Inhibition of xc⁻ transporter-mediated cystine uptake by sulfasalazine analogs

A series of sulfasalazine analogs were synthesized and tested for their ability to block cystine-glutamate antiporter system xc? using L-[(14)C]cystine as a substrate. Replacement of sulfasalazine's diazo group with an alkyne group led to an equally potent inhibitor, 2-hydroxy-5-((4-(N-pyridin-2-ylsulfamoyl)phenyl)ethynyl)benzoic acid 6. Our SAR studies also revealed that the carboxylate group of sulfasalazine is essential for its inhibitory activity while the phenolic hydroxyl group is dispensable. Truncated analogs lacking an N-pyridin-2-ylsulfamoyl moiety were less potent than sulfasalazine, but may serve as more tractable templates because of their low molecular weight by applying a variety of fragment growing approaches. Given that sulfasalazine is rapidly metabolized through cleavage of the diazo bond, these analogs may possess a more desirable pharmacological profile as system xc- blockers, in particular, for in vivo studies.     

Long-term effect of a simple nest-box on the reproductive efficiency and other life traits of an Aotus lemurinus lemurinus monkey colony: an animal model for malaria research

Background The long‐term effect of a PVC pipe nest‐box on the reproductive efficiency and other life traits of an Aotus monkey‐breeding colony have not been characterized. Methods and Results We analyzed laboratory records of the Gorgas Memorial Institute (GMI) Aotus monkey colony in Panama for the period 1999–2010 and found a 273% increase in the annual mean life births in the following 7 years after the introduction of a PVC pipe nest‐box in 2002, as well as increases in the mean body mass and survival of laboratory‐bred monkeys. Other life traits such as inter‐birth interval, parity, birth sex distribution, mortality, and longevity were also determined. Conclusions The use of a PVC pipe nest‐box significantly improved the reproductive efficiency and other life traits of the GMI Aotus breeding colony.     

Xylella fastidiosa disturbs nitrogen metabolism and causes a stress response in sweet orange Citrus sinensis cv. Pera

Xylella fastidiosa (Xf) is a fastidious bacterium that grows exclusively in the xylem of several important crop species, including grape and sweet orange (Citrus sinensis L. Osb.) causing Pierce disease and citrus variegated chlorosis (CVC), respectively. The aim of this work was to study the nitrogen metabolism of a highly susceptible variety of sweet orange cv. 'Pêra' (C. sinensis L. Osbeck) infected with Xf. Plants were artificially infected and maintained in the greenhouse until they have developed clear disease symptoms. The content of nitrogen compounds and enzymes of the nitrogen metabolism and proteases in the xylem sap and leaves of diseased (DP) and uninfected healthy (HP) plants was studied. The activity of nitrate reductase in leaves did not change in DP, however, the activity of glutamine synthetase was significantly higher in these leaves. Although amino acid concentration was slightly higher in the xylem sap of DP, the level dropped drastically in the leaves. The protein contents were lower in the sap and in leaves of DP. DP and HP showed the same amino acid profiles, but different proportions were observed among them, mainly for asparagine, glutamine, and arginine. The polyamine putrescine was found in high concentrations only in DP. Protease activity was higher in leaves of DP while, in the xylem sap, activity was detected only in DP. Bidimensional electrophoresis showed a marked change in the protein pattern in DP. Five differentially expressed proteins were identified (2 from HP and 3 from DP), but none showed similarity with the genomic (translated) and proteomic database of Xf, but do show similarity with the proteins thaumatin, mucin, peroxidase, ABC-transporter, and strictosidine synthase. These results showed that significant changes take place in the nitrogen metabolism of DP, probably as a response to the alterations in the absorption, assimilation and distribution of N in the plant.     

