Mateship and Money-Making: Shearing in Twentieth Century Australia

After the turmoil of the 1890s shearing contractors eliminated some of the frustration from shearers recruitment. At the same time closer settlement concentrated more sheep in small flocks in farming regions, replacing the huge leasehold pastoral empires which were at the cutting edge of wool expansion in the nineteenth century. Meanwhile the AWU succeeded in getting an award for the pastoral industry under the new arbitration legislation in 1907. Cultural and administrative influences, therefore, eased some of the bitter enmity which had made the annual shearing so unstable. Not all was plain sailing. A pattern of militancy re-emerged during World War I. Shearing shed unrest persisted throughout the interwar period and during World War II. In the 1930s a rival union with communist connections, the PWIU, was a major disruptive influence. Militancy was a factor in a major shearing strike in 1956, when the boom conditions of the early-1950s were beginning to fade. The economic system did not have satisfactory mechanisms to cope. Unionised shearers continued to be locked in a psyche of confrontation as wool profits eroded further in the 1970s. This ultimately led to the wide comb dispute, which occurred as wider pressures changed an economic order which had not been seriously challenged since Federation, and which the AWU had been instrumental in shaping. Shearing was always identified with bushworker ‘mateship’, but its larrikinism and irreverence to authority also fostered individualism, and an aggressive ‘moneymaking’ competitive culture. Early in the century, when old blade shearers resented the aggressive pursuit of tallies by fast men engaged by shearing contractors, tensions boiled over. While militants in the 1930s steered money-makers into collectivist versions of mateship, in the farming regions the culture of self-improvement drew others towards the shearing competitions taking root around agricultural show days. Others formed their own contracting firms and had no interest in confrontation with graziers. Late in the century New Zealanders arrived with combs an inch wider than those that had been standard for 70 years. It was the catalyst for the assertion of meritocracy over democracy, which had ruled since Federation

Statin Lactonization by Uridine 5'-Diphospho-glucuronosyltransferases (UGTs)

Contains fulltext : 152742.pdf (publisher's version ) (Closed access)Statins are cholesterol-lowering drugs that have proven to be effective in lowering the risk of major cardiovascular events. Although well tolerated, statin-induced myopathies are the most common side effects. Compared to their pharmacologically active acid form, statin lactones are more potent inducers of toxicity. They can be formed by glucuronidation mediated by uridine 5'-diphospho-glucuronosyltransferases (UGTs), but a systematic characterization of subtype specificity and kinetics of lactonization is lacking. Here, we demonstrate for six clinically relevant statins that only UGT1A1, 1A3, and 2B7 contribute significantly to their lactonization. UGT1A3 appeared to have the highest lactonization capacity with marked differences in statin conversion rates: pitavastatin >> atorvastatin > cerivastatin > lovastatin > rosuvastatin (simvastatin not converted). Using in silico modeling we could identify a probable statin interaction region in the UGT binding pocket. Polymorphisms in these regions of UGT1A1, 1A3, and 2B7 may be a contributing factor in statin-induced myopathies, which could be used in personalization of statin therapy with improved safety

Heterogeneous transport of digitalis-like compounds by P-glycoprotein in vesicular and cellular assays

Digitalis-like compounds (DLCs), the ancient medication of heart failure and Na,K-ATPase inhibitors, are characterized by their toxicity. Drug-drug interactions (DDIs) at absorption and excretion levels play a key role in their toxicity, hence, knowledge about the transporters involved might prevent these unwanted interactions. In the present study, the transport of fourteen DLCs with human P-glycoprotein (P-gp; ABCB1) was studied using a liquid chromatography-mass spectrometry (LC-MS) quantification method. DLC transport by P-gp overexpressing Madin-Darby canine kidney (MDCK) and immortalized human renal cells (ciPTEC) was compared to vesicular DLC transport. Previously, we identified convallatoxin as a substrate using membrane vesicles overexpressing P-gp; however, we could not measure transport of other DLCs in this assay (Gozalpour et al., 2014a). Here, we showed that lipophilic digitoxin, digoxigenin, strophanthidin and proscillaridin A are P-gp substrates in cellular accumulation assays, whereas the less lipophilic convallatoxin was not. P-gp function in the cellular accumulation assays depends on the entrance of lipophilic compounds by passive diffusion, whereas the vesicular transport assay is more appropriate for hydrophilic substrates. In conclusion, we identified digitoxin, digoxigenin, strophanthidin and proscillaridin A as P-gp substrates using cellular accumulation assays and recognized lipophilicity as an important factor in selecting a suitable transport assay

Effect of two dosages of sodium chloride intake on the blood pressure response to caffeinated coffee in humans in vivo

