Effect of farnesyltransferase inhibitor R115777 on mitochondria of plasmodium falciparum

The parasite Plasmodium falciparum causes severe malaria and is the most dangerous to humans. However, it exhibits resistance to their drugs. Farnesyltransferase has been identified in pathogenic protozoa of the genera Plasmodium and the target of farnesyltransferase includes Ras family. Therefore, the inhibition of farnesyltransferase has been suggested as a new strategy for the treatment of malaria. However, the exact functional mechanism of this agent is still unknown. In addition, the effect of farnesyltransferase inhibitor (FTIs) on mitochondrial level of malaria parasites is not fully understood. In this study, therefore, the effect of a FTI R115777 on the function of mitochondria of P. falciparum was investigated experimentally. As a result, FTI R115777 was found to suppress the infection rate of malaria parasites under in vitro condition. It also reduces the copy number of mtDNA-encoded cytochrome c oxidase III. In addition, the mitochondrial membrane potential (Delta psi m) and the green fluorescence intensity of MitoTracker were decreased by FTI R115777. Chloroquine and atovaquone were measured by the mtDNA copy number as mitochondrial non-specific or specific inhibitor, respectively. Chloroquine did not affect the copy number of mtDNA-encoded cytochrome c oxidase III, while atovaquone induced to change the mtDNA copy number. These results suggest that FTI R115777 has strong influence on the mitochondrial function of P. falciparum. It may have therapeutic potential for malaria by targeting the mitochondria of parasites.1133Ysciescopu

Simulating chemistry using quantum computers

The difficulty of simulating quantum systems, well-known to quantum chemists, prompted the idea of quantum computation. One can avoid the steep scaling associated with the exact simulation of increasingly large quantum systems on conventional computers, by mapping the quantum system to another, more controllable one. In this review, we discuss to what extent the ideas in quantum computation, now a well-established field, have been applied to chemical problems. We describe algorithms that achieve significant advantages for the electronic-structure problem, the simulation of chemical dynamics, protein folding, and other tasks. Although theory is still ahead of experiment, we outline recent advances that have led to the first chemical calculations on small quantum information processors.Comment: 27 pages. Submitted to Ann. Rev. Phys. Che

Small intestinal eosinophils regulate Th17 cells by producing IL-1 receptor antagonist

Eosinophils play proinflammatory roles in helminth infections and allergic diseases. Under steady-state conditions, eosinophils are abundantly found in the small intestinal lamina propria, but their physiological function is largely unexplored. In this study, we found that small intestinal eosinophils down-regulate Th17 cells. Th17 cells in the small intestine were markedly increased in the Delta dblGATA-1 mice lacking eosinophils, and an inverse correlation was observed between the number of eosinophils and that of Th17 cells in the small intestine of wild-type mice. In addition, small intestinal eosinophils suppressed the in vitro differentiation of Th17 cells, as well as IL-17 production by small intestinal CD4(+) T cells. Unlike other small intestinal immune cells or circulating eosinophils, we found that small intestinal eosinophils have a unique ability to constitutively secrete high levels of IL-1 receptor antagonist (IL-1Ra), a natural inhibitor of IL-1 beta. Moreover, small intestinal eosinophils isolated from IL-1Ra-deficient mice failed to suppress Th17 cells. Collectively, our results demonstrate that small intestinal eosinophils play a pivotal role in the maintenance of intestinal homeostasis by regulating Th17 cells via production of IL-1Ra.open111815sciescopu

A qualitative study of the views of patients with long-term conditions on family doctors in Hong Kong

<b>Background</b> Primary care based management of long-term conditions (LTCs) is high on the international healthcare agenda, including the Asia-Pacific region. Hong Kong has a 'mixed economy' healthcare system with both public and private sectors with a range of types of primary care doctors. Recent Hong Kong Government policy aims to enhance the management of LTCs in primary care possibly based on a 'family doctor' model. Patients' views on this are not well documented and the aim of the present study was to explore the views of patients with LTCs on family doctors in Hong Kong.<p></p> <b>Methods</b> The views of patients (with a variety of LTCs) on family doctors in Hong Kong were explored. Two groups of participants were interviewed; a) those who considered themselves as having a family doctor, b) those who considered themselves as not having a family doctor (either with a regular primary care doctor but not a family doctor or with no regular primary care doctor). In-depth individual semi-structured interviews were carried out with 28 participants (10 with a family doctor, 10 with a regular doctor, and 8 with no regular doctor) and analysed using the constant comparative method.<p></p> <b>Results</b> Participants who did not have a family doctor were familiar with the concept but regarded it as a 'luxury item' for the rich within the private healthcare system. Those with a regular family doctor (all private) regarded having one as important to their and their family's health. Participants in both groups felt that as well as the more usual family medicine specialist or general practitioner, traditional Chinese medicine practitioners also had the potential to be family doctors. However most participants attended the public healthcare system for management of their LTCs whether they had a family doctor or not. Cost, perceived need, quality, trust, and choice were all barriers to the use of family doctors for the management of their LTCs.<p></p> <b>Conclusions</b> Important barriers to the adoption of a 'family doctor' model of management of LTCs exist in Hong Kong. Effective policy implementation seems unlikely unless these complex barriers are addressed

