A high-content, multiplexed screen in human breast cancer cells identifies profilin-1 inducers with anti-migratory activities

Profilin-1 (Pfn-1) is a ubiquitously expressed actin-binding protein that is essential for normal cell proliferation and migration. In breast cancer and several other adenocarcinomas, Pfn-1 expression is downregulated when compared to normal tissues. Previous studies from our laboratory have shown that genetically modulating Pfn-1 expression significantly impacts proliferation, migration, and invasion of breast cancer cells in vitro, and mammary tumor growth, dissemination, and metastatic colonization in vivo. Therefore, small molecules that can modulate Pfn-1 expression could have therapeutic potential in the treatment of metastatic breast cancer. The overall goal of this study was to perform a multiplexed phenotypic screen to identify compounds that inhibit cell motility through upregulation of Pfn-1. Screening of a test cassette of 1280 compounds with known biological activities on an Oris™ Pro 384 cell migration platform identified several agents that increased Pfn-1 expression greater than two-fold over vehicle controls and exerted anti-migratory effects in the absence of overt cytotoxicity in MDA-MB-231 human breast cancer cells. Concentration-response confirmation and orthogonal follow-up assays identified two bona fide inducers of Pfn-1, purvalanol and tyrphostin A9, that confirmed in single-cell motility assays and Western blot analyses. SiRNA-mediated knockdown of Pfn-1 abrogated the inhibitory effect of tyrphostin A9 on cell migration, suggesting Pfn-1 is mechanistically linked to tyrphostin A9's anti-migratory activity. The data illustrate the utility of the high-content cell motility assay to discover novel targeted anti-migratory agents by integrating functional phenotypic analyses with target-specific readouts in a single assay platform. © 2014 Joy et al

Skin Lesion Analyser: An Efficient Seven-Way Multi-Class Skin Cancer Classification Using MobileNet

Skin cancer, a major form of cancer, is a critical public health problem with 123,000 newly diagnosed melanoma cases and between 2 and 3 million non-melanoma cases worldwide each year. The leading cause of skin cancer is high exposure of skin cells to UV radiation, which can damage the DNA inside skin cells leading to uncontrolled growth of skin cells. Skin cancer is primarily diagnosed visually employing clinical screening, a biopsy, dermoscopic analysis, and histopathological examination. It has been demonstrated that the dermoscopic analysis in the hands of inexperienced dermatologists may cause a reduction in diagnostic accuracy. Early detection and screening of skin cancer have the potential to reduce mortality and morbidity. Previous studies have shown Deep Learning ability to perform better than human experts in several visual recognition tasks. In this paper, we propose an efficient seven-way automated multi-class skin cancer classification system having performance comparable with expert dermatologists. We used a pretrained MobileNet model to train over HAM10000 dataset using transfer learning. The model classifies skin lesion image with a categorical accuracy of 83.1 percent, top2 accuracy of 91.36 percent and top3 accuracy of 95.34 percent. The weighted average of precision, recall, and f1-score were found to be 0.89, 0.83, and 0.83 respectively. The model has been deployed as a web application for public use at (https://saketchaturvedi.github.io). This fast, expansible method holds the potential for substantial clinical impact, including broadening the scope of primary care practice and augmenting clinical decision-making for dermatology specialists.Comment: This is a pre-copyedited version of a contribution published in Advances in Intelligent Systems and Computing, Hassanien A., Bhatnagar R., Darwish A. (eds) published by Chaturvedi S.S., Gupta K., Prasad P.S. The definitive authentication version is available online via https://doi.org/10.1007/978-981-15-3383-9_1

Identifying and quantifying heterogeneity in high content analysis: Application of heterogeneity indices to drug discovery

One of the greatest challenges in biomedical research, drug discovery and diagnostics is understanding how seemingly identical cells can respond differently to perturbagens including drugs for disease treatment. Although heterogeneity has become an accepted characteristic of a population of cells, in drug discovery it is not routinely evaluated or reported. The standard practice for cell-based, high content assays has been to assume a normal distribution and to report a well-to-well average value with a standard deviation. To address this important issue we sought to define a method that could be readily implemented to identify, quantify and characterize heterogeneity in cellular and small organism assays to guide decisions during drug discovery and experimental cell/tissue profiling. Our study revealed that heterogeneity can be effectively identified and quantified with three indices that indicate diversity, non-normality and percent outliers. The indices were evaluated using the induction and inhibition of STAT3 activation in five cell lines where the systems response including sample preparation and instrument performance were well characterized and controlled. These heterogeneity indices provide a standardized method that can easily be integrated into small and large scale screening or profiling projects to guide interpretation of the biology, as well as the development of therapeutics and diagnostics. Understanding the heterogeneity in the response to perturbagens will become a critical factor in designing strategies for the development of therapeutics including targeted polypharmacology. © 2014 Gough et al

