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Objectives: The excellent resolution offered by magnetic resonance imaging (MRI) has a trade-off in the form of scan duration. The purpose of the present study was to assess the clinical utility of echo-planar imaging mix (EPIMix), an echo-planar imaging-based MRI sequence for the brain with a short acquisition time. Materials and Methods: This was a retrospective observational study of 50 patients, who could benefit from faster MRI brain scans. The T1, T2, fluid attenuated inversion recovery, diffusion-weighted imaging (DWI), and T2*/susceptibility-weighted imaging sequences were acquired, conventionally and with EPIMix. Conventional and EPIMix images were assessed by two radiologists for overall quality, motion, and susceptibility artifacts and scored on a Likert scale. The scores given for conventional and EPIMix images were compared. The diagnostic performance of EPIMix was also assessed by the ability to detect clinically relevant findings. Results: The acquisition time for conventional MRI was 11 min and 45 s and for EPIMix 1 min and 15 s. All EPIMix images were sufficient for diagnostic use. On assessment of the diagnostic performance, it was excellent for ischemic and hemorrhagic strokes. Smaller lesions, lesions adjacent to bone, and post-operative tumors were difficult to identify. Moderate to perfect agreement (Kappa values 0.41-1) was seen between radiologists for all categories except skull base, calvarial, and orbital lesions. Image quality, artifact assessment showed excellent interobserver agreement (>90%) for the scores. All EPIMix images showed reduced motion artifacts. The EPIMix-DWI was comparable to conventional-DWI in terms of quality and artifacts. The remaining sequences showed reduced quality and increased susceptibility. Conclusion: The EPIMix has a significantly reduced acquisition time than conventional MRI and could be used instead of conventional MRI in situations demanding faster scans such as suspected acute ischemic or hemorrhagic stroke. In other clinical scenarios, it could help tailor the MRI examination for each patient. [ABSTRACT FROM AUTHOR]

Computed tomography angiography (CTA) derived thrombus enhancement characteristics can predict first-pass recanalization. We studied whether dynamic contrast kinetics within the clot in multiphase CTA can predict first-pass recanalization following stentriever thrombectomy. Patients with acute large vessel occlusive stroke evaluated with multiphasic CTA who underwent stentriever thrombectomy were selected. Thrombus perviousness on various phases including arterial, venous, and delayed phases was calculated. Thrombus attenuation gradient (TAG), defined as average attenuation difference between adjacent phases, was also evaluated and correlated with successful first-pass outcome (modified Treatment in Cerebral Ischemia score ≥2b). Of 69 patients, 32 (47%) had successful first-pass recanalization (group 1), and 37 (53%) required >1 attempt (group 2). TAG showed significant differences in arterial-plain and venous-arterial phases. The early increase in TAG was seen in group 1 in the arterial-plain phase, as opposed to group 2 (12.6 vs. 9, P = 0.01), which plateaued in the venous-arterial phase for group 1 and showed a further increase in group 2 (2.1 vs. 5.1, P = 0.02). A cutoff value of 9.2 HU for arterial-plain phase (P = 0.001) and 4.2 HU (P = 0.001) for venous-arterial phase was predictive of first-pass effect. Combining 2 metrics had an odds ratio of 2.8 for first-pass recanalization (P = 0.035). Accuracy evaluated in a validation cohort yielded 74%. Other features including histology were not significant. TAG evaluated from multiphase CTA can predict first-pass effect in stentriever thrombectomy. [ABSTRACT FROM AUTHOR]

Mathematical modeling of the emergent dynamics of gene regulatory networks (GRN) faces a double challenge of (a) dependence of model dynamics on parameters, and (b) lack of reliable experimentally determined parameters. In this paper we compare two complementary approaches for describing GRN dynamics across unknown parameters: (1) parameter sampling and resulting ensemble statistics used by RACIPE (RAndom CIrcuit PErturbation), and (2) use of rigorous analysis of combinatorial approximation of the ODE models by DSGRN (Dynamic Signatures Generated by Regulatory Networks). We find a very good agreement between RACIPE simulation and DSGRN predictions for four different 2- and 3-node networks typically observed in cellular decision making. This observation is remarkable since the DSGRN approach assumes that the Hill coefficients of the models are very high while RACIPE assumes the values in the range 1-6. Thus DSGRN parameter domains, explicitly defined by inequalities between systems parameters, are highly predictive of ODE model dynamics within a biologically reasonable range of parameters. [ABSTRACT FROM AUTHOR]

Multistability is central to biological systems. It plays a crucial role in adaptation, evolvability, and differentiation. The presence of positive feedback loops can enable multistability. The simplest of such feedback loops are (a) a mutual inhibition (MI) loop, (b) a mutual activation (MA) loop, and (c) self-activation. While it is established that all three motifs can give rise to bistability, the characteristic differences in the bistability exhibited by each of these motifs is relatively less understood. Here, we use dynamical simulations across a large ensemble of parameter sets and initial conditions to study the bistability characteristics of these motifs. Furthermore, we investigate the utility of these motifs for achieving coordinated expression through cyclic and parallel coupling amongst them. Our analysis revealed that MI-based architectures offer discrete and robust control over gene expression, multistability, and coordinated expression among multiple genes, as compared to MA-based architectures. We then devised a combination of MI and MA architectures to improve coordination and multistability. Such designs help enhance our understanding of the control structures involved in robust cell-fate decisions and provide a way to achieve controlled decision-making in synthetic systems. [ABSTRACT FROM AUTHOR]

