IN-VITRO CYTOTOXICITY AND CELL CYCLE ANALYSIS OF TWO NOVEL BIS-1, 2, 4-TRIAZOLE DERIVATIVES: 1,4-BIS[5-(5-MERCAPTO-1,3,4-OXADIAZOL-2-yl-METHYL)-THIO-4-(p-TOLYL)-1, 2,4-TRIAZOL-3-yl]-BUTANE (MNP-14) AND 1,4-BIS[5-(CARBETHOXY-METHYL)-THIO-4-(p-ETHOXY PHENYL)-1,2,4-TRIAZOL-3-yl]-BUTANE (MNP-16)

In the present study, we have tested the cytotoxic and DNA damage activity of two novel bis-1,2,4 triazole derivatives, namely 1,4-bis[5-(5-mercapto-1,3,4-oxadiazol-2-yl-methyl)-thio4-(p-tolyl)-1,2 ,4-triazol-3-yl]-butane (MNP-14) and 1,4-bis[5-(carbethoxy-methyl)-thio-4-(p-ethoxy phenyl) -1,2,4-triazol-3-yl]-butane (MNP-16). The effect of these molecules on cellular apoptosis was also determined. The in-vitro cytotoxicity was evaluated by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay as well as Trypan blue dye exclusion methods against human acute lymphoblastic leukemia (MOLT4) and lung cancer cells (A549). Our results showed that MNP-16 induced significant cytotoxicity (IC50 of 3-5 mu M) compared with MNP-14. The cytotoxicity induced by MNP-16 was time and concentration dependent. The cell cycle analysis by flow cytometry (fluorescence-activated cell sorting [FACS]) revealed that though there was a significant increase in the apoptotic population (sub-G1 phase) with an increased concentration of MNP-14 and 16, there was no cell cycle arrest. Further, the comet assay results indicated considerable DNA

Incremental Cycle Detection, Topological Ordering, and Strong Component Maintenance

We present two online algorithms for maintaining a topological order of a directed n-vertex acyclic graph as arcs are added, and detecting a cycle when one is created. Our first algorithm handles m arc additions in O(m(3/2)) time. For sparse graphs (m/n = O(1)), this bound improves the best previous bound by a logarithmic factor, and is tight to within a constant factor among algorithms satisfying a natural locality property. Our second algorithm handles an arbitrary sequence of arc additions in O(n(5/2)) time. For sufficiently dense graphs, this bound improves the best previous bound by a polynomial factor. Our bound may be far from tight: we show that the algorithm can take Omega(n(2)2 root(2lgn)) time by relating its performance to a generalization of the k-levels problem of combinatorial geometry. A completely different algorithm running in Theta (n(2) log n) time was given recently by Bender, Fineman, and Gilbert. We extend both of our algorithms to the maintenance of strong components, without affecting the asymptotic time bounds.

Albedo enhancement over land to counteract global warming: impacts on hydrological cycle

A recent modelling study has shown that precipitation and runoff over land would increase when the reflectivity of marine clouds is increased to counter global warming. This implies that large scale albedo enhancement over land could lead to a decrease in runoff over land. In this study, we perform simulations using NCAR CAM3.1 that have implications for Solar Radiation Management geoengineering schemes that increase the albedo over land. We find that an increase in reflectivity over land that mitigates the global mean warming from a doubling of CO2 leads to a large residual warming in the southern hemisphere and cooling in the northern hemisphere since most of the land is located in northern hemisphere. Precipitation and runoff over land decrease by 13.4 and 22.3%, respectively, because of a large residual sinking motion over land triggered by albedo enhancement over land. Soil water content also declines when albedo over land is enhanced. The simulated magnitude of hydrological changes over land are much larger when compared to changes over oceans in the recent marine cloud albedo enhancement study since the radiative forcing over land needed (-8.2 W m(-2)) to counter global mean radiative forcing from a doubling of CO2 (3.3 W m(-2)) is approximately twice the forcing needed over the oceans (-4.2 W m(-2)). Our results imply that albedo enhancement over oceans produce climates closer to the unperturbed climate state than do albedo changes on land when the consequences on land hydrology are considered. Our study also has important implications for any intentional or unintentional large scale changes in land surface albedo such as deforestation/afforestation/reforestation, air pollution, and desert and urban albedo modification.

Is meridional circulation important in modelling irregularities of the solar cycle?

We explore the importance of meridional circulation variations in modelling the irregularities of the solar cycle by using the flux transport dynamo model. We show that a fluctuating meridional circulation can reproduce some features of the solar cycle like the Waldmeier effect and the grand minimum. However, we get all these results only if the value of the turbulent diffusivity in the convection zone is reasonably high.

