Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington's disease patients.

Quantification of disease-associated proteins in the cerebrospinal fluid (CSF) has been critical for the study and treatment of several neurodegenerative disorders; however, mutant huntingtin protein (mHTT), the cause of Huntington's disease (HD), is at very low levels in CSF and, to our knowledge, has never been measured previously

Biomechanical investigation of a novel ratcheting arthrodesis nail

<p>Abstract</p> <p>Background</p> <p>Knee or tibiotalocalcaneal arthrodesis is a salvage procedure, often with unacceptable rates of nonunion. Basic science of fracture healing suggests that compression across a fusion site may decrease nonunion. A novel ratcheting arthrodesis nail designed to improve dynamic compression is mechanically tested in comparison to existing nails.</p> <p>Methods</p> <p>A novel ratcheting nail was designed and mechanically tested in comparison to a solid nail and a threaded nail using sawbones models (Pacific Research Laboratories, Inc.). Intramedullary nails (IM) were implanted with a load cell (Futek LTH 500) between fusion surfaces. Constructs were then placed into a servo-hydraulic test frame (Model 858 Mini-bionix, MTS Systems) for application of 3 mm and 6 mm dynamic axial displacement (n = 3/group). Load to failure was also measured.</p> <p>Results</p> <p>Mean percent of initial load after 3-mm and 6-mm displacement was 190.4% and 186.0% for the solid nail, 80.7% and 63.0% for the threaded nail, and 286.4% and 829.0% for the ratcheting nail, respectively. Stress-shielding (as percentage of maximum load per test) after 3-mm and 6-mm displacement averaged 34.8% and 28.7% (solid nail), 40.3% and 40.9% (threaded nail), and 18.5% and 11.5% (ratcheting nail), respectively. In the 6-mm trials, statistically significant increase in initial load and decrease in stress-shielding for the ratcheting vs. solid nail (<it>p </it>= 0.029, <it>p </it>= 0.001) and vs. threaded nail (<it>p </it>= 0.012, <it>p </it>= 0.002) was observed. Load to failure for the ratcheting nail; 599.0 lbs, threaded nail; 508.8 lbs, and solid nail; 688.1 lbs.</p> <p>Conclusion</p> <p>With significantly increase of compressive load while decreasing stress-shielding at 6-mm of dynamic displacement, the ratcheting mechanism in IM nails may clinically improve rates of fusion.</p

Bulk Mediated Surface Diffusion: Non Markovian Desorption with Finite First Moment

Here we address a fundamental issue in surface physics: the dynamics of adsorbed molecules. We study this problem when the particle's desorption is characterized by a non Markovian process, while the particle's adsorption and its motion in the bulk are governed by a Markovian dynamics. We study the diffusion of particles in a semi-infinite cubic lattice, and focus on the effective diffusion process at the interface $z = 1$. We calculate analytically the conditional probability to find the particle on the $z=1$ plane as well as the surface dispersion as functions of time. The comparison of these results with Monte Carlo simulations show an excellent agreement.Comment: 16 pages, 7 figs. European Physical Journal B (in press

Can early host responses to mycobacterial infection predict eventual disease outcomes?

