Artemisin combination therapy (ACT) is the main treatment option for malaria, which is caused by the intracellular parasite Plasmodium. However, increased resistance to ACT highlights the importance ...of finding new drugs. Recently, the aspartic proteases Plasmepsin IX and X (PMIX and PMX) were identified as promising drug targets. In this study, we describe dual inhibitors of PMIX and PMX, including WM382, that block multiple stages of the Plasmodium life cycle. We demonstrate that PMX is a master modulator of merozoite invasion and direct maturation of proteins required for invasion, parasite development, and egress. Oral administration of WM382 cured mice of P. berghei and prevented blood infection from the liver. In addition, WM382 was efficacious against P. falciparum asexual infection in humanized mice and prevented transmission to mosquitoes. Selection of resistant P. falciparum in vitro was not achievable. Together, these show that dual PMIX and PMX inhibitors are promising candidates for malaria treatment and prevention.
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•Specific compounds against P. falciparum Plasmepsin IX and X were identified•PMIX and PMX are modulators of parasite proteins for egress, invasion, and development•Anti-PMIX and anti-PMX compounds inhibit liver, blood, and mosquito stages of Plasmodium•One compound, WM382, can clear mouse models of P. berghei and P. falciparum parasites
We describe inhibitors of essential aspartic proteases from malaria parasites that block multiple life cycle stages. PMIX and PMX are master modulators processing proteins required for invasion, development, and egress. Administration of WM382 cured mice of malaria infection, showing that these inhibitors are promising candidates for malaria treatment and prevention.
Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the ...kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson’s disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.
Pigs are natural hosts for the same subtypes of influenza A viruses as humans and integrally involved in virus evolution with frequent interspecies transmissions in both directions. The emergence of ...the 2009 pandemic H1N1 virus illustrates the importance of pigs in evolution of zoonotic strains. Here we generated pig influenza-specific monoclonal antibodies (mAbs) from H1N1pdm09 infected pigs. The mAbs recognized the same two major immunodominant haemagglutinin (HA) epitopes targeted by humans, one of which is not recognized by post-infection ferret antisera that are commonly used to monitor virus evolution. Neutralizing activity of the pig mAbs was comparable to that of potent human anti-HA mAbs. Further, prophylactic administration of a selected porcine mAb to pigs abolished lung viral load and greatly reduced lung pathology but did not eliminate nasal shedding of virus after H1N1pdm09 challenge. Hence mAbs from pigs, which target HA can significantly reduce disease severity. These results, together with the comparable sizes of pigs and humans, indicate that the pig is a valuable model for understanding how best to apply mAbs as therapy in humans and for monitoring antigenic drift of influenza viruses in humans, thereby providing information highly relevant to making influenza vaccine recommendations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose: This exploratory study describes the emergent literacy skills of children with developmental language disorder (DLD) who speak Spanish, a language with a simple phonological structure and ...transparent orthography. We examine differences between children with DLD and their typically developing (TD) peers on a battery of emergent literacy measures. Method: Participants included 15 monolingual Spanish-speaking children with DLD (who did not present with cognitive difficulties) and 15 TD controls matched for age, gender, and socioeconomic status, ranging in age from 3;10 to 6;6 (years;months; Msubscript age = 4;11). All children completed a battery of comprehension-related emergent literacy tasks (narrative retell, print concept knowledge) and code-related emergent literacy tasks (beginning sound, rhyming awareness, alphabet knowledge, and name-writing ability). Results: On average, children with DLD performed significantly worse than TD controls on a battery of comprehension- and code-related emergent literacy measures. On all code-related skills except rhyming, children with DLD were more likely than their TD peers to score "at risk." Conclusions: The results suggest some universality in the effect of DLD on reading development. Difficulties with emergent literacy that are widely documented in English-speaking children with DLD were similarly observed in Spanish-speaking children with DLD. Future research should explore long-term reading outcomes in Spanish for children with DLD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Predicting Cyanobacteria dominance in lakes Downing, John A; Watson, Susan B; McCauley, Edward
Canadian journal of fisheries and aquatic sciences,
10/2001, Letnik:
58, Številka:
10
Journal Article
Recenzirano
A controversial precept of aquatic ecology asserts that low ratios of nitrogen to phosphorus (N:P) lead to noxious and sometimes toxic blooms of Cyanobacteria. Cyanobacteria dominance is a major risk ...to human and ecosystem health. The stoichiometric control of Cyanobacteria therefore has become central to freshwater resource management. This controversial concept is based on observed Cyanobacteria dominance in lakes with low N:P and the results of lab and field experiments. Here we analyze data from 99 of the temperate zone's most studied lakes and show that this model is flawed. We show that the risk of water quality degradation by Cyanobacteria blooms is more strongly correlated with variation in total P, total N, or standing algae biomass than the ratio of N:P. Risks associated with Cyanobacteria are therefore less associated with N:P ratios than a simple increase in nutrient concentrations and algal biomass.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the ...P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.
As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus’s main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique ...cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.
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