Callithrix penicillata as a nonhuman primate model for strongyloidiasis

In order to better understand experimental strongyloidiasis in small New World primates, and to evaluate aspects of reinfection and immunosuppression induced by glucocorticoids, nine specimens of Callithrix penicillata (Primates: Cebidae) were administered (by subcutaneous injection, sc) 3000 infective larvae of a strain of Strongyloides venezuelensis (Rhabditida: Strongyloididae) that had been maintained in successive passages through AKR/J mice since 1987. The mean prepatent period was 5.6 ± 0.7 days post-infection (DPI). The mean patent period of infection among the untreated animals (marmosets 1-7) was 123.4 ± 61.4 DPI. Two animals (marmosets 8 and 9) received dexamethasone (2.5 mg/kg, sc) for five consecutive days starting on the 20th day after infection, but this treatment did not alter the course of the infection, and the patent period for these animals was 100.5 ± 58.7 DPI (59 and 142, respectively). Stool examination showed that the highest quantities of parasite eggs were expelled between the 8th and 19th days after inoculation of the larvae. Thereafter, there was a gradual reduction in the number of parasite eggs in feces of all marmosets. During the chronic phase of the infection, before completely negative parasitological findings were obtained, the parasitological examinations were intermittently positive. Reinfection of three of these animals did not result in new positive examinations. However, given the receptiveness of these animals to initial infection with S. venezuelensis and their similarities to human beings, it is proposed that C. penicillata could be used as a nonhuman primate model for experimental strongyloidiasis.     

Arsenic metabolism and thioarsenicals

Arsenic has received considerable attention in the world, since it can lead to a multitude of toxic effects and has been recognized as a human carcinogen causing cancers. Here, we focus on the current state of knowledge regarding the proposed mechanisms of arsenic biotransformation, with a little about cellular uptake, toxicity and clinical utilization of arsenicals. Since pentavalent methylated metabolites were found in animal urine after exposure to iAs(III), methylation was considered to be a detoxification process, but the discovery of methylated trivalent intermediates and thioarsenicals in urine has diverted the view and gained much interest regarding arsenic biotransformation. To further investigate the partially understood phenomena relating to arsenic toxicity and the uses of arsenic as a drug, it is important to elucidate the exact pathways involved in metabolism of this metalloid, as the toxicity and the clinical uses of arsenic can be best recognized in context of its biotransformation. Thereby, in this perspective, we have focused on arsenic metabolic pathways including three proposed mechanisms: a classic pathway by Challenger in 1945, followed by a new metabolic pathway proposed by Hayakawa in 2005 involving arsenic-glutathione complexes, while the third is a new reductive methylation pathway that is proposed by our group involving As-protein complexes. According to previous and present in vivo and in vitro experiments, we conclude that the methylation reaction takes place with simultaneous reductive rather than stepwise oxidative methylation. In addition, production of pentavalent methylated arsenic metabolites are suggested to be as the end product of metabolism, rather than intermediates.     

Global assessment of experimental climate warming on tundra vegetation: heterogeneity over space and time

Understanding the sensitivity of tundra vegetation to climate warming is critical to forecasting future biodiversity and vegetation feedbacks to climate. In situ warming experiments accelerate climate change on a small scale to forecast responses of local plant communities. Limitations of this approach include the apparent site-specificity of results and uncertainty about the power of short-term studies to anticipate longer term change. We address these issues with a synthesis of 61 experimental warming studies, of up to 20 years duration, in tundra sites worldwide. The response of plant groups to warming often differed with ambient summer temperature, soil moisture and experimental duration. Shrubs increased with warming only where ambient temperature was high, whereas graminoids increased primarily in the coldest study sites. Linear increases in effect size over time were frequently observed. There was little indication of saturating or accelerating effects, as would be predicted if negative or positive vegetation feedbacks were common. These results indicate that tundra vegetation exhibits strong regional variation in response to warming, and that in vulnerable regions, cumulative effects of long-term warming on tundra vegetation - and associated ecosystem consequences - have the potential to be much greater than we have observed to date.     

Gene expression profiling through microarray analysis in Arabidopsis thaliana colonized by Pseudomonas putida MTCC5279, a plant growth promoting rhizobacterium

Plant growth promotion is a multigenic process under the influence of many factors; therefore an understanding of these processes and the functions regulated may have profound implications. Present study reports microarray analysis of Arabidopsis thaliana plants inoculated with Pseudomonas putida MTCC5279 (MTCC5279) which resulted in significant increase in growth traits as compared with non-inoculated control. The gene expression changes, represented by oligonucleotide array (24652 genes) have been studied to gain insight into MTCC5279 assisted plant growth promotion in Arabidopsis thaliana. MTCC5279 induced upregulated Arabidopsis thaliana genes were found to be involved in maintenance of genome integrity (At5g20850), growth hormone (At3g23890 and At4g36110), amino acid synthesis (At5g63890), abcissic acid (ABA) signaling and ethylene suppression (At2g29090, At5g17850), Ca⁺² dependent signaling (At3g57530) and induction of induced systemic resistance (At2g46370, At2g44840). The genes At3g32920 and At2g15890 which are suggested to act early in petal, stamen and embryonic development are among the downregulated genes. We report for the first time MTCC5279 assisted repression of At3g32920, a putative DNA repair protein involved in recombination and DNA strand transfer in a process of rapid meiotic and mitotic division.     

