2-Amino-3-aroyl-4,5-alkylthiophenes: Agonist allosteric enhancers at human A1 adenosine receptors

2-Amino-3-benzoylthiophenes are allosteric enhancers (AE) of agonist activity at the A₁ adenosine receptor. The present report describes syntheses and assays of the AE activity at the human A₁AR (hA₁AR) of a panel of compounds consisting of nine 2-amino-3-aroylthiophenes (3a-i), eight 2-amino-3-benzoyl-4,5-dimethylthiophenes (12a-h), three 3-aroyl-2-carboxy-4,5- dimethylthiophenes (15a-c), 10 2-amino-3-benzoyl-5,6-dihydro 4H-cyclopenta[b]thiophenes (17a-j), 14 2-amino-3-benzoyl-4,5,6,7-tetrahydrobenzo[b]thiophenes (18a-n), and 15 2-amino- 3-benzoyl-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophenes (19a-o). An in vitro assay employing the A₁AR agonist [¹²⁵I]ABA and membranes from CHO-K1 cells stably expressing the hA¹AR measured, as an index of AE activity, the ability of a candidate AE to stabilize the agonist- A₁AR-G protein ternary complex. Compounds 3a-i had little or no AE activity, and compounds 12a-h had only modest activity, evidence that AE activity depended absolutely on the presence of at least a methyl group at C-4 and C-5. Compounds 17a-c lacked AE activity, suggesting the 2-amino group is essential. Polymethylene bridges linked thiophene C-4 and C-5 of compounds 17a-j, 18a-n, and 19a-o. AE activity increased with the size of the -(CH₂)_n- bridge, n ) 3 < n ) 4 < n ) 5. The 3-carbethoxy substituents of 17a, 18a, and 19a did not support AE activity, but a 3-aroyl group did. Bulky (or hydrophobic) substituents at the meta and para positions of the 3-benzoyl group and also 3-naphthoyl groups greatly enhanced activity. Thus, the hA₁AR contains an allosteric binding site able to accommodate 3-aroyl substituents that are bulky and/or hydrophobic but not necessarily planar. A second region in the allosteric binding site interacts constructively with alkyl substituents at thiophene C-4 and/or C-5.

Penetration testing professional ethics : a conceptual model and taxonomy

In an environment where commercial software is continually patched to correct security flaws, penetration testing can provide organisations with a realistic assessment of their security posture. Penetration testing uses the same principles as criminal hackers to penetrate corporate networks and thereby verify the presence of software vulnerabilities. Network administrators can use the results of a penetration test to correct flaws and improve overall security. The use of hacking techniques, however, raises several ethical questions that centre on the integrity of the tester to maintain professional distance and uphold the profession. This paper discusses the ethics of penetration testing and presents our conceptual model and revised taxonomy.

Determination of drawbead contacts with variable bead penetration

In stamping operations, the sliding of the sheet metal over the drawbeads is of great importance. The geometry of the drawbead and the degree of penetration both influence material flow and alter the frictional effects between the work and the tool. The effect of drawbead penetration over drawbeads has been studied using the Drawbead Simulator (DBS) test. The contact phenomenon between the sheet and drawbeads was analysed by examining deformed samples with an image fitting technique. The results were compared with an FE simulation and with an approximate geometric analysis. The results give a useful relationship between the rates of change of the contact angle with increasing bead penetration.

A taxonomy of penetration testing ethics

In an environment where commercial software is continually patched to correct security flaws, penetration testing can provide organisations with a realistic assessment of their security posture. Penetration testing uses the same principles as criminal hackers to penetrate corporate networks and thereby verify the presence of software vulnerabilities. Network administrators can use the results of a penetration test to correct flaws and improve overall security. The use of hacking techniques, however, raises several ethical questions that centre on the integrity of the tester to maintain professional distance and uphold the profession. This paper discusses the ethics of penetration testing and presents our conceptual model and revised taxonomy.

Role of P-glycoprotein in limiting the brain penetration of glabridin, an active isoflavan from the root of Glycyrrhiza glabra.

