RECQL4 and p53 potentiate the activity of polymerase and maintain the integrity of the human mitochondrial genome

Germline mutations in RECQL4 and p53 lead to cancer predisposition syndromes, Rothmund-Thomson syndrome (RTS) and Li-Fraumeni syndrome (LFS), respectively. RECQL4 is essential for the transport of p53 to the mitochondria under unstressed conditions. Here, we show that both RECQL4 and p53 interact with mitochondrial polymerase (Pol gamma A/B2) and regulate its binding to the mitochondrial DNA (mtDNA) control region (D-loop). Both RECQL4 and p53 bind to the exonuclease and polymerase domains of Pol gamma A. Kinetic constants for interactions between Pol gamma A-RECQL4, Pol gamma A-p53 and Pol gamma B-p53 indicate that RECQL4 and p53 are accessory factors for Pol gamma A-Pol gamma B and Pol gamma A-DNA interactions. RECQL4 enhances the binding of Pol gamma A to DNA, thereby potentiating the exonuclease and polymerization activities of Pol gamma A/B2. To investigate whether lack of RECQL4 and p53 results in increased mitochondrial genome instability, resequencing of the entire mitochondrial genome was undertaken from multiple RTS and LFS patient fibroblasts. We found multiple somatic mutations and polymorphisms in both RTS and LFS patient cells. A significant number of mutations and polymorphisms were common between RTS and LFS patients. These changes are associated with either aging and/or cancer, thereby indicating that the phenotypes associated with these syndromes may be due to deregulation of mitochondrial genome stability caused by the lack of RECQL4 and p53. Summary: The biochemical mechanisms by which RECQL4 and p53 affect mtDNA replication have been elucidated. Resequencing of RTS and LFS patients' mitochondrial genome reveals common mutations indicating similar mechanisms of regulation by RECQL4 and p53.

Diffusion in an elastic medium: A model for macromolecule transport across the nuclear pore complex

Nuclear pore complexes (NPCs) are very selective filters that sit on the membrane of the nucleus and monitor the transport between the cytoplasm and the nucleoplasm. For the central plug of NPC two models have been suggested in the literature. The first suggests that the plug is a reversible hydrogel while the other suggests that it is a polymer brush. Here we propose a model for the transport of a protein through the plug, which is general enough to cover both the models. The protein stretches the plug and creates a local deformation, which together with the protein, we refer to as the bubble. We start with the free energy for creation of the bubble and consider its motion within the plug. The relevant coordinate is the center of the bubble which executes random walk. We find that for faster relaxation of the gel, the diffusion of the bubble is greater. (C) 2014 Elsevier-B.V. All rights reserved.

Controlling Conformations of Diketopyrrolopyrrole-Based Conjugated Polymers: Role of Torsional Angle

Transport of charge carriers through conjugated polymers is strongly influenced by the presence and distribution of structural disorders. In the present work, structural defects caused by the presence of torsional.. angle were investigated in a diketopyrrolopyrrole (DPP)-based conjugated polymer. Two new copolymers of DPP were synthesized with varying torsional angles to trace the role of structural disorder. The optical properties of these copolymers in solution and thin film reveal the strong influence of torsional angle on their photophysical properties. A strong influence was observed on carrier transport properties of polymers in organic field-effect transistors (OFET) device geometry. The polymers based on phenyl DPP with higher torsional angle (PPTDPP-OD-TEG) resulted in high threshold voltage with less charge carrier mobility as compared to the polymer based on thiophene DPP (2DPP-OD-TEG) bearing a lower torsional angle. Carrier mobility and the molecular orientation of the conjugated polymers were correlated on the basis of grazing incidence X-ray scattering measurements showing the strong role of torsional angle introduced in the form of structural disorder. The results presented in this Article provide a deep insight into the sensitivity of structural disorder and its impact on the device performance of DPP-based conjugated polymers.

Nonlinear preconditioning for efficient and accurate interface capturing in simulation of multicomponent compressible flows