Understanding the dynamical hallmarks of network motifs is one of the fundamental aspects of systems biology. Positive feedback loops constituting one or two nodes – self-activation, toggle switch, and double activation loops – are the commonly observed motifs in regulatory networks underlying cell-fate decision systems. Their individual dynamics are well studied; they are capable of exhibiting bistability. However, studies across various biological systems suggest that such positive feedback loops are interconnected with one another, and design principles of coupled bistable motifs remain unclear. What happens to the bistability or multistability traits and the phenotypic space (collection of phenotypes exhibited by a system) due to the couplings? In this study, we explore a set of such interactions using discrete and continuous simulation methods. Our results suggest that the most frequent states in coupled networks follow the ‘rules’ within a motif (double activation, toggle switch) and those across the two motifs in terms of how the two motifs have been coupled. Moreover, ‘hybrid’ states can be observed, too, where one of the above-mentioned ‘rules’ can be compromised, leading to a more diverse phenotypic repertoire. Furthermore, adding direct and indirect self-activations to these coupled networks can increase the frequency of multistability. Thus, our observations revealed specific dynamical traits exhibited by various coupled bistable motifs. [ABSTRACT FROM AUTHOR]

Elucidating the design principles of regulatory networks driving cellular decision-making has fundamental implications in mapping and eventually controlling cell-fate decisions. Despite being complex, these regulatory networks often only give rise to a few phenotypes. Previously, we identified two 'teams' of nodes in a small cell lung cancer regulatory network that constrained the phenotypic repertoire and aligned strongly with the dominant phenotypes obtained from network simulations (Chauhan et al., 2021). However, it remained elusive whether these 'teams' exist in other networks, and how do they shape the phenotypic landscape. Here, we demonstrate that five different networks of varying sizes governing epithelial-mesenchymal plasticity comprised of two 'teams' of players - one comprised of canonical drivers of epithelial phenotype and the other containing the mesenchymal inducers. These 'teams' are specific to the topology of these regulatory networks and orchestrate a bimodal phenotypic landscape with the epithelial and mesenchymal phenotypes being more frequent and dynamically robust to perturbations, relative to the intermediary/hybrid epithelial/mesenchymal ones. Our analysis reveals that network topology alone can contain information about corresponding phenotypic distributions, thus obviating the need to simulate them. We propose 'teams' of nodes as a network design principle that can drive cell-fate canalization in diverse decision-making processes. [ABSTRACT FROM AUTHOR]

Epithelial to Mesenchymal Transition (EMT) and its reverse—Mesenchymal to Epithelial Transition (MET) are hallmarks of metastasis. Cancer cells use this reversible cellular programming to switch among Epithelial (E), Mesenchymal (M), and hybrid Epithelial/Mesenchymal (hybrid E/M) state(s) and seed tumors at distant sites. Hybrid E/M cells are often more aggressive and metastatic than the "pure" E and M cells. Thus, identifying mechanisms to inhibit hybrid E/M cells can be promising in curtailing metastasis. While multiple gene regulatory networks (GRNs) based mathematical models for EMT/MET have been developed recently, identifying topological signatures enriching hybrid E/M phenotypes remains to be done. Here, we investigate the dynamics of 13 different GRNs and report an interesting association between "hybridness" and the number of negative/positive feedback loops across the networks. While networks having more negative feedback loops favor hybrid phenotype(s), networks having more positive feedback loops (PFLs) or many HiLoops–specific combinations of PFLs, support terminal (E and M) phenotypes. We also establish a connection between "hybridness" and network-frustration by showing that hybrid phenotypes likely result from non-reinforcing interactions among network nodes (genes) and therefore tend to be more frustrated (less stable). Our analysis, thus, identifies network topology-based signatures that can give rise to, as well as prevent, the emergence of hybrid E/M phenotype in GRNs underlying EMP. Our results can have implications in terms of targeting specific interactions in GRNs as a potent way to restrict switching to the hybrid E/M phenotype(s) to curtail metastasis. Author summary: Epithelial Mesenchymal Transition (EMT) is often if not invariably the driver of carcinoma cell progression toward high-grade malignancy. Hybrid epithelial mesenchymal (h E/M) cells have a higher propensity for metastasis than those on the terminal (E and M) ends of the EMT continuum. Therefore identifying mechanism that can stop cells from adopting hybrid phenotypes can be crucial in preventing metastasis. Recent studies while investigating gene regulatory networks (GRNs) underlying EMT have identified specific molecules that can stabilize h E/M phenotypes. We, however, argue that hybrid phenotypes can also have network topology basis and can result from specific gene-gene interactions. To support this claim, we analyzed 13 GRNs of different size and report that having many negative feedback loops in these networks favor hybrid phenotypes, while as having many positive feedback loops or many HiLoops–specific combinations of PFLs, support terminal phenotypes. We also establish a connection between "hybridness" and network-frustration by showing that hybrid phenotypes likely result from non-reinforcing gene interactions and therefore tend to be more frustrated (less stable). These results suggest that the design of future therapeutic approaches will have to consider gene-gene interactions rather than just a single gene. [ABSTRACT FROM AUTHOR]

