The effect of an alginate carrier on bone formation in a hydroxyapatite scaffold.

This study investigated the osteoconductive properties of a porous hydroxyapatite (HA) scaffold manufactured using a novel technique similar to the bread-making process, alone and in combination with an alginate polysaccharide fiber gel (HA/APFG putty) and autologous bone marrow aspirate (BMA). The hypothesis was that the HA/APFG putty would be as osteoconductive as granular HA and that the presence of BMA would further enhance bone formation in an ovine femoral condyle critical defect model. Thirty-six defects were created and either (1) porous HA granules, (2) HA/APFG putty, or (3) HA/APFG putty + BMA were implanted. After retrieval at 6 and 12 weeks, image analysis techniques were used to quantify bone apposition rates, new bone area, bone-HA scaffold contact, and implant resorption. At 6 weeks postsurgery, significantly lower bone apposition rates were observed in the HA/APFG putty group when compared to the HA (p = 0.014) and HA/APFG putty + BMA (p = 0.014) groups. At 12 weeks, significantly increased amounts of new bone formation were measured within the HA scaffold (33.56 ± 3.53%) when compared to both the HA/APFG putty (16.69 ± 2.7%; p = 0.043) and the defects containing HA/APFG putty + BMA (19.31 ± 3.8%; p = 0.043). The use of an APFG gel as a carrier for injectable CaP bone substitute materials delayed bone formation in this model compared to HA granules alone which enhanced bone formation especially within the interconnected smaller pores. Our results also showed that the addition of autologous BMA did not further enhance its osteoconductive properties. Further study is required to optimize the degradation rate of this APFG binding agent before using as a directly injectable material for repair of bone defect. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2015

Perturbation with Intrabodies Reveals That Calpain Cleavage Is Required for Degradation of Huntingtin Exon 1

Background: Proteolytic processing of mutant huntingtin (mHtt), the protein that causes Huntington's disease (HD), is critical for mHtt toxicity and disease progression. mHtt contains several caspase and calpain cleavage sites that generate N-terminal fragments that are more toxic than full-length mHtt. Further processing is then required for the degradation of these fragments, which in turn, reduces toxicity. This unknown, secondary degradative process represents a promising therapeutic target for HD. Methodology/Principal Findings: We have used intrabodies, intracellularly expressed antibody fragments, to gain insight into the mechanism of mutant huntingtin exon 1 (mHDx-1) clearance. Happ1, an intrabody recognizing the proline-rich region of mHDx-1, reduces the level of soluble mHDx-1 by increasing clearance. While proteasome and macroautophagy inhibitors reduce turnover of mHDx-1, Happ1 is still able to reduce mHDx-1 under these conditions, indicating Happ1-accelerated mHDx-1 clearance does not rely on these processes. In contrast, a calpain inhibitor or an inhibitor of lysosomal pH block Happ1-mediated acceleration of mHDx-1 clearance. These results suggest that mHDx-1 is cleaved by calpain, likely followed by lysosomal degradation and this process regulates the turnover rate of mHDx-1. Sequence analysis identifies amino acid (AA) 15 as a potential calpain cleavage site. Calpain cleavage of recombinant mHDx-1 in vitro yields fragments of sizes corresponding to this prediction. Moreover, when the site is blocked by binding of another intrabody, V_L12.3, turnover of soluble mHDx-1 in living cells is blocked. Conclusions/Significance: These results indicate that calpain-mediated removal of the 15 N-terminal AAs is required for the degradation of mHDx-1, a finding that may have therapeutic implications

Efficiency enhancement and angle-dependent color change in see-through organic photovoltaics using distributed Bragg reflectors

