RNA and β-Hemolysin of Group B Streptococcus Induce Interleukin-1β (IL-1β) by Activating NLRP3 Inflammasomes in Mouse Macrophages

The inflammatory cytokine IL-1β is critical for host responses against many human pathogens. Here, we define Group B Streptococcus (GBS)-mediated activation of the Nod-like receptor-P3 (NLRP3) inflammasome in macrophages. NLRP3 activation requires GBS expression of the cytolytic toxin, β-hemolysin, lysosomal acidification, and leakage. These processes allow the interaction of GBS RNA with cytosolic NLRP3. The present study supports a model in which GBS RNA, along with lysosomal components including cathepsins, leaks out of lysosomes and interacts with NLRP3 to induce IL-1β production.     

Four novel bis-(naphtho-gamma-pyrones) isolated from Fusarium species as inhibitors of HIV-1 integrase

Integration of viral DNA into host cell DNA is an essential step in retroviral (HIV-1) replication and is catalyzed by HIV-1 integrase. HIV-1 integrase is a novel therapeutic target and is the focus of efforts to identify effective inhibitors that will prevent/or cure HIV infections. Four novel naphtho-gamma-pyrones, belonging to the chaetochromin and ustilaginoidin family, were discovered as inhibitors of HIV-1 integrase from the screening of fungal extracts using a recombinant in vitro assay. These compounds inhibit both the coupled and strand transfer activity of HIV-1 integrase with IC(50) values of 1-3 and 4-12 microM, respectively. The discovery, structure elucidation, chemical modification and the structure-activity relationship of these compounds are described.     

Agricultural sustainability: concepts, principles and evidence

Concerns about sustainability in agricultural systems centre on the need to develop technologies and practices that do not have adverse effects on environmental goods and services, are accessible to and effective for farmers, and lead to improvements in food productivity. Despite great progress in agricultural productivity in the past half-century, with crop and livestock productivity strongly driven by increased use of fertilizers, irrigation water, agricultural machinery, pesticides and land, it would be over-optimistic to assume that these relationships will remain linear in the future. New approaches are needed that will integrate biological and ecological processes into food production, minimize the use of those non-renewable inputs that cause harm to the environment or to the health of farmers and consumers, make productive use of the knowledge and skills of farmers, so substituting human capital for costly external inputs, and make productive use of people's collective capacities to work together to solve common agricultural and natural resource problems, such as for pest, watershed, irrigation, forest and credit management. These principles help to build important capital assets for agricultural systems: natural; social; human; physical; and financial capital. Improving natural capital is a central aim, and dividends can come from making the best use of the genotypes of crops and animals and the ecological conditions under which they are grown or raised. Agricultural sustainability suggests a focus on both genotype improvements through the full range of modern biological approaches and improved understanding of the benefits of ecological and agronomic management, manipulation and redesign. The ecological management of agroecosystems that addresses energy flows, nutrient cycling, population-regulating mechanisms and system resilience can lead to the redesign of agriculture at a landscape scale. Sustainable agriculture outcomes can be positive for food productivity, reduced pesticide use and carbon balances. Significant challenges, however, remain to develop national and international policies to support the wider emergence of more sustainable forms of agricultural production across both industrialized and developing countries.     

A New Algorithm to Diagnose Atrial Ectopic Origin from Multi Lead ECG Systems - Insights from 3D Virtual Human Atria and Torso

Rapid atrial arrhythmias such as atrial fibrillation (AF) predispose to ventricular arrhythmias, sudden cardiac death and stroke. Identifying the origin of atrial ectopic activity from the electrocardiogram (ECG) can help to diagnose the early onset of AF in a cost-effective manner. The complex and rapid atrial electrical activity during AF makes it difficult to obtain detailed information on atrial activation using the standard 12-lead ECG alone. Compared to conventional 12-lead ECG, more detailed ECG lead configurations may provide further information about spatio-temporal dynamics of the body surface potential (BSP) during atrial excitation. We apply a recently developed 3D human atrial model to simulate electrical activity during normal sinus rhythm and ectopic pacing. The atrial model is placed into a newly developed torso model which considers the presence of the lungs, liver and spinal cord. A boundary element method is used to compute the BSP resulting from atrial excitation. Elements of the torso mesh corresponding to the locations of the placement of the electrodes in the standard 12-lead and a more detailed 64-lead ECG configuration were selected. The ectopic focal activity was simulated at various origins across all the different regions of the atria. Simulated BSP maps during normal atrial excitation (i.e. sinoatrial node excitation) were compared to those observed experimentally (obtained from the 64-lead ECG system), showing a strong agreement between the evolution in time of the simulated and experimental data in the P-wave morphology of the ECG and dipole evolution. An algorithm to obtain the location of the stimulus from a 64-lead ECG system was developed. The algorithm presented had a success rate of 93%, meaning that it correctly identified the origin of atrial focus in 75/80 simulations, and involved a general approach relevant to any multi-lead ECG system. This represents a significant improvement over previously developed algorithms.     