Background: Functional Endoscopic Sinus Surgery (FESS) is a surgical procedure used in the treatment of Chronic Rhinosinusitis (CRS). NCCT PNS is mandatory for all patients undergoing FESS and Rhinologist should know all the variations that can be found and diagnosed by CT scan. Purpose: The main aim of the study is to correlate the Computerized Tomography (CT) scan findings of Chronic Rhinosinusitis (CRS) with intra operative findings of Functional Endoscopic Sinus Surgery (FESS). Other objectives are to assess the clinical profile of patients with CRS and to determine the presence of anatomical variations. Material and Methods: All the patients were subjected to Diagnostic Nasal Endoscopy (DNE), CT Paranasal sinuses and findings recorded. The scoring systems used were Lund Mackay scoring system for CT scan. All the cases underwent FESS and the operative findings were correlated with preoperative CT findings. Statistical analysis was performed by calculating sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and Kappa's measure of agreement. Results: The Lund Mackay scores on CT scan were 5.42 on right side and 5.64 on left side. Kappa scores varied from 0-1.0. The findings related to septum, posterior ethmoids and sphenoid sinus have perfect agreement (kappa-1.0) with operative findings whereas frontal sinus and inferior turbinate have almost perfect agreement (kappa 0.81-0.99). Middle turbinate has substantial agreement with 0.79 kappa score. In maxillary sinus, anterior ethmoids and OMU, agreement was by chance. Conclusion: CT scan has excellent sensitivity and PPV for CRS but specificity and NPV is low in diagnosing disease in Osteomeatal unit (OMU), middle turbinate (MT) and anterior ethmoids. So, it should always be complimented by thorough history and DNE. [ABSTRACT FROM AUTHOR]

Metastasis is the cause of over 90% of cancer-related deaths. Cancer cells undergoing metastasis can switch dynamically between different phenotypes, enabling them to adapt to harsh challenges, such as overcoming anoikis and evading immune response. This ability, known as phenotypic plasticity, is crucial for the survival of cancer cells during metastasis, as well as acquiring therapy resistance. Various biochemical networks have been identified to contribute to phenotypic plasticity, but how plasticity emerges from the dynamics of these networks remains elusive. Here, we investigated the dynamics of various regulatory networks implicated in Epithelial–mesenchymal plasticity (EMP)—an important arm of phenotypic plasticity—through two different mathematical modelling frameworks: a discrete, parameter-independent framework (Boolean) and a continuous, parameter-agnostic modelling framework (RACIPE). Results from either framework in terms of phenotypic distributions obtained from a given EMP network are qualitatively similar and suggest that these networks are multi-stable and can give rise to phenotypic plasticity. Neither method requires specific kinetic parameters, thus our results emphasize that EMP can emerge through these networks over a wide range of parameter sets, elucidating the importance of network topology in enabling phenotypic plasticity. Furthermore, we show that the ability to exhibit phenotypic plasticity correlates positively with the number of positive feedback loops in a given network. These results pave a way toward an unorthodox network topology-based approach to identify crucial links in a given EMP network that can reduce phenotypic plasticity and possibly inhibit metastasis—by reducing the number of positive feedback loops. [ABSTRACT FROM AUTHOR]

Low-power design for test is the need of the hour for any system-on-chip designer. The low-power design techniques have been a major challenge to both the designer as well as the testing engineer. With so many advancements in low-power technology in the phase of register transfer logic design, functional verification, register transfer logic and physical synthesis and physical design. Design for test is not an exception to this. The low-power design-for-test techniques can be applied at various levels of the design-for-test flow as in the scan insertion stage, automatic test pattern generation simulations stage, testing stage, and so on. Some of the reasons for the high-power utilization in the design-for-test phase can be due to the external circuitry being inserted during the design phase and not used in the functional mode. The complete circuit will be active in the test mode only. In this paper, the focus will be primarily on reducing the power during the automatic test pattern generation scan synthesis phase. All the scan flops are connected by a common scan clock with a fixed frequency. The intention of this study is to divide the clock frequency by half and make sure that the power is reduced without affecting any timing violations. Since the scan clock frequency is low, it can be further divided to ensure that power is reduced without affecting the testing process of the chip. [ABSTRACT FROM AUTHOR]

Deviated nasal septum, empty nose syndrome, ENS6Q, inferior turbinate hypertrophy, paradoxical nasal obstruction, SNOT-22, survey, validated Overall, nasal obstruction is a rather nonspecific symptom for which both ENS and PNO patients may present with as their subjective complaint.1,4 However, it is felt that certain subjective symptoms are more representative of ENS. The empty nose syndrome 6-item questionnaire (ENS6Q): a diagnostic tool to distinguish empty nose syndrome from primary nasal obstruction. [Extracted from the article]

