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In image processing applications, image denoising is an emerging area that recovers the original image from noisy image, which is essential in the applications like pattern analysis. The main aim of this study is to propose an effective filtering technique with peer groups for effective image restoration processes. Existing bilateral filter has lower performance in smoothing the high curvature and high gradient regions due to nearby input signals are outliers that miss the filter window. In this research paper, a new approach is proposed that includes fuzzy-based approach and similarity function for filtering the mixed noise. In a peer group, the similarity function was adaptive to edge information and local noise level, which was utilised for detecting the similarity among pixels. In addition, a new filtering method modified trilateral filter (MTF) with improved generalised fuzzy peer group (IGFPG) is proposed to remove mixed impulse and adaptive white Gaussian noise from colour images. The modified trilateral filter includes Kikuchi algorithm and loopy belief propagation to solve the inference issues on the basis of passing local message. In this research work, the images were collected from KODAK dataset and a few real time multimedia images like Lena were also used for testing the effectiveness of the proposed methodology. The collected colour images were contaminated with adaptive white Gaussian noise (AWGN) of standard deviation σε[05,20] and impulse noise of probability pε[0.05, 0.20]. The proposed MTF-IGFPG method has the advantages of consider image photometric and geometric similarities. The local structural similarity and narrow spatial window is applied for smoothing the images to effectively preserve the images. From the simulation, the proposed MTF-IGFPG approach attained better performance related to the existing approaches in light of normalised colour difference (NCD), peak signal-to-noise ratio (PSNR), and mean absolute error (MAE). Hence, the proposed approach almost achieved PSNR of 36 dB, which shows 0.2 dB to 2 dB improvement than the existing methods.

Energy efficiency is one of the major challenges in the growing WSNs. Since communication offers a vast place in the consumption of energy, effective routing is the best solution to handle this problem. The lifetime improvement is an important problem since the majority of the WSNs function in an unattended environment, in which monitoring, as well as human access, is not possible in a practical manner. Clustering is one of the powerful approaches, which arranges the system operation for the enhanced lifetime of the network, improves energy efficiency, reduces the consumption of energy, and also attend the scalability of the network. To handle this issue, the present researchers have considered the usage of various clustering algorithms. Yet, the cluster head is burdened by the majority of the suggested algorithms in the process of cluster formation. To handle this problem, this paper plans to develop the energy-efficient clustering for WSN using the improved LEACH protocol. Here, the concept of a hybrid meta-heuristic algorithm is used for the optimal cluster head selection through energy-efficient clustering. The optimal solutions are rated based on the multi-objective function considering the objective constraints like energy, distance, delay, quality of service (QoS), load, and time of death. Communication between the sink node and cluster head uses the distance of separation as a parameter for reducing energy consumption. Two well-performing algorithms, like salp swarm algorithm (SSA) and grasshopper optimization algorithm (GOA) are merged to develop the proposed hybrid algorithm called salp-swarm grasshopper optimization (SS-GO). From the results, for 200 nodes, the normalized energy of SS-GO at 1400th round is 5.41%, 11.43%, 14.71%, and 25.81%, superior to GOA, SSO, O-EHO, and FU-CSA, respectively.Here, the performance of the proposed SS-GO is also higher in the other distance, delay, time of death node, and QOS. The performance of the introduced hybrid algorithm-based LEACH is evaluated in several different scenarios, and it is shown that the proposed protocol improves network lifetime in comparison to a number of the recent similar protocol.

The main intent of this paper is to implement the stability-aware energy-efficient clustering protocol in WSN. This paper plans to derive a multi-objective function with the constraints like energy, distance, delay, stability period, and intents to attain the objective by developing a new well-performing meta-heuristic algorithm called Opposition-based Elephant Herding Optimisation (O-EHO). The objective function diminishes the energy consumption of sensor nodes by optimum selection of cluster heads that leads to maintain the energy balance between the normal nodes. In this way, there is a remarkable enhancement in the performance parameters such as throughput, stability period, and network lifetime. It is proved that the network lifetime is enhanced by the stability period and thus it is considered as the most significant parameter. The experimental analysis proves the competitive performance of the proposed model over other heuristic methods.

In the data collection phase, the digital images are captured using sensors that often contaminated by noise (undesired random signal). In digital image processing task, enhancing the image quality and reducing the noise is a central process. Image denoising effectively preserves the image edges to a higher extend in the flat regions. Several adaptive filters (median filter, Gaussian filter, fuzzy filter, etc.) have been utilized to improve the smoothness of digital image, but these filters failed to preserve the image edges while removing noise. In this paper, a modified fuzzy set filter has been proposed to eliminate noise for restoring the digital image. Usually in fuzzy set filter, sixteen fuzzy rules are generated to find the noisy pixels in the digital image. In modified fuzzy set filter, a set of twenty-four fuzzy rules are generated with additional four pixel locations for determining the noisy pixels in the digital image. The additional eight fuzzy rules ease the process of finding the image pixels,whether it required averaging or not. In this scenario, the input digital images were collected from the underwater photography fish dataset. The efficiency of the modified fuzzy set filter was evaluated by varying degrees of Gaussian noise (0.01, 0.03, and 0.1 levels of Gaussian noise). For performance evaluation, Structural Similarity (SSIM), Mean Structural Similarity (MSSIM), Mean Square Error (MSE), Normalized Mean Square Error (NMSE), Universal Image Quality Index (UIQI), Peak Signal to Noise Ratio (PSNR), and Visual Information Fidelity (VIF) were used. The experimental results showed that the modified fuzzy set filter improved PSNR value up to 2-3 dB, MSSIM up to 0.12-0.03, and NMSE value up to 0.38-0.1 compared to the traditional filtering techniques.

