112 research outputs found
Alkylphosphocholines and quaternary ammonium compounds against acanthamoeba keratitis
No full textAcanthamoeba keratitis (AK) is a sight threatening infection caused by the free-living amoeba Acanthamoeba. This infection is largely associated with contact lens wear and the recent increase in AK incidences highlights the ineffectiveness of existing curative and preventative treatments. Current curative and protective treatments being active in part, only against the infective trophozoites and often inducing their conversion to the protective cysts is a major issue, particularly when the latter are the main cause of disease resurgences and relapses. These point to the need for the discovery of new drugs for curative and preventive treatments. Two structurally similar chemical classes, alkylphosphocholines (APCs) and quaternary ammonium compounds (QACs) that address these issues will be discussed in this review
Birmingham News sleeve BN0061276
No full textCity / Police promotions / The promotional ceremony for lieutenants and sergeants will be held on Monday, September 19, 1994, at 11:00 a.m., at Boutwell Auditorium (Exhibition Hall), located at 20th Street and 8th Avenue North. / The following persons will be promoted to lieutenant: / Ellison Beggs / Robert Boswell / Prentice Dixon / James Hope / Daniel Phillips / Rosalind Short / Eugene Thomas / Roy Williams / Andy Woods / The following persons will be promoted to sergeants: / Mike Ashworth / Clark P. Austin / Janice Blackwell / Earnest Burt / Grady Collier / Johnny Colley / Steven Corvin / Richard Davis / Nathaniel Dunn / Fred Ellison / Roderick Gadson / John Graham / John Greene III / Darius Hatcher / Herman Hinton / Henry Irby III / Suzanne Orange / Alfonso Reid / Fred Shaw / Cedric Stevens / Diane Thomas / William Walker / Michael Wallace / [Press release included
Structure and antiparasitic activity relationship of alkylphosphocholine analogues against Leishmania donovani
No full textMiltefosine (Milt) is the only oral treatment for visceral leishmaniasis (VL) but its use is associated with adverse effects e.g. teratogenicity, vomiting, diarrhoea. Understanding how its chemical structure induces cytotoxicity, whilst not compromising its anti-parasitic efficacy, could identify more effective compounds. Therefore, we systemically modified the compound’s head, tail and linker tested the in vitro activity of three alkylphosphocholines (APC) series against Leishmania donovani strains with different sensitivities to antimony. The analogue, APC12, with an alkyl carbon chain of 12 atoms, was also tested for anti-leishmanial in vivo activity in a murine VL model. All APCs produced had anti-leishmanial activity in the micromolar range (IC50 and IC90, 0.46 µM - >82.21 µM and 4.14 µM - 739.89 µM; 0.01 - >8.02 µM and 0.09 µM - 72.18 µM respectively against promastigotes and intracellular amastigotes). The analogue, APC12 was the most active, was 4–10 fold more effective than the parent Milt molecule (APC16), irrespective of the strain’s sensitivity to antimony. Intravenous administration of 40 mg/kg APC12 to L. donovani infected BALB/c mice reduced liver and spleen parasite burdens by 60 ± 11% and 60 ± 19% respectively while oral administration reduced parasite load in the bone marrow by 54 ± 34%. These studies confirm that it is possible to alter the Milt structure and produce more active anti-leishmanial compounds
Distinct roles in autophagy and importance in infectivity of the two ATG4 cysteine peptidases of leishmania major
No full textMacroautophagy in Leishmania, which is important for the cellular remodeling required during differentiation, relies upon the hydrolytic activity of two ATG4 cysteine peptidases (ATG4.1 and ATG4.2). We have investigated the individual contributions of each ATG4 to Leishmania major by generating individual gene deletion mutants (Δatg4.1 and Δatg4.2); double mutants could not be generated, indicating that ATG4 activity is required for parasite viability. Both mutants were viable as promastigotes and infected macrophages in vitro and mice, but Δatg4.2 survived poorly irrespective of infection with promastigotes or amastigotes, whereas this was the case only when promastigotes of Δatg4.1 were used. Promastigotes of Δatg4.2 but not Δatg4.1 were more susceptible than wild type promastigotes to starvation and oxidative stresses, which correlated with increased reactive oxygen species levels and oxidatively damaged proteins in the cells as well as impaired mitochondrial function. The antioxidant N-acetylcysteine reversed this phenotype, reducing both basal and induced autophagy and restoring mitochondrial function, indicating a relationship between reactive oxygen species levels and autophagy. Deletion of ATG4.2 had a more dramatic effect upon autophagy than did deletion of ATG4.1. This phenotype is consistent with a reduced efficiency in the autophagic process in Δatg4.2, possibly due to ATG4.2 having a key role in removal of ATG8 from mature autophagosomes and thus facilitating delivery to the lysosomal network. These findings show that there is a level of functional redundancy between the two ATG4s, and that ATG4.2 appears to be the more important. Moreover, the low infectivity of Δatg4.2 demonstrates that autophagy is important for the virulence of the parasite
Two pathways for cysteine biosynthesis in Leishmania major
No full textGenome mining and biochemical analyses have shown that Leishmania major possesses two pathways for cysteine synthesis - the de novo biosynthesis pathway comprising SAT (serine acetyltransferase) and CS (cysteine synthase) and the RTS (reverse trans-sulfuration) pathway comprising CBS (cystathionine β-synthase) and CGL (cystathionine γ-lyase). The LmjCS (L. major CS) is similar to the type A CSs of bacteria and catalyses the synthesis of cysteine using O-acetylserine and sulfide with Kms of 17.5 and 0.13 mM respectively. LmjCS can use sulfide provided by the action of MST (mercaptopyruvate sulfurtransferase) on 3-MP (3-mercaptopyruvate). LmjCS forms a bi-enzyme complex with Leishmania SAT (and Arabidopsis SAT), with residues Lys222, His226 and Lys227 of LmjCS being involved in the complex formation. LmjCBS (L. major CBS) catalyses the synthesis of cystathionine from homocysteine, but, unlike mammalian CBS, also has high cysteine synthase activity (but with the Km for sulfide being 10.7 mM). In contrast, LmjCS does not have CBS activity. CS was up-regulated when promastigotes were grown in medium with limited availability of sulfur amino acids. Exogenous methionine stimulated growth under these conditions and also the levels of intracellular cysteine, glutathione and trypanothione, whereas cysteine had no effect on growth or the intracellular cysteine levels, correlating with the low rate of transport of cysteine into the cell. These results suggest that cysteine is generated endogenously by promastigotes of Leishmania. The absence of CS from mammals and the clear differences between CBS of mammals and Leishmania suggest that each of the parasite enzymes could be a viable drug target
A multi-paradigm, whole system view of health and social care for age-related macular degeneration
No full textProtein turnover and differentiation in Leishmania.