Evolution of a Novel Appendage Ground Plan in Water Striders Is Driven by Changes in the Hox Gene Ultrabithorax

Water striders, a group of semi-aquatic bugs adapted to life on the water surface, have evolved mid-legs (L2) that are long relative to their hind-legs (L3). This novel appendage ground plan is a derived feature among insects, where L2 function as oars and L3 as rudders. The Hox gene Ultrabithorax (Ubx) is known to increase appendage size in a variety of insects. Using gene expression and RNAi analysis, we discovered that Ubx is expressed in both L2 and L3, but Ubx functions to elongate L2 and to shorten L3 in the water strider Gerris buenoi. Therefore, within hemimetabolous insects, Ubx has evolved a new expression domain but maintained its ancestral elongating function in L2, whereas Ubx has maintained its ancestral expression domain but evolved a new shortening function in L3. These changes in Ubx expression and function may have been a key event in the evolution of the distinct appendage ground plan in water striders

A Variational Method in Out of Equilibrium Physical Systems

A variational principle is further developed for out of equilibrium dynamical systems by using the concept of maximum entropy. With this new formulation it is obtained a set of two first-order differential equations, revealing the same formal symplectic structure shared by classical mechanics, fluid mechanics and thermodynamics. In particular, it is obtained an extended equation of motion for a rotating dynamical system, from where it emerges a kind of topological torsion current of the form $\epsilon_{ijk} A_j \omega_k$, with $A_j$ and $\omega_k$ denoting components of the vector potential (gravitational or/and electromagnetic) and $\omega$ is the angular velocity of the accelerated frame. In addition, it is derived a special form of Umov-Poynting's theorem for rotating gravito-electromagnetic systems, and obtained a general condition of equilibrium for a rotating plasma. The variational method is then applied to clarify the working mechanism of some particular devices, such as the Bennett pinch and vacuum arcs, to calculate the power extraction from an hurricane, and to discuss the effect of transport angular momentum on the radiactive heating of planetary atmospheres. This development is seen to be advantageous and opens options for systematic improvements.Comment: 22 pages, 1 figure, submitted to review, added one referenc

A single sub-km Kuiper Belt object from a stellar Occultation in archival data

The Kuiper belt is a remnant of the primordial Solar System. Measurements of its size distribution constrain its accretion and collisional history, and the importance of material strength of Kuiper belt objects (KBOs). Small, sub-km sized, KBOs elude direct detection, but the signature of their occultations of background stars should be detectable. Observations at both optical and X-ray wavelengths claim to have detected such occultations, but their implied KBO abundances are inconsistent with each other and far exceed theoretical expectations. Here, we report an analysis of archival data that reveals an occultation by a body with a 500 m radius at a distance of 45 AU. The probability of this event to occur due to random statistical fluctuations within our data set is about 2%. Our survey yields a surface density of KBOs with radii larger than 250 m of 2.1^{+4.8}_{-1.7} x 10^7 deg^{-2}, ruling out inferred surface densities from previous claimed detections by more than 5 sigma. The fact that we detected only one event, firmly shows a deficit of sub-km sized KBOs compared to a population extrapolated from objects with r>50 km. This implies that sub-km sized KBOs are undergoing collisional erosion, just like debris disks observed around other stars.Comment: To appear in Nature on December 17, 2009. Under press embargo until 1800 hours London time on 16 December. 19 pages; 7 figure

The sensory feedback mechanisms enabling couples to walk synchronously: An initial investigation

