Quantitative determination of sterols and other alcohols in overland flow from grazing land and possible source materials

Organic marker compounds (biomarkers) can be used to identify the sources of waterborne pollutants. This paper examines sterols and other alcohols in overland flow from pasture-based grazing systems, possible agricultural source materials and water extracts of these source materials as a preliminary step to developing chemical profiles that can be used for tracing pollutants. The biomarkers were quantified using gas chromatography and gas chromatography-mass spectrometry techniques. Analyses of plant material show that some pasture species contain unique compounds, enabling their identification. For example, Arctotheca calendula (capeweed) contains an as yet unidentified compound (Arctotheca m/z 163). Other pasture species that do not contain unique compounds do contain unique ratios of phytol, hexacosanol, octacosanol and 24-ethylcholesterol, enabling their identification. Analyses of faecal samples show that the ratios of sterols to stanols enable faeces to be distinguished from the pasture species, e.g. the ratio of 24-ethylcholesterol to 24-ethylcoprostanol was <1, generally <0.25 for faeces, while for most pasture species this ratio was >4. Using this ratio, qualitative apportioning of the sources of pollutants in overland flow to vegetation or faeces could be performed, but only in extreme cases (i.e. when the ratio <1 or >4). Decaying organic matter and surface soil appear to contain a composite of plant and faecal sterols. Sterols, being sparingly soluble in water and surface active, were not expected to be present in overland flow samples. Surprisingly, cholesterol and 24-ethylcoprostanol were found in both the particulate and filtrate fractions of most overland flow and water extracts of most source materials. Using the ratios of sterols to stanols, particulate organic material in water could be traced back to its broader source, i.e. vegetation or faeces.     

Thermodynamic Constants for Association of Isomeric Chlorobenzoic and Toluic Acids With 1,3-Diphenyl-guanidine in Benzene

This paper reports values of ΔF₂₅, ΔH, and ΔS₂₅ for the association of diphenylguanidine with the isomeric monochlorobenzoic acids and the isomeric toluic acids in benzene from spectrophotometric measurements at 25 and 30 °C, using bromophthalein magenta E (3′, 5′, 3″, 5″-tetrabromophenolphthalein ethyl ester) as the indicator. The results are compared with available data for other donor-acceptor associations in aprotic solvents which include the monomer-dimer equilibrium of benzoic acids, the association of tertiary amines with iodine, and the association of certain oxygen bases with phenols. The comparisons indicate that the value of the ratio ΔH/298ΔS is approximately constant in the following associations in aprotic solvents: (1) Association of phenolic or carboxylic acids with nitrogenous bases to form hydrogen bonded ion-pairs; (2) hydrogen bonding of weakly acidic phenols to nitrogenous bases; (3) association of tertiary amines with iodine. A somewhat smaller value for this ratio seems to apply to most associations of phenols with oxygen bases. Possible applications of these findings include estimation of other thermodynamic constants when one of the constants ΔF, ΔH, or ΔS is known, and clarification of the relative importance of ionic and covalent contributions in hydrogen bond formation.     

Misconduct by therapists.

Suggests that, in his retrospective review of malpractice claims against psychologists, R. H. Wright (see record 1982-22006-001) infers beyond the limits of the data he reports. Specifically, he suggests that, because there were so few complaints of sexual misconduct, stories of sex between psychologist and patient are substantially overstated. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Upregulation of Anti-Oxidative Stress Response Improves Metabolic Changes in L-Selectin-Deficient Mice but Does Not Prevent NAFLD Progression or Fecal Microbiota Shifts