Moving object detection is an essential step in several computer visions like salient object detection, visual object tracking, and video surveillance etc. Many existing methods have a drawback of low efficiency in the challenging scenes like dynamic background, camera jitter, and bad weather images. In this research, Unified model (Yolov3-Improved Non-Maximum Suppression (INMS)) method is proposed to increases the performance in moving object detection. The Change Detection net (CDNET) dataset was trained and also COCO 2014 and PascalVOC data sets were applied to analyse the performance of the developed model. The experimental analysis shows that the developed method has higher efficiency in detecting objects in camera jitter and dynamic background scene. The performance evaluation has been done using the precision, recall, IoU and the accuracy metrics for the proposed model. The results show that the developed model has the ability to effectively identify multiple objects in the dynamic background, while the existing method has the capacity to identify only single object.

Recent years have authenticated a dramatic increase in graph applications due to their advancements in their informative and social connectivity. In large-scale networks, graph data contains huge information and exhibits distinct characteristics. Traditional graph convolutional networks cannot handle the problem of covariate-shift in the neural-networks during analysing the patterns. This research presents an intelligence-based graph-classification model for citation networks by using normalised graph convolution networks to handle covariate-shift problem and provides greater regularisation with a decrement in loss to a greater extent. This problem is vanquished by utilising the normalisation constraint for the individual batch constructed as per network developed for graph-structures which eventually lead to building a robust model. The model classifies the underlying connectivity patterns of the structural and informative relationships with appropriate embeddings. This information is fed to neural-network and learns hidden layer representation that encode both local graphs and features of the nodes in the citation network.

Social media usage is one of the most popular online activities these days. In 2018, it is estimated that 2.65 billion people were using social media worldwide and these numbers are expected to reach almost 3.1 billion by 2021, the majority of whom are young people. With some notable exceptions, there are few studies that have been undertaken in the field of politics and social media. This study examines how usage of social media for political purpose influences the voting behavior of the voter in this realm. The authors test the proposition that using social media for political use offers a new pathway to their political participation, interest, and knowledge using path analysis. Results demonstrate that political use of social media impacted both levels of and growth in traditional political participation, interest, and knowledge during the 2019 election.

The paper proposes a complete modelling of finite state automata along with the associated classifier for texture classification. Pattern analysis of the texture image is performed by proposing a symbolic pattern-based algorithm. This algorithm is developed based on the symbolic dynamics and finite state automata theory for estimating the state transition of the texture variations. Texture image is divided into several partitions, i.e., texture, background of the texture, shadow of the texture, etc. Finite automata state transitions are used to extract the features from the symbolised image. A binary classifier is designed to classify the texture categories based on the feature extraction from the finite automata theory. Pattern analysis is performed on the KITH-TIPS dataset for ten varied categories of texture. 99.12% classification accuracy is achieved when compared with other state-of-art techniques. The experimental study shows the better efficiency of the proposed system when compared to other existing methods.

The nonlinear, steady state magnetohydrodynamics natural convection boundary layer flow, heat and mass transfer of an viscoelastic incompressible Jeffrey’s fluid from a vertical permeable cone with thermal radiation and heat generation/absorption effects is investigated in this article. The transformed conservation equations are solved numerically subject to physically appropriate boundary conditions using a versatile, implicit finite-difference Keller box technique. The Rosseland diffusion algebraic approximation is utilized to simulate thermal radiation effects. The surface of the cones is maintained at a constant temperature and concentration with mass flux present. Excellent correlation of the present results with previous studies is obtained to validate the numerical code. The influence of Deborah number (De), ratio of relaxation to retardation times ($$\lambda $$ λ ), radiation parameter (F), heat generation/absorption parameter ($$\Delta $$ Δ ), suction/injection parameter ($$f_{w}$$ fw ), magnetic parameter (M) and dimensionless tangential coordinate ($$\xi $$ ξ ) on velocity, temperature and concentration evolution in the boundary layer regime are examined in detail. Also, the effects of these parameters on local skin friction, heat transfer rate and mass transfer rateare investigated.

In this Viewpoint article, we asked four scientists working to target important, but so-called 'undruggable', proteins in cancer for their opinions on the most crucial advances, as well as the challenges and what the future holds for this important area of cancer research.

A numerical study is presented to analyze the nonlinear, non-isothermal, magnetohydrodynamic (MHD) free convection boundary layer flows of non-Newtonian tangent hyperbolic fluid past a vertical surface in a non-Darcy, isotropic, homogenous porous medium in the presence of Hall currents and Ionslip currents. The governing nonlinear coupled partial differential equations for momentum conservation in x and z directions, heat and mass conservation in the flow regime are transformed from an (x, y, z) coordinate system to ($$\upxi ,\upeta $$ ξ,η ) coordinate system in terms of dimensionless x-direction velocity ($$f^{\prime }$$ f′ ) and z-direction velocity (G), dimensionless temperature and concentration functions ($$\uptheta $$ θ and $$\upphi $$ ϕ ) under appropriate boundary conditions. Both Darcian and Forchheimer porous impedances are incorporated in both momentum equations. Computations are also provided for the variation of the x and z direction shear stress components and also heat and mass transfer rates. Increasing Weissenberg number (We) is observed to decrease primary and secondary velocity and concentration but increase temperature. It is found that the primary and secondary velocity is increased with increasing power law index (n) whereas the temperature and concentration are decreased. Increasing hall and Ionslip current ($$\beta _{e}$$ βe and $$\beta _{i}$$ βi ) is observed to increase primary velocity but decreases secondary velocity, temperature and concentration. Increasing magnetic parameter ($$N_{m}$$ Nm ) is seen to decrease primary velocity but decreases secondary velocity, temperature and concentration. Increasing Darcy number (Da) is found to increase primary and secondary velocity whereas decreases temperature and concentration. Increasing Forchheimer parameter (Fs) is seen to decrease primary and secondary velocity but increases temperature and concentration. The model finds applications in magnetic materials processing, MHD power generators and purification of crude oils.