Laboratory and Clinical Predictors of Disease Progression following Initiation of Combination Therapy in HIV-Infected Adults in Thailand

BACKGROUND: Data on determinants of long-term disease progression in HIV-infected patients on antiretroviral therapy (ART) are limited in low and middle-income settings. METHODS: Effects of current CD4 count, viral load and haemoglobin and diagnosis of AIDS-defining events (ADEs) after start of combination ART (cART) on death and new ADEs were assessed using Poisson regression, in patient aged ≥18 years within a multi-centre cohort in Thailand. RESULTS: Among 1,572 patients, median follow-up from cART initiation was 4.4 (IQR 3.6-6.3) years. The analysis of death was based on 60 events during 6,573 person-years; 30/50 (60%) deaths with underlying cause ascertained were attributable to infections. Analysis of new ADE included 192 events during 5,865 person-years; TB and Pneumocystis jiroveci pneumonia were the most commonly presented first new ADE (35% and 20% of cases, respectively). In multivariable analyses, low current CD4 count after starting cART was the strongest predictor of death and of new ADE. Even at CD4 above 200 cells/mm(3), survival improved steadily with CD4, with mortality rare at ≥500 cells/mm(3) (rate 1.1 per 1,000 person-years). Haemoglobin had a strong independent effect, while viral load was weakly predictive with poorer prognosis only observed at ≥100,000 copies/ml. Mortality risk increased following diagnosis of ADEs during cART. The decline in mortality rate with duration on cART (from 21.3 per 1,000 person-years within first 6 months to 4.7 per 1,000 person-years at ≥36 months) was accounted for by current CD4 count. CONCLUSIONS: Patients with low CD4 count or haemoglobin require more intensive diagnostic and treatment of underlying causes. Maintaining CD4≥500 cells/mm(3) minimizes mortality. However, patient monitoring could potentially be relaxed at high CD4 count if resources are limited. Optimal ART monitoring strategies in low-income settings remain a research priority. Better understanding of the aetiology of anaemia in patients on ART could guide prevention and treatment.     

The association between N-acetyltransferase 2 gene polymorphisms and pancreatic cancer

Pancreatic cancer has been linked with exposure to environmental chemicals, which generally require metabolic activation to highly reactive toxic or carcinogenic intermediates. N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2) are expressed primarily in extrahepatic and hepatic tissues, respectively. Both enzymes catalyze N- and O-acetylation of aromatic and heterocyclic amines. It is believed that these compounds are activated via O-acetylation and detoxified by N-acetylation. Several polymorphisms of these two genes have been associated with an increased risk of cancer. Twenty-seven cases of pancreatic cancer and 104 controls were included in this study. Blood was collected in EDTA-containing tubes, and genomic DNA was extracted from the white blood cells by using a high pure PCR template preparation kit. Genotyping of NAT2 polymorphisms was detected by a real time PCR instrument. There was a significant difference in the distribution of the NAT2*6A acetylators phenotype between cases and the controls. The odds ratio of pancreatic cancer for the NAT2*6A slow phenotype was 5.7 (95% CI = 1.27-25.55; p = 0.023) compared with the fast type. Our results suggest that slow acetylators have higher risk of developing pancreatic cancer than fast acetylators. NAT2 gene polymorphisms may be associated with genetic susceptibility to pancreatic cancer.     

Reversible pegylation prolongs the hypotensive effect of atrial natriuretic peptide

Natriuretic peptides (NP), including atrial natriuretic peptide (ANP), induce potent natriuresis and vasodilation and thereby generate hypotension in vivo. Despite intensive efforts, clinical application of NP as an antihypertensive agent is limited because of their short biological half-life and poor bioavailability. Recently, we have developed a strategy that facilitates slow release of peptides from PEG-peptide inactive conjugates, based on reversible pegylation. Peptides prepared by this approach undergo slow, spontaneous chemical hydrolysis at physiological conditions, releasing the native active peptide/protein drug from the inactive conjugates over prolonged periods. A PEG chain of 30 kDa was linked covalently to the alpha-amino side chain of the hormone via a MAL-Fmoc-NHS spacer, yielding PEG 30-Fmoc-ANP, a prodrug that releases the native hormone upon incubation at physiological conditions. Bolus administration of native ANP to Wistar rats receiving adrenaline yields a short, transitory effect in lowering blood pressure (BP), reaching a maximum at 2 min, and then returning to control values after 12 to 25 min. In contrast, administration of PEG 30-Fmoc-ANP lowered BP following a lag period of 50 min, and maintained low BP for a period exceeding 60 min. Saline or PEG 30-Fmoc-Alanine were not effective in lowering BP in Wistar rats. These results show that the novel compound, PEG 30-Fmoc-ANP, is a reversible pegylated prodrug derivative that facilitates a prolonged BP lowering effect in rats and may be considered as a candidate for development into an antihypertensive drug.     