Thisredundancyissuggestedbyobservations that demonstrate the presence of canalization in biochemical networks [as proposed by Waddington earlier (10)], where only a few dynamic perturbations to the network can alter the emergent network properties (11). (B) The corresponding effective graph representing the effectiveness score ofeachofthesixedges.(C)Look-uptruthtablecorrespondingtothe network inA.(D) Characterizing effectiveness of edges to nodes A andC.#(wildcard)representstheactivityofthenodewhichdoesnot affect the network output. Therefore, the effective graph may be more informative in terms of identifying the Achilles' heel in a regulatory network, reminiscent of another network reduction method to arrive at an "influence matrix" for a specific network (15). [Extracted from the article]

In this paper, an inductorless wideband balun-low noise amplifier (LNA) using current source loads, common-mode feedback (CMFB), asymmetric capacitive cross-coupling (CCC) and auxiliary common-source amplifier are proposed to obtain low noise figure (NF) and high gain. The asymmetric CCC boosts the gain and reduces the NF. The CMFB fixes the output to a common mode voltage. RMS detectors are proposed to realize a low-cost built-in self-test (BIST) circuit for measuring the gain of the LNA during its entire lifespan. The proposed balun-LNA is implemented in 0.18 µm CMOS process technology and the performance is studied through post-layout simulations. PVT and Monte Carlo simulations are performed to check for the robustness and yield of the circuit. From these analyses, it is found that the integrated average gain of the LNA obtained with and without the RMS detectors is 19.1 dB and 20.1 dB respectively in the 3 dB-band of 0.18–2 GHz. NF of the LNA in this band is 2.87 dB. The average IIP3, IIP2, and 1 dB compression points of the LNA are (−4.89 dBm, +28.57 dBm, −20.42 dBm) respectively. The proposed LNA dissipates a power of 4.9 mW with a supply of 1.2 V and requires an area of 0.04 mm2. [ABSTRACT FROM AUTHOR]

BACKGROUND This study was conducted to assess the contribution of MDCT (Multi-Detector Computed Tomography) contrast-enhanced coronary angiography to the clinical classification of benign and malignant coronary artery variations and abnormalities. METHODS This was a descriptive observational cross-sectional study carried out in a hospital setting among 200 patients who underwent MDCT coronary angiography at Fortis Hospital, Noida, between August 2016 and March 2018. The institutional ethics committee approved the study, and participants' signed informed consent was acquired. RESULTS Of the 200 patients in our investigation, 76 had variants, accounting for 38% of the cohort. These variants included variations in the dominance pattern (20%), conus branch variants (3%), SA nodal branch variants (0.5%), and ramus intermedius variants (14.5%). In terms of origin and course anomalies, LAD (Left Anterior Descending) and LCX (Left Circumflex Artery) have different origins and there is no LMCA (Left Main Coronary Artery). Two individuals in our sample had ectopic LMCA at the level of the sino-tubular junction and above the junction with the retroarterial and interarterial courses, while one patient had missing LMCA. Two percent of the population had an anomalous origin from the opposite coronary sinus (n = 1). CONCLUSION With MDCT coronary angiography, coronary artery variations and anomalies are most accurately detected. With MDCT angiography, a number of malignant anomalies that are challenging to diagnose by ICA can be quickly found. When a patient is having interventional procedures like cardiac catheterization, coronary angioplasty, and stenting, having prior knowledge of various defects is helpful. [ABSTRACT FROM AUTHOR]

Isolated Infection of central nervous system by the family Mucoraceae is a rare but life-threatening infection. We present a case of isolated cerebral mucormycosis in a 53-year-old immunocompetent woman without any rhinoorbital focus. She underwent excision biopsy followed by treatment with amphotericin B, resulting in resolution of symptoms clinically and the lesion radiologically. [ABSTRACT FROM AUTHOR]

Elucidating the design principles of regulatory networks driving cellular decision-making has important implications for understanding cell differentiation and guiding the design of synthetic circuits. Mutually repressing feedback loops between 'master regulators' of cell fates can exhibit multistable dynamics enabling "single-positive" phenotypes: (high A, low B) and (low A, high B) for a toggle switch, and (high A, low B, low C), (low A, high B, low C) and (low A, low B, high C) for a toggle triad. However, the dynamics of these two motifs have been interrogated in isolation in silico, but in vitro and in vivo, they often operate while embedded in larger regulatory networks. Here, we embed these motifs in complex larger networks of varying sizes and connectivity to identify hallmarks under which these motifs maintain their canonical dynamical behavior. We show that an increased number of incoming edges onto a motif leads to a decay in their canonical stand-alone behaviors. We also show that this decay can be exacerbated by adding self-inhibition but not self-activation loops on the 'master regulators'. These observations offer insights into the design principles of biological networks containing these motifs and can help devise optimal strategies for the integration of these motifs into larger synthetic networks. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, a third order shear deformation theory is used to study the behavior of laminated smart composite plate with magnetostrictive layers, while accounting for geometric nonlinearity in the von-Karman sense. A coupled analysis of magnetostrictive material is presented where Terfenol-D is used as a magnetostrictive material to control the responses of the laminated smart composite plates. A C0 finite element formulation is proposed for this purpose. The accuracy of the present formulation has been shown by comparison of the present results with those available in the literature. Some new results are also presented for future research in this field of study. [Copyright &y& Elsevier]