Selective Inhibition of Monoamine Oxidase B by Aminoethyl Substituted Benzyl Ethers

Aminoethyl 3-chlorobenzyl ether was shown previously (Ding, C.Z. and Silverman, R.B. (1993). Bioorg. Med. Chem. Lett., 3, 2077-2078) to be a potent and selective time-dependent, but reversible inhibitor of monoamine oxidase B (MAO B). Based on this result, a series of novel aminoethyl substituted benzyl ethers was synthesized and the compounds were examined as potential inhibitors of both isozymic forms of MAO. Each compound in the series inhibits both MAO A and MAO B competitively, and IC(50) values for each compound were determined. In general, the B isozyme is much more sensitive to these inhibitors than the A isozyme (except for the o- and p-substituted nitro analogues), in some cases by more than two orders of magnitude. The selectivity in favor of MAO B inhibition is relatively high for all of the meta-substituted analogues and quite low for all of the ortho-substituted analogues. Having the substituent at the ortho-position is most favorable for MAO A inhibition. With MAO B the meta-analogues were, in general, more potent than the corresponding ortho- and para-analogues with respect to their reversible binding constants. The meta-iodo analogue is the most potent analogue.     

Acetylcholine turnover estimation in brain by gas chromatography-mass spectrometry

A gas chromatograph/quadrupole mass spectrometer system has been employed to estimate the turnover of acetylcholine in mouse brain $\text{in vivo}$ following a pulse intravenous injection of choline, using discrete deuterium labelled variants of choline and acetylcholine as tracer and internal standards. There appear to be two functional pools with turnover rates of 1.4 and 7.9 nmol gm^?1min^?1.     

Resibufogenin corrects hypertension in a rat model of human preeclampsia

The study of the pathogenesis of preeclampsia has been hampered by a relative dearth of animal models. We developed a rat model of preeclampsia in which the excretion of a circulating inhibitor of Na/K ATPase, marinobufagenin (MBG), is elevated. These animals develop hypertension, proteinuria, and intrauterine growth restriction. The administration of a congener of MBG, resibufogenin (RBG), reduces blood pressure to normal in these animals, as is the case when given to pregnant animals rendered hypertensive by the administration of MBG. Studies of Na/K ATPase inhibition by MBG and RBG reveal that these agents are equally effective as inhibitors of the enzyme.     

Altered DNA methylation in leukocytes with trisomy 21

The primary abnormality in Down syndrome (DS), trisomy 21, is well known; but how this chromosomal gain produces the complex DS phenotype, including immune system defects, is not well understood. We profiled DNA methylation in total peripheral blood leukocytes (PBL) and T-lymphocytes from adults with DS and normal controls and found gene-specific abnormalities of CpG methylation in DS, with many of the differentially methylated genes having known or predicted roles in lymphocyte development and function. Validation of the microarray data by bisulfite sequencing and methylation-sensitive Pyrosequencing (MS-Pyroseq) confirmed strong differences in methylation (p<0.0001) for each of 8 genes tested: TMEM131, TCF7, CD3Z/CD247, SH3BP2, EIF4E, PLD6, SUMO3, and CPT1B, in DS versus control PBL. In addition, we validated differential methylation of NOD2/CARD15 by bisulfite sequencing in DS versus control T-cells. The differentially methylated genes were found on various autosomes, with no enrichment on chromosome 21. Differences in methylation were generally stable in a given individual, remained significant after adjusting for age, and were not due to altered cell counts. Some but not all of the differentially methylated genes showed different mean mRNA expression in DS versus control PBL; and the altered expression of 5 of these genes, TMEM131, TCF7, CD3Z, NOD2, and NPDC1, was recapitulated by exposing normal lymphocytes to the demethylating drug 5-aza-2'deoxycytidine (5aza-dC) plus mitogens. We conclude that altered gene-specific DNA methylation is a recurrent and functionally relevant downstream response to trisomy 21 in human cells.