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

Latent tuberculosis infection screening and treatment in congregate settings (TB FREE COREA): protocol for a prospective observational study in Korea

IntroductionSouth Korea regards tuberculosis (TB) incidence in congregate settings as a serious problem. To this end, systematic latent TB infection (LTBI) diagnosis and treatment were provided to approximately 1.2 million individuals in high-risk congregate settings.Methods and analysisWe designed a prospective cohort study of individuals tested for LTBI, based on the data collected on all persons screened for LTBI as part of the 2017 congregate settings programme in South Korea. Four types of databases are kept: LTBI screening database (personal information and LTBI test results), national health information (NHI) database (socio-demographic data and comorbidities), public healthcare information system (PHIS) database, and the Korean national TB surveillance system database (TB outcomes). Information regarding LTBI treatment at private hospitals and public health centres is collected from NHI and PHIS databases, respectively. The screening data are cleaned, duplicates are removed, and, where appropriate, re-coded to analyse specific exposures and outcomes. The primary objective is to compare the number of active TB cases prevented within 2 years between participants undergoing treatment and not undergoing treatment in the LTBI screening programme in congregate settings. Cascade of care for LTBI diagnosis and treatment will be evaluated among those with a positive LTBI test result. A Cox proportional hazards model will be applied to determine the risk factors for developing active TB.Ethics and disseminationThe protocol is approved by the institutional review boards of Incheon St. Mary’s Hospital, the Catholic University of Korea. Study results will be disseminated through peer-reviewed journals and conference presentations.Trial registration numberKCT000390

Characterizing the malignancy and drug resistance of cancer cells from their membrane resealing response

In this report, we showed that two tumor cell characteristics, namely the malignancy and drug-resistance status can be evaluated by their membrane resealing response. Specifically, membrane pores in a number of pairs of cancer and normal cell lines originated from nasopharynx, lung and intestine were introduced by nano-mechanical puncturing. Interestingly, such nanometer-sized holes in tumor cells can reseal ∼ 2-3 times faster than those in the corresponding normal cells. Furthermore, the membrane resealing time in cancer cell lines exhibiting resistance to several leading chemotherapeutic drugs was also found to be substantially shorter than that in their drug-sensitive counterparts, demonstrating the potential of using this quantity as a novel marker for future cancer diagnosis and drug resistance detection. Finally, a simple model was proposed to explain the observed resealing dynamics of cells which suggested that the distinct response exhibited by normal, tumor and drug resistant cells is likely due to the different tension levels in their lipid membranes, a conclusion that is also supported by direct cortical tension measurement.published_or_final_versio

Molecular orientation-dependent energetic shifts in solution-processed non-fullerene acceptors and their impact on organic photovoltaic performance

The non-fullerene acceptors (NFAs) employed in state-of-art organic photovoltaics (OPVs) often exhibit strong quadrupole moments which can strongly impact on material energetics. Herein, we show that changing the orientation of Y6, a prototypical NFA, from face-on to more edge-on by using different processing solvents causes a significant energetic shift of up to 210 meV. The impact of this energetic shift on OPV performance is investigated in both bilayer and bulk-heterojunction (BHJ) devices with PM6 polymer donor. The device electronic bandgap and the rate of non-geminate recombination are found to depend on the Y6 orientation in both bilayer and BHJ devices, attributed to the quadrupole moment-induced band bending. Analogous energetic shifts are also observed in other common polymer/NFA blends, which correlates well with NFA quadrupole moments. This work demonstrates the key impact of NFA quadruple moments and molecular orientation on material energetics and thereby on the efficiency of high-performance OPVs

Crossover from mesoscopic to universal phase for electron transmission in quantum dots

Measuring phase in coherent electron systems (mesoscopic systems) provides ample information not easily revealed by conductance measurements. Phase measurements in relatively large quantum dots (QDs) recently demonstrated a universal like phase evolution independent of dot size, shape, and occupancy. Explicitly, in Coulomb blockaded QDs the transmission phase increased monotonically by pi throughout each conductance peak, thereafter, in the conductance valleys the phase returned sharply to its base value. Expected mesoscopic features in the phase, related to spin degeneracy or to exchange effects, were never observed. Presently, there is no satisfactory full explanation for the observed phase universality. Unfortunately, the phase in a few-electron QDs, where it can be better understood was never measured. Here we report on such measurements on a small QD that occupy only 1-20 electrons. Such dot was embedded in one arm of a two path electron interferometer, with an electron counter near the dot. Unlike the repetitive behavior found in larger dots we found now mesoscopic features for dot occupation of less than some 10 electrons. An unexpected feature in this regime is a clear observation of the occupation of two different orbital states by the first two electrons - contrary to the recent publications. As the occupation increased the phase evolved and turned universal like for some 14 electrons and higher. The present measurements allowed us to determine level occupancy and parity. More importantly, they suggest that QDs go through a phase transition, from mesoscopic to universal like behavior, as the occupancy increases. These measurements help in singling out potential few theoretical models among the many proposed.Comment: 12 pages, 6 figure

A 5d/3d duality from relativistic integrable system

We propose and prove a new exact duality between the F-terms of supersymmetric gauge theories in five and three dimensions with adjoint matter fields. The theories are compactified on a circle and are subject to the Omega deformation. In the limit proposed by Nekrasov and Shatashvili, the supersymmetric vacua become isolated and are identified with the eigenstates of a quantum integrable system. The effective twisted superpotentials are the Yang-Yang functional of the relativistic elliptic Calogero-Moser model. We show that they match on-shell by deriving the Bethe ansatz equation from the saddle point of the five-dimensional partition function. We also show that the Chern-Simons terms match and extend our proposal to the elliptic quiver generalizations.Comment: 30 pages, 4 figures. v2: typo corrected, references adde