The following article from Plant Biology, 'Growth, ion homeostasis, photosynthesis and photosystem II efficiency of an obligate halophyte, Salicornia brachiata, under increasing salinity (p)' by A. K. Parida, C. M. Hari Kishore & B. Jha, published online on 1 April 2010 (DOI: ) in Wiley InterScience (), has been retracted by agreement between the authors, the journal Editor-in-Chief, Heinz Rennenberg and Blackwell Publishing Ltd. The retraction has been agreed due to concern about overlap with the article 'Relationship between the photosynthetic activity and the performance of Cakile maritima after long-term salt treatment' by Ahmed Debez, Hans-Werner Koyro, Claude Grignon, Chedly Abdelly, Bernhard Huchzermeyer published in Physiologia Plantarum (2008) vol. 133, 373-385. [ABSTRACT FROM AUTHOR]

Aurora kinases are essential for chromosomal segregation and cell division and thereby important for maintaining the proper genomic integrity. There are three classes of aurora kinases in humans: A, B, and C. Aurora kinase A is frequently overexpressed in various cancers. The link of the overexpression and tumorigenesis is yet to be understood. By employing virtual screening, we have found that anacardic acid, a pentadecane aliphatic chain containing hydroxylcarboxylic acid, from cashew nut shell liquid could be docked in Aurora kinases A and B. Remarkably, we found that anacardic acid could potently activate the Aurora kinase A mediated phosphorylation of histone H3, but at a similar concentration the activity of aurora kinase B remained unaffected in vitro. Mechanistically, anacardic acid induces the structural changes and also the autophosphorylation of the aurora kinase A to enhance the enzyme activity. This data thus indicate anacardic acid as the first small-molecule activator of Aurora kinase, which could be highly useful for probing the function of hyperactive (overexpressed) Aurora kinase A. [ABSTRACT FROM AUTHOR]

Reversible acetylation of nucleosomal histones and nonhistone proteins play pivotal roles in the regulation of all the DNA templated phenomenon. Dysfunction of the enzymes involved in the acetylation/deacetylation leads to several diseases. Therefore, these enzymes are the targets for new generation therapeutics. Here, we report the synthesis of trifluoromethyl phenyl benzamides and their effect on histone acetyltransferase (HAT) activity of p300. One of these benzamides, CTPB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide), was discovered as a potent activator of the p300 HAT activity. We have found that pentadecyl hydrocarbon chain of CTPB is required to activate the HAT only under certain context. Furthermore, our results show that the relative position of −CF3and −Cl in CTB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-benzamide) is also very critical for the activation. Surface-enhanced Raman spectroscopy (SERS) of p300 and the HAT activator complexes evidently suggest that the activation of HAT activity is achieved by the alteration of p300 structure. Therefore, apart from elucidating the chemical basis for small molecule mediated activation of p300, this report also describes, for the first time, Raman spectroscopic analysis of the complexes of histone-modifying enzymes and their modulators, which may be highly useful for therapeutic applications. [ABSTRACT FROM AUTHOR]

Three flavonoids, 5,7,2′,3′,4′-pentamethoxyflavone (1), 2′-hydroxy-2,4′,6′-tri methoxychalcone (2) and dihydroskullcapflavone I (3), together with 17,19,20-trihydroxy-5β, 8α H, 9β H,10α-labd-13-en-16,15-olactone (4), a known diterpenoid and six known flavonoids, 5-hydroxy-7,8-dimethoxyflavanone (5), 5-hydroxy-7,8,2′,3′,4′-pentamethoxyflavone (6), 5,2′-dihydroxy-7-methoxyflavanone (7), 5,2′-dihydroxy-7,8-dimethoxyflavone (8), 5,2′-dihydroxy-7-methoxyflavone (9) and 5,2′-dihydroxy-7-methoxyflavone 2′-O-β-d-glucopyranoside (10) were isolated from the whole plant of Andrographis lineata. The structures of these compounds were elucidated on the basis of spectral and chemical studies. [Copyright &y& Elsevier]

Adaptation and survival of cancer cells to various stress and growth factor conditions is crucial for successful metastasis. A double-negative feedback loop between two serine/threonine kinases AMPK (AMP-activated protein kinase) and Akt can regulate the adaptation of breast cancer cells to matrix-deprivation stress. This feedback loop can significantly generate two phenotypes or cell states: matrix detachment-triggered pAMPKhigh/ pAktlow state, and matrix (re)attachment-triggered pAkthigh/ pAMPKlow state. However, whether these two cell states can exhibit phenotypic plasticity and heterogeneity in a given cell population, i.e., whether they can co-exist and undergo spontaneous switching to generate the other subpopulation, remains unclear. Here, we develop a mechanism-based mathematical model that captures the set of experimentally reported interactions among AMPK and Akt. Our simulations suggest that the AMPK-Akt feedback loop can give rise to two co-existing phenotypes (pAkthigh/ pAMPKlow and pAMPKhigh/pAktlow) in specific parameter regimes. Next, to test the model predictions, we segregated these two subpopulations in MDA-MB-231 cells and observed that each of them was capable of switching to another in adherent conditions. Finally, the predicted trends are supported by clinical data analysis of The Cancer Genome Atlas (TCGA) breast cancer and pan-cancer cohorts that revealed negatively correlated pAMPK and pAkt protein levels. Overall, our integrated computational-experimental approach unravels that AMPK-Akt feedback loop can generate multi-stability and drive phenotypic switching and heterogeneity in a cancer cell population. [ABSTRACT FROM AUTHOR]