Single fluid schemes that rely on an interface function for phase identification in multicomponent compressible flows are widely used to study hydrodynamic flow phenomena in several diverse applications. Simulations based on standard numerical implementation of these schemes suffer from an artificial increase in the width of the interface function owing to the numerical dissipation introduced by an upwind discretization of the governing equations. In addition, monotonicity requirements which ensure that the sharp interface function remains bounded at all times necessitate use of low-order accurate discretization strategies. This results in a significant reduction in accuracy along with a loss of intricate flow features. In this paper we develop a nonlinear transformation based interface capturing method which achieves superior accuracy without compromising the simplicity, computational efficiency and robustness of the original flow solver. A nonlinear map from the signed distance function to the sigmoid type interface function is used to effectively couple a standard single fluid shock and interface capturing scheme with a high-order accurate constrained level set reinitialization method in a way that allows for oscillation-free transport of the sharp material interface. Imposition of a maximum principle, which ensures that the multidimensional preconditioned interface capturing method does not produce new maxima or minima even in the extreme events of interface merger or breakup, allows for an explicit determination of the interface thickness in terms of the grid spacing. A narrow band method is formulated in order to localize computations pertinent to the preconditioned interface capturing method. Numerical tests in one dimension reveal a significant improvement in accuracy and convergence; in stark contrast to the conventional scheme, the proposed method retains its accuracy and convergence characteristics in a shifted reference frame. Results from the test cases in two dimensions show that the nonlinear transformation based interface capturing method outperforms both the conventional method and an interface capturing method without nonlinear transformation in resolving intricate flow features such as sheet jetting in the shock-induced cavity collapse. The ability of the proposed method in accounting for the gravitational and surface tension forces besides compressibility is demonstrated through a model fully three-dimensional problem concerning droplet splash and formation of a crownlike feature. (C) 2014 Elsevier Inc. All rights reserved.

Mining Unit Tests for Discovery and Migration of Math APIs

Today's programming languages are supported by powerful third-party APIs. For a given application domain, it is common to have many competing APIs that provide similar functionality. Programmer productivity therefore depends heavily on the programmer's ability to discover suitable APIs both during an initial coding phase, as well as during software maintenance. The aim of this work is to support the discovery and migration of math APIs. Math APIs are at the heart of many application domains ranging from machine learning to scientific computations. Our approach, called MATHFINDER, combines executable specifications of mathematical computations with unit tests (operational specifications) of API methods. Given a math expression, MATHFINDER synthesizes pseudo-code comprised of API methods to compute the expression by mining unit tests of the API methods. We present a sequential version of our unit test mining algorithm and also design a more scalable data-parallel version. We perform extensive evaluation of MATHFINDER (1) for API discovery, where math algorithms are to be implemented from scratch and (2) for API migration, where client programs utilizing a math API are to be migrated to another API. We evaluated the precision and recall of MATHFINDER on a diverse collection of math expressions, culled from algorithms used in a wide range of application areas such as control systems and structural dynamics. In a user study to evaluate the productivity gains obtained by using MATHFINDER for API discovery, the programmers who used MATHFINDER finished their programming tasks twice as fast as their counterparts who used the usual techniques like web and code search, IDE code completion, and manual inspection of library documentation. For the problem of API migration, as a case study, we used MATHFINDER to migrate Weka, a popular machine learning library. Overall, our evaluation shows that MATHFINDER is easy to use, provides highly precise results across several math APIs and application domains even with a small number of unit tests per method, and scales to large collections of unit tests.

An open source massively parallel solver for Richards equation: Mechanistic modelling of water fluxes at the watershed scale

In this paper we present a massively parallel open source solver for Richards equation, named the RichardsFOAM solver. This solver has been developed in the framework of the open source generalist computational fluid dynamics tool box OpenFOAM (R) and is capable to deal with large scale problems in both space and time. The source code for RichardsFOAM may be downloaded from the CPC program library website. It exhibits good parallel performances (up to similar to 90% parallel efficiency with 1024 processors both in strong and weak scaling), and the conditions required for obtaining such performances are analysed and discussed. These performances enable the mechanistic modelling of water fluxes at the scale of experimental watersheds (up to few square kilometres of surface area), and on time scales of decades to a century. Such a solver can be useful in various applications, such as environmental engineering for long term transport of pollutants in soils, water engineering for assessing the impact of land settlement on water resources, or in the study of weathering processes on the watersheds. (C) 2014 Elsevier B.V. All rights reserved.

Thermally developing combined electroosmotic and pressure-driven flow of nanofluids in a microchannel under the effect of magnetic field

