Synthesis and antibacterial activity of some novel imidazole-based dicationic quinolinophanes

Synthesis of novel quinoline based dicationic benzimidazolophanes and imidazolophanes incorporating various spacer units is described. Some of the quinolinophanes 1b, 3a, 3b and 4a exhibit good antibacterial activity against most of the human pathogenic bacteria in the tested concentrations as compared to the other cyclophanes as well as the test control, streptomycin.     

Biological removal of carcinogenic chromium(VI) using mixed Pseudomonas strains

The contamination of soil and wastewaters with Cr(VI) is a major problem. It has been suggested that microbial methods for Cr(VI) reduction are better than chemical methods, as they do not add other ions or toxic chemicals to the environment. In this study an aerobic reduction of Cr(VI) to Cr(III) by employing mixed Pseudomonas cultures isolated from a marshy land has been reported. The role of chromium concentration, temperature, pH and additives on the microbial reduction of Cr(VI) has been investigated. NADH was found to enhance the rate of reduction of Cr(VI). Complete reduction of chromium(VI) has been possible even at chromium(VI) concentrations of 300 ppm. Ions like SO(4)(2-) and poly-phenols inhibited the metabolic activity relating to Cr(VI) reduction. Under optimal conditions 100 mg/L of Cr(VI) was completely reduced within 180 min.     

Case-Mix,Care Processes,and Outcomes in Medically-Ill Patients Receiving Mechanical Ventilation in a Low-Resource Setting from Southern India: A Prospective Clinical Case Series

Background

Mechanical ventilation is a resource intensive organ support treatment, and historical studies from low-resource settings had reported a high mortality. We aimed to study the outcomes in patients receiving mechanical ventilation in a contemporary low-resource setting.

Methods

We prospectively studied the characteristics and outcomes (disease-related, mechanical ventilation-related, and process of care-related) in 237 adults mechanically ventilated for a medical illness at a teaching hospital in southern India during February 2011 to August 2012. Vital status of patients discharged from hospital was ascertained on Day 90 or later.

Results

Mean age of the patients was 40 ± 17 years; 140 (51%) were men. Poisoning and envenomation accounted for 98 (41%) of 237 admissions. In total, 87 (37%) patients died in-hospital; 16 (7%) died after discharge; 115 (49%) were alive at 90-day assessment; and 19 (8%) were lost to follow-up. Weaning was attempted in 171 (72%) patients; most patients (78 of 99 [79%]) failing the first attempt could be weaned off. Prolonged mechanical ventilation was required in 20 (8%) patients. Adherence to head-end elevation and deep vein thrombosis prophylaxis were 164 (69%) and 147 (62%) respectively. Risk of nosocomial infections particularly ventilator-associated pneumonia was high (57.2 per 1,000 ventilator-days). Higher APACHE II score quartiles (adjusted HR [95% CI] quartile 2, 2.65 [1.19–5.89]; quartile 3, 2.98 [1.24–7.15]; quartile 4, 5.78 [2.45–13.60]), and new-onset organ failure (2.98 [1.94–4.56]) were independently associated with the risk of death. Patients with poisoning had higher risk of reintubation (43% vs. 20%; P = 0.001) and ventilator-associated pneumonia (75% vs. 53%; P = 0.001). But, their mortality was significantly lower compared to the rest (24% vs. 44%; P = 0.002).

Conclusions

The case-mix considerably differs from other settings. Mortality in this low-resource setting is similar to high-resource settings. But, further improvements in care processes and prevention of nosocomial infections are required.     

Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment

Cell-intrinsic checkpoints limit the proliferative capacity of primary cells in response to telomere dysfunction. It is not known, however, whether telomere dysfunction contributes to cell-extrinsic alterations that impair stem cell function and organ homeostasis. Here we show that telomere dysfunction provokes defects of the hematopoietic environment that impair B lymphopoiesis but increase myeloid proliferation in aging telomerase knockout (Terc(-/-)) mice. Moreover, the dysfunctional environment limited the engraftment of transplanted wild-type hematopoietic stem cells (HSCs). Dysfunction of the hematopoietic environment was age dependent and correlated with progressive telomere shortening in bone marrow stromal cells. Telomere dysfunction impaired mesenchymal progenitor cell function, reduced the capacity of bone marrow stromal cells to maintain functional HSCs, and increased the expression of various cytokines, including granulocyte colony-stimulating factor (G-CSF), in the plasma of aging mice. Administration of G-CSF to wild-type mice mimicked some of the defects seen in aging Terc(-/-) mice, including impairment of B lymphopoiesis and HSC engraftment. Conversely, inhibition of G-CSF improved HSC engraftment in aged Terc(-/-) mice. Taken together, these results show that telomere dysfunction induces alterations of the environment that can have implications for organismal aging and cell transplantation therapies.     