Capacitors realized using symmetric floating impedance scaling (SFIS) are area efficient. They are preferred for the implementation of fully differential filters for biomedical applications. The SFIS reported in the literature has poor accuracy and lower effective bandwidth. In this paper, a cross coupled symmetric floating impedance scaling (CC-SFIS) with enhanced bandwidth and accuracy is proposed. To evaluate its performance, a 500 pF capacitor is implemented in UMC 180 nm CMOS technology with a base capacitor (C b) of 10 pF using both CC-SFIS and source follower based SFIS (SF-SFIS). The magnitude and phase of the impedance of the capacitor realized using CC-SFIS and SF-SFIS are obtained through post-layout simulations. CC-SFIS requires 53.68% lower area, 62.39% lower power consumption, and 88% higher accuracy than SF-SFIS. Fully differential 2nd order Butterworth low pass filters with cutoff frequency of 100 Hz are implemented in UMC 180 nm technology using both CC-SFIS and SF-SFIS capacitors. Their performances are evaluated through simulation. From this, it is found that the deviation in the cut off frequency of the filter using CC-SFIS is smaller (2%) compared to that using SF-SFIS (40%) circuit. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

Hyperactive Insulin like growth factor-1-receptor (IGF1R) signalling is associated with development of therapy resistance in many cancers. We recently reported a pulsatile nature of IGF1R during acquirement of platinum-taxol resistance in Epithelial Ovarian Cancer (EOC) cells and a therapy induced upregulation in IGF1R expression in tumors of a small cohort of high grade serous EOC patients. Here, we report Runt-related transcription factor 1 (RUNX1) as a novel transcriptional regulator which along with another known regulator Forkhead Box O3 (FOXO3a), drives the dynamic modulation of IGF1R expression during platinum-taxol resistance development in EOC cells. RUNX1-FOXO3a cooperatively bind to IGF1R promoter and produce a transcriptional surge during onset of resistance and such co-operativity falls apart when cells attain maximal resistance resulting in decreased IGF1R expression. The intriguing descending trend in IGF1R and FOXO3a expressions is caused by a Protein Kinase B (AKT)-FOXO3a negative feedback loop exclusively present in the highly resistant cells eliciting the pulsatile behaviour of IGF1R and FOXO3a. In vivo molecular imaging revealed that RUNX1 inhibition causes significant attenuation of the IGF1R promoter activity, decreased tumorigenicity and enhanced drug sensitivity of tumors of early resistant cells. Altogether our findings delineate a dynamic interplay between several molecular regulators driving pulsatile IGF1R expression and identify a new avenue for targeting EOC through RUNX1-IGF1R axis during acquirement of chemoresistance. Unlabelled Image • RUNX1 is a novel regulator of IGF1R during chemoresistance development in EOC cells. • RUNX1 modulates FOXO3a mediated transcriptional surge in IGF1R at onset of resistance. • An active AKT-FOXO3a negative feedback loop leads to pulsatile dynamics of IGF1R. • RUNX1 inhibition in combination with platinum-taxol reverses resistance in EOC cells. [ABSTRACT FROM AUTHOR]

Two Inductorless balun low noise amplifiers (LNAs- LNA1, LNA2) are proposed in this paper to reduce the noise figure (NF) and improve the linearity. They use asymmetric capacitive cross-coupling (A-CCC) and auxiliary CS amplifier to reduce the NF. Robust derivative superposition is used in LNA2 to improve the 3rd order input intercept point, and hence the linearity. The proposed A-CCC balun-LNAs are implemented in 0.18 µm CMOS technology, and their performances are evaluated through post-layout simulations, PVT variation analysis and Monte Carlo simulations. From these studies, the average NF, gain and the 3dB-bandwidths of LNA1 and LNA2 obtained are (2.49 dB, 20 dB, 0.1–2.48 GHz) and (2.61 dB, 19.8 dB, 0.1–2.0 GHz) respectively. For a 1.2 V supply and an area of 0.02mm2, the power consumption of LNA1 and LNA2 are 4.9 mW and 5.8 mW, respectively. The performances of the proposed LNAs are also compared with other wideband LNAs reported in the literature. [ABSTRACT FROM AUTHOR]

A CG-CS wideband balun-LNA using asymmetric capacitive cross-coupling (A-CCC) and an auxiliary current reuse amplifier (ACRA) is reported in the literature. It achieves low noise figure (NF) and high gain at the cost of linearity. To improve the linearity, inductive loads are proposed. However, this is at the cost of increase in chip area. To overcome this problem, a balun-LNA using modified complementary derivative superposition and asymmetric CCC-DS techniques for the ACRA and A-CCC block respectively is proposed in this paper. It dispenses with the inductive loads. The balun-LNAs with and without the proposed linearization are implemented in UMC 180 nm CMOS technology with a supply of 1.2 V and are studied through post-layout simulations. It is found that the proposed LNA has +7.96 dBm increase in average IIP3 compared to the LNA without the proposed linearization. It achieves an average IIP3 of +5.49 dBm with a peak gain of 24.2 dB and minimum NF of 2.18 dB over the bandwidth of 1–3 GHz. The proposed LNA requires an area of 0.3 mm2 and a power of 6.95 mW. [ABSTRACT FROM AUTHOR]

