Ethics and the activity of philosophy in early Wittgenstein

Wittgenstein’s early work is well known for its seminal importance to the philosophy of language and logic during the second half of the 20th century and beyond. This thesis will explore some of the literature around aspects of his work that are less referenced, though equally important: ethics and the nature of the philosophical enterprise. This review of a portion of the surrounding literature, along with exegesis of the early texts with these particular aspects in mind, will contribute to a broader understanding of Wittgenstein as an ethical thinker

Medicinal History of North American \u3cem\u3eVeratrum\u3c/em\u3e

Plants belonging to the genus Veratrum have been used throughout history for their medicinal properties. During the nineteenth and twentieth centuries, phytochemical investigations revealed a host of steroidal alkaloids in Veratrum species, some of which are potent bioactives. This review discusses Veratrum species that grow in North America with a focus on the medicinal history of these plants and the steroidal alkaloids they contain. While significant reviews have been devoted to singularly describing the plant species within the genus Veratrum (botany), the staggering breadth of alkaloids isolated from these and related plants (phytochemistry), and the intricacies of how the various alkaloids act on their biological targets (physiology and biochemistry), this review will straddle the margins of the aforementioned disciplines in an attempt to provide a unified, coherent picture of the Veratrum plants of North America and the medicinal uses of their bioactive steroidal alkaloids

In vitro synergy and enhanced murine brain penetration of saquinavir coadministered with mefloquine.

Highly active antiretroviral therapy has substantially improved prognosis in human immunodeficiency virus (HIV). However, the integration of proviral DNA, development of viral resistance, and lack of permeability of drugs into sanctuary sites (e.g., brain and lymphocyte) are major limitations to current regimens. Previous studies have indicated that the antimalarial drug chloroquine (CQ) has antiviral efficacy and a synergism with HIV protease inhibitors. We have screened a panel of antimalarial compounds for activity against HIV-1 in vitro. A limited efficacy was observed for CQ, mefloquine (MQ), and mepacrine (MC). However, marked synergy was observed between MQ and saquinavir (SQV), but not CQ in U937 cells. Furthermore, enhancement of the antiviral activity of SQV and four other protease inhibitors (PIs) by MQ was observed in MT4 cells, indicating a class specific rather than a drug-specific phenomenon. We demonstrate that these observations are a result of inhibition of multiple drug efflux proteins by MQ and that MQ also displaces SQV from orosomucoid in vitro. Finally, coadministration of MQ and SQV in CD-1 mice dramatically altered the tissue distribution of SQV, resulting in a >3-fold and >2-fold increase in the tissue/blood ratio for brain and testis, respectively. This pharmacological enhancement of in vitro antiviral activity of PIs by MQ now warrants further examination in vivo

Chemical genetics of seed germination : modulation of a key step in abscisic acid biosynthesis

Cold conditions during imbibition can result in slow or no germination in some maize seed, leading to sub-optimal crop density and uniformity and loss of yield. A novel seed treatment is required that restores germination in seed batches that perform poorly under cold conditions. Germination of seed batches from different varieties was characterised following imbibition under cold conditions which permit no or slow germination. Hydroxamic acid inhibitors of 9-cis-epoxycarotenoid dioxygenase (NCED) stimulate germination through ABA biosynthesis inhibition in other species and had a small significant effect in increasing the proportion of normal seedlings after cold imbibition. This indicated that normal germination of maize may be inhibited by dormancy-related mechanisms during or after imbibition in cold conditions. The maize NCED (ZmNCED) family was characterised. D2 and D4 inhibit other enzymes in the carotenoid cleavage dioxygenase family and exhibit relatively weak inhibition of NCED. ZmNCEDs were cloned for in vitro enzyme inhibition studies to aid identification of NCED-specific inhibitors. An RT-qPCR assay for measuring ZmNCED expression was developed. Seed ZmNCED expression and ABA concentration was elevated under cold conditions, compared to optimal germination conditions. An assay was developed to screen for germination stimulating compounds. 965 of a diverse library of 5074 compounds were identified as potential germination stimulators. Germination stimulating activity was replicated in 171 of these compounds, with some more efficacious than D4. Germination stimulating activity of 88 compounds related to the current lead compound, D4, was assessed at concentrations of 10 ppb to 10 ppm. Compounds were identified that, at less than 10 ppm stimulated germination more than D4 at 312 ppm. The mode-of-action of these compounds will need to be determined and may yield novel targets for germination stimulation. Thus novel seed treatments for improving germination of low vigour maize seed lots under cold conditions could be based on NCED inhibition or the action of the newly identified compounds

The fluorescence response of chlortetracycline-loaded human neutrophils is modulated by prostaglandin E1, but not by cyclic nucleotides