In the present study, the heat transfer characteristics of thermally developing magnetohydroclynamic flow of nanofluid through microchannel are delineated by following a semi analytical approach. The combined influences of pressure driven flow, electroosmotic transport and magnetic field is taken into account for the analysis of the complex microscale thermal transport processes. Solutions for the normalized temperature distributions and the Nusselt number variations, considering the simultaneous interplay of electrokinetic effects (electroosmosis), magnetic effects, Joule heating and viscous dissipation are obtained, for constant wall temperature condition. Particular attention is paid to assess the role of nanolluids in altering the transport phenomena, through variations in the effective nanoparticle volume fractions, as well as the aggregate structure of the particulate phases. It is observed that magnetohydrodynamic effect reduces advective transport of the liquid resulting in gradual reduction of heat transfer. Increase in nanoparticle volume fraction shows decrease in heat transfer. Similar effects are observed with increase in aggregate sizes of the nanoparticles. The effect of the nanofluids on system irreversibility is also studied through entropy generation analysis due to flow and heat transfer in the microchannel. Total entropy generation is found to be dominant at the thermally developing region of the microchannel, whereas it drops sharply at the thermally developed region. Presence of nanoparticles in the base fluid reduces the total entropy generation in the microchannel, thereby indicating decrease in thermodynamic irreversibility with increasing nanoparticle volume fraction. (C) 2014 Elsevier Ltd. All rights reserved.

Protamine-carboxymethyl cellulose magnetic nanocapsules for enhanced delivery of anticancer drugs against drug resistant cancers

Multidrug resistance is a major therapeutic challenge faced in the conventional chemotherapy. Nanocarriers are beneficial in the transport of chemotherapeutics by their ability to bypass the P-gp efflux in cancers. Most of the P-gp inhibitors under phase II clinical trial are facing failures and hence there is a need to develop a suitable carrier to address P-gp efflux in cancer therapy. Herein, we prepared novel protamine and carboxymethyl cellulose polyelectrolyte multi-layered nanocapsules modified with Fe3O4 nanoparticles for the delivery of doxorubicin against highly drug resistant HeLa cells. The experimental results revealed that improved cellular uptake, enhanced drug intensity profile with greater percentage of apoptotic cells was attained when doxorubicin loaded magnetic nanocapsules were used in the presence of external magnetic field. Hence, we conclude that this magnetic field assisted nanocapsule system can be used for delivery of chemotherapeutics for potential therapeutic efficacy at minimal dose in multidrug resistant cancers. From the Clinical Editor: Many cancer drugs fail when cancer cells become drug resistant. Indeed, multidrug resistance (MDR) is a major therapeutic challenge. One way that tumor cells attain MDR is by over expression of molecular pumps comprising of P-glycoprotein (P-gp) and multidrug resistant proteins (MRP), which can expel chemotherapeutic drugs out of the cells. In this study, the authors prepared novel protamine and carboxymethyl cellulose polyelectrolyte multi-layered nanocapsules modified with Fe3O4 nanoparticles for the delivery of doxorubicin. The results show that there was better drug delivery and efficacy even against MDR tumor cells. (C) 2015 Elsevier Inc. All rights reserved.

Sources of black carbon aerosols in South Asia and surrounding regions during the Integrated Campaign for Aerosols, Gases and Radiation Budget (ICARB)

This study examines differences in the surface black carbon (BC) aerosol loading between the Bay of Bengal (BoB) and the Arabian Sea (AS) and identifies dominant sources of BC in South Asia and surrounding regions during March-May 2006 (Integrated Campaign for Aerosols, Gases and Radiation Budget, ICARB) period. A total of 13 BC tracers are introduced in the Weather Research and Forecasting Model coupled with Chemistry to address these objectives. The model reproduced the temporal and spatial variability of BC distribution observed over the AS and the BoB during the ICARB ship cruise and captured spatial variability at the inland sites. In general, the model underestimates the observed BC mass concentrations. However, the model-observation discrepancy in this study is smaller compared to previous studies. Model results show that ICARB measurements were fairly well representative of the AS and the BoB during the pre-monsoon season. Elevated BC mass concentrations in the BoB are due to 5 times stronger influence of anthropogenic emissions on the BoB compared to the AS. Biomass burning in Burma also affects the BoB much more strongly than the AS. Results show that anthropogenic and biomass burning emissions, respectively, accounted for 60 and 37% of the average +/- standard deviation (representing spatial and temporal variability) BC mass concentration (1341 +/- 2353 ng m(-3)) in South Asia. BC emissions from residential (61 %) and industrial (23 %) sectors are the major anthropogenic sources, except in the Himalayas where vehicular emissions dominate. We find that regional-scale transport of anthropogenic emissions contributes up to 25% of BC mass concentrations in western and eastern India, suggesting that surface BC mass concentrations cannot be linked directly to the local emissions in different regions of South Asia.

