Potency and pharmacokinetics of broad spectrum and isoform-specific p110 gamma and delta inhibitors in cancers

Emerging data on cancer suggesting that target-based therapy is promising strategy in cancer treatment. PI3K-AKT pathway is extensively studied in many cancers; several inhibitors target this pathway in different levels. Recent finding on this pathway uncovered the therapeutic applications of PI3K-specific inhibitors; PI3K, AKT, and mTORC broad spectrum inhibitors. Noticeably, class I PI3K isoforms, p110 and p110 catalytic subunits have rational therapeutic application than other isoforms. Therefore, three classes of inhibitors: isoform-specific, dual-specific and broad spectrum were selected for molecular docking and dynamics. First, p110 structure was modelled; active site was analyzed. Then, molecular docking of each class of inhibitors were studied; the docked complexes were further used in 1.2ns molecular dynamics simulation to report the potency of each class of inhibitor. Remarkably, both the studies retained the similar kind of protein ligand interactions. GDC-0941, XL-147 (broad spectrum); TG100-115 (dual-specific); and AS-252424, PIK-294 (isoform-specific) were found to be potential inhibitors of p110 and p110, respectively. In addition to that pharmacokinetic properties are within recommended ranges. Finally, molecular phylogeny revealed that p110 and p110 are evolutionarily divergent; they probably need separate strategies for drug development.

Elucidating the cancer-specific genetic alteration spectrum of glioblastoma derived cell lines from whole exome and RNA sequencing

Cell lines derived from tumor tissues have been used as a valuable system to study gene regulation and cancer development. Comprehensive characterization of the genetic background of cell lines could provide clues on novel genes responsible for carcinogenesis and help in choosing cell lines for particular studies. Here, we have carried out whole exome and RNA sequencing of commonly used glioblastoma (GBM) cell lines (U87, T98G, LN229, U343, U373 and LN18) to unearth single nucleotide variations (SNVs), indels, differential gene expression, gene fusions and RNA editing events. We obtained an average of 41,071 SNVs out of which 1,594 (3.88%) were potentially cancer-specific. The cell lines showed frequent SNVs and indels in some of the genes that are known to be altered in GBM-EGFR, TP53, PTEN, SPTA1 and NF1. Chromatin modifying genes-ATRX, MLL3, MLL4, SETD2 and SRCAP also showed alterations. While no cell line carried IDH1 mutations, five cell lines showed hTERT promoter activating mutations with a concomitant increase in hTERT transcript levels. Five significant gene fusions were found of which NUP93-CYB5B was validated. An average of 18,949 RNA editing events was also obtained. Thus we have generated a comprehensive catalogue of genetic alterations for six GBM cell lines.

Elucidating the cancer-specific genetic alteration spectrum of glioblastoma derived cell lines from whole exome and RNA sequencing

Cell lines derived from tumor tissues have been used as a valuable system to study gene regulation and cancer development. Comprehensive characterization of the genetic background of cell lines could provide clues on novel genes responsible for carcinogenesis and help in choosing cell lines for particular studies. Here, we have carried out whole exome and RNA sequencing of commonly used glioblastoma (GBM) cell lines (U87, T98G, LN229, U343, U373 and LN18) to unearth single nucleotide variations (SNVs), indels, differential gene expression, gene fusions and RNA editing events. We obtained an average of 41,071 SNVs out of which 1,594 (3.88%) were potentially cancer-specific. The cell lines showed frequent SNVs and indels in some of the genes that are known to be altered in GBM-EGFR, TP53, PTEN, SPTA1 and NF1. Chromatin modifying genes-ATRX, MLL3, MLL4, SETD2 and SRCAP also showed alterations. While no cell line carried IDH1 mutations, five cell lines showed hTERT promoter activating mutations with a concomitant increase in hTERT transcript levels. Five significant gene fusions were found of which NUP93-CYB5B was validated. An average of 18,949 RNA editing events was also obtained. Thus we have generated a comprehensive catalogue of genetic alterations for six GBM cell lines.

Size and temperature dependence of the photoluminescence properties of NIR emitting ternary alloyed mercury cadmium telluride quantum dots

Exciton-phonon coupling and nonradiative relaxation processes have been investigated in near-infrared (NIR) emitting ternary alloyed mercury cadmium telluride (CdHgTe) quantum dots. Organically capped CdHgTe nanocrystals of sizes varying from 2.5-4.2 nm have been synthesized where emission is in the NIR region of 650-855 nm. Temperature-dependent (15-300 K) photoluminescence (PL) and the decay dynamics of PL at 300 K have been studied to understand the photophysical properties. The PL decay kinetics shows the transition from triexponential to biexponential on increasing the size of the quantom dots (QDs), informing the change in the distribution of the emitting states. The energy gap is found to be following the Varshni relation with a temperature coefficient of 2.1-2.8 x 10(-4) eV K-1. The strength of the electron-phonon coupling, which is reflected in the Huang and Rhys factor S, is found in the range of 1.17-1.68 for QDs with a size of 2.5-4.2 nm. The integrated PL intensity is nearly constant until 50 K, and slowly decreases up to 140 K, beyond which it decreases at a faster rate. The mechanism for PL quenching with temperature is attributed to the presence of nonradiative relaxation channels, where the excited carriers are thermally stimulated to the surface defect/trap states. At temperatures of different region (<140 K and 140-300 K), traps of low (13-25 meV) and high (65-140 meV) activation energies seem to be controlling the quenching of the PL emission. The broadening of emission linewidth is found to due to exciton-acoustic phonon scattering and exciton-longitudinal optical (LO) phonon coupling. The exciton-acoustic phonon scattering coefficient is found to be enhanced up to 55 MU eV K-1 due to a stronger confinement effect. These findings give insight into understanding the photophysical properties of CdHgTe QDs and pave the way for their possible applications in the fields of NIR photodetectors and other optoelectronic devices.