Human neutrophils preloaded with chlortetracycline, commonly used as a probe of membrane-bound calcium, demonstrate a prompt decrease in fluorescence when exposed to surface stimuli such as the chemotactic peptide fMet--Leu--Phe. The fluorescence response was highly sensitive to preincubation with prostaglandin E1. This effect was apparently not due to elevated levels of cAMP since exogenous dibutyryl-cAMP did not alter the chlortetracycline fluorescence response to fMet--Leu--Phe. This is one of the few instances of prostaglandin E1 affecting neutrophils at physiologic concentrations, dissociated from changes in cellular cyclic nucleotide levelsPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25080/1/0000511.pd

Antimicrobial use Guidelines for Treatment of Respiratory Tract Disease in Dogs and Cats: Antimicrobial Guidelines Working Group of the International Society for Companion Animal Infectious Diseases

Respiratory tract disease can be associated with primary or secondary bacterial infections in dogs and cats and is a common reason for use and potential misuse, improper use, and overuse of antimicrobials. There is a lack of comprehensive treatment guidelines such as those that are available for human medicine. Accordingly, the International Society for Companion Animal Infectious Diseases convened a Working Group of clinical microbiologists, pharmacologists, and internists to share experiences, examine scientific data, review clinical trials, and develop these guidelines to assist veterinarians in making antimicrobial treatment choices for use in the management of bacterial respiratory diseases in dogs and cats.M.R. Lappin, J. Blondeau, D. Boothe, E.B. Breitschwerdt, L. Guardabassi, D.H. Lloyd, M.G. Papich, S.C. Rankin, J.E. Sykes, J. Turnidge, and J.S. Wees

Suppressed Far-UV stellar activity and low planetary mass-loss in the WASP-18 system

WASP-18 hosts a massive, very close-in Jupiter-like planet. Despite its young age (R′HK activity parameter lies slightly below the basal level; there is no significant time-variability in the log R′HK value; there is no detection of the star in the X-rays. We present results of far-UV observations of WASP-18 obtained with COS on board of HST aimed at explaining this anomaly. From the star’s spectral energy distribution, we infer the extinction (E(B − V) ≈ 0.01mag) and then the ISM column density for a number of ions, concluding that ISM absorption is not the origin of the anomaly. We measure the flux of the four stellar emission features detected in the COS spectrum (C II, C III, C IV, Si IV). Comparing the C II/C IV flux ratio measured for WASP-18 with that derived from spectra of nearby stars with known age, we see that the far-UV spectrum of WASP-18 resembles that of old (>5Gyr), inactive stars, in stark contrast with its young age. We conclude that WASP-18 has an intrinsically low activity level, possibly caused by star-planet tidal interaction, as suggested by previous studies. Re-scaling the solar irradiance reference spectrum to match the flux of the Si IV line, yields an XUV integrated flux at the planet orbit of 10.2 erg s−1 cm−2. We employ the rescaled XUV solar fluxes to model of the planetary upper atmosphere, deriving an extremely low thermal mass-loss rate of 10−20MJ Gyr−1. For such high-mass planets, thermal escape is not energy limited, but driven by Jeans escape

Detection and characterization of proteinase K-sensitive disease-related prion protein with thermolysin

Disease-related PrPSc [pathogenic PrP (prion protein)] is classically distinguished from its normal cellular precursor, PrPC(cellular PrP) by its detergent insolubility and partial resistance to proteolysis. Although molecular diagnosis of prion disease has historically relied upon detection of protease-resistant fragments of PrPSc using PK (proteinase K), it is now apparent that a substantial fraction of disease-related PrP is destroyed by this protease. Recently, thermolysin has been identified as a complementary tool to PK, permitting isolation of PrPSc in its full-length form. In the present study, we show that thermolysin can degrade PrPC while preserving both PK-sensitive and PK-resistant isoforms of disease-related PrP in both rodent and human prion strains. For mouse RML (Rocky Mountain Laboratory) prions, the majority of PK-sensitive disease-related PrP isoforms do not appear to contribute significantly to infectivity. In vCJD (variant Creutzfeldt–Jakob disease), the human counterpart of BSE (bovine spongiform encephalopathy), up to 90% of total PrP present in the brain resists degradation with thermolysin, whereas only ∼15% of this material resists digestion by PK. Detection of PK-sensitive isoforms of disease-related PrP using thermolysin should be useful for improving diagnostic sensitivity in human prion diseases

Isolation of Proteinase K-Sensitive Prions Using Pronase E and Phosphotungstic Acid

Disease-related prion protein, PrPSc, is classically distinguished from its normal cellular precursor, PrPC, by its detergent insolubility and partial resistance to proteolysis. Molecular diagnosis of prion disease typically relies upon detection of protease-resistant fragments of PrPSc using proteinase K, however it is now apparent that the majority of disease-related PrP and indeed prion infectivity may be destroyed by this treatment. Here we report that digestion of RML prion-infected mouse brain with pronase E, followed by precipitation with sodium phosphotungstic acid, eliminates the large majority of brain proteins, including PrPC, while preserving >70% of infectious prion titre. This procedure now allows characterization of proteinase K-sensitive prions and investigation of their clinical relevance in human and animal prion disease without being confounded by contaminating PrPC