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We present results of molecular dynamics simulations for two-dimensional repulsively interacting colloids driven by a one-dimensional asymmetric and commensurate ratchet potential, switching on and off stochastically. This drives a time-averaged directed current of colloids, exhibiting resonance with change in ratcheting frequency, where the resonance frequency itself depends nonmonotonically on density. Using scaling arguments, we obtain analytic results that show good agreement with numerical simulations. With increasing ratcheting frequency, we find nonequilibrium reentrant transitions between solid and modulated liquid phases.

We consider the single-file motion of colloidal particles interacting via short-range repulsion and placed in a traveling wave potential that varies periodically in time and space. Under suitable driving conditions, a directed time-averaged flow of colloids is generated. We obtain analytic results for the model using a perturbative approach to solve the Fokker-Planck equations. The predictions show good agreement with numerical simulations. We find peaks in the time-averaged directed current as a function of driving frequency, wavelength, and particle density and discuss possible experimental realizations. Surprisingly, unlike a closely related exclusion dynamics on a lattice, the directed current in the present model does not show current reversal with density. A linear response formula relating current response to equilibrium correlations is also proposed.

Background: Spondias pinnata has been reported for its efficient anticancer effects, but the studies were mostly focused on its extract., Objective: Since its bioactive compounds are largely unknown, this study was designed to characterize the lead components present in it and their anticancer activity against human glioblastoma cell line (U87)., Materials and Methods: Major compounds from the ethyl acetate fraction were isolated by column chromatography and their anticancer potentials against U87 cells were evaluated. Furthermore, flow cytometric and immunoblotting analyses were performed to demonstrate the mechanism of apoptosis inducing activity of methyl gallate (MG) against U87 cell line., Results: Four major compounds were isolated from the ethyl acetate fraction. Amongst these, two compounds showed promising activities and with the help of different spectroscopic methods they were identified as gallic acid and MG. Flow cytometric studies revealed that MG-induced apoptosis in U87 cells dose-dependently; the same was confirmed by activation of caspases through cleavage of endogenous substrate poly (adenosine diphosphate-ribose) polymerase. MG treatment also induced the expression of p53 and B-cell lymphoma-2-associated X and cleavage of BH3 interacting-domain with a concomitant decrease in B-cell lymphoma-2 expression. Moreover, MG-induced sustained phosphorylation of extracellular signal-regulated kinase (ERK1/2) in U87 cells with no change in the phosphorylation of other mitogen-activated protein kinases (c-Jun N-terminal of stress-activated protein kinases, p38)., Conclusion: MG is a potent antioxidant and it induces sustained ERK1/2 activation and apoptosis in human glioblastoma U87, and provide a rationale for evaluation of MG for other brain carcinoma cell lines for the advancement of glioblastoma therapy.

We present a model of ant traffic considering individual ants as self-propelled particles undergoing single-file motion on a one-dimensional trail. Recent experiments on unidirectional ant traffic in well-formed natural trails showed that the collective velocity of ants remains approximately unchanged, leading to the absence of jamming even at very high densities [John et al., Phys. Rev. Lett. 102, 108001 (2009)]. Assuming a feedback control mechanism of self-propulsion force generated by each ant using information about the distance from the ant in front, our model captures all the main features observed in the experiment. The distance headway distribution shows a maximum corresponding to separations within clusters. The position of this maximum remains independent of average number density. We find a non-equilibrium first-order transition, with the formation of an infinite cluster at a threshold density where all the ants in the system suddenly become part of a single cluster.

Aims: This study was aimed to evaluate different phytochemical constituents and the ameliorating effect of 70% methanol extract of Euglena tuba (ETME) on iron overload-induced liver injury, along with its in vitro iron-chelating and DNA protection effects., Methods and Results: Phytochemicals of ETME were identified by GC-MS analysis. Iron chelation and protection of Fenton reaction-induced DNA damage was conducted in vitro. Post oral administration of ETME to iron-overloaded mice, the levels of serum parameters, antioxidant enzymes, liver iron, lipid peroxidation, protein carbonyl and hydroxyproline contents were measured. ETME showed inhibition of lipid peroxidation, protein oxidation and liver fibrosis. The serum markers and liver iron were lessened, whereas enhanced levels of liver antioxidant enzymes were detected in ETME-treated group. Furthermore, the histopathological observations also substantiated the protective effects of the extract., Conclusions: Several bioactive compounds identified by GC-MS may be the basis of hepatoprotective as well as antioxidant and iron-chelating effect of ETME., Significance and Impact of the Study: Currently available iron-chelating agents show several side effects and limitations which may be overcome by ETME, which suggest its benefit against pathology of iron overload-linked diseases. Hence, ETME can be used as a promising hepatoprotective agent., (© 2014 The Society for Applied Microbiology.)

Intracellular pathogens such as Salmonella enterica serovar Typhimurium (S. Typhimurium) manipulate their host cells through the interplay of various virulence factors. A multitude of such virulence factors are encoded on the genome of S. Typhimurium and are usually organized in pathogenicity islands. The virulence-associated genomic stretch of STM3117-3120 has structural features of pathogenicity islands and is present exclusively in non-typhoidal serovars of Salmonella. It encodes metabolic enzymes predicted to be involved in methylglyoxal metabolism. STM3117-encoded lactoylglutathione lyase significantly impacts the proliferation of intracellular Salmonella. The deletion mutant of STM3117 (Δlgl) fails to grow in epithelial cells but hyper-replicates in macrophages. This difference in proliferation outcome was the consequence of failure to detoxify methylglyoxal by Δlgl, which was also reflected in the form of oxidative DNA damage and upregulation of kefB in the mutant. Within macrophages, the toxicity of methylglyoxal adducts elicits the potassium efflux channel (KefB) in the mutant which subsequently modulates the acidification of mutant-containing vacuoles (MCVs). The perturbation in the pH of the MCV milieu and bacterial cytosol enhances the Salmonella pathogenicity island 2 translocation in Δlgl, increasing its net growth within macrophages. In epithelial cells, however, the maturation of Δlgl-containing vacuoles were affected as these non-phagocytic cells maintain less acidic vacuoles compared to those in macrophages. Remarkably, ectopic expression of Toll-like receptors 2 and 4 on epithelial cells partially restored the survival of Δlgl. This study identified a novel metabolic enzyme in S. Typhimurium whose activity during intracellular infection within a given host cell type differentially affected the virulence of the bacteria., (© 2014 The Authors.)