Coupled Mechanisms of Precipitation and Atomization in Burning Nanofluid Fuel Droplets

Understanding the combustion characteristics of fuel droplets laden with energetic nanoparticles (NP) is pivotal for lowering ignition delay, reducing pollutant emissions and increasing the combustion efficiency in next generation combustors. In this study, first we elucidate the feedback coupling between two key interacting mechanisms, namely, secondary atomization and particle agglomeration; that govern the effective mass fraction of NPs within the droplet. Second, we show how the initial NP concentration modulates their relative dominance leading to a masterslave configuration. Secondary atomization of novel nanofuels is a crucial process since it enables an effective transport of dispersed NPs to the flame (a pre-requisite condition for NPs to burn). Contrarily, NP agglomeration at the droplet surface leads to shell formation thereby retaining NPs inside the droplet. In particular, we show that at dense concentrations shell formation (master process) dominates over secondary atomization (slave) while at dilute particle loading it is the high frequency bubble ejections (master) that disrupt shell formation (slave) through its rupture and continuous outflux of NPs. This results in distinct combustion residues at dilute and dense concentrations, thereby providing a method of manufacturing flame synthesized microstructures with distinct morphologies.

Plasmonic Lipid Bilayer Membranes for Enhanced Detection Sensitivity of Biolabeling Fluorophores

Plasmonics based sensing, using the surface plasmon resonance of metal nanoparticles, has been effectively demonstrated in various applications. Extending this methodology to cell and artificial lipid bilayer membranes is extremely beneficial in enhancing the sensitivity of the detection of binding and cellular transport of molecules across such membranes. Here, the creation of an artificial plasmonic biomembrane template is demonstrated and used to show the enhanced detection sensitivity of certain widely used biomarker molecules. The efficacy of these templates is explained in terms of the ability of the hydrophobic polymer grafted gold nanoparticles used to organize, penetrate, and fluidize the membranes. The enhancement of photoluminescence of the dye molecules used occurs over a reasonably large spectral range as compared to the plasmon resonance of gold nanoparticles. The results could, possibly, be extended to cellular membranes with relevant modifications, as well as to the detection of any other biological molecule appropriately labeled with fluorescent dye molecules, and demonstrate the versatility of these plasmonic bioinspired platforms as potential biochemical sensors.

Luffa acutangula agglutinin: Primary structure determination and identification of a tryptophan residue involved in its carbohydrate-binding activity using mass spectrometry

A lectin from phloem exudates of Luffa acutangula (ridge gourd) was purified on chitin affinity chromatography and characterized for its amino acid sequence and to study the role of tryptophan in its activity. The purified lectin was subjected to various proteolytic digestions, and the resulting peptides were analyzed by liquid chromatography coupled electrospray ionization ion trap mass spectrometer. The peptide precursor ions were fragmented by collision-induced dissociation or electron transfer dissociation experiments, and a manual interpretation of MS/MS was performed to deduce amino acid sequence. This gave rise to almost complete sequence coverage of the lectin which showed high-sequence similarity with deduced sequences of phloem lectins present in the database. Chemical modification of lysine, tyrosine, histidine, arginine, aspartic acid, and glutamic acid residues did not inhibit the hemagglutinating activity. However, the modification of tryptophan residues using N-bromosuccinimide showed the loss of hemagglutinating activity. Additionally, the mapping of tryptophan residues was performed to determine the extent and number of residues modified, which revealed that six residues per molecule were oxidized suggesting their accessibility. The retention of the lectin activity was seen when the modifications were performed in the presence of chitooligosaccharides due to protection of a tryptophan residue (W-102) in the protein. These studies taken together have led to the identification of a particular tryptophan residue (W-102) in the activity of the lectin. (c) 2015 IUBMB Life, 67(12):943-953, 2015

Bulk-Induced 1/f Noise at the Surface of Three-Dimensional Topological Insulators

Slow intrinsic fluctuations of resistance, also known as the flicker noise or 1/f-noise, in the surface transport of strong topological insulators (TIs) is a poorly understood phenomenon. Here, we have systematically explored the 1/f-noise in field-effect transistors (FET) of mechanically exfoliated Bi1.6Sb0.4Te2Se TI films when transport occurs predominantly via the surface states. We find that the slow kinetics of the charge disorder within the bulk of the TI induces mobility fluctuations at the surface, providing a new source of intrinsic 1/f-noise that is unique to bulk TI systems. At small channel thickness, the noise magnitude can be extremely small, corresponding to the phenomenological Hooge parameter gamma(H) as low as approximate to 10(-4), but it increases rapidly when channel thickness exceeds similar to 1 mu m. From the temperature (T)-dependence of noise, which displayed sharp peaks at characteristic values of T, we identified generation-recombination processes from interband transitions within the TI bulk as the dominant source of the mobility fluctuations in surface transport. Our experiment not only establishes an intrinsic microscopic origin of noise in TI surface channels, but also reveals a unique spectroscopic information on the impurity bands that can be useful in bulk TI systems in general.