Search results for " Bruce"

Robert E. Lee in Love and War written by John Jakes : comparison with accounts by historians Foote, Catton and McPherson

2005

Zvaigžņotā Debess: 2009, Vasara (204)

2009

Contents: E.Conners. The Trojan Asteroids ; V.Šmēlings. Men on the Moon! ; E.Bervalds. Astronomical Domes and “Sauna” ; Z.Alksne, A.Alksnis. Sakurai’s Object Fails to Escape Own Dust ; Z.Alksne, A.Alksnis. R CrB Stars Surrounded by Dust Clouds ; M.Gills. April Started with Astronomy ; A.Alksnis. First Stamps Dedicated to Astronomy by Latvia’s Post-Office ; I.Pundure. Arturs Balklavs and Astronomy of Latvia (till 1969) ; M.Sudārs. Satellite Collisions – What Threat Do They Pose? ; I.Vilks. Dwarf Planets Names in Latvian ; Announcement on the 2nd International Symposium on Dark-sky Parks: 14-19 September 2009, Slovenia ; A.Andžāns. The Best Way to Fight Darkness Is to Switch on Light (Intervi…

Evaluation of curcumin irreversibility

2019

Dear Editor,We would like to reply to the letter to the Editor of Steverding (2018) on our research article “Drug combination studies of curcumin and genistein against rhodesain of Trypanosoma bruc...

African trypanosomes expressing multiple VSGs are rapidly eliminated by the host immune system

2019

Significance Many parasites escape the host immune system by undergoing antigenic variation, a process in which surface antigens are regularly shed and replaced by new ones. Trypanosoma brucei employs multiple sophisticated molecular mechanisms to ensure the expression of a homogeneous VSG coat. We generated a mutant parasite that expresses multiple distinct VSGs and studied the consequences of having a multi-VSG coat during an infection. We showed that expression of multiple VSGs makes the parasites more vulnerable to the immune response, which can now control the trypanosomes from the onset of the infection, allowing most mice to survive. In the future, trypanosome infections may be treat…

Fine-tuning the extent and dynamics of binding cleft opening as a potential general regulatory mechanism in parvulin-type peptidyl prolyl isomerases

2017

AbstractParvulins or rotamases form a distinct group within peptidyl prolyl cis-trans isomerases. Their exact mode of action as well as the role of conserved residues in the family are still not unambiguously resolved. Using backbone S2 order parameters and NOEs as restraints, we have generated dynamic structural ensembles of three distinct parvulins, SaPrsA, TbPin1 and CsPinA. The resulting ensembles are in good agreement with the experimental data but reveal important differences between the three enzymes. The largest difference can be attributed to the extent of the opening of the substrate binding cleft, along which motional mode the three molecules occupy distinct regions. Comparison w…

Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors.

2018

Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei (T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors (Ki < 10 nM), preventing the cell-growth of Trypanosoma brucei rhodesiense (IC50 < 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a noncovalent binding mode of this ligand class due to oxidation of the catalytic Cys25 to a sulfenic acid (Cys–SOH) during crystallization. The P-glycoprotein efflux ratio was mea…

Bistacrines as potential antitrypanosomal agents

2017

Human African Trypanosomiasis (HAT) is caused by two subspecies of the genus Trypanosoma, namely Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. The disease is fatal if left untreated and therapy is limited due to only five non-adequate drugs currently available. In preliminary studies, dimeric tacrine derivatives were found to inhibit parasite growth with IC50-values in the nanomolar concentration range. This prompted the synthesis of a small, but smart library of monomeric and dimeric tacrine-type compounds and their evaluation of antiprotozoal activity. Rhodesain, a lysosomal cathepsin-L like cysteine protease of T. brucei rhodesiense is essential for parasite survival a…

Optimization of Triazine Nitriles as Rhodesain Inhibitors: Structure-Activity Relationships, Bioisosteric Imidazopyridine Nitriles, and X-ray Crystal…

2013

The cysteine protease rhodesain of Trypanosoma brucei parasites causing African sleeping sickness has emerged as a target for the development of new drug candidates. Based on a triazine nitrile moiety as electrophilic headgroup, optimization studies on the substituents for the S1, S2, and S3 pockets of the enzyme were performed using structure-based design and resulted in inhibitors with inhibition constants in the single-digit nanomolar range. Comprehensive structure-activity relationships clarified the binding preferences of the individual pockets of the active site. The S1 pocket tolerates various substituents with a preference for flexible and basic side chains. Variation of the S2 subs…

Urticaria and bacterial infections

2014

The association between urticaria and infectious diseases has been discussed for >100 years. However, a causal relationship with underlying or precipitating infection is difficult to establish. The purpose of this work was to perform a systematic analysis of the published cases of urticaria associated with bacterial infections. We give an umbrella breakdown of up-to-date systematic reviews and other important publications on the complex association of urticaria and bacterial infections. We did a Medline search, for English language articles published until January 2014, using the key words "urticaria" and "bacteria/bacterial disease"; a second analysis was performed in groups of bacteria an…

Identification of highly effective antitrypanosomal compounds in essential oils from the Apiaceae family

2018

The Apiaceae family encompasses aromatic plants of economic importance employed in foodstuffs, beverages, perfumery, pharmaceuticals and cosmetics. Apiaceae are rich sources of essential oils because of the wealth of secretory structures (ducts and vittae) they are endowed with. The Apiaceae essential oils are available on an industrial level because of the wide cultivation and disposability of the bulky material from which they are extracted as well as their relatively cheap price. In the fight against protozoal infections, essential oils may represent new therapeutic options. In the present work, we focused on a panel of nine Apiaceae species (Siler montamon, Sison amomum, Echinophora spi…