Towards understanding the myometrial physiome: approaches for the construction of a virtual physiological uterus

Premature labour (PTL) is the single most significant factor contributing to neonatal morbidity in Europe with enormous attendant healthcare and social costs. Consequently, it remains a major challenge to alleviate the cause and impact of this condition. Our ability to improve the diagnosis and treatment of women most at risk of PTL is, however, actually hampered by an incomplete understanding of the ways in which the functions of the uterine myocyte are integrated to effect an appropriate biological response at the multicellular whole organ system. The level of organization required to co-ordinate labouring uterine contractile effort in time and space can be considered immense. There is a multitude of what might be considered mini-systems involved, each with their own regulatory feedback cycles, yet they each, in turn, will influence the behaviour of a related system. These include, but are not exclusive to, gestational-dependent regulation of transcription, translation, post-translational modifications, intracellular signaling dynamics, cell morphology, intercellular communication and tissue level morphology. We propose that in order to comprehend how these mini-systems integrate to facilitate uterine contraction during labour (preterm or term) we must, in concert with biological experimentation, construct detailed mathematical descriptions of our findings. This serves three purposes: firstly, providing a quantitative description of series of complex observations; secondly, proferring a database platform that informs further testable experimentation; thirdly, advancing towards the establishment of a virtual physiological uterus and in silico clinical diagnosis and treatment of PTL

Towards precision medicine for hypertension: a review of genomic, epigenomic, and microbiomic effects on blood pressure in experimental rat models and humans

Compelling evidence for the inherited nature of essential hypertension has led to extensive research in rats and humans. Rats have served as the primary model for research on the genetics of hypertension resulting in identification of genomic regions that are causally associated with hypertension. In more recent times, genome-wide studies in humans have also begun to improve our understanding of the inheritance of polygenic forms of hypertension. Based on the chronological progression of research into the genetics of hypertension as the "structural backbone," this review catalogs and discusses the rat and human genetic elements mapped and implicated in blood pressure regulation. Furthermore, the knowledge gained from these genetic studies that provide evidence to suggest that much of the genetic influence on hypertension residing within noncoding elements of our DNA and operating through pervasive epistasis or gene-gene interactions is highlighted. Lastly, perspectives on current thinking that the more complex "triad" of the genome, epigenome, and the microbiome operating to influence the inheritance of hypertension, is documented. Overall, the collective knowledge gained from rats and humans is disappointing in the sense that major hypertension-causing genes as targets for clinical management of essential hypertension may not be a clinical reality. On the other hand, the realization that the polygenic nature of hypertension prevents any single locus from being a relevant clinical target for all humans directs future studies on the genetics of hypertension towards an individualized genomic approach

Linear approaches to intramolecular Förster Resonance Energy Transfer probe measurements for quantitative modeling

Numerous unimolecular, genetically-encoded Forster Resonance Energy Transfer (FRET) probes for monitoring biochemical activities in live cells have been developed over the past decade. As these probes allow for collection of high frequency, spatially resolved data on signaling events in live cells and tissues, they are an attractive technology for obtaining data to develop quantitative, mathematical models of spatiotemporal signaling dynamics. However, to be useful for such purposes the observed FRET from such probes should be related to a biological quantity of interest through a defined mathematical relationship, which is straightforward when this relationship is linear, and can be difficult otherwise. First, we show that only in rare circumstances is the observed FRET linearly proportional to a biochemical activity. Therefore in most cases FRET measurements should only be compared either to explicitly modeled probes or to concentrations of products of the biochemical activity, but not to activities themselves. Importantly, we find that FRET measured by standard intensity-based, ratiometric methods is inherently non-linear with respect to the fraction of probes undergoing FRET. Alternatively, we find that quantifying FRET either via (1) fluorescence lifetime imaging (FLIM) or (2) ratiometric methods where the donor emission intensity is divided by the directly-excited acceptor emission intensity (denoted R<sub>alt</sub>) is linear with respect to the fraction of probes undergoing FRET. This linearity property allows one to calculate the fraction of active probes based on the FRET measurement. Thus, our results suggest that either FLIM or ratiometric methods based on R<sub>alt</sub> are the preferred techniques for obtaining quantitative data from FRET probe experiments for mathematical modeling purpose

The Quantized Hall Insulator: A New Insulator in Two-Dimensions

Quite generally, an insulator is theoretically defined by a vanishing conductivity tensor at the absolute zero of temperature. In classical insulators, such as band insulators, vanishing conductivities lead to diverging resistivities. In other insulators, in particular when a high magnetic field (B) is added, it is possible that while the magneto-resistance diverges, the Hall resistance remains finite, which is known as a Hall insulator. In this letter we demonstrate experimentally the existence of another, more exotic, insulator. This insulator, which terminates the quantum Hall effect series in a two-dimensional electron system, is characterized by a Hall resistance which is approximately quantized in the quantum unit of resistance h/e^2. This insulator is termed a quantized Hall insulator. In addition we show that for the same sample, the insulating state preceding the QHE series, at low-B, is of the HI kind.Comment: 4 page