Context dependent splicing functions of Bud31/Ycr063w define its role in budding and cell cycle progression

The yeast Bud31 protein, a Prp19 complex (NTC) member, aids spliceosome assembly and thus promotes efficient pre-mRNA splicing. The bud31 null cells show mild budding abnormalities at optimal growth temperatures and, at higher temperatures, have growth defects with aberrant budding. Here we have assessed cell cycle transitions which require Bud31. We find Bud31 facilitates passage through G1-S regulatory point (Start) but is not needed for G2-M transition or for exit from mitosis. To co-relate Bud31 functions in cell division with splicing, we studied the splicing status of transcripts that encode proteins involved in budding. We find Bud31 promotes efficient splicing of only some of these pre-mRNAs, for example, ARP2 and SRC1. Wild type cells have a long and a short isoform of SRC1 mRNA and protein, out of which the shorter mRNA splice variant is predominant. bud31 Delta cells show inefficient SRC1 splicing and entirely lack the shorter SRC1 spliced mRNA isoform. Yeast PRP17, another NTC sub-complex member, is also required for G1-S and G2-M cell cycle transitions. We examined genetic interactions between BUD31 and PRP17. While both factors were needed for efficient cell cycle dependent gene expression, our data indicate that distinct pre-mRNAs depend on each of these non-essential splicing factors.

TURBULENT PUMPING OF MAGNETIC FLUX REDUCES SOLAR CYCLE MEMORY AND THUS IMPACTS PREDICTABILITY OF THE SUN'S ACTIVITY

Prediction of the Sun's magnetic activity is important because of its effect on space environment and climate. However, recent efforts to predict the amplitude of the solar cycle have resulted in diverging forecasts with no consensus. Yeates et al. have shown that the dynamical memory of the solar dynamo mechanism governs predictability, and this memory is different for advection- and diffusion-dominated solar convection zones. By utilizing stochastically forced, kinematic dynamo simulations, we demonstrate that the inclusion of downward turbulent pumping of magnetic flux reduces the memory of both advection- and diffusion-dominated solar dynamos to only one cycle; stronger pumping degrades this memory further. Thus, our results reconcile the diverging dynamo-model-based forecasts for the amplitude of solar cycle 24. We conclude that reliable predictions for the maximum of solar activity can be made only at the preceding minimum-allowing about five years of advance planning for space weather. For more accurate predictions, sequential data assimilation would be necessary in forecasting models to account for the Sun's short memory.

Development of a New Generation of Vectors for Gene Expression, Gene Replacement, and Protein-Protein Interaction Studies in Mycobacteria

Escherichia coli-mycobacterium shuttle vectors are important tools for gene expression and gene replacement in mycobacteria. However, most of the currently available vectors are limited in their use because of the lack of extended multiple cloning sites (MCSs) and convenience of appending an epitope tag(s) to the cloned open reading frames (ORFs). Here we report a new series of vectors that allow for the constitutive and regulatable expression of proteins, appended with peptide tag sequences at their N and C termini, respectively. The applicability of these vectors is demonstrated by the constitutive and induced expression of the Mycobacterium tuberculosis pknK gene, coding for protein kinase K, a serine-threonine protein kinase. Furthermore, a suicide plasmid with expanded MCS for creating gene replacements, a plasmid for chromosomal integrations at the commonly used L5 attB site, and a hypoxia-responsive vector, for expression of a gene(s) under hypoxic conditions that mimic latency, have also been created. Additionally, we have created a vector for the coexpression of two proteins controlled by two independent promoters, with each protein being in fusion with a different tag. The shuttle vectors developed in the present study are excellent tools for the analysis of gene function in mycobacteria and are a valuable addition to the existing repertoire of vectors for mycobacterial research.

Comparison of one cycle control of charge and current for bi-directional boost rectifiers

Classical control and one cycle control of current are popular methods used to modulate pulses in active rectifiers for ac-dc power conversion. One cycle control has lower control complexity and can be implemented using linear analog circuits when compared with the classical approach. However, it also suffers from problems such as instability and offsets in current that is severe at light load conditions. A control strategy for bidirectional boost rectifiers based on one cycle control of charge is proposed for that overcomes these limitations. The integral of sensed current, which represents charge, is compared with a non-linear carrier, which is modified for ac-dc power conversion. This generates the gating signals for the switching devices. The modifications required for the control law governing one cycle control of charge is derived in the paper. Detailed simulation studies are carried out to compare one cycle control of current with the proposed method for ac-dc power conversion, which are validated on a laboratory hardware prototype.

