New promising techniques for depositing hydroxyapatite (HA) and calcium phosphate (CaP) coatings on medical devices are continuously being investigated. Given the vast number of experimental ...deposition process currently available, this review will focus only on CaP and/or HA coatings produced using the sputtering process. This review will discuss the characterization of sputtered CaP coatings before and after post-deposition treatments and tissue responses to some of the characterized coating surfaces. From the studies observed in the literature, current research on sputtered CaP coatings has shown some promises that may eliminate some of the problems associated with the plasma-spraying process. It has been generally accepted that sputtered HA and CaP coatings improve bone strength and initial osseointegration rate. However, optimal coating properties required to achieve maximal bone response are yet to be reported. As such, the use of well-characterized sputtered CaP and/or HA surfaces in the evaluation of biological responses should be well documented to avoid controversial results. In addition, future investigations of the sputtering process should include clinical trials, to continue the understanding of bone responses to coated-implant surfaces of different properties, and the possibility of coupling sputtered HA and CaP coatings with growth factors.
MicroRNA-mediated gene silencing is a fundamental mechanism in the regulation of gene expression. It remains unclear how the efficiency of RNA silencing could be influenced by RNA-binding proteins ...associated with the microRNA-induced silencing complex (miRISC). Here we report that fused in sarcoma (FUS), an RNA-binding protein linked to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), interacts with the core miRISC component AGO2 and is required for optimal microRNA-mediated gene silencing. FUS promotes gene silencing by binding to microRNA and mRNA targets, as illustrated by its action on miR-200c and its target ZEB1. A truncated mutant form of FUS that leads its carriers to an aggressive form of ALS, R495X, impairs microRNA-mediated gene silencing. The C. elegans homolog fust-1 also shares a conserved role in regulating the microRNA pathway. Collectively, our results suggest a role for FUS in regulating the activity of microRNA-mediated silencing.
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•FUS associates with miRISC components AGO2 and miRNAs and their target transcripts•FUS is required for optimal miRNA-mediated gene silencing•C. elegans FUS homolog is involved in miRNA-mediated silencing•ALS-linked FUS R495X mutant impedes miRNA-mediated silencing
Zhang et al. find that the RNA-binding protein FUS is required for miRNA-mediated gene silencing. FUS interacts with Argonaute, microRNAs, and target transcripts, promoting interactions that lead to gene silencing.
Osteoblasts have recently been found to play a role in regulating glucose metabolism through secretion of osteocalcin. It is unknown, however, how this osteoblast function is regulated ...transcriptionally. As FoxO1 is a forkhead family transcription factor known to regulate several key aspects of glucose homeostasis, we investigated whether its expression in osteoblasts may contribute to its metabolic functions. Here we show that mice lacking Foxo1 only in osteoblasts had increased pancreatic beta cell proliferation, insulin secretion, and insulin sensitivity. The ability of osteoblast-specific FoxO1 deficiency to affect metabolic homeostasis was due to increased osteocalcin expression and decreased expression of Esp, a gene that encodes a protein responsible for decreasing the bioactivity of osteocalcin. These results indicate that FoxO1 expression in osteoblasts contributes to FoxO1 control of glucose homeostasis and identify FoxO1 as a key modulator of the ability of the skeleton to function as an endocrine organ regulating glucose metabolism.
Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to ...evaluate the efficacy of bococizumab in patients at high cardiovascular risk.
In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow-up was 10 months.
At 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of -56.0% in the bococizumab group and +2.9% in the placebo group, for a between-group difference of -59.0 percentage points (P<0.001) and a median reduction from baseline of 64.2% (P<0.001). In the lower-risk, shorter-duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter 1.8 mmol per liter and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval CI, 0.80 to 1.22; P=0.94). In the higher-risk, longer-duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter 2.6 mmol per liter and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P=0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P=0.08). Injection-site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P<0.001).
In two randomized trials comparing the PCSK9 inhibitor bococizumab with placebo, bococizumab had no benefit with respect to major adverse cardiovascular events in the trial involving lower-risk patients but did have a significant benefit in the trial involving higher-risk patients. (Funded by Pfizer; SPIRE-1 and SPIRE-2 ClinicalTrials.gov numbers, NCT01975376 and NCT01975389 .).