The inattentive eye often will not notice it, but synchronization among human walking partners is quite common. In this first investigation of this phenomenon, we studied its frequency and the mechanisms that contribute to this form of "entrainment." Specifically, by modifying the available communication links between two walking partners, we isolated the feedback mechanisms that enable couples to synchronize their stepping pattern when they walk side-by-side. Although subjects were unaware of the research aims and were not specifically asked to walk in synchrony, we observed synchronized walking in almost 50% of the walking trials, among couples who do not usually walk together. The strongest in-phase synchrony occurred in the presence of tactile feedback (i.e., handholding), perhaps because of lower and upper extremity coupling driven in part by arm swing. Interestingly, however, even in the absence of visual or auditory communication, couples also frequently walked in synchrony while 180 degrees out-of-phase, likely using different feedback mechanisms. These findings may partially explain how patients with certain gait disorders and disturbed rhythm enhance their gait when they walk with a partner and suggest alternative interventions that might improve the stepping pattern. Further, this preliminary investigation highlights the relatively ubiquitous nature of an interesting phenomenon that has not previously been studied and suggests that further work is needed to better understand the mechanisms that entrain the gait of two walking partners and allows couples to walk in synchrony with minimal or no conscious effort

Constraining noncommutative field theories with holography

An important window to quantum gravity phenomena in low energy noncommutative (NC) quantum field theories (QFTs) gets represented by a specific form of UV/IR mixing. Yet another important window to quantum gravity, a holography, manifests itself in effective QFTs as a distinct UV/IR connection. In matching these two principles, a useful relationship connecting the UV cutoff $\Lambda_{\rm UV}$, the IR cutoff $\Lambda_{\rm IR}$ and the scale of noncommutativity $\Lambda_{\rm NC}$, can be obtained. We show that an effective QFT endowed with both principles may not be capable to fit disparate experimental bounds simultaneously, like the muon $g-2$ and the masslessness of the photon. Also, the constraints from the muon $g-2$ preclude any possibility to observe the birefringence of the vacuum coming from objects at cosmological distances. On the other hand, in NC theories without the UV completion, where the perturbative aspect of the theory (obtained by truncating a power series in $\Lambda_{\rm NC}^{-2}$) becomes important, a heuristic estimate of the region where the perturbative expansion is well-defined $E/ \Lambda_{\rm NC} \lesssim 1$, gets affected when holography is applied by providing the energy of the system $E$ a $\Lambda_{\rm NC}$-dependent lower limit. This may affect models which try to infer the scale $\Lambda_{\rm NC}$ by using data from low-energy experiments.Comment: 4 pages, version to be published in JHE

Meson-meson Scattering in QCD-like Theories

We discuss meson-meson scattering at next-to-next-to-leading order in the chiral expansion for QCD-like theories with general $n$ degenerate flavours for the cases with a complex, real and pseudo-real representation. I.e. with global symmetry and breaking pattern $SU(n)_L\times SU(n)_R\to SU(n)_V$, $SU(2n)\to SO(2n)$ and $SU(2n)\to Sp(2n)$. We obtain fully analytical expressions for all these cases. We discuss the general structure of the amplitude and the structure of the possible intermediate channels for all three cases. We derive the expressions for the lowest partial wave scattering length in each channel and present some representative numerical results. We also show various relations between the different cases in the limit of large $n$.Comment: 61 page

Pressure balance in the multiphase ISM of cosmologically simulated disc galaxies

Pressure balance plays a central role in models of the interstellar medium (ISM), but whether and how pressure balance is realized in a realistic multiphase ISM is not yet well understood. We address this question by using a set of FIRE-2 cosmological zoom-in simulations of Milky Way-mass disc galaxies, in which a multiphase ISM is self-consistently shaped by gravity, cooling, and stellar feedback. We analyse how gravity determines the vertical pressure profile as well as how the total ISM pressure is partitioned between different phases and components (thermal, dispersion/turbulence, and bulk flows). We show that, on average and consistent with previous more idealized simulations, the total ISM pressure balances the weight of the overlying gas. Deviations from vertical pressure balance increase with increasing galactocentric radius and with decreasing averaging scale. The different phases are in rough total pressure equilibrium with one another, but with large deviations from thermal pressure equilibrium owing to kinetic support in the cold and warm phases, which dominate the total pressure near the mid-plane. Bulk flows (e.g. inflows and fountains) are important at a few disc scale heights, while thermal pressure from hot gas dominates at larger heights. Overall, the total mid-plane pressure is well-predicted by the weight of the disc gas and we show that it also scales linearly with the star formation rate surface density (ςSFR). These results support the notion that the Kennicutt-Schmidt relation arises because ςSFR and the gas surface density (ςg) are connected via the ISM mid-plane pressure