Within the Rayleigh-Helmholtz model of active Brownian particles, activity is due to a nonlinear velocity-dependent force. In the presence of external trapping potential or constant force, the steady state of the system breaks detailed balance producing a net entropy. Using molecular dynamics simulations, we obtain the probability distributions of entropy production in these steady states. The distribution functions obey fluctuation theorems for entropy production. Using the simulation, we further show that the steady-state response function obeys a modified fluctuation-dissipation relation.

The recent discovery of genes encoding the mitochondrial calcium (Ca(2+)) uniporter has revealed new opportunities for studying how abnormal Ca(2+) signals cause disease. Ca(2+) transport across the mitochondrial inner membrane is highly regulated, and the uniporter is the channel that acts as a major portal for Ca(2+) influx. Low amounts of mitochondrial Ca(2+) can boost ATP synthesis, but excess amounts, such as following cytoplasmic Ca(2+) overload in heart failure, triggers mitochondrial failure and cell death. In fact, precisely because mitochondrial Ca(2+) transport is so tightly regulated, a fundamental understanding of how the uniporter functions is necessary. Two key uniporter features allow Ca(2+) influx without mitochondrial damage during normal physiology. First, the channel is significantly more selective than other known Ca(2+) channels. This prevents the permeation of other ions and uncoupling of the electrochemical gradient. Second, the uniporter becomes active at only high Ca(2+) concentrations, preventing a resting leak of cytoplasmic Ca(2+) itself. Now possessing the identities of the various proteins forming the uniporter, we can proceed with efforts to define the molecular determinants of permeation, selectivity and Ca(2+)-regulation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Unstable generation of free radicals in the body are responsible for many degenerative diseases. A bloom forming algae Euglena tuba growing abundantly in the aquatic habitats of Cachar district in the state of Assam in North-East India was analysed for its phytochemical contents, antioxidant activity as well as free radical scavenging potentials., Results: Based on the ability of the extract in ABTS•+ radical cation inhibition and Fe3+ reducing power, the obtained results revealed the prominent antioxidant activity of the algae, with high correlation coefficient of its TEAC values to the respective phenolic and flavonoid contents. The extract had shown its scavenging activity for different free radicals and 41.89 ± 0.41 μg/ml, 5.83 ± 0.07 μg/ml, 278.46 ± 15.02 μg/ml and 223.25 ± 4.19 μg/ml were determined as the IC50 values for hydroxyl, superoxide, nitric oxide and hypochlorous acid respectively, which are lower than that of the corresponding reference standards. The phytochemical analysis also revealed that the phenolics, flavonoids, alkaloids, tannins and carbohydrates are present in adequate amount in the extract which was confirmed by HPLC analysis., Conclusions: The results showed that 70% methanol extract of the algae possesses excellent antioxidant and free radical scavenging properties.

The objective of the present study was to assess the in vitro anticancer activity of 70% methanolic extract of Terminalia belerica (TBME) against human lung (A549) and human breast (MCF-7) carcinoma and its possible mechanism. TBME showed significant cytotoxicity to both A549 and MCF-7 cells, whereas, no cytotoxicity was found in non-malignant WI-38 cells. Flow cytometric analysis was then performed and 100 μg/ml of TBME was selected as the effective concentration inducing apoptosis in A549 and MCF-7. At this concentration, TBME caused DNA fragmentation pattern of apoptosis. Furthermore, mechanism of apoptosis induction was demonstrated using western blotting and Bax/Bcl-2 ratio in both types of the cells was found increased, which leads to the activation of caspase cascade along with the cleavage of PARP. These results suggested that TBME is able to induce anticancer effects on both lung and breast cancer cell lines through the modulation of Bcl-2 family proteins.

Objective: To compare the effects of prophylactic indomethacin versus expectant management on short-term respiratory outcomes in extremely low-birth-weight (ELBW) infants., Methods: This was a retrospective cohort study of ELBW infants with gestational age less than 28 weeks, born at a level III neonatal intensive care unit from 2004 to 2009. Patients were grouped based on whether they received prophylactic indomethacin or expectant treatment. The key outcome was the cumulative number of days of mechanical ventilation. Other outcomes were cumulative number of days supplemental oxygen and continuous positive airway pressure (CPAP) were required; duration of hospital stay; mortality; and other morbidities such as necrotizing enterocolitis and intraventricular hemorrhage. Multivariable linear regression was performed with treatment group and seven covariates, defined a priori, as predictor variables and cumulative number of days of mechanical ventilation as the outcome., Results: There were 144 infants in the prophylaxis group and 221 infants in the expectant treatment group. At baseline, the Score for Neonatal Acute Physiology-Perinatal Extension, incidence of respiratory distress syndrome, and usage of antenatal corticosteroids were significantly higher in the prophylaxis group. The cumulative number of days of mechanical ventilation, supplemental oxygen, and CPAP were significantly higher in the prophylaxis group. On multivariable linear regression, after adjusting for confounders, use of prophylactic indomethacin (unstandardized β coefficient = 12.4; 95% confidence interval [CI]: 6.6, 18.1; p < 0.001), birth weight (β =  -0.025; 95% CI: -0.05, -0.001; p = 0.043), and gestation (β =  -4.5; 95% CI: -7.24, -1.8; p = 0.001) were the independent predictors of cumulative number of days of mechanical ventilation., Conclusion: ELBW infants who received prophylactic indomethacin had significantly longer cumulative number of days of mechanical ventilation, supplemental oxygen, and CPAP. Prophylactic indomethacin is an independent predictor of cumulative number of days of mechanical ventilation., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

This study was conducted to profile nutritional risk factors in a population of community-dwelling older adults in Kolkata, India. We applied the short version of the Mini Nutritional Assessment-Short Form (MNA-SF) questionnaire among 500 participants (65 to 75 years)--263 males and 237 females. The prevalence of undernutrition was 8.8% in females and 4.9% in males; a risk of undernutrition was found in 24.5% females and 17.5% males. All those with undernutrition or at-risk were studied further using the full version of the MNA. Data regarding education, occupation, socioeconomic status, and food intake pattern were also collected. Females had a significantly lower (P < 0.01) education level than males; 73.4% males were financially independent, whereas 72.7% females were financially dependent on others. Moderate appetite loss was commonly found (64.9%), and in 24.3% of the participants appetite loss was severe. Digestive and chewing problems were present in 32.4% and 21.6% of study participants, respectively. The rate of psychological stress and/or acute disease 3 months prior to study was 47%, and 62.2% of the study population were taking 3 or more medicines per day. Weight loss of greater than 3 kg and of 1 to 3 kg during past 3 months of the study period was observed in 27% and 32.5% of the population, respectively. Undernourished individuals were also found to consume fewer protein-rich foods. We hypothesize that low education levels and lack of financial independence were the strongest underlying causes of high undernutrition in this population, particularly, among females.

