Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by the depletion of the ubiquitously expressed survival motor neuron (SMN) protein. While the genetic cause of SMA has ...been well documented, the exact mechanism(s) by which SMN depletion results in disease progression remain elusive. A wide body of evidence has highlighted the involvement and dysregulation of autophagy in SMA. Autophagy is a highly conserved lysosomal degradation process which is necessary for cellular homeostasis; defects in the autophagic machinery have been linked with a wide range of neurodegenerative disorders, including amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease. The pathway is particularly known to prevent neurodegeneration and has been suggested to act as a neuroprotective factor, thus presenting an attractive target for novel therapies for SMA patients. In this review, (a) we provide for the first time a comprehensive summary of the perturbations in the autophagic networks that characterize SMA development, (b) highlight the autophagic regulators which may play a key role in SMA pathogenesis and (c) propose decreased autophagic flux as the causative agent underlying the autophagic dysregulation observed in these patients.
The aim of the study was to assess the roughness, structure and bond strength with zirconia of four grit-blasting treatments combined with three silane types, the reactivity of which was evaluated, ...as well.
The grit-blasted treatments performed on zirconia (Lava) were alumina (ALU), CoJet (COJ), SilJet (SLJ) and SilJet Plus (SJP, with silica-encapsulated silane). The other two silanes selected were the S-Bond (SB, prehydrolyzed) and Clearfil Ceramic Primer Plus (CP, prehydrolyzed with 10-MDP). The activity of the silanols in the silanes was evaluated by FTIR spectroscopy. Optical profilometry and Raman microspectroscopy were used for the assessment of roughness (Sa, Sz, Sdr parameters) and structure (monoclinic volume-Vm) of zirconia, before (REF) and after grit-blasting, and a shear bond strength (SBS) with a flowable resin composite, for the investigation of the bonding capacity of the treatments.
Only SB demonstrated reactive silanols. CP and the SJP silanes were mostly in a polymerized siloxane state. Roughness was increased after grit-blasting as follows: ALU>SLJ,SJP>COJ>REF (Sa,Sz) and ALU>SLJ,COJ,SJP>REF (Sdr). ALU demonstrated the highest Vm (7.52%) from all other treatments (4.16–4.81%) and the REF (0%). COJ and SLJ showed the highest SBS (14–15.94MPa) regardless of the silane type used. SJP showed no significant differences from SLJ-SB and COJ-SB. Weibull analysis showed a reliability (β) ranking of COJ, SJP, SLJ, ALU-CP>ALU-SB>REF and a characteristic life (η) ranking of COJ, SLJ, ≥SLJ-SB, SJP, ALU≥ALU-SB,REF-CP>REF-SB.
The reactivity of the silanes used showed great variations to support a predictable effect in all treatments. CP with deactivated silanols demonstrated a) the most reliable and strongest treatment with a silica-rich powder (COJ), despite the lowest Sa,Sz substrate values and b) high strength with a low-silica powder (SLJ) with higher Sa,Sz substrate values. Therefore, it may be concluded that 10-MDP greatly contributes to the bonding mechanism of the silane containing primers.
The aim of the study was to evaluate the performance of six commercially available universal dental adhesives: Adhese Universal (ADU), All-Bond Universal (ABU), Clearfil Universal Bond Quick (CBQ), ...G-Premio Bond (GPB), Prelude One (PRO) and Scotchbond Universal (SBU). The properties tested were: (a) degree of C=C conversion (DC%); (b) Vickers micro-hardness (VHN); (c) extent of oxygen inhibition (OI/μm), all related with the adhesive film properties; (d) extent of dentin demineralisation (DM%), insoluble salt formation (AS%); and (e) shear bond strength (SBS, self-etch mode) related to the adhesive-dentin interactions. Statistical analysis (α = 0.05) was performed by one-way ANOVA and Tukey's test (DC%, VHN, OI, DM% AS%) and Weibull analysis (SBS,
). The DC ranged from 67.2-82.5% (all >GPB), OI from 5.6-18.6 μm (SBU > ADU, GPB, ABU > CBQ > PRO), microhardness from 1.1-6.6 VHN (SBU > ADU > ABU > CBQ > PRO > GPB: not measurable), DM from 69.3% (GPB) to 16-12.5% (CBQ, SBU, ADU) and 13.2-10.6% (ABU, ADU, PRO), in homogeneous groups and AS from 26-15.9% (ABU, CBQ > GPB, PRO, ADU, SBU). For SBS the
(characteristic life) ranged from 29.3-16.6 MPa (CBQ, ADU, ABU, SBU > PRO > GPB), the
(reliability) from 5.1-9.7 (
> 0.05). All failure modes were of mixed type (adhesive and composite cohesive). Although all these adhesives were based on the 10-methacryloyloxydecyl dihydrogen phosphate (10-MDP) adhesive monomer, the different co-monomers, solvents and catalysts led to variations in their film properties, reactivity and bonding capacity with dentin.
To evaluate the silane status in commercially available products and their bonding capacity with polished glass-ceramic surfaces before and after hydrofluoric (HF) acid-etching.