An estimate of equilibrium sensitivity of global terrestrial carbon cycle using NCAR CCSM4

Increasing concentrations of atmospheric CO2 influence climate, terrestrial biosphere productivity and ecosystem carbon storage through its radiative, physiological and fertilization effects. In this paper, we quantify these effects for a doubling of CO2 using a low resolution configuration of the coupled model NCAR CCSM4. In contrast to previous coupled climate-carbon modeling studies, we focus on the near-equilibrium response of the terrestrial carbon cycle. For a doubling of CO2, the radiative effect on the physical climate system causes global mean surface air temperature to increase by 2.14 K, whereas the physiological and fertilization on the land biosphere effects cause a warming of 0.22 K, suggesting that these later effects increase global warming by about 10 % as found in many recent studies. The CO2-fertilization leads to total ecosystem carbon gain of 371 Gt-C (28 %) while the radiative effect causes a loss of 131 Gt-C (10 %) indicating that climate warming damps the fertilization-induced carbon uptake over land. Our model-based estimate for the maximum potential terrestrial carbon uptake resulting from a doubling of atmospheric CO2 concentration (285-570 ppm) is only 242 Gt-C. This highlights the limited storage capacity of the terrestrial carbon reservoir. We also find that the terrestrial carbon storage sensitivity to changes in CO2 and temperature have been estimated to be lower in previous transient simulations because of lags in the climate-carbon system. Our model simulations indicate that the time scale of terrestrial carbon cycle response is greater than 500 years for CO2-fertilization and about 200 years for temperature perturbations. We also find that dynamic changes in vegetation amplify the terrestrial carbon storage sensitivity relative to a static vegetation case: because of changes in tree cover, changes in total ecosystem carbon for CO2-direct and climate effects are amplified by 88 and 72 %, respectively, in simulations with dynamic vegetation when compared to static vegetation simulations.

Supercritical carbon dioxide Brayton cycle for concentrated solar power

Supercritical carbon dioxide based Brayton cycle for possible concentrated solar power applications is investigated and compared with trans- and sub-critical operations of the same fluid. Thermal efficiency, specific work output and magnitude of irreversibility generation are used as some of the performance indicators. While the thermal efficiency increases almost linearly with low side pressure in the sub- and trans-critical cycles, it attains a maximum in the supercritical regime at 85 bar after which there are diminishing returns on increasing the low side pressure. It is also found that supercritical cycle is capable of producing power with a thermal efficiency of >30% even at a lower source temperature (820K) and accounting for foreseeable non-idealities albeit with a higher turbine inlet pressure (similar to 300 bar) which is not matched by a conventional sub-critical cycle even with a high source temperature of 978K. The reasons for lower efficiency than in an ideal cycle are extracted from an irreversibility analysis of components, namely, compressor, regenerator, turbine and gas cooler. Low sensitivity to the source temperature and extremely small volumetric flow rates in the supercritical cycle could offset the drawback of high pressures through a compact system.

Propyl-2-(8-(3,4-Difluorobenzyl)-2 `,5 `-Dioxo-8-AzaspiroBicyclo3.2.1] Octane-3,4 `-Imidazolidine]-1 `-yl) Acetate Induces Apoptosis in Human Leukemia Cells through Mitochondrial Pathway following Cell Cycle Arrest

Background: Due to the functional defects in apoptosis signaling molecules or deficient activation of apoptosis pathways, leukemia has become an aggressive disease with poor prognosis. Although the majority of leukemia patients initially respond to chemotherapy, relapse is still the leading cause of death. Hence targeting apoptosis pathway would be a promising strategy for the improved treatment of leukemia. Hydantoin derivatives possess a wide range of important biological and pharmacological properties including anticancer properties. Here we investigated the antileukemic activity and mechanism of action of one of the potent azaspiro hydantoin derivative, (ASHD). Materials and Methods: To investigate the antileukemic efficacy of ASHD, we have used MTT assay, cell cycle analysis by FACS, tritiated thymidine incorporation assay, Annexin V staining, JC1 staining and western blot analysis. Results: Results showed that ASHD was approximately 3-fold more potent than the parent compounds in inducing cytotoxicity. Tritiated thymidine assay in conjunction with cell cycle analysis suggests that ASHD inhibited the growth of leukemic cells. The limited effect of ASHD on cell viability of normal cells indicated that it may be specifically directed to cancer cells. Translocation of phosphatidyl serine, activation of caspase 3, caspase 9, PARP, alteration in the ratio of BCL2/BAD protein expression as well as the loss of mitochondrial membrane potential suggests activation of the intrinsic pathway of apoptosis. Conclusion: These results could facilitate the future development of novel hydantoin derivatives as chemotherapeutic agents for leukemia.