Diagnostic tests used for Johne’s disease in sheep either have poor sensitivity and specificity or only detect disease in later stages of infection. Predicting which of the infected sheep are likely to become infectious later in life is currently not feasible and continues to be a major hindrance in disease control. We conducted this longitudinal study to investigate if a suite of diagnostic tests conducted in Mycobacterium avium subspecies paratuberculosis (MAP) exposed lambs at 4 months post infection can accurately predict their clinical status at 12 months post infection. We tracked cellular and humoral responses and quantity of MAP shedding for up to 12 months post challenge in 20 controls and 37 exposed sheep. Infection was defined at necropsy by tissue culture and disease spectrum by lesion type. Data were analysed using univariable and multivariable logistic regression models and a subset of variables from the earliest period post inoculation (4 months) was selected for predicting disease outcomes later on (12 months). Sensitivity and specificity of tests and their combinations in series and parallel were determined. Early elevation in faecal MAP DNA quantity and a lower interferon gamma (IFNγ) response were significantly associated with sheep becoming infectious as well as progressing to severe disease. Conversely, early low faecal MAP DNA and higher interleukin-10 responses were significantly associated with an exposed animal developing protective immunity. Combination of early elevated faecal MAP DNA or lower IFNγ response had the highest sensitivity (75%) and specificity (81%) for identifying sheep that would become infectious. Collectively, these results highlight the potential for combined test interpretation to aid in the early prediction of sheep susceptibility to MAP infection. KEYWORDS: Paratuberculosis; diagnostic tests; Mycobacterium; faecal DNA; Johne’s disease; interferon gamma.This work was supported by Meat and Livestock Australia and by Cattle Council of Australia, Sheepmeat Council of Australia and WoolProducers Australia through Animal Health Australia

Carcinomas assemble a filamentous CXCL12-keratin-19 coating that suppresses T cell-mediated immune attack.

Cancer immunotherapy frequently fails because most carcinomas have few T cells, suggesting that cancers can suppress T cell infiltration. Here, we show that cancer cells of human pancreatic ductal adenocarcinoma (PDA), colorectal cancer, and breast cancer are coated with transglutaminase-2 (TGM2)-dependent covalent CXCL12-keratin-19 (KRT19) heterodimers that are organized as filamentous networks. Since a dimeric form of CXCL12 suppresses the motility of human T cells, we determined whether this polymeric CXCL12-KRT19 coating mediated T cell exclusion. Mouse tumors containing control PDA cells exhibited the CXCL12-KRT19 coating, excluded T cells, and did not respond to treatment with anti-PD-1 antibody. Tumors containing PDA cells not expressing either KRT19 or TGM2 lacked the CXCL12-KRT19 coating, were infiltrated with activated CD8+ T cells, and growth was suppressed with anti-PD-1 antibody treatment. Thus, carcinomas assemble a CXCL12-KRT19 coating to evade cancer immune attack

Spectroscopy, MOST Photometry, and Interferometry of MWC 314: Is it an LBV or an interacting binary?

MWC 314 is a bright candidate luminous blue variable that resides in a fairly close binary system, with an orbital period of 60.753$\pm$0.003 d. We observed MWC 314 with a combination of optical spectroscopy, broad-band ground- and space-based photometry, as well as with long baseline, near-infrared interferometry. We have revised the single-lined spectroscopic orbit and explored the photometric variability. The orbital light curve displays two minima each orbit that can be partially explained in terms of the tidal distortion of the primary that occurs around the time of periastron. The emission lines in the system are often double-peaked and stationary in their kinematics, indicative of a circumbinary disc. We find that the stellar wind or circumbinary disc is partially resolved in the K\prime-band with the longest baselines of the CHARA Array. From this analysis, we provide a simple, qualitative model in an attempt to explain the observations. From the assumption of Roche Lobe overflow and tidal synchronisation at periastron, we estimate the component masses to be M1 $\approx 5$ M$_\odot$ and M2$\approx 15$ M$_\odot$, which indicates a mass of the LBV that is extremely low. In addition to the orbital modulation, we discovered two pulsational modes with the MOST satellite. These modes are easily supported by a low-mass hydrogen-poor star, but cannot be easily supported by a star with the parameters of an LBV. The combination of these results provides evidence that the primary star was likely never a normal LBV, but rather is the product of binary interactions. As such, this system presents opportunities for studying mass-transfer and binary evolution with many observational techniques.Comment: 26 pages, 7 figures, 5 tables, 2 appendices with 7 additional tables and 2 additional figures. Accepted for publication in MNRA

Identification of distinct conformations associated with monomers and fibril assemblies of mutant huntingtin