Purpose. Glabridin is a major active constituent of Glycyrrhiza glabra which is commonly used in the treatment of cardiovascular and central nervous system (CNS) diseases. Recently, we have found that glabridin is a substrate of P-glycoprotein (PgP/MDR1). This study aimed to investigate the role of PgP in glabridin penetration across the blood–brain barrier (BBB) using several in vitro and in vivo models.
Materials and Methods. Cultured primary rat brain microvascular endothelial cells (RBMVECs) were used in the uptake, efflux and transcellular transport studies. A rat bilateral in situ brain perfusion model was used to investigate the brain distribution of glabridin. The brain and tissue distribution of glabridin in rats with or without coadministered verapamil or quinidine were examined with correction for the tissue residual blood. In addition, the brain distribution of glabridin in mdr1a(-/-) mice was compared with the wild-type mice. Glabridin in various biological matrices was determined by a validated liquid chromatography mass spectrometric method.
Results. The uptake and efflux of glabridin in cultured RBMVECs were ATP-dependent and significantly altered in the presence of a PgP or multi-drug resistance protein (Mrp1/2) inhibitor (e.g. verapamil or MK-571). A polarized transport of glabridin was found in RBMVEC monolayers with
facilitated efflux from the abluminal (BL) to luminal (AP) side. Addition of a PgP or Mrp1/2 inhibitor in both luminal and abluminal sides attenuated the polarized transport across RBMVECs. In a bilateral in situ brain perfusion model, the uptake of glabridin into the cerebrum increased from 0.42 T 0.09% at 1 min to 9.27 T 1.69% (ml/100 g tissue) at 30 min and was significantly greater than that for sucrose. Coperfusion of a PgP or Mrp1/2 inhibitor significantly increased the brain distribution of glabridin by 33.6j142.9%. The rat brain levels of glabridin were only about 27% of plasma levels when corrected by tissue residual blood and it was increased to up to 44% when verapamil or quinidine was coadministered. The area under the brain concentration-time curve (AUC) of glabridin in mdr1a(-/-) mice was 6.0-fold higher than the wild-type mice.
Conclusions. These findings indicate that PgP limits the brain penetration of glabridin through the BBB and PgP may cause drug resistance to glabridin (licorice) therapy for CNS diseases and potential drugglabridin interactions. However, further studies are needed to explore the role of other drug transporters (e.g. Mrp1-4) in restricting the brain penetration of glabridin.

Importance of the contribution of Australians to the penetration of China by the China Inland Mission in the period 1888-1953, with particular reference to the work of Australian women missionaries

