Virus-Induced Inflammation And Central Nervous System Development

Congenital human cytomegalovirus (HCMV) infection is a complex cause of central nervous system (CNS) disease. Infection with HCMV during pregnancy results in virus transmission across the placenta and infection of the fetus. With a seroconversion rate in pregnant women between 1% and 4%, HCMV is the most frequently transmitted virus from mother to developing child. Each year between 2,000 and 4,000 infants will suffer from long-term neurologic deficits as a result of congenital infection. The well documented CNS sequelae resulting from congenital HCMV infection have described a wide range of damage without a specific set of pathologic markers for disease. Together these findings have left the mechanism(s) underlying aberrant CNS development and neurologic disease in congenitally infected infants difficult to pinpoint. Congenital HCMV infection results in focal areas of encephalitis and gliosis in the developing brain; however CNS pathology appears symmetric and diffuse. These findings suggest that cytopathology resulting from direct viral infection is limited and likely cannot account for the global CNS damage reported following in utero HCMV infection. In order to study the mechanism(s) of CMV infection underlying abnormal CNS development, we developed a mouse model characterized by perhiperhal infection of newborn mice with non-lethal doses of murine cytomegalovirus (MCMV). In our model, viral replication and spread are similar to that reported following human CMV infection. Additionally, MCMV infection of neonatal mice recapitulates several aspects of the CNS pathology documented following congenital HCMV infection. MCMV infection of newborn mice results in a large induction of inflammatory responses within the CNS coinciding with the appearance of CNS pathology. For this reason, we hypothesized that soluble mediators of inflammation alter the normal development of the brain. Utilizing this model, we have shown that modulating host inflammatory responses to MCMV infection corrects developmental abnormalities in the neonatal mouse brain. In addition, our work has revealed a potentially damaging infiltrating monocyte population within the CNS of MCMV infected neonates. Further studies utilizing this mouse model may elucidate specific mechanisms of CNS disease subsequent to CMV infection during development, leading to new therapeutic interventions for the treatment of infants congenitally infected with HCMV

Shear bond strength between veneering ceramics and ceria-stabilized zirconia/alumina

STATEMENT OF PROBLEM: Ceria-stabilized tetragonal ZrO(2)/Al(2)O(3) nanocomposite (Ce-TZP/A) offers superior properties compared to yttria-stabilized zirconia (Y-TZP). However, the bond quality to veneering ceramics has not been investigated. PURPOSE: The purpose of this study was to evaluate the bond strength of different veneering ceramics to Ce-TZP/A. MATERIAL AND METHODS: Cubes of Ce-TZP/A (NANOZR) (edge length, 10 mm) were layered with veneering ceramics (5 mm in thickness) with or without application of a liner and sheared at the interface. The effect of different surface treatments (polished with 3-mum diamond paste or airborne-particle abraded) was evaluated with 1 veneering ceramic (Cerabien ZR). Shear bond strength of 5 additional veneering ceramics (IPS e.max, Initial ZR, Triceram, Vintage ZR, or VITA VM 9) to polished Ce-TZP/A was measured (n=10). Polished Y-TZP (Hint-ELs ZrO(2) HIP) veneered with 2 ceramics (Cerabien ZR, Vintage ZR) served as the control. Mean shear bond strength values (MPa) were calculated. The means were statistically analyzed with 2-way ANOVA for the effect of surface treatment and liner, 2-way ANOVA for the effect of different veneering ceramic brands and liner, and 3-way ANOVA for the effect of substrate, veneering ceramic brands, and liner, as well as 1-way ANOVA for the differences between the veneering ceramics. A post hoc Scheffé test was used (alpha=.05). RESULTS: The effects of surface treatment (P=.007) or application of liner (P<.001) were significant. Shear bond strength with different veneering ceramics showed bond strength values with means ranging between 14.2 +/-1.7 MPa (IPS e.max with liner) and 27.5 +/-4.2 MPa (VITA VM 9). A significant difference was found between the results of shear bond tests with Y-TZP and Ce-TZP/A (P=.022). The application of a liner on Y-TZP had no significant effect. CONCLUSIONS: Airborne-particle abrasion is not necessary to enhance the shear bond strength of the evaluated veneering ceramics to Ce-TZP/A. Liners impair the shear bond strength of veneering ceramics to Ce-TZP/A