Observation of Size-Dependent Electron-Phonon Scattering and Temperature-Dependent Photoluminescence Quenching in Triangular-Shaped Silver Nanoparticles

Research studies on plasmonic properties of triangular-shaped silver nanoparticles might lead to several interesting applications. However, in this work, triangular-shaped silver nanoparticles have been synthesized by simple solvothermal technique and reported the effect of size on the electron-phonon scattering in the synthesized materials by analyzing their temperature-dependent photoluminescence (PL) emission characteristics. It has been observed that total integrated PL emission intensity is quenched by 33 % with the increase in temperature from 278 to 323 K. The observed decrease in PL emission intensity has been ascribed to the increase of electron-phonon scattering rate with the increase in temperature. The values of electron-phonon coupling strength (S) for synthesized samples have been evaluated by theoretical fitting of the experimentally obtained PL emission data. Smaller sized triangular nanoparticle has been found to exhibit stronger temperature dependence in PL emission, which strongly suggests that smaller sized triangular silver nanostructures have better electron-phonon coupling.

Time-Instant Sampling Based Encoding of Time-Varying Acoustic Spectrum

The inner ear has been shown to characterize an acoustic stimuli by transducing fluid motion in the inner ear to mechanical bending of stereocilia on the inner hair cells (IHCs). The excitation motion/energy transferred to an IHC is dependent on the frequency spectrum of the acoustic stimuli, and the spatial location of the IHC along the length of the basilar membrane (BM). Subsequently, the afferent auditory nerve fiber (ANF) bundle samples the encoded waveform in the IHCs by synapsing with them. In this work we focus on sampling of information by afferent ANFs from the IHCs, and show computationally that sampling at specific time instants is sufficient for decoding of time-varying acoustic spectrum embedded in the acoustic stimuli. The approach is based on sampling the signal at its zero-crossings and higher-order derivative zero-crossings. We show results of the approach on time-varying acoustic spectrum estimation from cricket call signal recording. The framework gives a time-domain and non-spatial processing perspective to auditory signal processing. The approach works on the full band signal, and is devoid of modeling any bandpass filtering mimicking the BM action. Instead, we motivate the approach from the perspective of event-triggered sampling by afferent ANFs on the stimuli encoded in the IHCs. Though the approach gives acoustic spectrum estimation but it is shallow on its complete understanding for plausible bio-mechanical replication with current mammalian auditory mechanics insights.

Comparison of Matching Pursuit Algorithm with Other Signal Processing Techniques for Computation of the Time-Frequency Power Spectrum of Brain Signals

Signals recorded from the brain often show rhythmic patterns at different frequencies, which are tightly coupled to the external stimuli as well as the internal state of the subject. In addition, these signals have very transient structures related to spiking or sudden onset of a stimulus, which have durations not exceeding tens of milliseconds. Further, brain signals are highly nonstationary because both behavioral state and external stimuli can change on a short time scale. It is therefore essential to study brain signals using techniques that can represent both rhythmic and transient components of the signal, something not always possible using standard signal processing techniques such as short time fourier transform, multitaper method, wavelet transform, or Hilbert transform. In this review, we describe a multiscale decomposition technique based on an over-complete dictionary called matching pursuit (MP), and show that it is able to capture both a sharp stimulus-onset transient and a sustained gamma rhythm in local field potential recorded from the primary visual cortex. We compare the performance of MP with other techniques and discuss its advantages and limitations. Data and codes for generating all time-frequency power spectra are provided.

Distributed Nonparametric Sequential Spectrum Sensing under Electromagnetic Interference

We propose a distributed sequential algorithm for quick detection of spectral holes in a Cognitive Radio set up. Two or more local nodes make decisions and inform the fusion centre (FC) over a reporting Multiple Access Channel (MAC), which then makes the final decision. The local nodes use energy detection and the FC uses mean detection in the presence of fading, heavy-tailed electromagnetic interference (EMI) and outliers. The statistics of the primary signal, channel gain and the EMI is not known. Different nonparametric sequential algorithms are compared to choose appropriate algorithms to be used at the local nodes and the Fe. Modification of a recently developed random walk test is selected for the local nodes for energy detection as well as at the fusion centre for mean detection. We show via simulations and analysis that the nonparametric distributed algorithm developed performs well in the presence of fading, EMI and outliers. The algorithm is iterative in nature making the computation and storage requirements minimal.

Tuning Photoluminescence Response by Electric Field in Electrically Soft Ferroelectrics

We show that an electrically soft ferroelectric host can be used to tune the photoluminescence (PL) response of rare-earth emitter ions by external electric field. The proof of this concept is demonstrated by changing the PL response of the Eu3+ ion by electric field on a model system Eu-doped 0.94(Na1/2Bi1/2TiO3)-0.06(BaTiO3). We also show that new channels of radiative transitions, forbidden otherwise, open up due to positional disorder in the system, which can as well be tuned by electric field.