A distributed Bragg reflector (DBR) is conducted as a bottom reflector in see-through organic photovoltaics (OPVs) with an active layer of poly(3-hexylthiophene) and phenyl-C61-butyric acid methyl ester (P3HT:PCBM). The DBR consists of alternative layers of the high-and low-refractive index materials of Ta2O5 (n = 2.16) and SiO2 (n = 1.46). The DBR selectively reflects the light within a specific wavelength region (490 nm-630 nm) where the absorbance of P3HT: PCBM is maximum. The see-through OPVs fabricated on DBR exhibit efficiency enhancement by 31% compared to the device without DBR. Additionally, the angle-dependent transmittance of DBR is analysed using optical simulation and verified by experimental results. As the incident angle of light increases, peak of reflectance shifts to shorter wavelength and the bandwidth gets narrower. This unique angle-dependent optical properties of DBR allows the facile color change of see-through OPVs. (C) 2016 AIP Publishing LLC.open1110sciescopu

Specific involvement of atypical PKCζ/PKMζ in spinal persistent nociceptive processing following peripheral inflammation in rat.

BACKGROUND: Central sensitization requires the activation of various intracellular signalling pathways within spinal dorsal horn neurons, leading to a lowering of activation threshold and enhanced responsiveness of these cells. Such plasticity contributes to the manifestation of chronic pain states and displays a number of features of long-term potentiation (LTP), a ubiquitous neuronal mechanism of increased synaptic strength. Here we describe the role of a novel pathway involving atypical PKCζ/PKMζ in persistent spinal nociceptive processing, previously implicated in the maintenance of late-phase LTP. RESULTS: Using both behavioral tests and in vivo electrophysiology in rats, we show that inhibition of this pathway, via spinal delivery of a myristoylated protein kinase C-ζ pseudo-substrate inhibitor, reduces both pain-related behaviors and the activity of deep dorsal horn wide dynamic range neurons (WDRs) following formalin administration. In addition, Complete Freund's Adjuvant (CFA)-induced mechanical and thermal hypersensitivity was also reduced by inhibition of PKCζ/PKMζ activity. Importantly, this inhibition did not affect acute pain or locomotor behavior in normal rats and interestingly, did not inhibited mechanical allodynia and hyperalgesia in neuropathic rats. Pain-related behaviors in both inflammatory models coincided with increased phosphorylation of PKCζ/PKMζ in dorsal horn neurons, specifically PKMζ phosphorylation in formalin rats. Finally, inhibition of PKCζ/PKMζ activity decreased the expression of Fos in response to formalin and CFA in both superficial and deep laminae of the dorsal horn. CONCLUSIONS: These results suggest that PKCζ, especially PKMζ isoform, is a significant factor involved in spinal persistent nociceptive processing, specifically, the manifestation of chronic pain states following peripheral inflammation

A Prospective Evaluation of Quick Intraoperative Parathyroid Hormone Assay at the Time of Skin Closure in Predicting Clinically Relevant Hypocalcemia after Thyroidectomy

BACKGROUND: Post-thyroidectomy hypocalcemia is a major contributing factor in delayed hospital discharge and dissuading surgeons from ambulatory thyroidectomy. We prospectively evaluated the accuracy and reliability of quick parathyroid hormone level measurement at skin closure (PTH-SC) in predicting clinically relevant hypocalcemia (i.e., patients requiring calcium +/- calcitriol supplements on hospital discharge). METHODS: Of the 117 patients who underwent a total or completion total thyroidectomy and PTH-SC, 17 (14.5 %) had hypocalcemic symptoms or adjusted calcium 1 pmol/L) had a higher specificity (95.0 %) and AUC (0.887) than serial calcium monitoring or PTH-D1 alone. Although 3/98 of patients with PTH-SC >1 pmol/L required calcium supplements on discharge, they required only the minimum amount to maintain normocalcemia. CONCLUSION: PTH-SC is an accurate and reliable means of predicting clinically relevant hypocalcemia. It would be reasonable to discharge those with PTH-SC >1 pmol/L on the same operative day as the risk of life-threatening hypocalcemia would seem unlikely.published_or_final_versio