The present study investigates the ability of two genus of duckweed (Lemna minor and Spirodela polyrhiza) to phytoremediate cadmium from aqueous solution. Duckweed was exposed to six different cadmium concentrations, such as, 0.5,1.0,1.5, 2.0, 2.5, and 3.0 mg/L and the experiment was continued for 22 days. Water samples were collected periodically for estimation of residual cadmium content in aqueous solution. At the end of treatment period plant samples were collected and accumulated cadmium content was measured. Cadmium toxicity was observed through relative growth factor and changes in chlorophyll content Experimental results showed that Lemna minor and Spirodela polyrhiza were capable of removing 42-78% and 52-75% cadmium from media depending upon initial cadmium concentrations. Cadmium was removed following pseudo second order kinetic model Maximum cadmium accumulation in Lemna minor was 4734.56 mg/kg at 2 mg/L initial cadmium concentration and 7711.00 mg/kg in Spirodela polyrhiza at 3 mg/L initial cadmium concentration at the end of treatment period. Conversely in both cases maximum bioconcentration factor obtained at lowest initial cadmium concentrations, i.e., 0.5 mg/L, were 3295.61 and 4752.00 for Lemna minor and Spirodela polyrhiza respectively. The present study revealed that both Lemna minor and Spirodela polyrhiza was potential cadmium accumulator.

This report highlights the phytochemical analysis, antioxidant potential and anticancer activity against breast carcinoma of 70% methanolic extract of lichen, Parmotrema reticulatum (PRME). Phytochemical analysis of PRME confirms the presence of various phytoconstituents like alkaloids, carbohydrates, flavonoids, glycosides, phenols, saponins, tannins, anthraquinones, and ascorbic acid; among which alkaloids, phenols and flavonoids are found in abundant amount. High performance liquid chromatography (HPLC) analysis of PRME revealed the presence of catechin, purpurin, tannic acid and reserpine. Antioxidant activity was evaluated by nine separate methods. PRME showed excellent hydroxyl and hypochlorous radical scavenging as well as moderate DPPH, superoxide, singlet oxygen, nitric oxide and peroxynitrite scavenging activity. Cytotoxicity of PRME was tested against breast carcinoma (MCF-7), lung carcinoma (A549) and normal lung fibroblast (WI-38) using WST-1 method. PRME was found cytotoxic against MCF-7 cells with an IC50 value 130.03 ± 3.11 µg/ml while negligible cytotoxicity was observed on A549 and WI-38 cells. Further flow cytometric study showed that PRME halted the MCF-7 cells in S and G2/M phases and induces apoptosis in dose as well as time dependent manner. Cell cycle arrest was associated with downregulation of cyclin B1, Cdk-2 and Cdc25C as well as slight decrease in the expression of Cdk-1 and cyclin A1 with subsequent upregulation of p53 and p21. Moreover PRME induced Bax and inhibited Bcl-2 expression, which results in increasing Bax/Bcl-2 ratio and activation of caspase cascade. This ultimately leads to PARP degradation and induces apoptosis in MCF-7 cells. It can be hypothesised from the current study that the antioxidant and anticancer potential of the PRME may reside in the phytoconstitutents present in it and therefore, PRME may be used as a possible source of natural antioxidant that may be developed to an anticancer agent.

The mitochondrial uniporter is a highly selective calcium channel in the organelle's inner membrane. Its molecular components include the EF-hand-containing calcium-binding proteins mitochondrial calcium uptake 1 (MICU1) and MICU2 and the pore-forming subunit mitochondrial calcium uniporter (MCU). We sought to achieve a full molecular characterization of the uniporter holocomplex (uniplex). Quantitative mass spectrometry of affinity-purified uniplex recovered MICU1 and MICU2, MCU and its paralog MCUb, and essential MCU regulator (EMRE), a previously uncharacterized protein. EMRE is a 10-kilodalton, metazoan-specific protein with a single transmembrane domain. In its absence, uniporter channel activity was lost despite intact MCU expression and oligomerization. EMRE was required for the interaction of MCU with MICU1 and MICU2. Hence, EMRE is essential for in vivo uniporter current and additionally bridges the calcium-sensing role of MICU1 and MICU2 with the calcium-conducting role of MCU.