High sodium intake increases cardiovascular risk by increasing blood pressure. The intake of coffee elevates blood pressure acutely. Preclinical evidence shows that this action of caffeine is enhanced by high salt intake. We hypothesised that high sodium intake augments the acute blood pressure response to coffee in humans. A randomised cross-over study (n = 15) was performed comparing the effect of lower (6 g/d; LS) with higher (12 g/d; HS) sodium chloride diet on blood pressure before and 2 h after regular coffee intake. Baseline blood pressure was 115 +/- 4/84 +/- 2/68 +/- 1 during LS and 121 +/- 4/89 +/- 2/69 +/- 1 mmHg during HS (SBP/Mean Arterial Pressure (MAP)/DBP; mean +/- SE, p 0.3 for SBP, DBP; p > 0.05 for MAP). Sodium intake does not relevantly modulate the impact of regular coffee consumption on blood pressure

Interaction of Digitalis-Like Compounds with Liver Uptake Transporters NTCP, OATP1B1, and OATP1B3

Contains fulltext : 138326.pdf (publisher's version ) (Closed access)Digitalis-like compounds (DLCs) such as digoxin, digitoxin, and ouabain, also known as cardiac glycosides, are among the oldest pharmacological treatments for heart failure. The compounds have a narrow therapeutic window, while at the same time, DLC pharmacokinetics is prone to drug-drug interactions at the transport level. Hepatic transporters organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and Na(+)-dependent taurocholate co-transporting polypeptide (NTCP) influence the disposition of a variety of drugs by mediating their uptake from blood into hepatocytes. The interaction of digoxin, digitoxin, and ouabain with hepatic uptake transporters has been studied before. However, here, we systematically investigated a much wider range of structurally related DLCs for their capability to inhibit or to be transported by these transporters in order to better understand the relation between the activity and chemical structure of this compound type. We studied the uptake and inhibitory potency of a series of 14 structurally related DLCs in Chinese hamster ovary cells expressing NTCP (CHO-NTCP) and human embryonic kidney cells expressing OATP1B1 and OATP1B3 (HEK-OATP1B1 and HEK-OATP1B3). The inhibitory effect of the DLCs was measured against taurocholic acid (TCA) uptake in CHO-NTCP cells and against uptake of beta-estradiol 17-beta-d-glucuronide (E217betaG) in HEK-OATP1B1 and HEK-OATP1B3 cells. Proscillaridin A was the most effective inhibitor of NTCP-mediated TCA transport (IC50 = 22 muM), whereas digitoxin and digitoxigenin were the most potent inhibitors of OATP1B1 and OAPTP1B3, with IC50 values of 14.2 and 36 muM, respectively. Additionally, we found that the sugar moiety and hydroxyl groups of the DLCs play different roles in their interaction with NTCP, OATP1B1, and OATP1B3. The sugar moiety decreases the inhibition of NTCP and OATP1B3 transport activity, whereas it enhances the inhibitory potency against OATP1B1. Moreover, the hydroxyl group at position 12 reinforces the inhibition of NTCP but decreases the inhibition of OATP1B1 and OATP1B3. To investigate whether DLCs can be translocated, we quantified their uptake in transporter-expressing cells by LC-MS. We demonstrated that convallatoxin, ouabain, dihydroouabain, and ouabagenin are substrates of OATP1B3. No transport was observed for the other compounds in any of the studied transporters. In summary, this work provides a step toward an improved understanding of the interaction of DLCs with three major hepatic uptake transporters. Ultimately, this can be of use in the development of DLCs that are less prone to transporter-mediated drug-drug interactions

Collective invasion induced by an autocrine purinergic loop through connexin-43 hemichannels

Progression of epithelial cancers predominantly proceeds by collective invasion of cell groups with coordinated cell-cell junctions and multicellular cytoskeletal activity. Collectively invading breast cancer cells express the gap junction protein connexin-43 (Cx43), yet whether Cx43 regulates collective invasion remains unclear. We here show that Cx43 mediates gap-junctional coupling between collectively invading breast cancer cells and, via hemichannels, adenosine nucleotide/nucleoside release into the extracellular space. Using molecular interference and rescue strategies, we identify that Cx43 hemichannel function, but not intercellular communication, induces leader cell activity and collective migration through the engagement of the adenosine receptor 1 (ADORA1) and AKT signaling. Accordingly, pharmacological inhibition of ADORA1 or AKT signaling caused leader cell collapse and halted collective invasion. ADORA1 inhibition further reduced local invasion of orthotopic mammary tumors in vivo, and joint up-regulation of Cx43 and ADORA1 in breast cancer patients correlated with decreased relapse-free survival. This identifies autocrine purinergic signaling, through Cx43 hemichannels, as a critical pathway in leader cell function and collective invasion

Human multidrug resistance protein 4 (MRP4) is a cellular efflux transporter for paracetamol glutathione and cysteine conjugates

Contains fulltext : 221726.pdf (Publisher’s version ) (Open Access