This article presents the nonlinear, steady boundary layer flow and heat transfer of an incompressible Tangent Hyperbolic non-Newtonian fluid from a Horizontal Circular Cylinder in the presence of magnetic field and Biot number effects. The transformed conservation equations are solved numerically subject to physically appropriate boundary conditions using a second-order accurate implicit finite-difference Keller Box technique. The numerical code is validated with previous studies. The influence of a number of emerging non-dimensional parameters, namely the Weissenberg number (We), power law index (n), Prandtl number (Pr), Biot number $$(\upgamma )$$ (γ) , the magnetic parameter (M) and dimensionless tangential coordinate ($$\xi $$ ξ ) on velocity and temperature evolution on the boundary layer regime are examined in detail. Furthermore, the effects of these parameters on surface heat transfer rate and local skin frictionare also investigated. Validation with earlier Newtonianstudies is presented and excellent correlation achieved. It is found that the velocity, skin friction and heat transfer rate reduce with increasing We. Whereas, there is slight increase in temperature. Increasing nis observed to increase the velocity and heat transfer rate but decreases temperature and skin friction. An increasing $$\upgamma $$ γ is seen to increase velocity, temperature, local skin friction and heat transfer rate. And an increasing Mis found to decrease velocity, skin friction and heat transfer rate but increases the temperature. The study is relevant to chemical materials processing applications.

Waste heat recovery is one of the energy conservation options. About 30% of heat produced by diesel engines that are coupled to electric power generators are carried away by exhaust gases as waste part of the heat energy produced. In the present work, CFD and experimental analysis was made to study the utilisation of the waste heat energy carried by exhaust gases to obtain hot water used for various purposes in commercial buildings, hostels, etc. The effect of fins arranged on the outer periphery of inner cylinder is also studied. Fin arrangement increases the heat transfer rate by reducing the charging time of TESS. Theoretical, numerical and experimental results were compared and found that the values are closer about 10%. The performance of the TESS is evaluated by calculating performance characteristics such as charging and discharging rates and 14% of heat can be recovered from the 30% energy being wasted.

In depth understanding of dental caries progression and improved diagnostic methodologies to assess early demineralization has enabled development of novel remineralizing therapeutics. Hence, an emerging goal of modern dentistry is to manage non-cavitated carious lesions non-invasively through remineralization.

Research outcome on merger of discrete short length fibres like steel fibre, polypropylene fibre (PPF), alkali resistant fibre (ARF) etc. to produce fibre reinforced concrete (FRC) gave a momentous thrust to FRC to use it for shrinkage resistance, crack bridging as well as improving the tensile load carrying resilience. Continuous research is going on FRC by incorporation of various size/shape combinations of similar fibre material or combinations of different fibre material to further improve the performance of FRC. The challenge of using combinations of various industrial by products having reactive and slow pozzolanic nature as part replacement of cement to reduce greenhouse gas emissions is also experimented world over for achieving sustainability in concrete construction activities. These pozzolanic materials [supplementary cementitious materials (SCM)] are also useful in proportioning self compacting concrete (SCC) which offer higher quantities of powder size material (0.125 mm size) as required for achieving qualifying characteristics of SCC. Innovations for improving the SCC to use it in fast track construction and repair projects is being made by several researches, by the way of incorporating various reactive material to attain fast setting, early strength and combine different fibres in to the SCC to have resistance to shrinkage, cracks and develop enough tensile strength in early age for opening the structure to users. Hence there exists a vast scope for research in FRC for improvement of performance by the way of incorporation of compatible materials and fibre combinations. In this study two types of hybrid fibre reinforced self compacting concrete were proportioned with part replacement of cement with metakaolin as reactive SCM and ground granulated blast furnace slag as normal reactive SCM. Various combinations of PPF and ARF investigated in SCC mix with a target to achieve 1 day compressive strength of 25 N/mm2and split tensile strength of 2 N/mm2for use in fast track construction and repair works. Mechanical strength tests and durability tests at early ages as well as up to 56 days conducted.

This study describes the characterization of a novel kinase inhibitor, ON123300, which inhibits CDK4/6 (cyclin-dependent kinases 4 and 6) and phosphatidylinositol 3 kinase-d (PI3K-d) and exhibits potent activity against mantle cell lymphomas (MCLs) both in vitroand in vivo. We examined the effects of PD0332991 and ON123300 on cell cycle progression, modulation of the retinoblastoma (Rb) and PI3K/AKT pathways, and the induction of apoptosis in MCL cell lines and patient-derived samples. When Granta 519 and Z138C cells were incubated with PD0332991 and ON123300, both compounds were equally efficient in their ability to inhibit the phosphorylation of Rb family proteins. However, only ON123300 inhibited the phosphorylation of proteins associated with the PI3K/AKT pathway. Cells treated with PD0332991 rapidly accumulated in the G0/G1phase of cell cycle as a function of increasing concentration. Although ON123300-treated cells arrested similarly at lower concentrations, higher concentrations resulted in the induction of apoptosis, which was not observed in PD0332991-treated samples. Mouse xenograft assays also showed a strong inhibition of MCL tumor growth in ON123300-treated animals. Finally, treatment of ibrutinib-sensitive and -resistant patient-derived MCLs with ON123300 also triggered apoptosis and inhibition of the Rb and PI3K/AKT pathways, suggesting that this compound might be an effective agent in MCL, including ibrutinib-resistant forms of the disease.