Background: Intravenous (IV) beta-blockade is currently a Class IIa recommendation in early management of patients with acute coronary syndromes (ACS) without obvious contraindications., Methods: We searched the PubMed, EMBASE and the Cochrane Register for Controlled Clinical Trials for randomized clinical trials from 1965 through December, 2011, comparing intravenous beta-blockers administered within 12 hours of presentation of ACS with standard medical therapy and/or placebo. The primary outcome assessed was the risk of short-term (in-hospital mortality-with maximum follow up duration of 90 days) all-cause mortality in the intervention group versus the comparator group. The secondary outcomes assessed were ventricular tachyarrhythmias, myocardial reinfarction, cardiogenic shock, and stroke. Pooled treatment effects were estimated using relative risk with Mantel-Haenszel risk ratio, using a random-effects model., Results: Sixteen studies enrolling 73,396 participants met the inclusion ⁄ exclusion criteria. In- hospital mortality was reduced 8% with intravenous beta-blockers, RR=0.92 (95% CI, 0.86-1.00; p=0.04) when compared with controls. Moreover, intravenous beta-blockade reduced the risk of ventricular tachyarrhythmias (RR=0.61; 95 % CI 0.47-0.79; p=0.0003) and myocardial reinfarction (RR=0.73, 95 % CI 0.59-0.91; p=0.004) without increase in the risk of cardiogenic shock, (RR=1.02; 95% CI 0.77-1.35; p=0.91) or stroke (RR=0.58; 95 % CI 0.17-1.98; p=0.38)., Conclusions: Intravenous beta-blockers early in the course of appropriate patients with ACS appears to be associated with significant reduction in the risk of short-term cardiovascular outcomes, including a reduction in the risk of all-cause mortality., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Hypertension is a major public health problem worldwide. However, limited information is available regarding the risk factors for hypertension in postmenopausal women, particularly in urban populations in developing countries such as India. To investigate whether adiposity measures, serum lipids and lipoproteins as well as fasting plasma glucose can predict the risk of hypertension in a population based sample of postmenopausal women in Kolkata, India, we conducted a cross-sectional study of 415 postmenopausal women (aged 40 to 85), selected by cluster sampling from 12 wards of Kolkata. After multivariate adjustment, apolipoprotein B (apo B) and waist circumference (WC) showed the strongest association with hypertension. The risk of hypertension in the highest tertile compared with the lowest tertile was 2.57 (95% confidence interval = 1.00-6.61) for apo B and 2.55 (95% confidence interval = 1.07-6.06) for WC. Apo B and WC were the strongest risk factors for predicting hypertension among postmenopausal women in Kolkata.

Examples of self-propulsion in strongly fluctuating environments are abundant in nature, e.g., molecular motors and pumps operating in living cells. Starting from the Langevin equation of motion, we develop a stochastic thermodynamic description of noninteracting self-propelled particles using simple models of velocity-dependent forces. We derive fluctuation theorems for entropy production and a modified fluctuation-dissipation relation, characterizing the linear response in nonequilibrium steady states. We study these notions in a simple model of molecular motors, and in the Rayleigh-Helmholtz and energy-depot models of self-propelled particles.

Background: Transient receptor potential (TRP) channels are a superfamily of broadly expressed ion channels with diverse physiological roles. TRPC1, TRPC3, and TRPC6 are believed to contribute to cardiac hypertrophy in mouse models. Human mutations in TRPM4 have been linked to progressive familial heart block. TRPM7 is a divalent-permeant channel and kinase of unknown function, recently implicated in the pathogenesis of atrial fibrillation; however, its function in ventricular myocardium remains unexplored., Methods and Results: We generated multiple cardiac-targeted knockout mice to test the hypothesis that TRPM7 is required for normal ventricular function. Early cardiac Trpm7 deletion (before embryonic day 9; TnT/Isl1-Cre) results in congestive heart failure and death by embryonic day 11.5 as a result of hypoproliferation of the compact myocardium. Remarkably, Trpm7 deletion late in cardiogenesis (about embryonic day 13; αMHC-Cre) produces viable mice with normal adult ventricular size, function, and myocardial transcriptional profile. Trpm7 deletion at an intermediate time point results in 50% of mice developing cardiomyopathy associated with heart block, impaired repolarization, and ventricular arrhythmias. Microarray analysis reveals elevations in transcripts of hypertrophy/remodeling genes and reductions in genes important for suppressing hypertrophy (Hdac9) and for ventricular repolarization (Kcnd2) and conduction (Hcn4). These transcriptional changes are accompanied by action potential prolongation and reductions in transient outward current (Ito; Kcnd2). Similarly, the pacemaker current (If; Hcn4) is suppressed in atrioventricular nodal cells, accounting for the observed heart block., Conclusions: Trpm7 is dispensable in adult ventricular myocardium under basal conditions but is critical for myocardial proliferation during early cardiogenesis. Loss of Trpm7 at an intermediate developmental time point alters the myocardial transcriptional profile in adulthood, impairing ventricular function, conduction, and repolarization.

Mitochondrial calcium (Ca(2+)) import is a well-described phenomenon regulating cell survival and ATP production. Of multiple pathways allowing such entry, the mitochondrial Ca(2+) uniporter is a highly Ca(2+)-selective channel complex encoded by several recently-discovered genes. However, the identity of the pore-forming subunit remains to be established, since knockdown of all the candidate uniporter genes inhibit Ca(2+) uptake in imaging assays, and reconstitution experiments have been equivocal. To definitively identify the channel, we use whole-mitoplast voltage-clamping, the technique that originally established the uniporter as a Ca(2+) channel. We show that RNAi-mediated knockdown of the mitochondrial calcium uniporter (MCU) gene reduces mitochondrial Ca(2+) current (I MiCa ), whereas overexpression increases it. Additionally, a classic feature of I MiCa , its sensitivity to ruthenium red inhibition, can be abolished by a point mutation in the putative pore domain without altering current magnitude. These analyses establish that MCU encodes the pore-forming subunit of the uniporter channel. DOI:http://dx.doi.org/10.7554/eLife.00704.001.

This study evaluated the ameliorating effect of 70% methanol extract of Acacia catechu heartwood, or Katha (ACME) on liver injury induced by iron overload. Iron overload in mice was caused by intraperitoneal administration of 100 mg/kg iron-dextran. ACME was administered orally for 21 days, starting from the day after the first iron-dextran injection. The biochemical markers of hepatic damage and liver iron, protein carbonyl, and hydroxyproline contents were measured in response to the oral administration of ACME. Apart from those, the release of iron from ferritin by ACME was further assessed to determine the efficiency of ACME as an iron-chelating drug. Treatment with different doses of ACME (50, 100, and 200 mg/kg body weight) showed dose-dependent reductions in liver iron, lipid peroxidation, protein oxidation, liver fibrosis, serum enzymes, and ferritin. The antioxidant enzymes levels were enhanced and the reductive release of ferritin iron increased significantly with gradually increasing concentrations of ACME. These results indicate that ACME has a potent hepatoprotective action against hepatic damage induced by iron overload in mice, probably by ameliorating the antioxidant defense activities and reductively releasing ferritin iron.

Dual singlet-triplet fluorescence-phosphorescence emitting compounds demonstrate that plasmonic surface enhancement is controlled solely by the underlying oscillator strength of a transition: metal-free compounds with weak spin-orbit coupling show no enhancement in phosphorescence efficiency even though fluorescence is amplified.

