherin family of cell adhesion molecules, has been identified as a risk gene for attention-deficit/hyperactivity disorder (ADHD) and various comorbid neurodevelopmental and psychiatric conditions, including depression, substance abuse, autism spectrum disorder and violent behavior, while the mechanism whereby CDH13 dysfunction influences pathogenesis of neuropsychiatric disorders remains elusive. Here we explored the potential role of CDH13 in the inhibitory modulation of brain activity by investigating synaptic function of GABAergic interneurons. Cellular and subcellular distribution of CDH13 was analyzed in the murine hippocampus and a mouse model with a targeted inactivation of Cdh13 was generated to evaluate how CDH13 modulates synaptic activity of hippocampal interneurons and behavioral domains related to psychopathologic (endo)phenotypes. We show that CDH13 expression in the cornu ammonis (CA) region of the hippocampus is confined to distinct classes of interneurons. Specifically, CDH13 is expressed by numerous parvalbumin and somatostatin-expressing interneurons located in the stratum oriens, where it localizes to both the soma and the presynaptic compartment. Cdh13(-/-) mice show an increase in basal inhibitory, but not excitatory, synaptic transmission in CA1 pyramidal neurons. Associated with these alterations in hippocampal function, Cdh13(-/-) mice display deficits in learning and memory. Taken together, our results indicate that CDH13 is a negative regulator of inhibitory synapses in the hippocampus, and provide insights into how CDH13 dysfunction may contribute to the excitatory/inhibitory imbalance observed in neurodevelopmental disorders, such as ADHD and autism.

MMT-supported Ag nanoparticles for chitosan nanocomposites: structural properties and antibacterial activity.

Multifunctional bionanocomposites have been prepared by loading chitosan matrix with silver-montmorillonite antimicrobial nanoparticles obtained by replacing Na(+) ions of natural montmorillonite with silver ions. This filler has been chosen for its twofold advantage to serve as silver supporting material and to confer new and better performance to the obtained material. It has been proved that the achievement of the intercalation of chitosan into the silicate galleries of montomorillonite as well as the interaction between chitosan and Ag ions and silver particles lead to an enhancement of the thermal stability, to an improvement of mechanical strengths and to a reduction of the liquid water uptake of the obtained bionanocomposites. Results also show that silver ions are released in a steady and prolonged manner providing, after 24 h, a significant reduction in the microbial growth of Pseudomonas spp.

Fast curing of restorative materials through the soft light energy release.

OBJECTIVE: The effect of a novel light curing process, namely soft light energy release (SLER), on shrinkage, mechanical strength and residual stress of four dental restorative materials (DEI experience, Gradia Direct, Enamel Plus HFO and Venus) was investigated. METHODS: Composite specimens were fast cured through high level of power density and soft light energy release. Temperature, linear shrinkage and light power measurements were acquired in parallel in order to assess the effect of light modulation on temperature and shrinkage profiles during the light curing process and the following dark reaction phase. The small punch test and Raman spectroscopy were adopted to investigate the effect of SLER on mechanical strength and on internal stress, respectively. RESULTS: The soft light energy release photo-polymerization allows to reduce of about 20% the shrinkage rate and to increase the strength of fast light cured specimens. In addition, a more relaxed and homogeneous internal stress distribution was observed. SIGNIFICANCE: Properties of fast cured restorative materials can be improved by adopting the soft light energy release process.

Cis-acting genomic elements of the Pas1 locus control Kras mutability in lung tumors.

The Pas1 locus is the major tumor modifier of lung tumorigenesis in mouse inbred strains. Of six genes contained in a conserved haplotype, three (Casc1, Kras and Ifltd1) have been proposed as Pas1 candidates, but mechanistic evidence is sparse. Herein, we examined urethane-induced lung tumorigenesis in a new mouse model developed by replacing the Kras gene with an Hras gene in the susceptible A/J-type Pas1 locus and crossing these mice with either C57BL/6J or A/J mice. Heterozygous mice carrying the Hras-replacement gene were more susceptible than wild-type mice to lung carcinogenesis, indicating that Hras replacement not only compensates for Kras functions, but is more active. Indeed, most lung tumors carried a Gln61Leu mutation in the Hras-replacement gene, whereas no mutations were observed in the endogenous Hras gene. Thus, the context of the Kras locus determined mutability of ras genes. In mice carrying the Hras-replacement gene, the mutation frequency affecting the wild-type Kras gene was much higher when this gene was located in the A/J type than in the C57BL/6J-type Pas1 locus (12 versus 0%, -log P=5.0). These findings identify cis-acting elements in the Pas1 locus as the functional components controlling genetic susceptibility to lung tumorigenesis by modulating mutability of the Kras gene.

[Risk factors in calcium urolithiasis]. / Fattori di rischio nell'urolitiasi calcica.

The aim of the study has been to evaluate, retrospectively, if the association of urolithiasis different pathogenetic factors increases stone formation and recurrences. The study included 41 children, 20 males and 21 females, aged 3-15 years, divided into three groups: patients with hypercalciuric or normocalciuric urolithiasis and isolated hypercalciuria. In all of them renal function, blood and urinary pH, serum and urinary electrolytic levels, citraturia (dosed with anenzymatic quantitative method), oxalaturia (enzymatic colorimetric method), urinary glycosaminoglycans (dosed by means of cetylpyridinum chloride precipitation and quantitative analysis) have been considered. Statistical analysis was done using Student's "t"-test, with p < 0.05. In all children with hypercalciuric urolithiasis who during the follow-up presented a decreased citraturia, the number of recurrences increased and was above two. The children who during the follow-up remained hypercalciuric without urolithiasis, in spite of the high familiarity, presented an increased citraturia. In conclusion the association between hypercalciuria and low citraturia increases the risk of stone formation and recurrences in children with calcic urolithiasis.