Intrinsic Mitochondrial Membrane Potential and Associated Tumor Phenotype Are Independent of MUC1 Over-Expression

We have established previously that minor subpopulations of cells with stable differences in their intrinsic mitochondrial membrane potential (Δψm) exist within populations of mammary and colonic carcinoma cells and that these differences in Δψm are linked to tumorigenic phenotypes consistent with increased probability of participating in tumor progression. However, the mechanism(s) involved in generating and maintaining stable differences in intrinsic Δψm and how they are linked to phenotype are unclear. Because the mucin 1 (MUC1) oncoprotein is over-expressed in many cancers, with the cytoplasmic C-terminal fragment (MUC1 C-ter) and its integration into the outer mitochondrial membrane linked to tumorigenic phenotypes similar to those of cells with elevated intrinsic Δψm, we investigated whether endogenous differences in MUC1 levels were linked to stable differences in intrinsic Δψm and/or to the tumor phenotypes associated with the intrinsic Δψm. We report that levels of MUC1 are significantly higher in subpopulations of cells with elevated intrinsic Δψm derived from both mammary and colonic carcinoma cell lines. However, using siRNA we found that down-regulation of MUC1 failed to significantly affect either the intrinsic Δψm or the tumor phenotypes associated with increased intrinsic Δψm. Moreover, whereas pharmacologically mediated disruption of the Δψm was accompanied by attenuation of tumor phenotype, it had no impact on MUC1 levels. Therefore, while MUC1 over-expression is associated with subpopulations of cells with elevated intrinsic Δψm, it is not directly linked to the generation or maintenance of stable alterations in intrinsic Δψm, or to intrinsic Δψm associated tumor phenotypes. Since the Δψm is the focus of chemotherapeutic strategies, these data have important clinical implications in regard to effectively targeting those cells within a tumor cell population that exhibit stable elevations in intrinsic Δψm and are most likely to contribute to tumor progression

Oral immunization of haemaggulutinin H5 expressed in plant endoplasmic reticulum with adjuvant saponin protects mice against highly pathogenic avian influenza A virus infection

Pandemics in poultry caused by the highly pathogenic avian influenza (HPAI) A virus occur too frequently globally, and there is growing concern about the HPAI A virus due to the possibility of a pandemic among humans. Thus, it is important to develop a vaccine against HPAI suitable for both humans and animals. Various approaches are underway to develop such vaccines. In particular, an edible vaccine would be a convenient way to vaccinate poultry because of the behaviour of the animals. However, an edible vaccine is still not available. In this study, we developed a strategy of effective vaccination of mice by the oral administration of transgenic Arabidopsis plants (HA-TG) expressing haemagglutinin (HA) in the endoplasmic reticulum (ER). Expression of HA in the ER resulted in its high-level accumulation, N-glycosylation, protection from proteolytic degradation and long-term stability. Oral administration of HA-TG with saponin elicited high levels of HA-specific systemic IgG and mucosal IgA responses in mice, which resulted in protection against a lethal influenza virus infection with attenuated inflammatory symptoms. Based on these results, we propose that oral administration of freeze-dried leaf powders from transgenic plants expressing HA in the ER together with saponin is an attractive strategy for vaccination against influenza A virus.X111411Ysciescopu

The association of cold weather and all-cause and cause-specific mortality in the island of Ireland between 1984 and 2007