The products tested ...were Calibra Silane Coupling Agent/CS, G-Multi Primer/GM, Kerr Silane Primer/KS, Monobond Plus/MB and Scotchbond Universal Adhesive/SB. The silane status was studied by 13C nuclear magnetic resonance spectroscopy (13C-NMR). The roughness parameters of polished (group A) and HF acid-etched (group B) lithium disilicate glass-ceramic surfaces were measured by optical profilometry (n = 5/group). The interaction of the products with group A and B ceramic surfaces was examined by attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR). The shear strength (SBS) of a flowable composite bonded to the ceramic surfaces (groups A, B) was assessed before (NS) and after silane treatment (n = 20/group, product).
The NMR analysis showed the presence of silanol monomers only in CS. Methoxylated-siloxane adducts were found in GM, silanol–siloxane adducts in MB, SB, and siloxane polymers in KS. Acid-etching greatly increased Sa, Sz, Sdr, Sc and Sv parameters (p < 0.001) and ATR-FTIR analysis demonstrated evidence of bonding with the substrate in CS. Weibull analysis of SBS revealed the following rankings in characteristic life (p < 0.05): CS > SB,KS,MB > GM > NS (group A) and CS > GM > SB,KS,MB,NS (group B). The most reliable treatment in both groups was CS. For the same silane treatment, the SBS of group B were significantly higher from group A. Failures were mainly of adhesive type, except of several partial resin cohesive failures found in group B.
The chemical bonding capacity of the silanes was highest in products with silanol monomers. Acid-etching increased bond strength to a level that neutralized the silane contribution in products with silanol–siloxane adducts and siloxane polymers, providing thus bond strength values similar to silane-free treatments.
The aim of the study was to evaluate the stability, reactivity, and bond strength with a lithium disilicate ceramic of a self-etch silane primer (Monobond Etch and Prime/MEP). The stability was ...evaluated by
H-,
P-NMR spectroscopy (before/after aging), and the reactivity by micro MIR-FTIR spectroscopy on Ge surfaces (0, 1, 24 h) using a prehydrolyzed silane primer (Calibra Silane Coupling Agent/CLB), as a control. The effect of MEP vs. 5% HF-etching on ceramic roughness was assessed by optical profilometry. The shear bond strength (SBS) of a resin composite bonded to polished ceramic surfaces treated with MEP, HF without silane (HF+NS), HF+CLB, and HF+MEP (n = 20) was evaluated after storage in water (A: 37 °C/1 week, B: 5000×/5-55 °C and C: 100 °C/24 h). Aging did not affect the silanol groups of MEP, but only the phosphate co-monomer. Silanols were reactive forming siloxanes, but exhibited lower consumption rate than CLB. HF-etching induced significantly higher values than MEP, in all the roughness parameters tested (Sa, Sz, Sdr, Sc, Sv), with the greatest differences found in Sdr and Sv. For SBS, MEP was inferior to all treatments/storage conditions, except of HF+NS in A, where the values were similar. However, on a HF-etched substrate, MEP provided highest strength and reliability.
Mutations in Cu/Zn superoxide dismutase 1 (SOD1) lead to Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease that disproportionately affects glutamatergic and cholinergic motor neurons. ...Previous work with SOD1 overexpression models supports a role for SOD1 toxic gain of function in ALS pathogenesis. However, the impact of SOD1 loss of function in ALS cannot be directly examined in overexpression models. In addition, overexpression may obscure the contribution of SOD1 loss of function in the degeneration of different neuronal populations. Here, we report the first single-copy, ALS knock-in models in C. elegans generated by transposon- or CRISPR/Cas9- mediated genome editing of the endogenous sod-1 gene. Introduction of ALS patient amino acid changes A4V, H71Y, L84V, G85R or G93A into the C. elegans sod-1 gene yielded single-copy/knock-in ALS SOD1 models. These differ from previously reported overexpression models in multiple assays. In single-copy/knock-in models, we observed differential impact of sod-1 ALS alleles on glutamatergic and cholinergic neurodegeneration. A4V, H71Y, G85R, and G93A animals showed increased SOD1 protein accumulation and oxidative stress induced degeneration, consistent with a toxic gain of function in cholinergic motor neurons. By contrast, H71Y, L84V, and G85R lead to glutamatergic neuron degeneration due to sod-1 loss of function after oxidative stress. However, dopaminergic and serotonergic neuronal populations were spared in single-copy ALS models, suggesting a neuronal-subtype specificity previously not reported in invertebrate ALS SOD1 models. Combined, these results suggest that knock-in models may reproduce the neurotransmitter-type specificity of ALS and that both SOD1 loss and gain of toxic function differentially contribute to ALS pathogenesis in different neuronal populations.