Novel mechanism of inhibition of rat kidney-type glutaminase by bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES)

The release of GA (mitochondrial glutaminase) from neurons following acute ischaemia or during chronic neurodegenerative diseases may contribute to the propagation of glutamate excitotoxicity. Thus an inhibitor that selectively inactivates the released GA may limit the accumulation of excess glutamate and minimize the loss of neurological function that accompanies brain injury. The present study examines the mechanism of inactivation of rat KGA (kidney GA isoform) by the small-molecule inhibitor BPTES [bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide]. BPTES is a potent inhibitor of KGA, but not of the liver GA isoform, glutamate dehydrogenase or gamma-glutamyl transpeptidase. Kinetic studies indicate that, with respect to glutamine, BPTES has a K(i) of approx. 3 microM. Moreover, these studies suggest that BPTES inhibits the allosteric activation caused by phosphate binding and promotes the formation of an inactive complex. Gel-filtration chromatography and sedimentation-velocity analysis were used to examine the effect of BPTES on the phosphate-dependent oligomerization of KGA. This established that BPTES prevents the formation of large phosphate-induced oligomers and instead promotes the formation of a single oligomeric species with distinct physical properties. Sedimentation-equilibrium studies determined that the oligomer produced by BPTES is a stable tetramer. Taken together, the present work indicates that BPTES is a unique and potent inhibitor of rat KGA and elucidates a novel mechanism of inactivation.     

Future ocean climate homogenizes communities across habitats through diversity loss and rise of generalist species

Predictions of the effects of global change on ecological communities are largely based on single habitats. Yet in nature, habitats are interconnected through the exchange of energy and organisms, and the responses of local communities may not extend to emerging community networks (i.e., metacommunities). Using large mesocosms and meiofauna communities as a model system, we investigated the interactive effects of ocean warming and acidification on the structure of marine metacommunities from three shallow‐water habitats: sandy soft‐bottoms, marine vegetation, and rocky reef substrates. Primary producers and detritus—key food sources for meiofauna—increased in biomass under the combined effect of temperature and acidification. The enhanced bottom‐up forcing boosted nematode densities but impoverished the functional and trophic diversity of nematode metacommunities. The combined climate stressors further homogenized meiofauna communities across habitats. Under present‐day conditions metacommunities were structured by habitat type, but under future conditions they showed an unstructured random pattern with fast‐growing generalist species dominating the communities of all habitats. Homogenization was likely driven by local species extinctions, reducing interspecific competition that otherwise could have prevented single species from dominating multiple niches. Our findings reveal that climate change may simplify metacommunity structure and prompt biodiversity loss, which may affect the biological organization and resilience of marine communities.     

Recent and rapid population growth and range expansion of the Lyme disease tick vector,Ixodes scapularis,in North America

Migration is a primary force of biological evolution that alters allele frequencies and introduces novel genetic variants into populations. Recent migration has been proposed as the cause of the emergence of many infectious diseases, including those carried by blacklegged ticks in North America. Populations of blacklegged ticks have established and flourished in areas of North America previously thought to be devoid of this species. The recent discovery of these populations of blacklegged ticks may have resulted from either in situ growth of long‐established populations that were maintained at very low densities or by migration and colonization from established populations. These alternative evolutionary hypotheses were investigated using Bayesian phylogeographic approaches to infer the origin and migratory history of recently detected blacklegged tick populations in the Northeastern United States. The data and results indicate that newly detected tick populations are not the product of in situ population growth from a previously established population but from recent colonization resulting in a geographic range expansion. This expansion in the geographic range proceeded primarily through progressive and local migration events from southern populations to proximate northern locations although long‐distance migration events were also detected.     