This paper proposes a low noise amplifier (LNA) which can be reconfigured to operate in two frequency bands at low power. The LNA employs self-cascode devices in current-reuse configuration to enable lower supply voltage operation without compromising the gain. A quasi-differential structure is used to achieve high linearity and good common-mode rejection. The proposed LNA is designed to operate in (3.1–4.7 GHz: Band1) and (5.0–7.2 GHz: Band2) in the 5G frequency spectrum. It is implemented in 65 nm UMC-LL CMOS process technology using 0.6V, and its performance is evaluated using post layout, PVT and Monte Carlo simulations. The proposed LNA requires an area of 0.03276 mm2. The power dissipation, maximum gain, minimum noise figure, average IIP3, IIP2 of the LNA operating in Band1 and Band2 are found to be (0.97 ​mW, 17.6 ​dB, 2.20 ​dB, +0.72dBm, +46.49dBm) and (0.485 ​mW, 12.1 ​dB, 3.31 ​dB, +0.12dBm, +42.60dBm) respectively. [ABSTRACT FROM AUTHOR]

Phenotypic (non-genetic) heterogeneity has significant implications for the development and evolution of organs, organisms, and populations. Recent observations in multiple cancers have unraveled the role of phenotypic heterogeneity in driving metastasis and therapy recalcitrance. However, the origins of such phenotypic heterogeneity are poorly understood in most cancers. Here, we investigate a regulatory network underlying phenotypic heterogeneity in small cell lung cancer, a devastating disease with no molecular targeted therapy. Discrete and continuous dynamical simulations of this network reveal its multistable behavior that can explain co- existence of four experimentally observed phenotypes. Analysis of the network topology uncovers that multistability emerges from two teams of players that mutually inhibit each other, but members of a team activate one another, forming a ‘toggle switch’ between the two teams. Deciphering these topological signatures in cancer-related regulatory networks can unravel their ‘latent’ design principles and offer a rational approach to characterize phenotypic heterogeneity in a tumor. [ABSTRACT FROM AUTHOR]

While phenotypic plasticity is a critical factor contributing to tumor heterogeneity, molecular mechanisms underlying this process are largely unknown. Here we report that breast cancer cells display phenotypic diversity in response to hypoxia or normoxia microenvironments by operating a reciprocal positive feedback regulation of HPIP and HIF-1α. We show that under hypoxia, HIF-1α induces HPIP expression that establishes cell survival, and also promotes cell migration/invasion, EMT and metastatic phenotypes in breast cancer cells. Mechanistic studies revealed that HPIP interacts with SRP14, a component of signal recognition particle, and stimulates MMP9 synthesis under hypoxic stress. Whereas, in normoxia, HPIP stabilizes HIF-1α, causing the Warburg effect to support cell growth. Concurrently, mathematical modelling corroborates this reciprocal feedback loop in enabling cell-state transitions in cancer cells. Clinical data indicate that elevated levels of HPIP and HIF-1α correlate with unfavorable prognosis and shorter survival rates in breast cancer subjects. Together, this data shows a reciprocal positive feedback loop between HPIP and HIF-1α that was unknown hitherto. It unveils how the tumor microenvironment influences phenotypic plasticity that has an impact on tumor growth and metastasis and, further signifies considering this pathway as a potential therapeutic target in breast cancer. [ABSTRACT FROM AUTHOR]

This work investigates on the impact of octanol with neem biodiesel (NBD) on diesel engine characteristics. Two different fuel blends are prepared by changing the n-octanol content in NBD from 10 to 20% on a volume basis. Results from this work revealed that with an increase in volume percentage in NBD generated a higher heat release rate and in-cylinder pressure at premixed combustion. Further, with an increase in volume percentage in NBD improved BTE than neat NBD. Fuel consumption has lowered by 2.4% with higher octanol content in NBD. The excess oxygen present in octanol lowered CO, HC, NO and smoke emissions by 5.7%, 6.2%, 4.4% and 6.7% respectively when compared to NBD. Overall, adding 20% of octanol to NBD improved the performance aspects with lowered emissions. This research work reveals that 20% of Octanol and 80% of BD can optimize diesel engine emissions, combustion, and performance with undergoing any modifications. [ABSTRACT FROM AUTHOR]

Highlights: [•] NPM1 and Aurora Kinases play important roles in mitosis. [•] NPM1 is phosphorylated by Aurora Kinase B predominantly at Ser125 during mitosis. [•] Ser125-phosphorylated NPM1 localizes in the midbody region during cytokinesis. [•] Ser125-phosphorylated NPM1 levels are high in oral tumor tissues. [•] Aurora Kinase B along with NPM1 overexpression may facilitate oncogenesis. [ABSTRACT FROM AUTHOR]