Inspired by recent experiments on the spatial organization of bacterial chromosomes, we consider a type of "bottle-brush" polymer consisting of a flexible backbone chain, to which flexible side loops are connected. We show that such a model with an open linear backbone spontaneously adopts a helical structure with a well-defined pitch when confined to small cylindrical volume. This helicity persists over a range of sizes and aspect ratios of the cylinder, provided the packing fraction of the chain is suitably large. We analyze these results in terms of the interplay between the effective stiffness and actual intrachain packing effects caused by the side loops in response to the confinement.

Starting from the pioneering work of Agarwal [G. S. Agarwal, Zeitschrift für Physik 252, 25 (1972)], we present a unified derivation of a number of modified fluctuation-dissipation relations (MFDR) that relate response to small perturbations around nonequilibrium steady states to steady-state correlations. Using this formalism we show the equivalence of velocity forms of MFDR derived using continuum Langevin and discrete master equation dynamics. The resulting additive correction to the Einstein relation is exemplified using a flashing ratchet model of molecular motors., (© 2012 American Physical Society)

Introduction: Extensive studies have gone into understanding the differential role of the innate and adaptive arms of the immune system in the context of various diseases. Receptor-ligand interactions are responsible for mediating cross-talk between the innate and adaptive arms of the immune system, so as to effectively counter the pathogenic challenge. While TLRs remain the best studied innate immune receptor, many other receptor families are now coming to the fore for their role in various pathologies. Research has focused on the discovery of novel agonists and antagonists for these receptors as potential therapeutics., Areas Covered: In this review, we present an overview of the recent advances in the discovery of drugs targeting important receptors such as G-protein coupled receptors, TRAIL-R, IL-1β receptor, PPARs, etc. All these receptors play a critical role in the modulation of the immune response. We focus on the recent paradigms applied for the generation of specific and effective therapeutics for these receptors and their status in clinical trials., Expert Opinion: Non-specific activation by antagonist/agonist is a difficult problem to dodge. This demands innovation in ligand designing with the use of strategies such as allosterism and dual-specific ligands. Rigorous preclinical and clinical studies are required in transforming a compound to a therapeutic.

We extend a recently proposed model [Chaudhuri et al., Europhys. Lett. 87, 20003 (2009)] aiming to describe the formation of fascicles of axons during neural development. The growing axons are represented as paths of interacting directed random walkers in two spatial dimensions. To mimic turnover of axons, whole paths are removed and new walkers are injected with specified rates. In the simplest version of the model, we use strongly adhesive short-range inter-axon interactions that are identical for all pairs of axons. We generalize the model to adhesive interactions of finite strengths and to multiple types of axons with type-specific interactions. The dynamic steady state is characterized by the position-dependent distribution of fascicle size and fascicle composition. With distance in the direction of axon growth, the mean fascicle size and emergent time scales grow monotonically, while the degree of sorting of fascicles by axon type has a maximum at a finite distance. To understand the emergence of slow time scales, we develop an analytical framework to analyze the interaction between neighboring fascicles.

Prostate cancer (PCa) is one of the most common types of cancer in men in the United States and is the second leading cause of cancer related death in men. Clinically, secreted prostate specific antigen (PSA) has gained recognition because of its proteolytic activity being directly linked to PCa cell proliferation leading to disease initiation and progression. Using phage display technology, we identified four distinct cyclical peptides. These peptides apart from differences in their amino acid sequence, elicited minimal cross reactive antibody responses against each other. One of the four peptides analyzed produced an antibody response that recognizes the PSA protein. We demonstrate that the synthetic PSA peptide mimics identified in our study are immunologically active and produce neutralizing activity and this has relevance and utility for prostate cancer disease progression., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Few studies have examined dietary patterns in relation to cardiovascular risk factors in Asian populations, particularly in India. The present study was undertaken to explore dietary patterns in a general urban Bengalee population of women in West Bengal, India, and their association with cardiovascular risk factors. We performed a cross-sectional study of 701 women (aged 35 years and above) selected by cluster sampling from twelve different wards of the Kolkata Municipal Corporation (Kolkata, India). The following three major dietary patterns were identified: the 'vegetable, fruits and pulses' pattern (characterised by higher intakes of dark-yellow and green leafy vegetables, sweets, fruits, pulses, nuts, poultry and eggs, and lower intake of mustard oil); the 'hydrogenated and saturated fat and vegetable oil' pattern (characterised by higher intakes of butter, hydrogenated oil, ghee, vegetable oil, mustard oil, condiments, sweets, fish, high-fat dairy and refined grain); the 'red meat and high-fat dairy' pattern (characterised by higher intakes of red meat, high-fat dairy products, whole grain, high-energy drinks and condiments, and lower intakes of fish, refined grain and low-fat dairy products). The vegetable, fruits and pulses pattern was inversely associated with serum total cholesterol (TC), LDL-cholesterol and non-HDL-cholesterol (HDL-C) concentrations (P < 0·05 for all). The hydrogenated and saturated fat and vegetable oil pattern was positively associated with BMI, waist circumference (WC) and HDL-C concentration (P < 0·05 for all). In this Bengalee population, these three major dietary patterns were observed, and the dietary patterns were independently associated with BMI, WC and serum TC concentrations in women.

Heat shock proteins such as gp96 are immunogenic and are widely used as vaccines in immunotherapy of cancers. The present study focuses on the use of peptide mimotopes as immunotherapeutic vaccines for prostate cancer. To this end, we developed a 15-mer gp96 peptide mimotope specifically reactive to MAT-LyLu gp96-peptide complex using combinatorial single-chain antibody and peptide phage display library. The immunogenicity of the synthesized gp96 mimotope was analyzed initially in normal BALB/c mice in combination with various adjuvants such as complete Freund's adjuvant (CFA), aluminum salts (ALUM), granulocyte-macrophage colony-stimulating factor (GM-CSF), and liposome, of which CFA served as a positive control. The antibody response was determined and found that the gp96 mimotope with ALUM showed a significant increase in antibody titer, followed by GM-CSF and liposomes. Further, the T cell (CD4(+) and CD8(+)) populations from splenocytes, as well as IgG isotypes, interleukin-4, and interleukin-5 of gp96 mimotope with ALUM-immunized animals, were analyzed. The results suggest that the gp96 mimotope may elicit a potent and effective antitumor antibody response. Further, the study identifies ALUM and GM-CSF as adjuvant options to drive an appropriate protective immune response as these adjuvants have prior use in humans.