In this article, we investigate the non-linear steady free convection heat and mass transfer of an incompressible Jeffrey’s non-Newtonian fluid from a permeable horizontal isothermal cylinder in a non-Darcy porous medium. A non-Darcy drag force model is employed to simulate the effects of linear porous media drag and second-order Forchheimer drag. The transformed conservation equations are solved numerically subject to physically appropriate boundary conditions using a versatile, implicit, finite difference technique. The numerical code is validated with previous studies. The influence of a number of emerging non-dimensional parameters, namely Deborah number (De), surface suction parameter (fw), Prandtl number (Pr), ratio of relaxation to retardation times (λ), Darcy number (Da), Forchheimer inertial parameter (Λ) and dimensionless tangential coordinate (ξ) on velocity, temperature and concentration evolution in the boundary layer regime are examined in detail. Furthermore, the effects of these parameters on surface heat transfer rate, mass transfer rate and local skin friction are also investigated. It is observed that velocity decreases with increasing Deborah number and Forchheimer parameter, whereas temperature and concentration are enhanced. Increasing λand Daenhances velocity but reduces temperature and concentration. The heat transfer rate and mass transfer rate are found to decrease with increasing Deborah number, De, and increase with increasing λ. Local skin friction is found to decrease with a rise in Deborah number whereas it is elevated with increasing values of relaxation to retardation time ratio (λ). Increasing suction decelerates the flow and also cools the boundary layer, i.e., reduces temperature and also concentration. With increasing tangential coordinate, the flow is decelerated; whereas, the temperature and concentration are enhanced.

From early history, builders, manufacturers, and engineers continued to develop composites of wide assortments of materials. Furthermore, chemical upheaval changed the composite development of plastics such as polyvinyl, polystyrene, etc., and reinforcement was reinforced essential to provide strength and rigidity. At present composites finds many applications in every aspects of day to day life. The utilization of raw materials like coal, baggase and agricultural wastes are used in large scales in industries for power generation and food production. The utilization of these fuels causing huge environmental pollution liberating in the form of ashes. These ashes can be utilized in effective way for manufacturing and structural applications with their incorporation in polymer matrix composites. To enhance the mechanical properties and in reducing the manufacturing cost, these industrial wastes plays a major role. The present research work mainly focuses on the influence of Coal Fly Ash (CFA), Silicon Carbide (SiC) and a mixture of CFA & SiC as filler materials on the mechanical behavior of Epoxy Glass fiber composite. Various types of composites are fabricated by manual hand lay-up process with varying weight percentages of the filler materials and epoxy resin as matrix material. The filler materials weight proportions are taken as 5%, 10% and 15%. The prepared composites are cut into tests specimen as per the ASTM standards of mechanical characterization. The mechanical properties of the composites (like Tensile strength (ASTM D3039/D3039M: 2017), Flexural strength (ASTM D790: 2015), Impact strength (ASTM D 229 el: 2019), Interlaminar shear strength (ASTM D2240: 2015), Hardness (ASTM D2240: 2015)) are determined by using corresponding testing machines and it is observed that the properties exhibited by the composites are enhanced with the incorporation of CFA, SiC & mixture of CFA and SiC when compared with the unfilled composites. So, these composites are considered a multifunctional composite material where the individual fillers are used in some applications and the combined proportions are used in different applications. They replace the existing materials that are very high in cost and cause more pollution at the time of manufacturing. These composites give the ability to improve and increase the efficiency, autonomy, and life expectancy of a structure.

Dispersing small amounts of solid nano particles into base-fluid has a significant impact on the thermo-physical properties of the base-fluid. These properties are utilized for effective capture and transportation of solar energy. This paper attempts key idea for harvesting solar energy by using alumina nanofluid in concentrating parabolic trough collectors. An experimental study is carried out to investigate the performance of a parabolic trough collector using Al2O3-H2O based nanofluid. Results clearly indicate that at same ambient, inlet temperatures, flow rate, concentration ratio etc. hike in thermal efficiency is around 5-10 % compared to the conventional Parabolic Trough Collector (PTC). Further, the effect of various parameters such as concentration ratio, receiver length, fluid velocity, volume fraction of nano particles has been studied. The different flow rates employed in the experiment are 2 ml/s, 4 ml/s and 6 ml/s. Volumetric concentration of 0.02%, 0.04% and 0.06% has been studied in the experiment. Surfactants are not introduced to avoid bubble formation. Tracking mode of parabolic trough collector is manual. Results also reveal that Al2O3-H2O based nanofluid has higher efficiency at higher flow rates.

The purpose of thermal energy storage systems (TES) is to store the heat energy supplied to it for a considerable time period and give the energy back when ever need arise. On many of occasions, part of the heat energy of various systems is unutilized. If this excess heat energy be stored in such systems as TESS, utilization of energy improves. If the use of such systems is widespread, fuel is conserved and national economy is saved.Different materials can be used in TESS to store heat energy and in the present work two such materials, which are popular phase change materials (PCM) namely (a) Paraffin (b) Stearic acid are used and subsequently the performance of the TESS is studied. The PCMs are used in the form of spherical capsules made up of high density poly ethylene (HDPE) of diameter 58 mm. Charging time and amount of heat energy recovered are studied for the two PCMs mentioned above and compared. Though paraffin as PCM gives little better heat energy recovery, performance of both the materials are almost the same. Hence as the cost of stearic acid is less when compared to paraffin on economical grounds and on ease of availability basis stearic acid has advantages over paraffin.

Many clays in situ are lightly overconsolidated with overconsolidation ratio ranging between 1.0 and 4.0 due to various reasons. However, the conventional theories used for analysis of radial consolidation assume the soils to be normally consolidated. For lightly OC Clays, phase transition occurs from overconsolidated to normally consolidated state due to increase of effective stress beyond the preconsolidation stress during the consolidation process under external loading. This paper presents a comparison of the results of linear and non-linear theories of radial consolidation of lightly OC clays. The effects of overconsolidation ratio, stress increment ratio and recompression to virgin compression compressibility ratio are studied. While the pore pressure dissipation rate with time is relatively slower, the rate of change of degree of settlement is relatively faster in the case of non-linear theory compared to that in the linear theory of radial consolidation of lightly OC clays. The difference in the results of linear and non-linear theories is significant only in the intermediate stages of consolidation of lightly OC soils.