Drug resistance, a major challenge in cancer therapy, is typically attributed to mutations and genetic heterogeneity. Emerging evidence suggests that dynamic cellular interactions and group behavior also contribute to drug resistance. However, the underlying mechanisms remain poorly understood. Here, we present a new mathematical approach with game theoretical underpinnings that we developed to model real-time growth data of non-small cell lung cancer (NSCLC) cells and discern patterns in response to treatment with cisplatin. We show that the cisplatin-sensitive and cisplatin-tolerant NSCLC cells, when co-cultured in the absence or presence of the drug, display dynamic group behavior strategies. Tolerant cells exhibit a 'persister-like' behavior and are attenuated by sensitive cells; they also appear to 'educate' sensitive cells to evade chemotherapy. Further, tolerant cells can switch phenotypes to become sensitive, especially at low cisplatin concentrations. Finally, switching treatment from continuous to an intermittent regimen can attenuate the emergence of tolerant cells, suggesting that intermittent chemotherapy may improve outcomes in lung cancer. [ABSTRACT FROM AUTHOR]

It has been shown that anxiety and stress responses are modulated by substance P (SP) released within the amygdala. However, there is an important gap in our knowledge concerning the mechanisms regulating extracellular SP in this brain region. To study a possible self-regulating role of SP, we used a selective neurokinin-1 (NK1) receptor antagonist to investigate whether blockade of NK1 receptors results in altered basal and/or stress-evoked SP release in the medial amygdala (MeA), a critical brain area for a functional involvement of SP transmission in enhanced anxiety responses induced by stressor exposure. In vitro binding and functional receptor assays revealed that L-822429 represents a potent and selective rat NK1 receptor antagonist. Intra-amygdaloid administration of L-822429 via inverse microdialysis enhanced basal, but attenuated swim stress-induced SP release, while the low-affinity enantiomer of L-822429 had no effect. Using light and electron microscopy, synaptic contacts between SP-containing fibres and dendrites expressing NK1 receptors was demonstrated in the medial amygdala. Our findings suggest self-regulatory capacity of SP-mediated neurotransmission that differs in the effect on basal and stress-induced release of SP. Under basal conditions endogenous SP can serve as a signal that tonically inhibits its own release via a NK1 receptor-mediated negative feedback action, while under stress conditions SP release is further facilitated by activation of NK1 receptors, likely leading to high local levels of SP and activation of receptors to which SP binds with lower affinity. [ABSTRACT FROM AUTHOR]

Astrocytoma is the most common type of brain cancer constituting more than half of all brain tumors. With an aim to identify markers describing astrocytoma progression, we have carried out microarray analysis of astrocytoma samples of different grades using cDNA microarray containing 1152 cancer-specific genes. Data analysis identified several differentially regulated genes between normal brain tissue and astrocytoma as well as between grades II/III astrocytoma and glioblastoma multiforme (GBM; grade IV). We found several genes known to be involved in malignancy including Achaete-scute complex-like 1 (Drosophila) (ASCL1; Hash 1). As ASCL has been implicated in neuroendocrine, medullary thyroid and small-cell lung cancers, we chose to examine the role of ASCL1 in the astrocytoma development. Our data revealed that ASCL1 is overexpressed in progressive astrocytoma as evidenced by increased levels of ASCL1 transcripts in 85.71% (6/7) of grade II diffuse astrocytoma (DA), 90% (9/10) of grade III anaplastic astrocytoma (AA) and 87.5% (7/8) of secondary GBMs, while the majority of primary de novo GBMs expressed similar to or less than normal brain levels (66.67%; 8/12). ASCL1 upregulation in progressive astrocytoma is accompanied by inhibition of Notch signaling as seen by uninduced levels of HES1, a transcriptional target of Notch1, increased levels of HES6, a dominant-negative inhibitor of HES1-mediated repression of ASCL1, and increased levels of Notch ligand Delta1, which is capable of inhibiting Notch signaling by forming intracellular Notch ligand autonomous complexes. Our results imply that inhibition of Notch signaling may be an important early event in the development of grade II DA and subsequent progression to grade III AA and secondary GBM. Furthermore, ASCL1 appears to be a putative marker to distinguish primary GBM from secondary GBM.Oncogene (2005) 24, 7073–7083. doi:10.1038/sj.onc.1208865; published online 15 August 2005 [ABSTRACT FROM AUTHOR]

Integrative Analysis and Machine Learning Based Characterization of Single Circulating Tumor Cells. Conflicts of Interest The authors declare no conflict of interest. References 1 Iyer A., Gupta K., Sharma S., Hari K., Lee Y.F., Ramalingam N., Yap Y.S., West J., Bhagat A.A., Subramani B.V. Integrative Analysis and Machine Learning based Characterization of Single Circulating Tumor Cells. [Extracted from the article]

We collated publicly available single-cell expression profiles of circulating tumor cells (CTCs) and showed that CTCs across cancers lie on a near-perfect continuum of epithelial to mesenchymal (EMT) transition. Integrative analysis of CTC transcriptomes also highlighted the inverse gene expression pattern between PD-L1 and MHC, which is implicated in cancer immunotherapy. We used the CTCs expression profiles in tandem with publicly available peripheral blood mononuclear cell (PBMC) transcriptomes to train a classifier that accurately recognizes CTCs of diverse phenotype. Further, we used this classifier to validate circulating breast tumor cells captured using a newly developed microfluidic system for label-free enrichment of CTCs. [ABSTRACT FROM AUTHOR]