Multifunctional Properties of Multistage Spark Plasma Sintered HA-BaTiO3-Based Piezobiocomposites for Bone Replacement Applications

This work reports the processing-microstructure-property correlation of novel HA-BaTiO3-based piezobiocomposites, which demonstrated the bone-mimicking functional properties. A series of composites of hydroxyapatite (HA) with varying amounts of piezoelectric BaTiO3 (BT) were optimally processed using uniquely designed multistage spark plasma sintering (SPS) route. Transmission electron microscopy imaging during in situ heating provides complementary information on the real-time observation of sintering behavior. Ultrafine grains (0.50m) of HA and BT phases were predominantly retained in the SPSed samples. The experimental results revealed that dielectric constant, AC conductivity, piezoelectric strain coefficient, compressive strength, and modulus values of HA-40wt% BT closely resembles with that of the natural bone. The addition of 40wt% BT enhances the long-crack fracture toughness, compressive strength, and modulus by 132%, 200%, and 165%, respectively, with respect to HA. The above-mentioned exceptional combination of functional properties potentially establishes HA-40wt% BT piezocomposite as a new-generation composite for orthopedic implant applications.

Monotonic and low cycle fatigue behavior of an O+B2 alloy at high temperatures

Low cycle fatigue behavior of an O+B2 alloy was evaluated at 650 degrees C in ambient atmosphere under fully reversed total axial strain controlled mode. Three different microstructures, namely equiaxed O plus aged B2 (fine O plates in B2 matrix), lenticular O laths plus aged B2 and a pancake composite microstructure comprising equiaxed alpha 2, lenticular O and aged B2, were selected to study the effect of microstructure on low cycle fatigue behavior in this class of alloys. Distinct well-defined trends were observed in the cyclic stress-strain response curves depending on the microstructure. The cyclic stress response was examined in terms of softening or hardening and correlated with microstructural features and dislocation behavior. Fatigue life was analyzed in terms of standard Coffin-Manson and Basquin plots and for all microstructures a prevailing elastic strain regime was identified, with a single slope for microstructures equiaxed and composite and a double slope for lenticular O laths. (c) 2014 Elsevier B.V. All rights reserved.

A modeling study of the processes of surface salinity seasonal cycle in the Bay of Bengal

In response to the Indian Monsoon freshwater forcing, the Bay of Bengal exhibits a very strong seasonal cycle in sea surface salinity (SSS), especially near the mouths of the Ganges-Brahmaputra and along the east coast of India. In this paper, we use an eddy-permitting (similar to 25 km resolution) regional ocean general circulation model simulation to quantify the processes responsible for this SSS seasonal cycle. Despite the absence of relaxation toward observations, the model reproduces the main features of the observed SSS seasonal cycle, with freshest water in the northeastern Bay, particularly during and after the monsoon. The model also displays an intense and shallow freshening signal in a narrow (similar to 100 km wide) strip that hugs the east coast of India, from September to January, in good agreement with high-resolution measurements along two ships of opportunity lines. The mixed layer salt budget confirms that the strong freshening in the northern Bay during the monsoon results from the Ganges-Brahmaputra river discharge and from precipitation over the ocean. From September onward, the East India Coastal Current transports this freshwater southward along the east coast of India, reaching the southern tip of India in November. The surface freshening results in an enhanced vertical salinity gradient that increases salinity of the surface layer by vertical processes. Our results reveal that the erosion of the freshwater tongue along the east coast of India is not driven by northward horizontal advection, but by vertical processes that eventually overcome the freshening by southward advection and restore SSS to its premonsoon values. The salinity-stratified barrier layer hence only acts as a ``barrier'' for vertical heat fluxes, but is associated with intense vertical salt fluxes in the Bay of Bengal.

POLAR NETWORK INDEX AS A MAGNETIC PROXY FOR THE SOLAR CYCLE STUDIES

The Sun has a polar magnetic field which oscillates with the 11 yr sunspot cycle. This polar magnetic field is an important component of the dynamo process which operates in the solar convection zone and produces the sunspot cycle. We have direct systematic measurements of the Sun's polar magnetic field only from about the mid-1970s. There are, however, indirect proxies which give us information about this field at earlier times. The Ca-K spectroheliograms taken at the Kodaikanal Solar Observatory during 1904-2007 have now been digitized with 4k x 4k CCD and have higher resolution (similar to 0.86 arcsec) than the other available historical data sets. From these Ca-K spectroheliograms, we have developed a completely new proxy (polar network index, hereafter PNI) for the Sun's polar magnetic field. We calculate PNI from the digitized images using an automated algorithm and calibrate our measured PNI against the polar field as measured by the Wilcox Solar Observatory for the period 1976-1990. This calibration allows us to estimate the polar fields for the earlier period up to 1904. The dynamo calculations performed with this proxy as input data reproduce reasonably well the Sun's magnetic behavior for the past century.