No full textLeishmania occurs in several developmental forms and thus undergoes complex cell differentiation events during its life-cycle. Those are required to allow the parasite to adapt to the different environmental conditions. The sequencing of the genome of L. major has facilitated the identification of the parasite’s vast arsenal of proteolytic enzymes, a few of which have already been carefully studied and found to be important for the development and virulence of the parasite. This review focuses on these peptidases and their role in the cellular differentiation of Leishmania through their key involvement in a variety of degradative pathways in the lysosomal and autophagy networks
Ships' Boys and Charity in the Mid-Eighteenth Century: The London Marine Society (1756-1772).
No full textPhDThis study has three principal aims: to research the circumstances of mid-eighteenthcentury
ships' boys, to look at the role the sea service played for contemporary youths
with no family connections to the maritime world, and to deliver an institutional history
of the Marine Society in its early years. Though present in significant numbers on board
eighteenth-century vessels, ships' boys have rarely been considered by historians. The
lack of research can partly be explained by the lack of source material, which is why the
records of the London Marine Society, a charity that had made it its task to recruit boys
for the sea service, are so valuable. The Marine Society was one of the most prominent
charities in the wave of voluntary associations that emerged in the mid-eighteenth
century, and this thesis aims to add to the historiography of the charity movement by
investigating the Society's origins, how and by whom it was run and financed, and how
successful its work was.
To fulfil the first two aims, the backgrounds, motives and fates of the Marine
Society's Seven-Years-War recruits were explored, drawing on the Society's registers of
recruits and minutes, and the Royal Navy's muster books. The Society's institutional
history was traced with the help of its minutes of committee meetings and its subscription
lists, through contemporary newspapers and journals, and pamphlets written by the key
figures.
Going to sea as a boy during the Seven Years War was extremely dangerous, as the
high casualty rate among the Marine-Society boys shows, yet if the youth managed to
survive, being a sailor promised him a faster route to the (economic) independence of an
adult than most land-based apprenticeships available to the children of the lower strata.
The sea service could take on a dual character for such children: it could be a
(near-)coercive institution where authorities or relatives sent a destitute or troublesome
boy, but at the same time to the impoverished or non-conformist youth himself the sea
could appear as the escape from his misery or from a society to which he was unable to
conform. The Marine Society itself was not merely a recruitment project, but something
that was deeply rooted in the concern about London's troubles with youth
unemployment, misbehaviour and crime. The Society's impact on naval manpower
during the Seven Years War has hitherto been overestimated; however, its contribution
to the preservation of sailors through the effective typhus prevention measures it
undertook has never received due recognition
3-Mercaptopyruvate sulfurtransferase of Leishmania contains an unusual C-terminal extension and is involved in thioredoxin and antioxidant metabolism
No full textCytosolic 3-mercaptopyruvate sulfurtransferases (EC 2.8.1.2) of Leishmania major and Leishmania mexicana have been cloned, expressed as active enzymes inEscherichia coli, and characterized. The leishmanial single-copy genes predict a sulfurtransferase that is structurally peculiar in possessing a C-terminal domain of some 70 amino acids. Homologous genes of Trypanosoma cruzi andTrypanosoma brucei encode enzymes with a similar C-terminal domain, suggesting that this feature, not known in any other sulfurtransferase, is a characteristic of trypanosomatid parasites. Short truncations of the C-terminal domain resulted in misfolded inactive proteins, demonstrating that the domain plays some key role in facilitating correct folding of the enzymes. The leishmanial recombinant enzymes exhibited high activity toward 3-mercaptopyruvate and catalyzed the transfer of sulfane sulfur to cyanide to form thiocyanate. They also used thiosulfate as a substrate and reduced thioredoxin as the accepting nucleophile, the latter being oxidized. The enzymes were expressed in all life cycle stages, and the expression level was increased under peroxide or hypo-sulfur stress. The results are consistent with the enzymes having an involvement in the synthesis of sulfur amino acids per se or iron-sulfur centers of proteins and the parasite's management of oxidative stress
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