The N-terminal fragments of mutant huntingtin (mHTT) misfold and assemble into oligomers, which ultimately bundle into insoluble fibrils. Conformations unique to various assemblies of mHTT remain unknown. Knowledge on the half-life of various multimeric structures of mHTT is also scarce. Using a panel of four new antibodies named PHP1–4, we have identified new conformations in monomers and assembled structures of mHTT. PHP1 and PHP2 bind to epitopes within the proline-rich domain (PRD), whereas PHP3 and PHP4 interact with motifs formed at the junction of polyglutamine (polyQ) and polyproline (polyP) repeats of HTT. The PHP1- and PHP2-reactive epitopes are exposed in fibrils of mHTT exon1 (mHTTx1) generated from recombinant proteins and mHTT assemblies, which progressively accumulate in the nuclei, cell bodies and neuropils in the brains of HD mouse models. Notably, electron microscopic examination of brain sections of HD mice revealed that PHP1- and PHP2-reactive mHTT assemblies are present in myelin sheath and in vesicle-like structures. Moreover, PHP1 and PHP2 antibodies block seeding and subsequent fibril assembly of mHTTx1 in vitro and in a cell culture model of HD. PHP3 and PHP4 bind to epitopes in full-length and N-terminal fragments of monomeric mHTT and binding diminishes as the mHTTx1 assembles into fibrils. Interestingly, PHP3 and PHP4 also prevent the aggregation of mHTTx1 in vitro highlighting a regulatory function for the polyQ-polyP motifs. These newly detected conformations may affect fibril assembly, stability and intercellular transport of mHTT

Behavioral Changes in Aging but Not Young Mice after Neonatal Exposure to the Polybrominated Flame Retardant DecaBDE

BACKGROUND: After several decades of commercial use, the flame-retardant chemicals polybrominated diphenyl ethers (PBDEs) and their metabolites are pervasive environmental contaminants and are detected in the human body. Decabrominated diphenyl ether (decaBDE) is currently the only PBDE in production in the United States. OBJECTIVES: Little is known about the health effects of decaBDE. In the present study we examined the effects of neonatal decaBDE exposure on behavior in mice at two ages. METHODS: Neonatal male and female C57BL6/J mice were exposed to a daily oral dose of 0, 6, or 20 mg/kg decaBDE from postnatal days 2 through 15. Two age groups were examined: a cohort that began training during young adulthood and an aging cohort of littermates that began training at 16 months of age. Both cohorts were tested on a series of operant procedures that included a fixed-ratio I schedule of reinforcement, a fixed-interval (FI) 2-min schedule, and a light-dark visual discrimination. RESULTS: We observed minimal effects on the light-dark discrimination in the young cohort, with no effects on the other tasks. The performance of the aging cohort was significantly affected by decaBDE. On the FI schedule, decaBDE exposure increased the overall response rate. On the light-dark discrimination, older treated mice learned the task more slowly, made fewer errors on the first-response choice of a trial but more perseverative errors after an initial error, and had lower latencies to respond compared with controls. Effects were observed in both dose groups and sexes on various measures. CONCLUSIONS: These findings suggest that neonatal decaBDE exposure produces effects on behavioral tasks in older but not younger animals. The behavioral mechanisms responsible for the pattern of observed effects may include increased impulsivity, although further research is required

Science Requirements and Conceptual Design for a Polarized Medium Energy Electron-Ion Collider at Jefferson Lab

This report presents a brief summary of the science opportunities and program of a polarized medium energy electron-ion collider at Jefferson Lab and a comprehensive description of the conceptual design of such a collider based on the CEBAF electron accelerator facility.Comment: 160 pages, ~93 figures This work was supported by the U.S. Department of Energy, Office of Nuclear Physics, under Contract No. DE-AC05-06OR23177, DE-AC02-06CH11357, DE-AC05-060R23177, and DESC0005823. The U.S. Government retains a non-exclusive, paid-up, irrevocable, world-wide license to publish or reproduce this manuscript for U.S. Government purpose