Paraffin-Based Process for Producing Layered Composites with Cellular Microstructures

A paraffin-based process that results in high-strength bimaterial ceramic layered composites is reported. The process facilitates rolling, folding, and shape retention at room temperature and allows the transition from a laminar to a cellular microstructure during deformation. The strength of sintered alumina/zirconia/alumina composites reached 700 MPa, higher than that of conventional zirconia-toughened alumina composites containing dispersed particles

Myogenic Progenitor Cells Control Extracellular Matrix Production by Fibroblasts during Skeletal Muscle Hypertrophy

Satellite cells, the predominant stem cell population in adult skeletal muscle, are activated in response to hypertrophic stimuli and give rise to myogenic progenitor cells (MPCs) within the extracellular matrix (ECM) that surrounds myofibers. This ECM is composed largely of collagens secreted by interstitial fibrogenic cells, which influence satellite cell activity and muscle repair during hypertrophy and aging. Here we show that MPCs interact with interstitial fibrogenic cells to ensure proper ECM deposition and optimal muscle remodeling in response to hypertrophic stimuli. MPC-dependent ECM remodeling during the first week of a growth stimulus is sufficient to ensure long-term myofiber hypertrophy. MPCs secrete exosomes containing miR-206, which represses Rrbp1, a master regulator of collagen biosynthesis, in fibrogenic cells to prevent excessive ECM deposition. These findings provide insights into how skeletal stem and progenitor cells interact with other cell types to actively regulate their extracellular environments for tissue maintenance and adaptation

Potential Benefits of Combined Statin and Metformin Therapy on Resistance Training Response in Older Individuals

Metformin and statins are currently the focus of large clinical trials testing their ability to counter age-associated declines in health, but recent reports suggest that both may negatively affect skeletal muscle response to exercise. However, it has also been suggested that metformin may act as a possible protectant of statin-related muscle symptoms. The potential impact of combined drug use on the hypertrophic response to resistance exercise in healthy older adults has not been described. We present secondary statin analyses of data from the MASTERS trial where metformin blunted the hypertrophy response in healthy participants (\u3e65 years) following 14 weeks of progressive resistance training (PRT) when compared to identical placebo treatment (n = 94). Approximately one-third of MASTERS participants were taking prescribed statins. Combined metformin and statin resulted in rescue of the metformin-mediated impaired growth response to PRT but did not significantly affect strength. Improved muscle fiber growth may be associated with medication-induced increased abundance of CD11b+/CD206+ M2-like macrophages. Sarcopenia is a significant problem with aging and this study identifies a potential interaction between these commonly used drugs which may help prevent metformin-related blunting of the beneficial effects of PRT

Long-Lasting Impairments in Quadriceps Mitochondrial Health, Muscle Size, and Phenotypic Composition Are Present After Non-Invasive Anterior Cruciate Ligament Injury