Unsteady magneto hydrodynamic (MHD) free convection flow of a viscous, incompressible and electrically conducting, well known non-Newtonian fluid named as Kuvshinski fluid past an infinite vertical porous plate in the presence of homogeneous chemical reaction, radiation absorption and heat source/sink is studied analytically. The plate is assumed to move with a constant velocity in the direction of fluid flow. A magnetic field of uniform strength is applied perpendicular to the plate, which absorbs the fluid with a suction that varies with time. The dimensionless governing equations are solved analytically using two terms harmonic and non-harmonic functions. The expressions for the fields of velocity, temperature and concentration are obtained. With the aid of these the expressions for skin friction, Nusselt number and Sherwood number are derived. The effects of various physical parameters on the flow quantities are studied through graphs and tables. For the validity, we have checked our results with previously published work and found in good agreement. Velocity decreases for an increase in visco elastic parameter α2, heat absorption coefficient φ, the chemical reaction parameter γ , the magnetic field parameter M, the Prandtl number Pr, the Schmidt number Sc, and increases for increase in Grashof number Gm, the radiation absorption parameter Q 1

The epithelium of the pulmonary airway is specially differentiated to provide defense against environmental insults, but also subject to dysregulated differentiation that results in lung disease. The current paradigm for airway epithelial differentiation is a one‐step program whereby a p63+basal epithelial progenitor cell generates a ciliated or secretory cell lineage, but the cue for this transition and whether there are intermediate steps are poorly defined. Here, we identify transcription factor Myb as a key regulator that permits early multilineage differentiation of airway epithelial cells. Myb+cells were identified as p63−and therefore distinct from basal progenitor cells, but were still negative for markers of differentiation. Myb RNAi treatment of primary‐culture airway epithelial cells and Mybgene deletion in mice resulted in a p63−population with failed maturation of Foxj1+ciliated cells as well as Scbg1a1+and Muc5ac+secretory cells. Consistent with these findings, analysis of whole genome expression of Myb‐deficient cells identified Myb‐dependent programs for ciliated and secretory cell differentiation. Myb+cells were rare in human airways but were increased in regions of ciliated cells and mucous cell hyperplasia in samples from subjects with chronic obstructive pulmonary disease. Together, the results show that a p63−Myb+population of airway epithelial cells represents a distinct intermediate stage of differentiation that is required under normal conditions and may be heightened in airway disease. StemCells2014;32:3245–3256

YBa2Cu3Oy(YBCO) foam samples show an open, porous foam structure, which may have benefits for many applications of high-Tcsuperconductors. As the basic material of these foams is a pseudo-single crystalline material with the directional growth initiated by a seed crystal similar to standard melt-textured samples, the texture of YBCO is a very important parameter. Therefore, we analysed the local texture and grain orientation of the individual struts forming the foam by means of atomic force microscopy (AFM) and electron backscatter diffraction (EBSD). Due to the processing route starting with Y2BaCuO5(211), a two-phase analysis must be performed, so a high surface quality is necessary to enable an automated EBSD scan. Good quality Kikuchi patterns were obtained from both the YBCO and 211 phases. We found an inhomogeneous distribution of the residual 211 particles, which are mainly randomly oriented and have sizes ranging between 200 nm and 15 μm. In contrast to this, the YBCO matrix shows a dominating orientation with cracks with a typical distance of 1–10 μm. Furthermore, the analysis of strut cross-sections reveals that the entire strut is converted to the YBCO phase.

To evaluate and compare retention and caries occurance following placement of Clinpro and FUJI VII fissure sealants, by two different techniques simultaneously in unsealed, contralateral young permanent molars of 7- to 10-year-old children affected by mild to moderate dental fluorosis at various recall intervals of 1 week, 1, 3, 6 and 12 months. 80 schoolchildren with mild to moderate dental fluorosis were assigned to Group A and Group B with 40 children in each group. In Group A Clinpro fissure sealant and in Group B Fuji VII fissure sealant was used. In both the groups fissure sealants were applied by conventional fissure sealant technique (CST) on one side and enameloplasty sealant technique (EST) on the other side of the same arch. The applied fissure sealants were evaluated clinically for retention and caries incidence. Clinpro fissure sealant showed a retention rate of 95% when compared with Fuji VII (57.5%) at the end of 12 months, which was statistically significant. Regarding techniques, EST showed better results than CST in both the groups. Comparison of groups with respect to retention and techniques at different time periods was performed using Mann–Whitney Utest (p< 0.05). Comparison of different time periods with respect to retention and technique in all the groups was performed using Wilcoxon matched pairs test by ranks (p< 0.05). Clinpro fissure sealant showed better retention at all treatment intervals, when compared with Fuji VII. Further follow-up is required to study the efficacy of the fissure sealant placement techniques.

A Correction to this paper has been published: https://doi.org/10.1038/s41388-020-01632-1

In the generation of the acutely transforming avian retrovirus E26, both myb and ets genes have been transduced, leading to the production of a Gag-Myb-Ets fusion protein. This co-occurrence of v-myb and v-ets oncogenes suggests that the two might have a functional relationship. To look for such a relationship, we tested the transcriptional activation activity of Myb alone or with coexpressed Ets-1 or Ets-2. Using the promoter of the v-Myb-inducible mim-1 gene as a target, we found that full-length c-Myb gene products were poor activators of transcription, while an oncogenic (truncated) form of this protein was a strong trans-activator. However, coexpression of Ets-2 with full-length or truncated forms of Myb greatly increased trans-activation. Coexpression of Ets-1, Fos, Jun, or Myc with Myb did not increase trans-activation of the mim-1 promoter. The ability of Myb and Ets-2 to transactivate was cooperative, since Ets-2 alone gave little or no activation. Bacterially synthesized Ets-2 protein was found to bind specifically to the mim-1 promoter, suggesting that it may be a target for both Myb and Ets proteins. Thus, Myb and Ets proteins can cooperate in transcriptional activation, and their co-occurrence in the E26 virus may reflect a functional relationship between these two oncoproteins. Truncated forms of Myb may have a reduced need for cooperating factors such as Ets-2, and this might constitute an important mechanism associated with oncogenic activation.