Aim2 deficiency in mice suppresses the expression of the inhibitory Fcgamma receptor (FcgammaRIIB) through the induction of the IFN-inducible p202, a lupus susceptibility protein

Murine Aim2 and Ifi202 genes (encoding for the Aim2 and p202 proteins) are members of the IFN-inducible Ifi200 gene family. The Aim2 deficiency in mice activates IFN signaling and stimulates the expression of the lupus susceptibility gene, the Ifi202, located within the NZB autoimmunity 2 (Nba2) interval. Given that the deficiency in the expression of the Fcgr2b gene (encoding for the inhibitory FcγRIIB receptor) is associated with increased lupus susceptibility in mice, we investigated whether the Aim2 protein could regulate the expression of Fcgr2b gene. In this article, we report that Aim2 deficiency in mice suppresses the expression of the FcγRIIB receptor. Interestingly, the Fcgr2b-deficient cells expressed increased levels of the IFN-β, activated IFN signaling, and expressed reduced levels of the Aim2 protein. Treatment of splenic cells with IFN-α or -γ reduced levels of the FcγRIIB mRNA and protein and also decreased the activity of the FcγRIIB p(-729/+585) Luc reporter. Moreover, levels of the FcγRIIB receptor were significantly higher in the Stat1-deficient splenic cells than in the wild-type cells. Accordingly, increased expression of IFN-β in lupus-prone B6.Nba2-ABC mice, as compared with non-lupus-prone C57BL/6 (B6) or B6.Nba2-C mice, was associated with reduced expression of the FcγRIIB receptor. Notably, overexpression of the p202 protein in cells decreased the expression of the Aim2 gene, activated the IFN response, and suppressed the expression of the Fcgr2b gene. These observations demonstrate that the expression of Aim2 protein is required to maintain the expression of the Fcgr2b gene and also predict epistatic interactions between the Ifi200 genes and the Fcgr2b gene within the Nba2 interval.     

Inflammation in Mice Ectopically Expressing Human Pyogenic Arthritis,Pyoderma Gangrenosum,and Acne (PAPA) Syndrome-associated PSTPIP1 A230T Mutant Proteins

Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne Syndrome (PAPA syndrome) is an autoinflammatory disease caused by aberrant production of the proinflammatory cytokine interleukin-1. Mutations in the gene encoding proline serine threonine phosphatase-interacting protein-1 (PSTPIP1) have been linked to PAPA syndrome. PSTPIP1 is an adaptor protein that interacts with PYRIN, the protein encoded by the Mediterranean Fever (MEFV) gene whose mutations cause Familial Mediterranean Fever (FMF). However, the pathophysiological function of PSTPIP1 remains to be elucidated. We have generated mouse strains that either are PSTPIP1 deficient or ectopically express mutant PSTPIP1. Results from analyzing these mice suggested that PSTPIP1 is not an essential regulator of the Nlrp3, Aim2, or Nlrc4 inflammasomes. Although common features of human PAPA syndrome such as pyogenic arthritis and skin inflammation were not recapitulated in the mouse model, ectopic expression of the mutant but not the wild type PSTPIP1 in mice lead to partial embryonic lethality, growth retardation, and elevated level of circulating proinflammatory cytokines.     

Astrocyte control of fetal cortical neuron glutathione homeostasis: up-regulation by ethanol