We study the response of one-dimensional diffusive systems, consisting of particles interacting via symmetric or asymmetric exclusion, to time-periodic driving from two reservoirs coupled to the ends. The dynamical response of the system can be characterized in terms of the structure factor. We find an interesting frequency-dependent response; the current-carrying majority excitons cyclically crosses over from a short wavelength mode to a long wavelength mode with an intermediate regime of coexistence. This effect being boundary driven decays inversely with system size. Analytic calculations show that this behavior is common to diffusive systems, both in the absence and presence of correlations.

A number of recent experiments have provided detailed observations of the configurations of long DNA strands under nano-to-micrometer-sized confinement. We therefore revisit the problem of an excluded volume polymer chain confined between two parallel plates with varying plate separation. We show that the nonmonotonic behavior of the overall size of the chain as a function of plate separation, seen in computer simulations and reproduced by earlier theories, can already be predicted on the basis of scaling arguments. However, the behavior of the size in a plane parallel to the plates, a quantity observed in recent experiments, is predicted to be monotonic, in contrast to the experimental findings. We analyze this problem in depth with a mean-field approach that maps the confined polymer onto an anisotropic Gaussian chain, which allows the size of the polymer to be determined separately in the confined and unconfined directions. The theory allows the analytical construction of a smooth crossover between the small-plate-separation de Gennes regime and the large-plate-separation Flory regime. The results show good agreement with molecular dynamics simulations in the presence of a Langevin heat bath and confirm the scaling predictions.

Excitonic transitions in organic semiconductors are associated with large oscillator strength that limits the excited-state lifetime and can in turn impede long-range exciton migration. We present perylene-based emissive H-aggregate nanowires where the lowest energy state is only weakly coupled to the ground state, thus dramatically enhancing lifetime. Exciton migration occurs by thermally activated hopping, leading to luminescence quenching on topological wire defects. An atomic force microscope tip can introduce local topological quenchers by distorting the H-aggregate structure, demonstrating long-range exciton migration at room temperature and offering a potential route to writing fluorescent "nanobarcodes" and excitonic circuits.

Background: Recent research has focused on the use of inflammatory biomarkers in the prediction of cardiovascular risk. However, information is scant regarding the association between these inflammatory markers with other cardiovascular risk factors in Asian Indians, particularly in women., Objective: To explore the association between inflammatory markers such as high-sensitivity C-reactive protein (hs-CRP) and white blood cell (WBC) count and cardiovascular risk factors such as overall and central adiposity, blood pressure, lipid and lipoprotein variables and fasting glucose., Methods: We conducted a cross-sectional analysis on 100 women aged 35-80 years. Participants were selected following cluster sampling methodology from 12 different randomly selected urban wards of Kolkata Municipal Corporation., Results: Hs-CRP has a significant association with body mass index (BMI) ( p < 0.001) and waist circumference (WC) (p = 0.002). Significant inverse associations were observed between high-density lipoprotein cholesterol (HDL-C) and both inflammatory markers, hs-CRP (p = 0.031) and WBC count, (p = 0.014). Apolipoprotein A1 (Apo A1) was also negatively associated with hs-CRP. WBC count has significant correlation with fasting glucose and total cholesterol (TC) /HDL-C ratio. Using logistic regression, adjusting for age, BMI (odds ratio/OR, 1.186; confidence interval/CI, 1.046-1.345; p = 0.008) and WC (OR, 1.045; CI, 1.005-1.087; p = 0.027) were the covariates significantly associated with hs-CRP., Conclusion: In the present study, risk factors like BMI, WC, and HDL-C and apo A1 show significant association with hs-CRP. WBC count was significantly correlated with HDL-C, fasting glucose, TC/HDL-C ratio in women.

In a convergent modular synthesis, a very efficient pathway to shape-persistent molecular spoked wheels has been developed and applied according to the covalent-template concept. The structurally defined two-dimensional (2D) oligo(phenylene-ethynylene-butadiynylene)s (OPEBs) presented here are about 8 nm sized hydrocarbons of high symmetry. 48 alkyl chains attached to the molecular plane (hexyl and hexadecyl, respectively) guarantee a high solubility of the compounds. The structure and uniformity of these defined, stable, D(6h) symmetrical compounds is verified by MALDI-MS, GPC analysis, and high-temperature (HT) (1)H and (13)C NMR. Detailed photophysical measurements of nonaggregated molecules in solution (as confirmed by dynamic light scattering (DLS)) focus on the identification of chromophores by comparison with suitable model compounds. Moreover, time-resolved measurements including fluorescence lifetime and depolarization support the chromophore assignment and reveal the occurrence of intramolecular energy transfer. Scanning tunneling microscope (STM) characterization at the solid/liquid interface demonstrates the efficient self-assembly of the OPEBs into hexagonal 2D crystalline layers with a periodicity determined by both the size of the OPEB backbone and the length of peripheral side chains. Atomic force microscope (AFM) studies show a very different assembly behavior of the two spoked wheel molecules, on both graphite and mica. While the hexyl-substituted wheel can form stacked superstructures, hexadecyl groups prevent any ordering in the film aside from the monolayer directly in contact with the surface.

Exercise increases oxygen consumption and causes a disturbance of intracellular pro-oxidant-antioxidant homeostasis. Athletes are exposed to acute and chronic stress that may lead to increased generation of oxidative species. Hence oxidative stress increases in athletes. Administration of antioxidant like alpha-tocopherol as supplementation may reduce the cell damage caused due to oxidative stress. In the present study, our aim was to study the effects of alpha-tocopherol supplementation on the cardiopulmonary fitness in endurance athletes (cyclists) and non-athletes. Our study included 40 cyclists who were trained under District Youth Service & Sports Office. 40 controls were randomly selected from student group of B.L.D.E.A's Medical College. Alpha-tocopherol (Vitamin E) 200 mg/day for 21 days wasgiven to study group and placebo was given to placebo group. Various physiological parameters like heart rate, blood pressure, respiratory rate were recorded, for assessing cardiopulmonary fitness: Physical Fitness Index (PFI) and VO2 max ml/min/kg were recorded before and after supplementation of vitamin E in athletes, and were compared with placebo group before and after supplementation of placebo and also with non-athletes. The results obtained from present study indicate that antioxidant like alpha-tocopherol supplementation did not contribute significantly to improve the cardiopulmonary fitness of endurance athletes.