Seminalplasmin, an antibacterial protein present in bovine seminal plasma, is shown to be a potent inhibitor of reverse transcriptases (RNA-dependent DNA nucleotidyltransferases). Seminalplasmin inhibits RNA-directed, hybrid-directed, and DNA-directed DNA-polymerizing activities of purified reverse transcriptase from avian myeloblastosis virus and from crude viral lysates of several retroviruses by binding to the enzyme, at least in the case of avian myeloblastosis virus. Seminalplasmin does not inhibit significantly DNA synthesis either by Escherichia coli DNA polymerase I, or a mammalian alpha-DNA polymerase. The presence of seminalplasmin in the seminal fluid could provide protection to the male and/or the female reproductive tract against retroviruses.

BackgroundMyelodysplastic Syndrome (MDS) is characterized by ineffective clonal hematopoiesis with peripheral blood cytopenias, leading to death from infection or bleeding. Azacitidine (AZA), a hypomethylating agent (HMA) is the standard of care for treatment of MDS patients (pts) with higher-risk MDS [Silverman LR, The Myelodysplastic Syndrome in Cancer Medicine, Editors: R.J. Bast, et al. 2017]. Responses to AZA occur in 50% of pts with significant effects on hematopoiesis ranging from improvement in a single lineage to complete restoration of blood counts and transfusion independence [Silverman LR, et al. Leukemia, 1993]. AZA treatment is associated with global DNA hypomethylation, including human endogenous retroviruses (HEV) which further activates innate immune signaling [Chiappinelli KB, et al.Cell, 2015]. The exact mechanism by which AZA improves hematopoiesis is unknown. AZA improves overall survival of pts, yet despite this, 100% of pts ultimately fail treatment with worsening cytopenias or transformation to leukemia [Silverman LR, et al. B. J Clin Oncol, 2002; Cancer, 2011]. Thus, understanding the mechanism of resistance and identification of targets which can reverse HMA failure and improve hematopoiesis in MDS pts is critical. Our clinical data demonstrate that AZA combined with Rigosertib (RIGO), a novel Ras mimetic that inhibits Ras/Raf signaling [Athuluri-Divakar SK, et al.Cell, 2016], yields a response rate of 54% of pts who were HMA failures [Navada SC, et al. EHA 2019]. The response was associated with significant improvement in hematopoiesis and represents a critical observation in overcoming the epigenetic clinical resistance phenotype. The precise mechanism that leads to reversal of the resistance phenotype is poorly understood.

Navada: Onconova Therapeutics Inc: Research Funding. Reddy:Onconova Therapeutics Inc: Research Funding. Silverman:Celgene: Research Funding; Medimmune: Research Funding; Onconova Therapeutics Inc: Patents & Royalties, Research Funding.

ABSTRACTBlood-stage malaria vaccines that target single Plasmodium falciparumantigens involved in erythrocyte invasion have not induced optimal protection in field trials. Blood-stage malaria vaccine development has faced two major hurdles, antigenic polymorphisms and molecular redundancy, which have led to an inability to demonstrate potent, strain-transcending, invasion-inhibitory antibodies. Vaccines that target multiple invasion-related parasite proteins may inhibit erythrocyte invasion more efficiently. Our approach is to develop a receptor-blocking blood-stage vaccine against P. falciparumthat targets the erythrocyte binding domains of multiple parasite adhesins, blocking their interaction with their receptors and thus inhibiting erythrocyte invasion. However, with numerous invasion ligands, the challenge is to identify combinations that elicit potent strain-transcending invasion inhibition. We evaluated the invasion-inhibitory activities of 20 different triple combinations of antibodies mixed in vitroagainst a diverse set of six key merozoite ligands, including the novel ligands P. falciparumapical asparagine-rich protein (PfAARP), EBA-175 (PfF2), P. falciparumreticulocyte binding-like homologous protein 1 (PfRH1), PfRH2, PfRH4, and Plasmodiumthrombospondin apical merozoite protein (PTRAMP), which are localized in different apical organelles and are translocated to the merozoite surface at different time points during invasion. They bind erythrocytes with different specificities and are thus involved in distinct invasion pathways. The antibody combination of EBA-175 (PfF2), PfRH2, and PfAARP produced the most efficacious strain-transcending inhibition of erythrocyte invasion against diverse P. falciparumclones. This potent antigen combination was selected for coimmunization as a mixture that induced balanced antibody responses against each antigen and inhibited erythrocyte invasion efficiently. We have thus demonstrated a novel two-step screening approach to identify a potent antigen combination that elicits strong strain-transcending invasion inhibition, supporting its development as a receptor-blocking malaria vaccine.

The cell cycle is regulated in part by cyclins and their associated serine/threonine cyclin-dependent kinases, or CDKs. CDK4, in conjunction with the D-type cyclins, mediates progression through the G1phase when the cell prepares to initiate DNA synthesis. Although CDK4-null mutant mice are viable and cell proliferation is not significantly affected in vitrodue to compensatory roles played by other CDKs, this gene plays a key role in mammalian development and cancer. This review discusses the role that CDK4 plays in cell cycle control, normal development, and tumorigenesis as well as how small molecule inhibitors of CDK4 can be used to treat disease.