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.This article has been made available through the Brunel Open Access Publishing Fund.Background This study aimed to assess the relationship between cold temperature and daily mortality in the Republic of Ireland (ROI) and Northern Ireland (NI), and to explore any differences in the population responses between the two jurisdictions. Methods A time-stratified case-crossover approach was used to examine this relationship in two adult national populations, between 1984 and 2007. Daily mortality risk was examined in association with exposure to daily maximum temperatures on the same day and up to 6 weeks preceding death, during the winter (December-February) and cold period (October-March), using distributed lag models. Model stratification by age and gender assessed for modification of the cold weather-mortality relationship. Results In the ROI, the impact of cold weather in winter persisted up to 35 days, with a cumulative mortality increase for all-causes of 6.4% (95%CI=4.8%-7.9%) in relation to every 1oC drop in daily maximum temperature, similar increases for cardiovascular disease (CVD) and stroke, and twice as much for respiratory causes. In NI, these associations were less pronounced for CVD causes, and overall extended up to 28 days. Effects of cold weather on mortality increased with age in both jurisdictions, and some suggestive gender differences were observed. Conclusions The study findings indicated strong cold weather-mortality associations in the island of Ireland; these effects were less persistent, and for CVD mortality, smaller in NI than in the ROI. Together with suggestive differences in associations by age and gender between the two Irish jurisdictions, the findings suggest potential contribution of underlying societal differences, and require further exploration. The evidence provided here will hope to contribute to the current efforts to modify fuel policy and reduce winter mortality in Ireland

Experimental loophole-free violation of a Bell inequality using entangled electron spins separated by 1.3 km

For more than 80 years, the counterintuitive predictions of quantum theory have stimulated debate about the nature of reality. In his seminal work, John Bell proved that no theory of nature that obeys locality and realism can reproduce all the predictions of quantum theory. Bell showed that in any local realist theory the correlations between distant measurements satisfy an inequality and, moreover, that this inequality can be violated according to quantum theory. This provided a recipe for experimental tests of the fundamental principles underlying the laws of nature. In the past decades, numerous ingenious Bell inequality tests have been reported. However, because of experimental limitations, all experiments to date required additional assumptions to obtain a contradiction with local realism, resulting in loopholes. Here we report on a Bell experiment that is free of any such additional assumption and thus directly tests the principles underlying Bell's inequality. We employ an event-ready scheme that enables the generation of high-fidelity entanglement between distant electron spins. Efficient spin readout avoids the fair sampling assumption (detection loophole), while the use of fast random basis selection and readout combined with a spatial separation of 1.3 km ensure the required locality conditions. We perform 245 trials testing the CHSH-Bell inequality $S \leq 2$ and find $S = 2.42 \pm 0.20$. A null hypothesis test yields a probability of $p = 0.039$ that a local-realist model for space-like separated sites produces data with a violation at least as large as observed, even when allowing for memory in the devices. This result rules out large classes of local realist theories, and paves the way for implementing device-independent quantum-secure communication and randomness certification.Comment: Raw data will be made available after publicatio

Stress induced polarization of immune-neuroendocrine phenotypes in Gallus gallus

Immune-neuroendocrine phenotypes (INPs) stand for population subgroups differing in immune-neuroendocrine interactions. While mammalian INPs have been characterized thoroughly in rats and humans, avian INPs were only recently described in Coturnix coturnix (quail). To assess the scope of this biological phenomenon, herein we characterized INPs in Gallus gallus (a domestic hen strain submitted to a very long history of strong selective breeding pressure) and evaluated whether a social chronic stress challenge modulates the individuals’ interplay affecting the INP subsets and distribution. Evaluating plasmatic basal corticosterone, interferon-γ and interleukin-4 concentrations, innate/acquired leukocyte ratio, PHA-P skin-swelling and induced antibody responses, two opposite INP profiles were found: LEWIS-like (15% of the population) and FISCHER-like (16%) hens. After chronic stress, an increment of about 12% in each polarized INP frequency was found at expenses of a reduction in the number of birds with intermediate responses. Results show that polarized INPs are also a phenomenon occurring in hens. The observed inter-individual variation suggest that, even after a considerable selection process, the population is still well prepared to deal with a variety of immune-neuroendocrine challenges. Stress promoted disruptive effects, leading to a more balanced INPs distribution, which represents a new substrate for challenging situations.Fil: Nazar, Franco Nicolas. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; ArgentinaFil: Estevez, Inma. Centro de Investigación. Neiker - Tecnalia; EspañaFil: Correa, Silvia Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Marin, Raul Hector. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentin

Silver nanowire-based transparent, flexible, and conductive thin film

The fabrication of transparent, conductive, and uniform silver nanowire films using the scalable rod-coating technique is described in this study. Properties of the transparent conductive thin films are investigated, as well as the approaches to improve the performance of transparent silver nanowire electrodes. It is found that silver nanowires are oxidized during the coating process. Incubation in hydrogen chloride (HCl) vapor can eliminate oxidized surface, and consequently, reduce largely the resistivity of silver nanowire thin films. After HCl treatment, 175 Ω/sq and approximately 75% transmittance are achieved. The sheet resistivity drops remarkably with the rise of the film thickness or with the decrease of transparency. The thin film electrodes also demonstrated excellent flexible stability, showing < 2% resistance change after over 100 bending cycles