Machine Learning Methods for Prediction of CDK-Inhibitors

Progression through the cell cycle involves the coordinated activities of a suite of cyclin/cyclin-dependent kinase (CDK) complexes. The activities of the complexes are regulated by CDK inhibitors (CDKIs). Apart from its role as cell cycle regulators, CDKIs are involved in apoptosis, transcriptional regulation, cell fate determination, cell migration and cytoskeletal dynamics. As the complexes perform crucial and diverse functions, these are important drug targets for tumour and stem cell therapeutic interventions. However, CDKIs are represented by proteins with considerable sequence heterogeneity and may fail to be identified by simple similarity search methods. In this work we have evaluated and developed machine learning methods for identification of CDKIs. We used different compositional features and evolutionary information in the form of PSSMs, from CDKIs and non-CDKIs for generating SVM and ANN classifiers. In the first stage, both the ANN and SVM models were evaluated using Leave-One-Out Cross-Validation and in the second stage these were tested on independent data sets. The PSSM-based SVM model emerged as the best classifier in both the stages and is publicly available through a user-friendly web interface at http://bioinfo.icgeb.res.in/cdkipred

A Flavonoid, Luteolin, Cripples HIV-1 by Abrogation of Tat Function

Despite the effectiveness of combination antiretroviral treatment (cART) against HIV-1, evidence indicates that residual infection persists in different cell types. Intensification of cART does not decrease the residual viral load or immune activation. cART restricts the synthesis of infectious virus but does not curtail HIV-1 transcription and translation from either the integrated or unintegrated viral genomes in infected cells. All treated patients with full viral suppression actually have low-level viremia. More than 60% of treated individuals also develop minor HIV-1 –associated neurocognitive deficits (HAND) due to residual virus and immune activation. Thus, new therapeutic agents are needed to curtail HIV-1 transcription and residual virus. In this study, luteolin, a dietary supplement, profoundly reduced HIV-1 infection in reporter cells and primary lymphocytes. HIV-1inhibition by luteolin was independent of viral entry, as shown by the fact that wild-type and VSV–pseudotyped HIV-1 infections were similarly inhibited. Luteolin was unable to inhibit viral reverse transcription. Luteolin had antiviral activity in a latent HIV-1 reactivation model and effectively ablated both clade-B- and -C -Tat-driven LTR transactivation in reporter assays but had no effect on Tat expression and its sub-cellular localization. We conclude that luteolin confers anti–HIV-1 activity at the Tat functional level. Given its biosafety profile and ability to cross the blood-brain barrier, luteolin may serve as a base flavonoid to develop potent anti–HIV-1 derivatives to complement cART

Alteration in Superoxide Dismutase 1 Causes Oxidative Stress and p38 MAPK Activation Following RVFV Infection

Rift Valley fever (RVF) is a zoonotic disease caused by Rift Valley fever virus (RVFV). RVFV is a category A pathogen that belongs to the genus Phlebovirus, family Bunyaviridae. Understanding early host events to an infectious exposure to RVFV will be of significant use in the development of effective therapeutics that not only control pathogen multiplication, but also contribute to cell survival. In this study, we have carried out infections of human cells with a vaccine strain (MP12) and virulent strain (ZH501) of RVFV and determined host responses to viral infection. We demonstrate that the cellular antioxidant enzyme superoxide dismutase 1 (SOD1) displays altered abundances at early time points following exposure to the virus. We show that the enzyme is down regulated in cases of both a virulent (ZH501) and a vaccine strain (MP12) exposure. Our data demonstrates that the down regulation of SOD1 is likely to be due to post transcriptional processes and may be related to up regulation of TNFα following infection. We also provide evidence for extensive oxidative stress in the MP12 infected cells. Concomitantly, there is an increase in the activation of the p38 MAPK stress response, which our earlier published study demonstrated to be an essential cell survival strategy. Our data suggests that the viral anti-apoptotic protein NSm may play a role in the regulation of the cellular p38 MAPK response. Alterations in the host protein SOD1 following RVFV infection appears to be an early event that occurs in multiple cell types. Activation of the cellular stress response p38 MAPK pathway can be observed in all cell types tested. Our data implies that maintaining oxidative homeostasis in the infected cells may play an important role in improving survival of infected cells

Track A Basic Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138319/1/jia218438.pd

Continuous People Crowd Monitoring defined as a Regression Problem using Radar Networks

Radar-based human activity recognition in crowded environments using regression approaches is addressed. Whereas previous research has focused on single activities and subjects, the problem of continuous activity recognition involving up to five individuals moving in arbitrary directions in an indoor area is introduced. To treat the problem, a regression-based approach is used, which offers innovative insights into creating robust and accurate systems for monitoring human activities.Novel approaches utilizing LSTM or CNN regression techniques with Linear Regression and Support Vector Machine regressor are compared on extracted features from radar data through the Histogram of Oriented Gradients and Principal Component Analysis. These approaches are rigorously evaluated by a Leave-One-Group-Out method, with performance assessed using common regression metrics such as the RMSE. The most promising outcomes were observed for crowds of three and five individuals, with respective RMSE of approximately 0.4 and 0.6. These results were primarily achieved by utilizing the micro-Doppler (µD) Spectrogram or range-Doppler data domain.Green Open Access added to TU Delft Institutional Repository 'You share, we take care!' - Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Microwave Sensing, Signals & System

The effects of childhood maltreatment on epigenetic regulation of stress-response associated genes: an intergenerational approach

While biological alterations associated with childhood maltreatment (CM) have been found in affected individuals, it remains unknown to what degree these alterations are biologically transmitted to the next generation. We investigated intergenerational effects of maternal CM on DNA methylation and gene expression in N=113 mother-infant dyads shortly after parturition, additionally accounting for the role of the FKBP5 rs1360780 genotype. Using mass array spectrometry, we assessed the DNA methylation of selected stress-response-associated genes (FK506 binding protein 51 [FKBP5], glucocorticoid receptor [NR3C1], corticotropin-releasing hormone receptor 1 [CRHR1]) in isolated immune cells from maternal blood and neonatal umbilical cord blood. In mothers, CM was associated with decreased levels of DNA methylation of FKBP5 and CRHR1 and increased NR3C1 methylation, but not with changes in gene expression profiles. Rs1360780 moderated the FKBP5 epigenetic CM-associated regulation profiles in a gene x environment interaction. In newborns, we found no evidence for any intergenerational transmission of CM-related methylation profiles for any of the investigated epigenetic sites. These findings support the hypothesis of a long-lasting impact of CM on the biological epigenetic regulation of stress-response mediators and suggest for the first time that these specific epigenetic patterns might not be directly transmitted to the next generation