Hematopoietic stem and progenitor cells are often undesired targets of chemotherapies, leading to hematopoietic suppression requiring careful clinical management. Whether microRNAs control hematopoietic injury response is largely unknown. We report an in vivo gain-of-function screen and the identification of miR-150 as an inhibitor of hematopoietic recovery upon 5-fluorouracil-induced injury. Utilizing a bone marrow transplant model with a barcoded microRNA library, we screened for barcode abundance in peripheral blood of recipient mice before and after 5-fluorouracil treatment. Overexpression of screen-candidate miR-150 resulted in significantly slowed recovery rates across major blood lineages, with associated impairment of bone marrow clonogenic potential. Conversely, platelets and myeloid cells from miR-150 null marrow recovered faster after 5-fluorouracil treatment. Heterozygous knockout of c-myb, a conserved target of miR-150, partially phenocopied miR-150-forced expression. Our data highlight the role of microRNAs in controlling hematopoietic injury response and demonstrate the power of in vivo functional screens for studying microRNAs in normal tissue physiology.

The differentiation of myeloid progenitors to mature, terminally differentiated cells is a highly regulated process. Here, we showed that conditional disruption of the c-mybproto-oncogene in adult mice resulted in dramatic reductions in CMP, GMP and MEP myeloid progenitors, leading to a reduction of neutrophils, basophils, monocytes and platelets in peripheral blood. In addition, c-mybplays a critical role at multiple stages of myeloid development, from multipotent CMP and bipotent GMP to unipotent CFU-G and CFU-M progenitor cells. c-mybcontrols the differentiation of these cells and is required for the proper commitment, maturation and normal differentiation of CMPs and GMPs. Specifically, c-mybregulates the precise commitment to the megakaryocytic and granulo-monocytic pathways and governs the granulocytic-monocytic lineage choice. c-mybis also required for the commitment along the granulocytic pathway for early myeloid progenitor cells and for the maturation of committed precursor cells along this pathway. On the other hand, disruption of the c-mybgene favors the commitment to the monocytic lineage, although monocytic development was abnormal with cells appearing more mature with atypical CD41 surface markers. These results demonstrate that c-mybplays a pivotal role in the regulation of multiple stages in adult myelogenesis.

The development of inhibitors against Abl has changed the landscape for the treatment of chronic myelogenous leukemia (CML) and cancer in general. Beginning with the monumental discovery and approval of imatinib for CML, a second generation of inhibitors, nilotinib and dasatinib, has now gained approval for the treatment of CML. Notably, these second-generation inhibitors are active against many of the mutations in the Abl kinase that confer resistance to imatinib. However, resistance remains a major problem, and new inhibitors such as ponatinib and GNF2/GNF5 have been developed, with activity towards the common gatekeeper T315I mutation. We review here the mechanisms of Abl inhibition with an emphasis on structural elements that are important for the selectivity and design of new molecules. In particular, we focus on how changes in the conformation of the P-loop, the activation loop, the DFG motif, and other structural elements of Abl have been instrumental in developing an understanding of inhibitor binding.

Seven exclosure sites located on Mauna Kea, Hawaii and established in the 1960s and 70s were sampled to characterize long-term response of the mamane (Sophora chrysophylla) forest to protection from feral sheep grazing, and to assess impacts of non-native plant species and recurrent sheep presence on forest recovery. The forest provides essential habitat for an endangered bird, the palila (Loxoides bailleui). Vegetation was sampled inside exclosures during 1972–1976, 1998, and 2009, and also outside exclosures during 2009. Patterns of response varied among exclosures, but overall, mamane trees and native shrubs showed increasing cover between the 1970s and 1998, then a slowed rate of increase in cover or a decline between 1998 and 2009. Cover of native herbaceous vegetation showed variable trends between the 1970s and 1998, and then appeared to decline between 1998 and 2009. Mamane height class distributions inside exclosures indicated that recruitment was initially high but then declined as heights shifted toward larger size classes, and presumably an older age distribution. We found limited evidence of a negative effect of non-native species on forest regrowth, but the effect was not consistent over time or among sites. Recurrent sheep presence outside exclosures negatively affected mamane canopy density and perhaps tree density at all sites, and mamane condition at some sites. Our results indicate that the mamane forest has shown substantial regrowth inside exclosures at some sites, especially those protected the longest. However, these exclosures represent a small portion of the mamane forest. Sheep presence continues to impact mamane recovery outside exclosures, and thus habitat quality for the palila.

Although transplant centers are required to educate patients about kidney transplantation (KT) and living donation (LD), little is known about the educational format, and cultural and linguistic competence necessary for patients to make informed treatment decisions. This study surveyed US transplant administrators about education provided concerning KT and LD and culturally and linguistically competent care. Transplant administrators were invited to participate in an anonymous Internet‐based survey about education format, education providers, promoting LD, culturally and linguistically competent care and center characteristics. Most (61%) transplant administrators contacted (N = 280/461) completed the survey. Most administrators (91%) reported that their center provides any type of formal education in their pre‐KT evaluation. Education was mostly provided by: nurses (97%), social workers (72%) and surgeons (55%), and predominantly as one‐on‐one (80%) versus group discussions (60%). Education was primarily delivered through written materials (93%). Written educational materials in Spanish (86%) and the provision of interpreters (82%) were emphasized over educational sessions in Spanish (39%), or employing bilingual (51%) and bicultural staff (39%). Half (55%) promoted LD as the best option. Transplant centers need to take greater efforts to consistently provide appropriate education, promote LD, and provide culturally and linguistically competent care to ensure effective communication with all patients.

Although transplant centers are required to educate patients about kidney transplantation (KT) and living donation (LD), little is known about the educational format, and cultural and linguistic competence necessary for patients to make informed treatment decisions. This study surveyed US transplant administrators about education provided concerning KT and LD and culturally and linguistically competent care. Transplant administrators were invited to participate in an anonymous Internet-based survey about education format, education providers, promoting LD, culturally and linguistically competent care and center characteristics. Most (61%) transplant administrators contacted (N = 280/461) completed the survey. Most administrators (91%) reported that their center provides any type of formal education in their pre-KT evaluation. Education was mostly provided by: nurses (97%), social workers (72%) and surgeons (55%), and predominantly as one-on-one (80%) versus group discussions (60%). Education was primarily delivered through written materials (93%). Written educational materials in Spanish (86%) and the provision of interpreters (82%) were emphasized over educational sessions in Spanish (39%), or employing bilingual (51%) and bicultural staff (39%). Half (55%) promoted LD as the best option. Transplant centers need to take greater efforts to consistently provide appropriate education, promote LD, and provide culturally and linguistically competent care to ensure effective communication with all patients.