Abstract Background New-onset diabetes after transplantation (NODAT) is a serious metabolic complication that may follow renal transplantation. Matrix metalloproteinases (MMPs) contribute to insulin ...insufficiency and beta-cell dysfunction in a rat model. The MMP-2 concentrations were lower in patients with type 2 diabetes mellitus, and the plasma MMPs levels were related to diabetes. Similar to the pathogenesis of type 2 diabetes mellitus, insulin resistance and insulin secretion dysfunction occur in patients with the development of NODAT. Therefore, we examined the association between NODAT and 11 single-nucleotide polymorphisms (SNPs) located within the 3 genes of MMPs that might be related to NODAT. Methods A total of 309 renal transplant recipients without a history of diabetes were included in this study. DNA was extracted from the blood samples of recipients, and we analyzed the association between the development of NODAT and a panel of 11 SNPs within 3 MMP genes (MMP-1, MMP-2, and MMP-3). Results In terms of allele frequencies, rs243849*C (MMP-2) was significantly higher in patients with NODAT. Two of the 11 (18.1%) SNPs were significantly associated with NODAT development after adjusting for age, sex, and tacrolimus usage: MMP-2 (rs1132896) and MMP-2 (rs243849). In the multiple logistic regression analysis, these 2 SNPs were significantly associated with the development of NODAT in the codominant and recessive or codominant and dominant models. Conclusions MMP-2 gene rs1132896 and rs243849 polymorphisms may serve as genetic markers for the development of NODAT. The exact molecular mechanisms still must be clarified.
The cJun N-terminal kinase 1 (JNK1) is implicated in diet-induced obesity. Indeed, germline ablation of the murine Jnk1 gene prevents diet-induced obesity. Here we demonstrate that selective ...deficiency of JNK1 in the murine nervous system is sufficient to suppress diet-induced obesity. The failure to increase body mass is mediated, in part, by increased energy expenditure that is associated with activation of the hypothalamic-pituitary-thyroid axis. Disruption of thyroid hormone function prevents the effects of nervous system JNK1 deficiency on body mass. These data demonstrate that the hypothalamic-pituitary-thyroid axis represents an important target of metabolic signaling by JNK1.
Statement of Problem. Little information exists regarding the filler morphology and loading of composites with respect to their effects on selected mechanical properties and fracture toughness. ...Purpose. The objectives of this study were to: (1) classify commercial composites according to filler morphology, (2) evaluate the influence of filler morphology on filler loading, and (3) evaluate the effect of filler morphology and loading on the hardness, flexural strength, flexural modulus, and fracture toughness of contemporary composites. Material and Methods. Field emission scanning electron microscopy/energy dispersive spectroscopy was used to classify 3 specimens from each of 14 commercial composites into 4 groups according to filler morphology. The specimens (each 5 × 2.5 × 15 mm) were derived from the fractured remnants after the fracture toughness test. Filler weight content was determined by the standard ash method, and the volume content was calculated using the weight percentage and density of the filler and matrix components. Microhardness was measured with a Vickers hardness tester, and flexural strength and modulus were measured with a universal testing machine. A 3-point bending test (ASTM E-399) was used to determine the fracture toughness of each composite. Data were compared with analysis of variance followed by Duncan's multiple range test, both at the P<.05 level of significance. Results. The composites were classified into 4 categories according to filler morphology: prepolymerized, irregular-shaped, both prepolymerized and irregular-shaped, and round particles. Filler loading was influenced by filler morphology. Composites containing prepolymerized filler particles had the lowest filler content (25% to 51% of filler volume), whereas composites containing round particles had the highest filler content (59% to 60% of filler volume). The mechanical properties of the composites were related to their filler content. Composites with the highest filler by volume exhibited the highest flexural strength (120 to 129 MPa), flexural modulus (12 to 15 GPa), and hardness (101 to 117 VHN). Fracture toughness was also affected by filler volume, but maximum toughness was found at a threshold level of approximately 55% filler volume. Conclusion. Within the limitations of this study, the commercial composites tested could be classified by their filler morphology. This property influenced filler loading. Both filler morphology and filler loading influenced flexural strength, flexural modulus, hardness, and fracture toughness. (J Prosthet Dent 2002;87:642-9.)