We demonstrate high resolution transmission microscopy in a conventional two-photon wide-field fluorescence microscope by exploiting nonlinear white light generation from clusters of silver nanoparticles placed beneath the specimen. Surface-enhanced two-photon luminescence occurs at nanoparticle hot spots in the form of spectrally broad, spatially confined light which can be exploited to determine the transmission properties of a sample placed on the silver nanoparticles. We demonstrate the versatility of the technique by revealing individual crystalline domains formed in the diffuse biological photonic crystals of the scales of a beetle. We can identify submicron changes between photonic crystal facets as well as the occurrence of stacked domains invisible to surface-sensitive methods. Control over wavelength, polarization, and pulse shape promises selective addressing of hot spots in nanoparticle assemblies for motionless spatial scanning of the transmission properties with subdiffraction resolution.

The concept of cancer immunotherapy provides a fresh perspective as it is not associated with many of the drawbacks of conventional therapies such as chemotherapy, radiotherapy and surgery. When fully activated the immune system has immense potential as is evident from mis-matched transplanted organs undergoing rapid immunological attack and rejection. However, the development of immune strategies for cancer therapy has been associated with challenges of their own. Early attempts at cancer vaccination were carried out in an empirical manner that did not always lead to reproducibility. This led to a search of tumor associated antigens with the belief that specific targeting of these antigens would lead to successful tumor elimination. Active vaccination with TAA peptides or passive vaccination with specific lymphocytes against these TAAs did not however demonstrate encouraging results in clinical trials. This was mainly because of the lack of an activating immune response which is required for continuous stimulation of lymphocytes and also because of the selection of tumor escape variants that did not express the particular TAA. On the positive side, attempts at characterizing TAAs illuminated the molecular changes that attribute a malignant phenotype to cancer cells. Attempts at cytokine therapy were also met with challenges of high systemic toxicity and a lack of specific lymphocyte activation. It was therefore realized that an ideal vaccinating agent should be able to combine the effects of both these therapeutic strategies, i.e., it should be able to induce an innate immune response which can be tailored to a tumor specific adaptive immune response. By this, the immunosuppressive tumor environment can be altered to become immune activating, thus facilitating the infiltration of myeloid and lymphoid cells that can act in concert leading to tumor regression. In this regard, immunotherapeutic approaches such as DNA vaccines, dendritic cell based vaccines, HSP based vaccines and gene transfer technology, are being developed and further refined to overcome their inherent limitations. Animal experiments with these therapeutic modalities have demonstrated exciting results, although their evaluation in clinical trials has not indicated exceptional tumor protection in a large percentage of the patients. These observations only further underscore the multivariate and dynamic nature of the immune system and the many ways in which tumor cells modulate themselves and their surroundings to escape immune surveillance. Assessment of successful therapeutic intervention will require periodic evaluations of the suppressive nature of the tumor microenvironment accompanied by qualitative and quantitative measurements of lymphocyte responses in patients. With the development of advanced genetic technologies and continuous identification of tumor antigens, the field of cancer immunotherapy is progressing at an exciting pace giving us hope for the advent of effective treatment modalities that will prolong tumor free survival and enhance the quality of life in patients with malignant disease.

Neovascularization is critical for tumor growth and development. The cellular mediators for this process are yet to be defined. We discovered that bone marrow-derived endothelial progenitor cells (BM-EPC), having the phenotype (CD133+, CD34+, VEGFR-2+), initiate neovascularization in response to TG1-1 mammary cells implanted in the inguinal mammary gland of Tie-2 GFP transgenic mice. The fluorescence tag allowed for tracing the migration of green fluorescent protein-tagged endothelial progenitor cells to tumor tissues. We discovered that 17-beta estradiol supplementation of ovariectomized mice significantly enhanced BM-EPC-induced neovascularization and secretion of angiogenic factors within the tumor microenvironment. Cell-based system analyses showed that estrogen-stimulated BM-EPCs secreted paracrine factors which enhanced TG1-1 cell proliferation and migration. Furthermore, TG1-1 cell medium supplemented with estrogen-induced BM-EPC mediated tubulogenesis, which was an experimental in vivo representation of the neovasculature. Our data provide evidence of BM-EPC mammary tumor cell interactions and identify a novel cellular mediator of tumor progression that can be exploited clinically.

We show using computer simulations and mean field theory that a system of particles in two dimensions, when laterally confined by a pair of parallel hard walls within a quasi-one-dimensional channel, possesses several anomalous structural and mechanical properties not observed in the bulk. Depending on the density rho and the distance between the walls Ly, the system shows structural characteristics analogous to a weakly modulated liquid, a strongly modulated smectic, a triangular solid, or a buckled phase. At fixed rho, a change in Ly leads to many re-entrant discontinuous transitions involving changes in the number of layers parallel to the confining walls depending crucially on the commensurability of interlayer spacing with Ly. The solid shows resistance to elongation but not to shear. When strained beyond the elastic limit, it fails undergoing plastic deformation but surprisingly, as the strain is reversed, the material completely recovers and returns to its original undeformed state. We obtain the phase diagram from mean field theory and finite size simulations and discuss the effect of fluctuations.