Australians, in the main, are unaware of the role which Australia played in the evangelization of China in the late nineteenth and the first half of the twentieth century. Most would never have heard of the China Inland Mission (CIM), the largest of the Protestant bodies which penetrated the Middle Kingdom, and few would know of the contribution that its Australian contingent, which consistently comprised about a tenth of the CIM's numbers, made towards the Christianization of that vast country. This thesis aims to raise the level of awareness in this area. Academic researchers have not totally neglected to examine the proselytization of China, and historians of the stature of Latourette have not let it escape their attention. However, most of the studies which have not merely fleetingly focused on the subject while viewing a larger canvas, have been North American, singling out the efforts of United States and Canadian bodies in introducing Christianity to the Chinese. Here, authors like Amerding, Bacon, Creighton, Gates, Hawkes, Ho, Ko, Mensendiek, Michell and Quale have left their mark. In the case of the present thesis, the outlook from which events played out in China are viewed is firmly based in Australia rather than North America. Earlier Australian research has been scarce, and is dominated by Loane and Dixon. Loane, evidently primarily working from Australasian Council minutes, mainly concentrates on the efforts of the CIM's Home Council, examining its endeavours decade by decade against a backdrop of contemporaneous events in China, and briefly referring to aspects of the lives of a cross-section of Australasian missionaries, without providing much idea about what they actually did in the field or what they achieved there. Because of its preoccupation with the Home Council, which never admitted women into its ranks, Loane's treatise is systemically biased towards men, though the more prominent of the women, like Mary Reed and Susie Garland, are given due recognition. The current thesis looks in detail at what Australians did in the field, the level of success they achieved, and at the particular contribution of Australian women towards the evangelization of China. Dixon took upon herself the formidable task of examining the endeavours of all missions in China which contained Australian missionaries. Because of the magnitude of her task, she could not focus to any great extent on particular missions, nor pursue in any detail the work of individual Australian missionaries. Like Loane, she was unable to explore what they actually did in the field or what they achieved there. Neither could she delve to any depth into the work of Australian women missionaries, though on the basis of the information she had accumulated, she drew the conclusion that Australian women had largely only brought about some unintended feminist consequences amongst Chinese women. This sweeping generalization failed to take into account the other very real social changes for Chinese women the Australian female missionaries quite purposely helped to bring about, and this thesis makes good that omission. This thesis studies aspects of the Australian missionary endeavour which both Loane and Dixon have neglected, thereby breaking new ground, and sets out to correct erroneous impressions which Dixon's dissertation has left on the historical record. One of these impressions concerned the longevity of the effect of the Australian effort in China. She had the View, writing in 1978, that the Chinese Church was moribund (a view shared by Varg and Lacy) , and that therefore the effects attributable to the endeavours of any nationality had proved fruitless, whereas the author is able to show, using modern-day sources, that the church has burgeoned in recent years thanks to earlier missionary endeavours and later neo-evangelistic efforts like Gospel radio, and now has a complement of perhaps 50 million adherents, making it second only to the United States in the size of its Protestant evangelical population. Another impression she left was that the Australian input into the evangelization of China can be largely dismissed because no totally Australian organization emerged, leaving the direction of Australia's effort in other hands. Contrary to that impression, the author shows that the Australian impact in China was significant and that Australians enjoyed more power than Dixon ever imagined. The author also shows that Australians were accepted as the equal of other nationalities in the CIM once they had acquired the necessary field expertise, a factor which doubtless also applied in respect of other missions with Australian components in China. Marchant has suggested that it is a fiction perpetuated by mission periodicals that Christianity spread and progressed in a determined manner in China. This thesis establishes that within the CIM's bailiwick, though there was some patchiness, Christianity progressed steadily and inexorably. One mission alone, the CIM, is concentrated upon, firstly in order to render the data manageable, secondly because it was the largest mission in China and had a sizeable Australian (including female) contingent, and thirdly because it exemplified many of the problems which would have been faced by missions in that country and their Australian components. The methodology employed is multifaceted. The written testimony of the missionaries themselves, contained in CIM periodicals, Field Bulletins, Monthly Notes, Annual Reports, autobiographies, personal files, diaries and letters is used to illustrate various aspects of the CIM's work in which Australians were engaged. This approach is augmented by other sources such as China and Australasian Home Council Minutes, missionary conference reports, Candidates' Books, biographies, and other selected material from archival holdings in Australia, Singapore, the United Kingdom, America and Canada. Statistics, especially ratio analyses and growth rate comparisons are used to demonstrate the relative success of different missions, missionaries and genders. Also employed are reminiscences of missionaries and descendants obtained by personal interview, and these are aggregated to provide some general conclusions. Data from these various sources have been synthesized to serve the central objective of demonstrating the importance of the contribution of Australians to the penetration of China by the CIM in the period 1888-1953 with particular reference to the work of Australian women missionaries.

Agonist allosteric enhancers at A1 adenosine receptors

Pharmaceutical agents that may be protective to the heart during ischemia were targeted in this project. Analogs to a lead compound containing potential cardioprotective properties were prepared. In the pharmacological evaluation five compounds were found to be more potent than the lead compound.

Boroxine ring compounds as dissociation enhancers in gel polyelectrolytes

In order to combine the advantages of both traditional gel electrolytes and polyelectrolytes, a novel polyelectrolyte which incorporates a boroxine ring-containing anion-trapping agent has been explored. Poly(lithium 2-acrylamido-2-methyl-1-propanesulfonate) (PAMPSLi), ethylene carbonate (EC) and tri(methoxyethoxyethoxyethoxy)boroxine (TME₃Bx) were combined to prepare various gel systems. The thermal properties and conductivities of these gels have been investigated. A conductivity of 10^−3.6 S cm⁻¹ at 20 °C has been achieved in a gel polyelectrolyte system with a molar ratio of [EC]:[TME3Bx]:[Li⁺]=24:1.7:1. Temperature-dependent NMR measurements indicated that a significant interaction exists between the boroxine ring and the polyelectrolyte.