Obesity is a major cause of insulin resistance, and weight loss is shown to improve glucose homeostasis. But the underlying mechanism and the role of inflammation remain unclear. Male C57BL/6 mice ...were fed a high-fat diet (HFD) for 12 wk. After HFD, weight loss was induced by changing to a low-fat diet (LFD) or exercise with continuous HFD. The weight loss effects on energy balance and insulin sensitivity were determined using metabolic cages and hyperinsulinemic euglycemic clamps in awake mice. Diet and exercise intervention for 3 wk caused a modest weight loss and improved glucose homeostasis. Weight loss dramatically reduced local inflammation in skeletal muscle, liver, and heart but not in adipose tissue. Exercise-mediated weight loss increased muscle glucose metabolism without affecting Akt phosphorylation or lipid levels. LFD-mediated weight loss reduced lipid levels and improved insulin sensitivity selectively in liver. Both weight loss interventions improved cardiac glucose metabolism. These results demonstrate that a short-term weight loss with exercise or diet intervention attenuates obesity-induced local inflammation and selectively improves insulin sensitivity in skeletal muscle and liver. Our findings suggest that local factors, not adipose tissue inflammation, are involved in the beneficial effects of weight loss on glucose homeostasis.
The paper presents a review of major features of the crystalline silicon on glass (CSG) technology, its achievements, limitations and challenges, and latest developments. CSG cells are fabricated by ...solid-state crystallisation (SPC) of 1.5–3.5µm thick precursor diodes prepared by PECVD or ebeam evaporation followed by thermal annealing, hydrogen passivation and metallisation. The highest efficiency of 10.4% was demonstrated on a PECVD minimodule on textured borosilicate glass. The best performing ebeam-evaporated cells on planar glass reached 8.6% efficiency. CSG cells were also produced on low-cost soda-lime glass with 8.1% and 7.1% efficiencies on PECVD and ebeam material respectively. The performance of SPC CSG cells is limited to below 11% because high defect density in SPC material limits VOC and 1.5–3.5µm cell thickness limits JSC. A breakthrough came about when thicker poly-Si films with low defect density on glass were prepared by liquid-phase crystallisation (Amkreutz, 2011) leading to development of the next generation, liquid-phase crystallised silicon on glass (LPCSG) solar cells. The best performing LPCSG cells are made by line-focus laser crystallisation of 10µm thick ebeam silicon films on dielectric layer coated borosilicate glass. High material quality is confirmed by low defect density observed in TEM images, high carrier mobilities, and minority carrier lifetime longer than 260ns. An intermediate dielectric layer can be SiCx, SiOx, SiNx or their combination and its properties are crucial for cell fabrication and performance. Dopants are introduced into the LPCSG cell absorber either during film deposition or diffused from doped intermediate layer during crystallisation. Light-trapping texture is formed on the exposed silicon surface by wet etching. A cell emitter is created by diffusion from spin-on-dopant source. Cell metallisation is based on point contacts between Al and cell emitter and absorber accessed through vias etched through cell layers to different depths. LPCSG cells outperformed CSG cells, with record VOC of 585mV and efficiency of 11.7%. Efficiencies above 13% are achievable by improving light-coupling and contacting.
•Efficiency of solid-phase crystallised Si on glass (CSG) solar cells prepared by low rate PECVD peaked at 10.4%.•CSG cell performance is limited due to high defect density in SPC Si films.•A few versatile and potent processes and techniques for solar cell fabrication have been developed within the CSG technology.•Liquid-phase crystallised Si on glass (LPCSG) films with low defect density and high electronic quality are obtained by diode laser crystallisation.•Solar cells fabricated from LPCSG films using the CSG technology have achieved 585mV open circuit voltage and 11.7% efficiency.
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