Abstract Neurodegenerative diseases impose a burden on society, yet for the most part, the mechanisms underlying neuronal dysfunction and death in these disorders remain unclear despite the ...identification of relevant disease genes. Given the molecular conservation in neuronal signaling pathways across vertebrate and invertebrate species, many researchers have turned to the nematode Caenorhabditis elegans to identify the mechanisms underlying neurodegenerative disease pathology. C. elegans can be engineered to express human proteins associated with neurodegeneration; additionally, the function of C. elegans orthologs of human neurodegenerative disease genes can be dissected. Herein, we examine major C. elegans neurodegeneration models that recapitulate many aspects of human neurodegenerative disease and we survey the screens that have identified modifier genes. This review highlights how the C. elegans community has used this versatile organism to model several aspects of human neurodegeneration and how these studies have contributed to our understanding of human disease.
The purpose of this study was to investigate the surface characteristics and color stability of gingiva-colored composite restorative materials (Anaxgum—ANG, Ceramage—CMG and Gradia Gum—GRG). The ...microstructure, composition, degree of conversion (DC %) and 3D roughness (Sa, Sz, Sdr, Sc) were examined by LV-SEM/EDS, ATR-FTIR and optical profilometry, respectively. For the color stability (CIE L*, a*, b* system) and hardness (HV), measurements were performed at baseline and after 30 days storage in distilled water, coffee and red wine. The ANG and GRG contain prepolymerized particles in aromatic and aliphatic resin matrices, respectively, whereas CMG contains inorganic zirconia silicate/silica particles, in an aromatic resin matrix, with a smaller particle size and a higher surface area fraction. Urethane monomers were mainly identified in CMG and GRG. The DC% showed statistically insignificant differences between the materials. The same applied for the roughness parameters, except for the greatest Sdr in CMG. ANG showed a color difference (ΔE) of > 3.3 after immersion in all media, CMG in coffee and wine and GRG only in coffee. Sc was the only roughness parameter demonstrating correlations with the ΔL*, Δb* and ΔE*. The HV values showed insignificant differences between the storage conditions per material. There are important differences in the color stability of the materials tested, which were mostly affected by the roughness parameters due to variations in their microstructure.
To improve the self-curing capacity and interfacial strength with dentine of dual-cured composite materials, touch-cure activators have been introduced. The aim of the study was to evaluate the ...effect of these activators on the hardness and conversion of dual-cured resin composite core build-up restoratives. The materials tested were Clearfil DC Core Plus (CF) and Gradia Core (GC) with the corresponding adhesives Clearfil S3 Bond Plus (for CF) and G-Premio Bond/G-Premio DCA activator (for GC). Disk-shaped specimens (n = 6/group) were prepared for the following groups: dual-cured, self-cured and self-cured in contact with the adhesive activators at the bottom surface. After a 3-week storage period (dark/dry/37 °C) the Martens hardness (HM) and degree of conversion (DC%) were determined for the previously mentioned groups and the top surfaces of groups in contact with the adhesives. A statistical analysis was performed by a one-way ANOVA and Holm–Sidak test per material and a Pearson’s correlation analysis (HM vs. DC%) at an α = 0.05. The self-cured specimens resulted in significantly lower HM and DC% values from the dual-cured group, as expected. However, in the presence of the adhesives with touch-cure activators, the conversion of the self-cured groups showed insignificant differences in HM and DC% from the dual-cured in both composite materials. The improvements on the bottom composite surfaces in contact with the adhesives did not extend to the entire specimen length. Nevertheless, improved interfacial curing may improve interfacial durability.
OBJECTIVETo evaluate the amount of methyl methacrylate (MMA) released in water from heat-cured polymethyl methacrylate (PMMA) denture base materials subjected to different cooling procedures. ...METHODOLOGYDisk-shaped specimens (Ø:17 mm, h:2 mm) were fabricated from Paladon 65 (PA), ProBase Hot (PB), Stellon QC-20 (QC) and Vertex Rapid Simplified (VE) denture materials using five different cooling procedures (n=3/procedure): A) Bench-cooling for 10 min and then under running water for 15 min; B) Cooling in water-bath until room temperature; C) Cooling under running water for 15 min; D) Bench-cooling, and E) Bench-cooling for 30 min and under running water for 15 min. A, B, D, E procedures were proposed by the manufacturers, while the C was selected as the fastest one. Control specimens (n=3/material) were fabricated using a long polymerization cycle and bench-cooling. After deflasking, the specimens were ground, polished and stored in individual containers with 10 ml of distilled water for seven days (37oC). The amount of water-eluted MMA was measured per container using isocratic ultra-fast liquid chromatography (UFLC). Data were analyzed using Student's and Welch's t-test (α=0.05). RESULTSMMA values below the lower quantification limit (LoQ=5.9 ppm) were registered in B, C, E (PA); E (PB) and B, D, E (QC) procedures, whereas values below the detection limit (LoD=1.96 ppm) were registered in A, D (PA); A, B, C, D (PB); C, D, E (VE) and in all specimens of the control group. A, B (VE) and A, C (QC) procedures yielded values ranging from 6.4 to 13.2 ppm with insignificant differences in material and procedure factors (p>0.05). CONCLUSIONSThe cooling procedures may affect the monomer elution from denture base materials. The Ε procedure may be considered a universal cooling procedure compared to the ones proposed by the manufacturers, with the lowest residual monomer elution in water.
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