Campbelllorentzen9193

These studies provide new insight into the assembly of the GlcNAc-1-phosphotransferase complex, and the functions of distinct domains of the α- and γ-subunits.Duchenne muscular dystrophy (DMD) is a classical monogenic disorder, a model disease for genomic studies and a priority candidate for regenerative medicine and gene therapy. Although the genetic cause of DMD is well known, the molecular pathogenesis of disease and the response to therapy are incompletely understood. Here, we describe analyses of protein, mRNA and microRNA expression in the tibialis anterior of the mdx mouse model of DMD. Notably, 3272 proteins were quantifiable and 525 identified as differentially expressed in mdx muscle (P less then 0.01). read more Therapeutic restoration of dystrophin by exon skipping induced widespread shifts in protein and mRNA expression towards wild-type expression levels, whereas the miRNome was largely unaffected. Comparison analyses between datasets showed that protein and mRNA ratios were only weakly correlated (r = 0.405), and identified a multitude of differentially affected cellular pathways, upstream regulators and predicted miRNA-target interactions. This study provides fundamental new insights into gene expression and regulation in dystrophic muscle.RNA dysregulation is a newly recognized disease mechanism in amyotrophic lateral sclerosis (ALS). Here we identify Drosophila fragile X mental retardation protein (dFMRP) as a robust genetic modifier of TDP-43-dependent toxicity in a Drosophila model of ALS. We find that dFMRP overexpression (dFMRP OE) mitigates TDP-43 dependent locomotor defects and reduced lifespan in Drosophila. TDP-43 and FMRP form a complex in flies and human cells. In motor neurons, TDP-43 expression increases the association of dFMRP with stress granules and colocalizes with polyA binding protein in a variant-dependent manner. Furthermore, dFMRP dosage modulates TDP-43 solubility and molecular mobility with overexpression of dFMRP resulting in a significant reduction of TDP-43 in the aggregate fraction. link2 Polysome fractionation experiments indicate that dFMRP OE also relieves the translation inhibition of futsch mRNA, a TDP-43 target mRNA, which regulates neuromuscular synapse architecture. Restoration of futsch translation by dFMRP OE mitigates Futsch-dependent morphological phenotypes at the neuromuscular junction including synaptic size and presence of satellite boutons. Our data suggest a model whereby dFMRP is neuroprotective by remodeling TDP-43 containing RNA granules, reducing aggregation and restoring the translation of specific mRNAs in motor neurons.SPOAN syndrome is a neurodegenerative disorder mainly characterized by spastic paraplegia, optic atrophy and neuropathy (SPOAN). Affected patients are wheelchair bound after 15 years old, with progressive joint contractures and spine deformities. SPOAN patients also have sub normal vision secondary to apparently non-progressive congenital optic atrophy. A potential causative gene was mapped at 11q13 ten years ago. Here we performed next-generation sequencing in SPOAN-derived samples. link3 While whole-exome sequencing failed to identify the causative mutation, whole-genome sequencing allowed to detect a homozygous 216-bp deletion (chr11.hg19g.66,024,557_66,024,773del) located at the non-coding upstream region of the KLC2 gene. Expression assays performed with patient's fibroblasts and motor neurons derived from SPOAN patients showed KLC2 overexpression. Luciferase assay in constructs with 216-bp deletion confirmed the overexpression of gene reporter, varying from 48 to 74%, as compared with wild-type. Knockdown and overexpression of klc2 in Danio rerio revealed mild to severe curly-tail phenotype, which is suggestive of a neuromuscular disorder. Overexpression of a gene caused by a small deletion in the non-coding region is a novel mechanism, which to the best of our knowledge, was never reported before in a recessive condition. Although the molecular mechanism of KLC2 up-regulation still remains to be uncovered, such example adds to the importance of non-coding regions in human pathology.

Hypertrophic cardiomyopathy (HCM) is a cause of sudden arrhythmic death, but the understanding of its pro-arrhythmic mechanisms and an effective pharmacological treatment are lacking. HCM electrophysiological remodelling includes both increased inward and reduced outward currents, but their role in promoting repolarisation abnormalities remains unknown. The goal of this study is to identify key ionic mechanisms driving repolarisation abnormalities in human HCM, and to evaluate anti-arrhythmic effects of single and multichannel inward current blocks.

Experimental ionic current, action potential (AP) and Ca(2+)-transient (CaT) recordings were used to construct populations of human non-diseased and HCM AP models (n=9118), accounting for inter-subject variability. Simulations were conducted for several degrees of selective and combined inward current block.