Gender differences in the relationship of ENPP1/PC-1 variants to obesity in a Turkish population

The ectoenzyme ENPP1 (also termed membrane glycoprotein PC-1 or ENPP1/PC-1) is an inhibitor of insulin-induced activation of the insulin receptor. There is evidence from previous studies that coding variants of ENPP1/PC-1 (K121Q) are associated with type 2 diabetes (T2D) and obesity. Studies in the general Turkish population have demonstrated: unique plasma lipid characteristics, a high prevalence of cardiovascular risk factors, and an increased prevalence of obesity and T2D. We investigated, therefore, the association of ENPP1/PC-1 variants with obesity and T2D in Turkish individuals. The TaqMan allelic discrimination assay was used for genotyping the relationship of ENPP1/PC-1 variants to obesity and T2D in a genetic association study of 1,553 genotyped, randomly selected subjects from the Turkish Heart Study. The K121Q (rs1044498) variant and other previously reported variants (rs997509, rs1799774, rs1044548, rs11964389, rs7754561) were analyzed. In this cohort, the minor allele frequency (MAF) of the K121Q variant was associated with obesity in male, but not in female subjects (male, odds ratio 1.64, 95% confidence interval 1.004-2.698, P = 0.048; female, odds ratio 1.003, 95% confidence interval 0.684-1.471, P = ns). In addition, the previously reported ENPP1/PC-1 "risk haplotype" (Q (rs1044498), delT (rs1799774), and G (rs7754561) alleles) was found to be associated with obesity in male, but not in female, subjects (P = 0.035). In contrast, there was no association of either the K121Q variant or the ENPP1/PC-1 haplotype with T2D. We find evidence that variants of ENPP1/PC-1 are associated with obesity in the male Turkish population; thus, these variants may contribute to the development of the obesity in these individuals.     

Express Attentional Re-Engagement but Delayed Entry into Consciousness Following Invalid Spatial Cues in Visual Search

Background

In predictive spatial cueing studies, reaction times (RT) are shorter for targets appearing at cued locations (valid trials) than at other locations (invalid trials). An increase in the amplitude of early P1 and/or N1 event-related potential (ERP) components is also present for items appearing at cued locations, reflecting early attentional sensory gain control mechanisms. However, it is still unknown at which stage in the processing stream these early amplitude effects are translated into latency effects.

Methodology/Principal Findings

Here, we measured the latency of two ERP components, the N2pc and the sustained posterior contralateral negativity (SPCN), to evaluate whether visual selection (as indexed by the N2pc) and visual-short term memory processes (as indexed by the SPCN) are delayed in invalid trials compared to valid trials. The P1 was larger contralateral to the cued side, indicating that attention was deployed to the cued location prior to the target onset. Despite these early amplitude effects, the N2pc onset latency was unaffected by cue validity, indicating an express, quasi-instantaneous re-engagement of attention in invalid trials. In contrast, latency effects were observed for the SPCN, and these were correlated to the RT effect.

Conclusions/Significance

Results show that latency differences that could explain the RT cueing effects must occur after visual selection processes giving rise to the N2pc, but at or before transfer in visual short-term memory, as reflected by the SPCN, at least in discrimination tasks in which the target is presented concurrently with at least one distractor. Given that the SPCN was previously associated to conscious report, these results further show that entry into consciousness is delayed following invalid cues.     

Activation of the oxygen-sensing signal cascade prevents mitochondrial injury after mouse liver ischemia-reperfusion

The mitochondrial permeability transition (MPT) plays an important role in hepatocyte death caused by ischemia-reperfusion (IR). This study investigated whether activation of the cellular oxygen-sensing signal cascade by prolyl hydroxylase inhibitors (PHI) protects against the MPT after hepatic IR. Ethyl 3,4-dihyroxybenzoate (EDHB, 100 mg/kg ip), a PHI, increased mouse hepatic hypoxia-inducible factor-1alpha and heme oxygenase-1 (HO-1). EDHB-treated and untreated mice were subjected to 1 h of warm ischemia to approximately 70% of the liver followed by reperfusion. Mitochondrial polarization, cell death, and the MPT were assessed by intravital confocal/multiphoton microscopy of rhodamine 123, propidium iodide, and calcein. EDHB largely blunted alanine aminotransferase (ALT) release and necrosis after reperfusion. In vehicle-treated mice at 2 h after reperfusion, viable cells with depolarized mitochondria were 72%, and dead cells were 2%, indicating that depolarization preceded necrosis. Mitochondrial voids excluding calcein disappeared, indicating MPT onset in vivo. NIM811, a specific inhibitor of the MPT, blocked mitochondrial depolarization after IR, further confirming that mitochondrial depolarization was due to MPT onset. EDHB decreased mitochondrial depolarization to 16% and prevented the MPT. Tin protoporphyrin (10 micromol/kg sc), an HO-1 inhibitor, partially abrogated protection by EDHB against ALT release, necrosis, and mitochondrial depolarization. In conclusion, IR causes the MPT and mitochondrial dysfunction, leading to hepatocellular death. PHI prevents MPT onset and liver damage through an effect mediated partially by HO-1.