Ethanol increases apoptotic neuron death in the developing brain and at least part of this may be mediated by oxidative stress. In cultured fetal rat cortical neurons, Ethanol increases levels of reactive oxygen species (ROS) within minutes of exposure and reduces total cellular glutathione (GSH) shortly thereafter. This is followed by onset of apoptotic cell death. These responses to Ethanol can be blocked by elevating neuron GSH with N-acetylcysteine or by co-culturing neurons with neonatal cortical astrocytes. We describe here mechanisms by which the astrocyte-neuron gamma-glutamyl cycle is up-regulated by Ethanol, enhancing control of neuron GSH in response to the pro-oxidant, Ethanol. Up to 6 days of Ethanol exposure had no consistent effects on activities of gamma-glutamyl cysteine ligase or glutathione synthetase, and GSH content remained unchanged (p < 0.05). However, glutathione reductase was increased with 1 and 2 day Ethanol exposures, 25% and 39% for 2.5 and 4.0 mg/mL Ethanol by 1 day, and 11% and 16% for 2.5 and 4.0 mg/mL at 2 days, respectively (p < 0.05). A 24 h exposure to 4.0 mg/mL Ethanol increased GSH efflux from astrocyte up to 517% (p < 0.05). Ethanol increased both gamma-glutamyl transpeptidase expression and activity on astrocyte within 24 h of exposure (40%, p = 0.05 with 4.0 mg/mL) and this continued for at least 4 days of Ethanol treatment. Aminopeptidase N activity on neurons increased by 62% and 55% within 1 h of Ethanol for 2.5 and 4.0 mg/mL concentration, respectively (p < 0.05), remaining elevated for 24 h of treatment. Thus, there are at least three key points of the gamma-glutamyl cycle that are up-regulated by Ethanol, the net effect being to enhance neuron GSH homeostasis, thereby protecting neurons from Ethanol-mediated oxidative stress and apoptotic death.     

An Indian scenario on renewable and sustainable energy sources with emphasis on algae

India is the fifth largest primary energy consumer and fourth largest petroleum consumer after USA, China, and Japan. Despite the global economic crisis, India’s economy is expected to grow at 6 to 8?%/year. There is an extreme dependence on petroleum products with considerable risks and environmental issues. Petroleum-derived transport fuels are of limited availability and contribute to global warming, making renewable biofuel as the best alternative. The focus on biogas and biomass-based energy, such as bioethanol and biohydrogen, will enhance cost-effectiveness and provide an opportunity for the rural community. Among all energy sources, microalgae have received, so far, more attention due to their facile adaptability to grow in the photobioreactors or open ponds, high yields, and multiple applications. Microalgae can produce a substantial amount of triacylglycerols as a storage lipid under photooxidative stress or other adverse environmental conditions. In addition to renewable biofuels, they can provide different types of high-value bioproducts added to their advantages, such as higher photosynthetic efficiency, higher biomass production, and faster growth compared to any other energy crops. The viability of first-generation biofuels production is, however, questionable because of the conflict with food supply. In the future, biofuels should ideally create the environmental, economic, and social benefits to the communities and reflect energy efficiency so as to plan a road map for the industry to produce third-generation biofuels.     

Confounding Effects of Benign Lung Diseases on Non-Small Cell Lung Cancer Serum Biomarker Discovery

Introduction

Lung cancer is the leading cause of cancer-related death worldwide. The discovery of new biomarkers could aid early diagnosis and monitoring of recurrence following tumor resection.

Methods

We have prospectively collected serum from 97 lung cancer patients undergoing surgery with curative intent and compared their serum proteomes with those of 100 noncancer controls (59 disease-free and 41 with a range of nonmalignant lung conditions). We initially analyzed serum from 67 lung cancer patients and 73 noncancer control subjects by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry using immobilized metal affinity capture ProteinChip arrays and subsequently validated our findings with an independent analysis of 30 lung cancer patients and 27 noncancer subjects.

Results

The data from both experiments show many significant differences between the serum proteomes of lung cancer patients and nondiseased control subjects, and a number of these polypeptides have been identified. However, the profiles of patients with benign lung diseases resembled those of lung cancer patients such that very few significant differences were found when these cohorts were compared.

Conclusions

This report provides clear evidence of the need to account for the confounding effects of benign diseases when designing lung cancer serum biomarker discovery projects.     

Interaction of polyethyleneimine‐anchored copper(II) complexes with tRNA studied by spectroscopy methods and biological activities

Ultraviolet–visible, emission and circular dichroism spectroscopic methods were used in transfer RNA (tRNA) interaction studies performed for polyethyleneimine–copper(II) complexes [Cu(phen)(l ‐Tyr)BPEI]ClO₄ (where phen =1,10‐phenanthroline, l ‐Tyr = l ‐tyrosine and BPEI = branched polyethyleneimine) with various degrees of coordination (x = 0.059, 0.149, 0.182) in the polymer chain. The results indicated that polyethyleneimine–copper(II) complexes bind with tRNA mostly through surface binding, although other binding modes, such as hydrogen bonding and van der Waals interactions, might also be present. Dye‐exclusion, sulforhodamine B and 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assays of a polyethyleneimine–copper(II) complex with a higher degree of coordination against different cancer cell lines proved that the complex exhibited cytotoxic specificity and a significant cancer cell inhibition rate. Antimicrobial screening showed activity against some human pathogens.