Simulated HCM cardiomyocytes exhibited prolonged AP and CaT, diastolic Ca(2+) overload and decreased CaT amplitude, in agreement with experiments. Repol abnormalities in HCM, and combined INCX, INaL and ICaL block as effective anti-arrhythmic therapies also able to partially reverse the HCM electrophysiological phenotype.The present research investigated the role of two sources of psychological need satisfaction (inside and outside a passionate activity) as determinants of harmonious (HP) and obsessive (OP) passion. Four studies were carried out with different samples of young and middle-aged adults (e.g., athletes, musicians; total N = 648). Different research designs (cross-sectional, mixed, longitudinal) were also used. Results showed that only a rigid engagement in a passionate activity (OP) was predicted by low levels of need satisfaction outside the passionate activity (in an important life context or in life in general), whereas both OP and a more favorable and balanced type of passion, HP were positively predicted by need satisfaction inside the passionate activity. Further, OP led to negative outcomes, and HP predicted positive outcomes. These results suggest that OP may represent a form of compensatory striving for psychological need satisfaction. It appears important to consider two distinct sources of need satisfaction, inside and outside the passionate activity, when investigating determinants of optimal and less optimal forms of activity engagement.

Different therapeutic concepts and methods have been proposed for improving dental implant outcomes in three specific clinical situations (i) the fresh extraction socket with alveolar ridge preservation protocols; (ii) the posterior maxilla with limited bone height with either the placement of regular-sized implants after sinus elevation and grafting or short dental implants and; (iii) the posterior mandible with limited bone height with either vertical bone augmentation and placement of implants or short dental implants.

Three systematic reviews, based on randomized and controlled clinical trials have evaluated the efficacy of these different therapeutic modalities in terms of dental implant outcomes.

Interventions aimed for alveolar ridge preservation have shown efficacy in terms of allowing the placement of dental implants and for reducing the need of further augmentation procedures at implant placement. Both therapeutic options, the placement of implants after sinus elevation and grafting or short derior mandible, but short implants resulted in fewer complications.

Several surgical techniques and prosthetic devices have been developed in the last decades, aiming to improve aesthetic, hygienic and functional outcomes that may affect the peri-implant tissues, such as procedures of bone and soft tissue augmentation and the use of custom-made abutments of titanium and zirconium.

Three systematic reviews, based on randomized clinical trials and prospective studies covering the above reported topics were analysed, and the detected evidence was exposed to interactive experts' discussion during the group's and general assembly's meetings of the 4th EAO Consensus Conference. The results are reported using the following abbreviations S-T short-term evidence, M-T medium-term evidence; L-T long-term evidence; LE limited evidence.

Soft tissue augmentation procedures may be indicated for the increase of soft tissue thickness and keratinized tissue, the reduction of interproximal peri-implant bone loss, and the coverage of shallow peri-implant soft tissue recessions (S-T, LE), Lthe soft tissues (S-T & L-T), and the stability of the augmented bone may play a role in the maintenance of the soft tissue position and dimensions (LE). No significant differences were observed between titanium and zirconia abutments when evaluating probing pocket depth, bleeding on probing, marginal bone levels and mucosal recessions. Zirconia abutments were associated with more biological complications but demonstrated superiority in terms of achieving natural soft tissue colour (S-T).

To investigate whether the height and volume of the soft tissues and peri-implant bone levels around dental implants are stable, when soft tissue augmentation has been performed.

Three operators conducted a search on electronic databases (MEDLINE, COCHRANE, EMBASE) and a hand searching on the main journals dealing with periodontology and implantology until 30 October 2014. Only articles that considered peri-implant soft tissue augmentation performed in a group of at least 10 patients and with a follow-up of at least 1 year were selected. The outcome variables were peri-implant attached/keratinized tissue width (KTW) changes, peri-implant marginal soft tissue level (PSL) changes, and peri-implant marginal bone level (PBL) changes. The review was performed according to the PRISMA statements.

Ten articles were selected for the qualitative synthesis, but only one meta-analysis was accomplished, indicating that 1 year after implant recession coverage procedures, a mean gain of 1.65 ± 0.01 mm (90% CrI [1.44; 1.85]) was observed.

There is no long-term evidence whether augmented soft tissues can be maintained over time and able to influence the peri-implant bone levels.

There is no long-term evidence whether augmented soft tissues can be maintained over time and able to influence the peri-implant bone levels.

Peri-implant hard-tissue augmentation is a widely used clinical procedure.

The present review aimed to analyse the current literature regarding medium- and long-term data concerning the stability of peri-implant tissues after hard-tissue augmentation prior or immediately with implant placement.

An electronic literature search was performed using Medline (PubMed) databases detecting clinical studies focusing on hard- and soft-tissue stability around dental implants placed either in augmented alveolar ridges or simultaneously with peri-implant bone grafting. The search was limited to articles published between 1995 and December 2014, focusing on clinical studies with a prospective study design assessing peri-implant bone and soft tissue stability over time with a minimum follow-up of 12 months. Recent publications were also searched manually to find any relevant studies that might have been missed using the search criteria noted above.

Thirty-seven articles met the inclusion criteria and were included in this systematic review.