State of the California current 2012-13: No such thing as an “average” year

This report reviews the state of the California Current System (CCS) between winter 2012 and spring 2013, and includes observations from Washington State to Baja California. During 2012, large-scale climate modes indicated the CCS remained in a cool, productive phase present since 2007. The upwelling season was delayed north of 42°N, but regions to the south, especially 33° to 36°N, experienced average to above average upwelling that persisted throughout the summer. Contrary to the indication of high production suggested by the climate indices, chlorophyll observed from surveys and remote sensing was below average along much of the coast. As well, some members of the forage assemblages along the coast experienced low abundances in 2012 surveys. Specifically, the concentrations of all lifestages observed directly or from egg densities of Pacific sardine, Sardinops sagax, and northern anchovy, Engraulis mordax, were less than previous years’ survey estimates. However, 2013 surveys and observations indicate an increase in abundance of northern anchovy. During winter 2011/2012, the increased presence of northern copepod species off northern California was consistent with stronger southward transport. Krill and small-fraction zooplankton abundances, where examined, were generally above average. North of 42°N, salps returned to typical abundances in 2012 after greater observed concentrations in 2010 and 2011. In contrast, salp abundance off central and southern California increased after a period of southward transport during winter 2011/2012. Reproductive success of piscivorous Brandt’s cormorant, Phalacrocorax penicillatus, was reduced while planktivorous Cassin’s auklet, Ptychoramphus aleuticus was elevated. Differences between the productivity of these two seabirds may be related to the available forage assemblage observed in the surveys. California sea lion pups from San Miguel Island were undernourished resulting in a pup mortality event perhaps in response to changes in forage availability. Limited biological data were available for spring 2013, but strong winter upwelling coastwide indicated an early spring transition, with the strong upwelling persisting into early summer

Natalizumab affects T-cell phenotype in multiple sclerosis: implications for JCV reactivation

The anti-CD49d monoclonal antibody natalizumab is currently an effective therapy against the relapsing-remitting form of multiple sclerosis (RRMS). Natalizumab therapeutic efficacy is limited by the reactivation of the John Cunningham polyomavirus (JCV) and development of progressive multifocal leukoencephalopathy (PML). To correlate natalizumab-induced phenotypic modifications of peripheral blood T-lymphocytes with JCV reactivation, JCV-specific antibodies (serum), JCV-DNA (blood and urine), CD49d expression and relative abundance of peripheral blood T-lymphocyte subsets were longitudinally assessed in 26 natalizumab-treated RRMS patients. Statistical analyses were performed using GraphPad Prism and R. Natalizumab treatment reduced CD49d expression on memory and effector subsets of peripheral blood T-lymphocytes. Moreover, accumulation of peripheral blood CD8+ memory and effector cells was observed after 12 and 24 months of treatment. CD4+ and CD8+ T-lymphocyte immune-activation was increased after 24 months of treatment. Higher percentages of CD8+ effectors were observed in subjects with detectable JCV-DNA. Natalizumab reduces CD49d expression on CD8+ T-lymphocyte memory and effector subsets, limiting their migration to the central nervous system and determining their accumulation in peripheral blood. Impairment of central nervous system immune surveillance and reactivation of latent JCV, can explain the increased risk of PML development in natalizumab-treated RRMS subjects

Relics as probes of galaxy cluster mergers

Galaxy clusters grow by mergers with other clusters and galaxy groups. These mergers create shocks within the intracluster medium (ICM). It is proposed that within the shocks particles can be accelerated to extreme energies. In the presence of a magnetic field these particles should then form large regions emitting synchrotron radiation, creating so-called radio relics. An example of a cluster with relics is CIZA J2242.8+5301. Here we present hydrodynamical simulations of idealized binary cluster collisions with the aim of constraining the merger scenario for this cluster. We conclude that by using the location, size and width of double radio relics we can set constraints on the mass ratios, impact parameters, timescales, and viewing geometries of binary cluster merger events.Comment: Accepted for publication in special issue of Journal of Astrophysics and Astronomy: conference proceedings of "Diffuse Relativistic Plasmas" conference, Bangalore, 1-4 March 2011, 4 pages, 2 figure

Hsp21potentiates antifungal drug tolerance in Candida albicans

Peer reviewedPublisher PD