Art. XIX.—On the Mugdhāvabodhamauktika, and its evidence as to Old Gujarātī

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Origin of Ultralow Friction andWear in Ultrananocrystalline Diamond

The impressively low friction and wear of diamond in humid environments is debated to originate from either the stability of the passivated diamond surface or sliding-induced graphitization/rehybridization of carbon. We find ultralow friction and wear for ultrananocrystalline diamond surfaces even in dry environments, and observe negligible rehybridization except for a modest, submonolayer amount under the most severe conditions (high load, low humidity). This supports the passivation hypothesis, and establishes a new regime of exceptionally low friction and wear for diamond

Attitudes and perceived social norms towards drug use among gay and bisexual men in Australia

Background: Gay and bisexual men (GBM) report distinctive patterns and contexts of drug use, yet little has been published about their attitudes towards drug use. Objectives: We developed measures of attitudes and perceived social norms towards drug use, and examined covariates of more accepting attitudes and norms among GBM in Australia. Methods: We analysed baseline data from the [removed for blinded review] study. This is an online prospective observational study of drug use among Australian GBM. We used principal components factor analysis to generate two attitudinal scales assessing “drug use for social and sexual enhancement” and “perceptions of drug risk”. A third perceived social norms scale examined “acceptability of drug use among gay friends”. Results: Among 2,112 participants, 61% reported illicit drug use in the preceding 6 months. Stronger endorsement of drug use for social and sexual engagement and lower perceptions of drug risk were found among men who were more socially engaged with other gay men and reported regular drug use and drug use for sex. In multivariate analyses, all three scales were associated with recent drug use (any use in the previous six months), but only the drug use for social and sexual enhancement scale was associated with regular (at least monthly) use. Conclusions: Drug use and sex are difficult to disentangle for some GBM, and health services and policies could benefit from a better understanding of attitudinal and normative factors associated with drug use in gay social networks, while recognising the role of pleasure in substance use

Influence of Surface Passivation on the Friction and Wear Behavior of Ultrananocrystalline Diamond and Tetrahedral Amorphous Carbon Thin Films

Highly sp3-bonded, nearly hydrogen-free carbon-based materials can exhibit extremely low friction and wear in the absence of any liquid lubricant, but this physical behavior is limited by the vapor environment. The effect of water vapor on friction and wear is examined as a function of applied normal force for two such materials in thin film form: one that is fully amorphous in structure (tetrahedral amorphous carbon, or ta-C) and one that is polycrystalline with sp3 to disordered sp2 bonding is observed, no crystalline graphite formation is observed for either film. Rather, the primary solid-lubrication mechanism is the passivation of dangling bonds by OH and H from the dissociation of vapor-phase H2O. This vapor-phase lubrication mechanism is highly effective, producing friction coefficients as low as 0.078 for ta-C and 0.008 for UNCD, and wear rates requiring thousands of sliding passes to produce a few nanometers of wear

Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS)

Background: Amyotrophic lateral sclerosis (ALS), a common late-onset neurodegenerative disease, is associated with fronto-temporal dementia (FTD) in 3-10% of patients. A mutation in CHMP2B was recently identified in a Danish pedigree with autosomal dominant FTD. Subsequently, two unrelated patients with familial ALS, one of whom also showed features of FTD, were shown to carry missense mutations in CHMP2B. The initial aim of this study was to determine whether mutations in CHMP2B contribute more broadly to ALS pathogenesis. Methodology/Principal Findings: Sequencing of CHMP2B in 433 ALS cases from the North of England identified 4 cases carrying 3 missense mutations, including one novel mutation, p. Thr104Asn, none of which were present in 500 neurologically normal controls. Analysis of clinical and neuropathological data of these 4 cases showed a phenotype consistent with the lower motor neuron predominant (progressive muscular atrophy (PMA)) variant of ALS. Only one had a recognised family history of ALS and none had clinically apparent dementia. Microarray analysis of motor neurons from CHMP2B cases, compared to controls, showed a distinct gene expression signature with significant differential expression predicting disassembly of cell structure; increased calcium concentration in the ER lumen; decrease in the availability of ATP; down-regulation of the classical and p38 MAPK signalling pathways, reduction in autophagy initiation and a global repression of translation. Transfection of mutant CHMP2B into HEK-293 and COS-7 cells resulted in the formation of large cytoplasmic vacuoles, aberrant lysosomal localisation demonstrated by CD63 staining and impairment of autophagy indicated by increased levels of LC3-II protein. These changes were absent in control cells transfected with wild-type CHMP2B. Conclusions/Significance: We conclude that in a population drawn from North of England pathogenic CHMP2B mutations are found in approximately 1% of cases of ALS and 10% of those with lower motor neuron predominant ALS. We provide a body of evidence indicating the likely pathogenicity of the reported gene alterations. However, absolute confirmation of pathogenicity requires further evidence, including documentation of familial transmission in ALS pedigrees which might be most fruitfully explored in cases with a LMN predominant phenotype

Application of ECH to the Study of Transport in ITER Baseline Scenario-like Discharges in DIII-D