(1) Background: Non-alcoholic fatty liver disease (NAFLD) is a growing global health problem. NAFLD progression involves a complex interplay of imbalanced inflammatory cell populations and inflammatory signals such as reactive oxygen species and cytokines. These signals can derive from the liver itself but also from adipose tissue or be mediated via changes in the gut microbiome. We analyzed the effects of a simultaneous migration blockade caused by L-selectin-deficiency and an enhancement of the anti-oxidative stress response triggered by hepatocytic Kelch-like ECH-associated protein 1 (Keap1) deletion on NAFLD progression. (2) Methods: L-selectin-deficient mice (Lsel^−/−Keap1^flx/flx) and littermates with selective hepatic Keap1 deletion (Lsel^−/−Keap1^Δhepa) were compared in a 24-week Western-style diet (WD) model. (3) Results: Lsel^−/−Keap1^Δhepa mice exhibited increased expression of erythroid 2-related factor 2 (Nrf2) target genes in the liver, decreased body weight, reduced epidydimal white adipose tissue with decreased immune cell frequencies, and improved glucose response when compared to their Lsel^−/−Keap1^flx/flx littermates. Although WD feeding caused drastic changes in fecal microbiota profiles with decreased microbial diversity, no genotype-dependent shifts were observed. (4) Conclusions: Upregulation of the anti-oxidative stress response improves metabolic changes in L-selectin-deficient mice but does not prevent NAFLD progression and shifts in the gut microbiota.     

Biochemical and Structural Characterization of XoxG and XoxJ and Their Roles in Lanthanide-Dependent Methanol Dehydrogenase Activity

Lanthanide (Ln)-dependent methanol dehydrogenases (MDHs) have recently been shown to be widespread in methylotrophic bacteria. Along with the core MDH protein, XoxF, these systems contain two other proteins, XoxG (a c-type cytochrome) and XoxJ (a periplasmic binding protein of unknown function), about which little is known. In this work, we have biochemically and structurally characterized these proteins from the methyltroph Methylobacterium extorquens AM1. In contrast to results obtained in an artificial assay system, assays of XoxFs metallated with La^III, Ce^III, and Nd^III using their physiological electron acceptor, XoxG, display Ln-independent activities, but the K_m for XoxG markedly increases from La to Nd. This result suggests that XoxG′s redox properties are tuned specifically for lighter Lns in XoxF, an interpretation supported by the unusually low reduction potential of XoxG (+172 mV). The X-ray crystal structure of XoxG provides a structural basis for this reduction potential and insight into the XoxG–XoxF interaction. Finally, the X-ray crystal structure of XoxJ reveals a large hydrophobic cleft and suggests a role in the activation of XoxF. These studies enrich our understanding of the underlying chemical principles that enable the activity of XoxF with multiple lanthanides in vitro and in vivo.     

Developing an Antibody–Drug Conjugate Approach to Selective Inhibition of an Extracellular Protein

Antibody–drug conjugates (ADCs) are a growing class of therapeutics that harness the specificity of antibodies and the cell-killing potency of small-molecule drugs. Beyond cytotoxics, there are few examples of the application of an ADC approach to difficult drug discovery targets. Here, we present the initial development of a non-internalising ADC, with a view to selectively inhibiting an extracellular protein. Employing the wellinvestigated matrix metalloproteinase-9 (MMP-9) as our model, we adapted a broad-spectrum, nonselective MMP inhibitor for conjugation and linked this to a MMP-9-targeting antibody. The resulting ADC fully inhibits MMP-9, and ELISA results suggest antibody targeting can direct a nonselective inhibitor.     

Divergent Synthesis of Novel Cylindrocyclophanes that Inhibit Methicillin-Resistant Staphylococcus aureus (MRSA)

The cylindrocyclophanes are a family of macrocyclic natural products reported to exhibit antibacterial activity. Little is known about the structural basis of this activity due to the challenges associated with their synthesis or isolation. We hypothesised that structural modification of the cylindrocyclophane scaffold could streamline their synthesis without significant loss of activity. Herein, we report a divergent synthesis of the cylindrocyclophane core enabling access to symmetrical macrocycles by means of a catalytic, domino cross-metathesis-ring-closing metathesis cascade, followed by late-stage diversification. Phenotypic screening identified several novel inhibitors of methicillin-resistant Staphylococcus aureus. The most potent inhibitor has a unique tetrabrominated [7,7]paracyclophane core with no known counterpart in nature. Together these illustrate the potential of divergent synthesis using catalysis and unbiased screening methods in modern antibacterial discovery.