Introduction: Despite rigorous rehabilitation aimed at restoring muscle health, anterior cruciate ligament (ACL) injury is often hallmarked by significant long-term quadriceps muscle weakness. Derangements in mitochondrial function are a common feature of various atrophying conditions, yet it is unclear to what extent mitochondria are involved in the detrimental sequela of quadriceps dysfunction after ACL injury. Using a preclinical, non-invasive ACL injury rodent model, our objective was to explore the direct effect of an isolated ACL injury on mitochondrial function, muscle atrophy, and muscle phenotypic transitions. Methods: A total of 40 male and female, Long Evans rats (16-week-old) were exposed to non-invasive ACL injury, while 8 additional rats served as controls. Rats were euthanized at 3, 7, 14, 28, and 56 days after ACL injury, and vastus lateralis muscles were extracted to measure the mitochondrial respiratory control ratio (RCR; state 3 respiration/state 4 respiration), mitochondrial reactive oxygen species (ROS) production, fiber cross sectional area (CSA), and fiber phenotyping. Alterations in mitochondrial function and ROS production were detected using two-way (sex:group) analyses of variance. To determine if mitochondrial characteristics were related to fiber atrophy, individual linear mixed effect models were run by sex. Results: Mitochondria-derived ROS increased from days 7 to 56 after ACL injury (30–100%, P \u3c 0.05), concomitant with a twofold reduction in RCR (P \u3c 0.05). Post-injury, male rats displayed decreases in fiber CSA (days 7, 14, 56; P \u3c 0.05), loss of IIa fibers (day 7; P \u3c 0.05), and an increase in IIb fibers (day 7; P \u3c 0.05), while females displayed no changes in CSA or phenotyping (P \u3e 0.05). Males displayed a positive relationship between state 3 respiration and CSA at days 14 and 56 (P \u3c 0.05), while females only displayed a similar trend at day 14 (P = 0.05). Conclusion: Long-lasting impairments in quadriceps mitochondrial health are present after ACL injury and play a key role in the dysregulation of quadriceps muscle size and composition. Our preclinical data indicate that using mitoprotective therapies may be a potential therapeutic strategy to mitigate alterations in muscle size and characteristic after ACL injury

Influence of cement thickness on resin-zirconia microtensile bond strength

PURPOSE: The aim of this study was to evaluate the influence of resin cement thickness on the microtensile bond strength between zirconium-oxide ceramic and resin cement. MATERIALS AND METHODS: Thirty-two freshly extracted molars were transversely sectioned at the deep dentin level and bonded to air-abraded zirconium oxide ceramic disks. The specimens were divided into 8 groups based on the experimental conditions (cement type: Rely X UniCem or Panavia F 2.0, cement thickness: 40 or 160 µm, storage: thermocycled or not). They were cut into microbeams and stored in 37℃ distilled water for 24 h. Microbeams of non-thermocycled specimens were submitted to a microtensile test, whereas those of thermocycled groups were thermally cycled for 18,000 times immediately before the microtensile test. Three-way ANOVA and Sheffe's post hoc tests were used for statistical analysis (α=95%). RESULTS: All failures occurred at the resin-zirconia interface. Thermocycled groups showed lower microtensile bond strength than non-thermocycled groups (P.05). The number of adhesive failures increased after thermocycling in all experimental conditions. No cohesive failure was observed in any experimental group. CONCLUSION: When resin cements of adhesive monomers are applied over air-abraded zirconia restorations, the degree of fit does not influence the resin-zirconia microtensile bond strength.ope

Characterisation of the immune repertoire of a humanised transgenic mouse through immunophenotyping and high-throughput sequencing

Immunoglobulin loci-transgenic animals are widely used in antibody discovery and increasingly in vaccine response modelling. In this study, we phenotypically characterised B-cell populations from the Intelliselect® Transgenic mouse (Kymouse) demonstrating full B-cell development competence. Comparison of the naïve B-cell receptor (BCR) repertoires of Kymice BCRs, naïve human, and murine BCR repertoires revealed key differences in germline gene usage and junctional diversification. These differences result in Kymice having CDRH3 length and diversity intermediate between mice and humans. To compare the structural space explored by CDRH3s in each species' repertoire, we used computational structure prediction to show that Kymouse naïve BCR repertoires are more human-like than mouse-like in their predicted distribution of CDRH3 shape. Our combined sequence and structural analysis indicates that the naïve Kymouse BCR repertoire is diverse with key similarities to human repertoires, while immunophenotyping confirms that selected naïve B-cells are able to go through complete development