Ablation of Nectin4 Binding Compromises CD46 Usage by a Hybrid Vesicular Stomatitis Virus/Measles Virus

Measles virus (MV) immunosuppression is due to infection of SLAM-positive immune cells, whereas respiratory shedding and virus transmission are due to infection of nectin4-positive airway epithelial cells. The vaccine lineage MV strain Edmonston (MV-Edm) acquired an additional tropism for CD46 which is the basis of its oncolytic specificity. VSVFH is a vesicular stomatitis virus (VSV) encoding the MV-Edm F and H entry proteins in place of G. The virus spreads faster than MV-Edm and is highly fusogenic and a potent oncolytic. To determine whether ablating nectin4 tropism from VSVFH might prevent shedding, increasing its safety profile as an oncolytic, or might have any effect on CD46 binding, we generated VSVFH viruses with H mutations that disrupt attachment to SLAM and/or nectin4. Disruption of nectin4 binding reduced release of VSVFH from the basolateral side of differentiated airway epithelia composed of Calu-3 cells. However, because nectin4 and CD46 have substantially overlapping receptor binding surfaces on H, disruption of nectin4 binding compromised CD46 binding and greatly diminished the oncolytic potency of these viruses on human cancer cells. Thus, our results support continued preclinical development of VSVFH without ablation of nectin4 binding.     

Trasplante renal en mayores de 60 años en un hospital de Colombia

Introduction

Kidney transplantation is the treatment of choice in patients with end- stage renal disease. Renal transplantation in without fear of ethical conflicts is the best treatment option in the elderly. The objective is to describe the demographic and clinical characteristics of patients over 60 years old with at least one year of renal transplantation in a single center of Colombia.

Methods

This is a cohort study of patients over 60 years old from a single center in Bogota, Colombia. About 28 patients were analyzed between June 2004 and March 2012.

Results

The mean age was 65 years old, with 89% males. The main cause of chronic kidney disease was diabetic nephropathy, followed by hypertensive nephrosclerosis. Most of them (96.4%) were deceased donor transplants with a mean age of 40 years old, cold ischemia time was 12 hours and there was a mismatch of 3.25 (±1.29). Major comorbidities were hypertension, diabetes, dyslipidemia, and coronary arterial disease. Almost 17% had delayed graft dysfunction. Serum creatinine at 6 and 12 months was 1.27 mg/dl (±0.31) and 1.25 mg/dl (±0.33), respectively. Only 10% of patients had acute cellular rejection. Humoral rejections were not documented. The patient survival at 1 year was 89.7%, and death-censored graft survival was 96.4%. The most frequent cause of death was acute myocardial infarction.

Conclusions

Proper selection of kidney transplant recipients shows satisfactory results in survival, with low morbidity in patients older than 60 years.     

Uric Acid Is Associated with Metabolic Syndrome in Children and Adults in a Community: The Bogalusa Heart Study

Background

Elevated serum uric acid (UA) is commonly found in subjects with metabolic syndrome (MetS). This study examined the association of UA with levels of individual MetS components and the degree of their clustering patterns in both children and adults.

Methods

The study sample consisted of 2614 children aged 4–18 years and 2447 adults aged 19–54 years. MetS components included body mass index (BMI), mean arterial pressure (MAP), triglycerides to high-density lipoprotein cholesterol ratio (TG/HDLC), and homeostasis model assessment of insulin resistance (HOMA). Observed/expected (O/E) ratio and intra-class correlation coefficient (ICC) were used as a measure of the degree of clustering of categorical and continuous MetS variables, respectively.

Results

UA was positively and significantly associated only with BMI in children but with all four components in adults. The odds ratio for MetS associated with 1 mg/dL increase of UA was 1.74 (p<0.001) in children and 1.92 (p<0.001) in adults. O/E ratios showed a significant, increasing trend with increasing UA quartiles in both children and adults for 3- and 4-variable clusters with p-values for trend <0.001, except for BMI-MAP-TG/HDLC and MAP-TG/HDLC-HOMA clusters in children and MAP-TG/HDLC-HOMA cluster in adults. ICCs of 3 and 4 components increased with increasing UA quartiles in children and adults.

Conclusions

These results indicate that UA may play a role in the development of MetS in both pediatric and adult populations alike, which may aid in the identification and treatment of high risk individuals for MetS and related clinical disorders in early life.