Hematopoiesis is the cumulative result of intricately regulated signaling pathways that are mediated by cytokines and their receptors. Studies conducted over the past 10 to 15 years have revealed that hematopoietic cytokine receptor signaling is largely mediated by a family of tyrosine kinases termed Janus kinases (JAKs) and their downstream transcription factors, termed STATs (signal transducers and activators of transcription). Aberrations in these pathways, such as those caused by the recently identified JAK2V617Fmutation and translocations of the JAK2 gene, are underlying causes of leukemias and other myeloproliferative disorders. This review discusses the role of JAK/STAT signaling in normal hematopoiesis as well as genetic abnormalities associated with myeloproliferative and myelodisplastic syndromes. This review also summarizes the status of several small molecule JAK2 inhibitors that are currently at various stages of clinical development. Several of these compounds appear to improve the quality of life of patients with myeloproliferative disorders by palliation of disease-related symptoms. However, to date, these agents do not seem to significantly affect bone marrow fibrosis, alter marrow histopathology, reverse cytopenias, reduce red cell transfusion requirements, or significantly reduce allele burden. These results suggest the possibility that additional mutational events might be associated with the development of these neoplasms, and indicate the need for combination therapies as the nature and significance of these additional molecular events is better understood.

The importance of the CDK4 protein in human cancer first became evident following the identification of a germ line mutation in the Cdk4locus that predisposes humans to melanoma.  This mutation results in substitution of arginine with cysteine at position 24 (R24C).  In an earlier study, we introduced the R24C mutation into the Cdk4 locus of mice using Cre-loxP-mediated "knock-in" technology and observed a very low incidence of spontaneous melanomas in Cdk4R24C/R24C mice.  This suggested that additional oncogenic mutations might be required for development of melanomas.  Here we report an increased incidence of spontaneous cutaneous melanoma in mice expressing the oncogene HRAS(G12V) in melanocytes on a Cdk4R24Cbackground.  Treatment of Tyr-HRas:Cdk4R24C/R24C mice with the carcinogen, DMBA/TPA resulted in a further increase in the number of nevi and melanomas developed when compared with Tyr-HRas:Cdk4+/+ mice.  In summary, in Tyr-HRas:Cdk4R24C/R24Cmice, we observed that activated CDK4 cooperates with the oncogenic HRAS(G12V)protein to increase the susceptibility of melanoma development in vivo.

Cyclin dependent kinase 4 (Cdk4) is a cell cycle regulator involved in early G1 cell cycle progression and has been indirectly implicated in angiogenesis in the Min mouse system, a mouse that harbors a mutation in the Apc gene. Apc+/Minmice when crossed with Ink4a/arf-/-mice, exhibited increased angiogenesis of colorectal tumors suggesting that dysregulation of Cdk4 (due to loss of Ink4a-mediated suppression) may contribute to enhanced angiogenesis. To demonstrate a direct role for Cdk4 in angiogenesis, we crossed mice that have an activated Cdk4, Cdk4R24C/R24Cmice, with Apc+/Minmice and examined levels of angiogenesis in intestinal tumors formed. Our results show an increase in the percentage of highly vascularized tumors in Cdk4R24C/R24C:ApcMin/+and Cdk4+/R24C:ApcMin/+mice compared to Cdk4+/+:ApcMin/+mice. In addition immunohistochemical analysis showed an increase in CD-31 staining localized to endothelial cells of Cdk4R24C/R24C:ApcMin/+mouse tumors, supporting the hypothesis of increased vasculature in these tumors. Further analysis showed an increase in the expression of the E2F1 target proteins Vegf-b and Cyclin A in Cdk4R24C/R24C:Apc+/Min intestinal tumors. Together these data suggest that the dysregulated Cdk4 gene plays an important role in angiogenesis during intestinal tumor formation and may in part act via increasing E2F1 target proteins. This is the first report to show that Cdk4 has a direct role in angiogenesis in vivo and may be an important drug target to reduce or prevent angiogenesis during intestinal tumor formation.

Here we report the discovery of ON044580, an a-benzoyl styryl benzyl sulfide that possesses potent inhibitory activity against two unrelated kinases, JAK2 and BCR-ABL, and exhibits cytotoxicity to human tumor cells derived from chronic myelogenous leukemia (CML) and myelodysplasia (MDS) patients or cells harboring a mutant JAK2 kinase. This novel spectrum of activity is explained by the non–ATP-competitive inhibition of JAK2 and BCR-ABL kinases. ON044580 inhibits mutant JAK2 kinase and the proliferation of JAK2V617F-positive leukemic cells and blocks the IL-3–mediated phosphorylation of JAK2 and STAT5. Interestingly, this compound also directly inhibits the kinase activity of both wild-type and imatinib-resistant (T315I) forms of the BCR-ABL kinase. Finally, ON044580 effectively induces apoptosis of imatinib-resistant CML patient cells. The apparently unrelated JAK2 and BCR-ABL kinases share a common substrate, STAT5, and such substrate competitive inhibitors represent an alternative therapeutic strategy for development of new inhibitors. The novel mechanism of kinase inhibition exhibited by ON044580 renders it effective against mutant forms of kinases such as the BCR-ABLT315Iand JAK2V617F. Importantly, ON044580 selectively reduces the number of aneuploid cells in primary bone marrow samples from monosomy 7 MDS patients, suggesting another regulatory cascade amenable to this agent in these aberrant cells. Data presented suggest that this compound could have multiple therapeutic applications including monosomy 7 MDS, imatinib-resistant CML, and myeloproliferative neoplasms that develop resistance to ATP-competitive agents.