Imposed static hip stretches substantially modulate the soleus H-reflex in people with an intact or injured spinal cord while stretch of the hip flexors affect the walking pattern in lower vertebrates and humans. The aim of this study was to assess the effects of dynamic hip stretches on the soleus H-reflex in supine spinal cord injured (SCI) subjects. Sinusoidal movements were imposed on the right hip joint at 0.2 Hz by a Biodex system. H-reflexes from the soleus muscle were recorded as the leg moved in flexion or extension. Stimuli were sent only once in every hip movement cycle that each lasted 5 s. Torque responses were recorded at the hip, knee, and ankle joints. A hip phase-dependent soleus H-reflex modulation was present in all subjects. The reflex was facilitated during hip extension and suppressed during hip flexion. There were no significant differences in pre- or post-stimulus soleus background activity between the two conditions. Oscillatory responses were present as the hip was maximally flexed. Sinusoidal hip stretches modulated the soleus H-reflex in a manner similar to that previously observed following static hip stretches. The amount of reflex facilitation depended on the angle of hip extension. Further research is needed on the afferent control of spinal reflex pathways in health and disease in order to better understand the neural control of movement in humans. This will aid in the development of rehabilitation strategies to restore motor function in these patients.

We study the interface between a solid trapped within a bath of liquid by a suitably shaped nonuniform external potential. Such a potential may be constructed using lasers, external electric or magnetic fields, or a surface template. We study a two-dimensional case where a thin strip of solid, created in this way, is surrounded on either side by a bath of liquid with which it can easily exchange particles. Since height fluctuations of the interface cost energy, this interface is constrained to remain flat at all length scales. However, when such a solid is stressed by altering the depth of the potential beyond a certain limit, it responds by relieving stress by novel interfacial fluctuations, which involve addition or deletion of entire lattice layers of the crystal. This "layering" transition is a generic feature of the system regardless of the details of the interaction potential. We show how such interfacial fluctuations influence mass, momentum, and energy transport across the interface. Tiny momentum impulses produce weak shock waves, which travel through the interface and cause the spallation of crystal layers into the liquid. Kinetic and energetic constraints prevent spallation of partial layers from the crystal, a fact which may be of some practical use. We also study heat transport through the liquid-solid interface and obtain the resistances in liquid, solid, and interfacial regions (Kapitza resistance) as the solid undergoes such layering transitions. Heat conduction, which shows strong signatures of the structural transformations, can be understood using a free volume calculation.

L-type calcium channels are composed of a pore, alpha1c (Ca(V)1.2), and accessory beta- and alpha2delta-subunits. The beta-subunit core structure was recently resolved at high resolution, providing important information on many functional aspects of channel modulation. In this study we reveal differential novel effects of five beta2-subunits isoforms expressed in human heart (beta(2a-e)) on the single L-type calcium channel current. These splice variants differ only by amino-terminal length and amino acid composition. Single-channel modulation by beta2-subunit isoforms was investigated in HEK293 cells expressing the recombinant L-type ion conducting pore. All beta2-subunits increased open probability, availability, and peak current with a highly consistent rank order (beta2a approximately = beta2b > beta2e approximately = beta2c > beta2d). We show graded modulation of some transition rates within and between deep-closed and inactivated states. The extent of modulation correlates strongly with the length of amino-terminal domains. Two mutant beta2-subunits that imitate the natural span related to length confirm this conclusion. The data show that the length of amino termini is a relevant physiological mechanism for channel closure and inactivation, and that natural alternative splicing exploits this principle for modulation of the gating properties of calcium channels.

The regulation of Ca(V)2.1 (P/Q-type) channels by calmodulin (CaM) showcases the powerful Ca(2+) decoding capabilities of CaM in complex with the family of Ca(V)1-2 Ca(2+) channels. Throughout this family, CaM does not simply exert a binary on/off regulatory effect; rather, Ca(2+) binding to either the C- or N-terminal lobe of CaM alone can selectively trigger a distinct form of channel modulation. Additionally, Ca(2+) binding to the C-terminal lobe triggers regulation that appears preferentially responsive to local Ca(2+) influx through the channel to which CaM is attached (local Ca(2+) preference), whereas Ca(2+) binding to the N-terminal lobe triggers modulation that favors activation via Ca(2+) entry through channels at a distance (global Ca(2+) preference). Ca(V)2.1 channels fully exemplify these features; Ca(2+) binding to the C-terminal lobe induces Ca(2+)-dependent facilitation of opening (CDF), whereas the N-terminal lobe yields Ca(2+)-dependent inactivation of opening (CDI). In mitigation of these interesting indications, support for this local/global Ca(2+) selectivity has been based upon indirect inferences from macroscopic recordings of numerous channels. Nagging uncertainty has also remained as to whether CDF represents a relief of basal inhibition of channel open probability (P(o)) in the presence of external Ca(2+), or an actual enhancement of P(o) over a normal baseline seen with Ba(2+) as the charge carrier. To address these issues, we undertake the first extensive single-channel analysis of Ca(V)2.1 channels with Ca(2+) as charge carrier. A key outcome is that CDF persists at this level, while CDI is entirely lacking. This result directly upholds the local/global Ca(2+) preference of the lobes of CaM, because only a local (but not global) Ca(2+) signal is here present. Furthermore, direct single-channel determinations of P(o) and kinetic simulations demonstrate that CDF represents a genuine enhancement of open probability, without appreciable change of activation kinetics. This enhanced-opening mechanism suggests that the CDF evoked during action-potential trains would produce not only larger, but longer-lasting Ca(2+) responses, an outcome with potential ramifications for short-term synaptic plasticity.

We show that the mechanical properties of a worm-like-chain (WLC) polymer, of contour length L and persistence length lambda such that t=L/lambda approximately O(1), depend both on the ensemble and the constraint on end orientations. In the Helmholtz ensemble, multiple minima in the free energy near t=4 persists for all kinds of orientational boundary conditions. The qualitative features of projected probability distribution of end-to-end vector depend crucially on the embedding dimensions. A mapping of the WLC model, to a quantum particle moving on the surface of a unit sphere, is used to obtain the statistical and mechanical properties of the polymer under various boundary conditions and ensembles. The results show excellent agreement with Monte Carlo simulations.

Epiploic appendagitis (EA) refers to primary or secondary inflammatory disease of the epiploic appendages: peritoneal pouches of subserosal fat, which run in parallel rows beside the taenia coli of the colon. It is an uncommon but self-limiting condition, which often mimics acute appendicitis or diverticulitis. An accurate diagnosis of EA can be made by performing an abdominal computed tomography scan. Establishing a correct preoperative diagnosis is important to avoid unnecessary exploratory laparoscopy or laparotomy. We report two cases of EA, which to our knowledge represent the first documented cases from India.