Recent DIII-D experiments in the ITER Baseline Scenario (IBS) have shown strong increases in fluctuations and correlated reduction of confinement associated with entering the electron-heating-dominated regime with strong electron cyclotron heating (ECH). The addition of 3.2 MW of 110 GHz EC power deposited at ρ~0.42 to IBS discharges with ~3 MW of neutral beam injection causes large increases in low-k and medium-k turbulent density fluctuations observed with Doppler backscatter (DBS), beam emission spectroscopy (BES) and phase-contrast imaging (PCI) diagnostics, correlated with decreases in the energy, particle, and momentum confinement times. Power balance calculations show the electron heat diffusivity χ[subscript e] increases significantly in the mid-radius region 0.4<ρ<0.8, which is roughly the same region where the DBS and BES diagnostics show the increases in turbulent density fluctuations. Confinement of angular momentum is also reduced during ECH. Studies with the TGYRO transport solver show that the model of turbulent transport embodied in the TGLF code quantitatively reproduces the measured transport in both the neutral beam (NB)-only and in the NB plus EC cases. A simple model of the decrease in toroidal rotation with EC power is set forth, which exhibits a bifurcation in the rotational state of the discharge.United States. Dept. of Energy (DE-FC02-04ER54698)United States. Dept. of Energy (DE-FC02-08ER54966)United States. Dept. of Energy (DE-AC03-09CH11466)United States. Dept. of Energy (DE-FG02-04ER54235)United States. Dept. of Energy (DE-FG0289ER53296)United States. Dept. of Energy (DE-FG02-08ER54999)United States. Dept. of Energy (DE-FG02-08ER54984)United States. Dept. of Energy (DE-FG02-04ER54461

IRAK4 mediates colitis-induced tumorigenesis and chemoresistance in colorectal cancer

Aberrant activation of the NF-κB transcription factors underlies chemoresistance in various cancer types, including colorectal cancer (CRC). Targeting the activating mechanisms, particularly with inhibitors to the upstream IκB kinase (IKK) complex, is a promising strategy to augment the effect of chemotherapy. However, clinical success has been limited, largely because of low specificity and toxicities of tested compounds. In solid cancers, the IKKs are driven predominantly by the Toll-like receptor (TLR)/IL-1 receptor family members, which signal through the IL-1 receptor-associated kinases (IRAKs), with isoform 4 (IRAK4) being the most critical. The pathogenic role and therapeutic value of IRAK4 in CRC have not been investigated. We found that IRAK4 inhibition significantly abrogates colitis-induced neoplasm in APCMin/+ mice, and bone marrow transplant experiments showed an essential role of IRAK4 in immune cells during neoplastic progression. Chemotherapy significantly enhances IRAK4 and NF-κB activity in CRC cells through upregulating TLR9 expression, which can in turn be suppressed by IRAK4 and IKK inhibitors, suggesting a feed-forward pathway that protects CRC cells from chemotherapy. Lastly, increased tumor phospho-IRAK4 staining or IRAK4 mRNA expression is associated with significantly worse survival in CRC patients. Our results support targeting IRAK4 to improve the effects of chemotherapy and outcomes in CRC

NeuroSAFE frozen section during robot-assisted radical prostatectomy (RARP): Peri-operative and Histopathological Outcomes from the NeuroSAFE PROOF Feasibility Randomised Controlled Trial

Objectives: To report on the methods, peri‐operative outcomes and histopathological concordance between frozen and final section from the NeuroSAFE PROOF Feasibility study (NCT03317990). Patients and Methods: Between May 2018 and March 2019 49 men at 2 UK centres underwent robot‐assisted robotic prostatectomy (RARP). 25 men were randomised to NeuroSAFE RARP (intervention arm) vs. 24 men to standard RARP (control arm). Frozen section was compared to final paraffin section margin assessment in the 25 men in the NeuroSAFE arm. Operation timings and complications were collected prospectively in both arms. Results: 50 NVB from 25 patients in the NeuroSAFE arm were analysed. When analysed by each pathological section (n=250, average 5 per side) we note sensitivity 100%, specificity 99.2%, AUC was 0.994 (95% CI 0.985 to 1, P= <.001). On an NVB basis (n=50) we note sensitivity of 100%, specificity 92.7%, and AUC of 0.963 (95% CI 0.914 to 1, p = <0.001. NeuroSAFE RARP lasted a mean 3 hours 16 minutes (knife to skin to off table, 95% CI 3 hrs 2 mins ‐ 3 hrs 30 mins) compared to 2 hours 14 minutes (2 hrs 2 mins ‐ 2 hours 25 mins, P=<0.001) for standard RARP. There was no morbidity associated with the additional length of operation in the NeuroSAFE arm. Conclusion: This feasibility study demonstrates the safety, the reproducibility and the excellent histopathological concordance of the NeuroSAFE technique in the NeuroSAFE PROOF trial. Though the technique increases the duration of RARP, this does not cause short‐term harm. Confirmation of feasibility has led to the opening of the fully powered NeuroSAFE PROOF RCT, which is currently underway at 4 sites in the UK