A-coupled-expanding and distributional chaos

The concept of A-coupled-expanding map, which is one of the more natural and useful ideas generalized the horseshoe map, is well known as a criterion of chaos. It is well known that distributional chaos is one of the concepts which reflect strong chaotic behaviour. In this paper, we focus the relations between A-coupled-expanding and distributional chaos. We prove two theorems that give sufficient conditions for a strictly A-coupled-expanding map to be distributionally chaotic in the senses of two kinds, where A is an irreducible transition matrix.Comment: 10 page

Exploring QSARs for Inhibitory Activity of Non-peptide HIV-1 Protease Inhibitors by GA-PLS and GA-SVM

The support vector machine (SVM) and partial least square (PLS) methods were used to develop quantitative structure activity relationship (QSAR) models to predict the inhibitory activity of non-peptide HIV-1 protease inhibitors. Genetic algorithm (GA) was employed to select variables that lead to the best-fitted models. A comparison between the obtained results using SVM with those of PLS revealed that the SVM model is much better than that of PLS. The root mean square errors of the training set and the test set for SVM model were calculated to be 0.2027, 0.2751, and the coefficients of determination (R(2)) are 0.9800, 0.9355 respectively. Furthermore, the obtained statistical parameter of leave-one-out cross-validation test (Q(2)) on SVM model was 0.9672, which proves the reliability of this model. The results suggest that TE2, Ui, GATS5e, Mor13e, ATS7m, Ss, Mor27e, and RDF035e are the main independent factors contributing to the inhibitory activities of the studied compounds.The authors would like to acknowledge the computational chemistry laboratory at Al-Quds University for providing Matlab software and for the time dedicated for performing the calculations of the study

AP-2α regulates migration of GN-11 neurons via a specific genetic programme involving the Axl receptor tyrosine kinase

<p>Abstract</p> <p>Background</p> <p>Neuronal migration is a crucial process that allows neurons to reach their correct target location to allow the nervous system to function properly. AP-2α is a transcription factor essential for neural crest cell migration and its mutation results in apoptosis within this cell population, as demonstrated by genetic models.</p> <p>Results</p> <p>We down-modulated AP-2α expression in GN-11 neurons by RNA interference and observe reduced neuron migration following the activation of a specific genetic programme including the Adhesion Related Kinase (<it>Axl</it>) gene. We prove that <it>Axl </it>is able to coordinate migration per se and by ChIP and promoter analysis we observe that its transcription is directly driven by AP-2α via the binding to one or more functional AP-2α binding sites present in its regulatory region. Analysis of migration in AP-2α null mouse embryo fibroblasts also reveals an essential role for AP-2α in cell movement via the activation of a distinct genetic programme.</p> <p>Conclusion</p> <p>We show that AP-2α plays an essential role in cell movement via the activation of cell-specific genetic programmes. Moreover, we demonstrate that the AP-2α regulated gene <it>Axl </it>is an essential player in GN-11 neuron migration.</p

Absence of Face-specific Cortical Activity in the Complete Absence of Awareness: Converging Evidence from Functional Magnetic Resonance Imaging and Event-related Potentials

In this study, we explored the neural correlates of perceptual awareness during a masked face detection task. To assess awareness more precisely than in previous studies, participants employed a 4-point scale to rate subjective visibility. An event-related fMRI and a high-density ERP study were carried out. Imaging data showed that conscious face detection was linked to activation of fusiform and occipital face areas. Frontal and parietal regions, including the pre-SMA, inferior frontal sulcus, anterior insula/frontal operculum, and intraparietal sulcus, also responded strongly when faces were consciously perceived. In contrast, no brain area showed face-selective activity when participants reported no impression of a face. ERP results showed that conscious face detection was associated with enhanced N170 and also with the presence of a second negativity around 300 msec and a slow positivity around 415 msec. Again, face-related activity was absent when faces were not consciously perceived. We suggest that, under conditions of backward masking, ventral stream and fronto-parietal regions show similar, strong links of face-related activity to conscious perception and stress the importance of a detailed assessment of awareness to examine activity related to unseen stimulus events

Spatial and Temporal Factors Affecting Human Visual Recognition Memory

The current thesis investigated the effects of a variety of spatial and temporal factors on visual recognition memory in human adults. Continuous recognition experiments investigated the effect of lag (the number of items intervening between study and test) on recognition of a variety of stimulus sets (common objects, face-like stimuli, fractals, trigrams), and determined that recognition of common objects was superior to that of other stimulus types. This advantage was largely eradicated when common objects of only one class (birds) were tested. Continuous recognition confounds the number of intervening items with the time elapsed between study and test presentations of stimuli. These factors were separated in an experiment comparing recognition performance at different rates of presentation. D-prime scores were affected solely by the number of intervening items, suggesting an interference-based explanation for the effect of lag. The role of interference was investigated further in a subsequent experiment examining the effect of interitem similarity on recognition. A higher level of global similarity amongst stimuli was associated with a lower sensitivity of recognition. Spatial separation between study and test was studied using same/different recognition of face-like stimuli, and spatial shifts between study and test locations. An initial study found a recognition advantage for stimuli that were studied and tested in the same peripheral location. However, the introduction of eye-tracking apparatus to verify fixation resulted in the eradication of this effect, suggesting that it was an artefact of uncontrolled fixation. Translation of both face-like and fractal stimuli between areas of different eccentricity, with different spatial acuities, did decrease recognition sensitivity, suggesting a partial positional specificity of visual memory. These phenomena were unaffected by 180 degree rotation. When interfering stimuli were introduced between study and test trials, translation invariance at a constant eccentricity broke down

Mechanistic insights into the roles and activities of polymerases in host and viral replication

Polymerases are vital enzymes in the continuation of life, responsible for the replication of genetic material and the conversion of genetic information to necessary products. A large subset of these polymerases is dedicated to the high-fidelity replication and repair of DNA in the cell cycle of organisms. In addition, viruses utilize polymerases in order to produce DNA or RNA used to synthesize products for virion assembly. With such an important role, polymerases have been a focus in many therapeutic studies of cancer and antiviral treatments. This dissertation focuses on three different polymerases, PrimPol, human immunodeficiency virus (HIV) reverse transcriptase (RT), and DNA polymerase α (Polα). The goal of this work was to understand their overall mechanisms and roles not only in the context of replication and repair, but also in antiviral therapies. HIV treatment, typically referred to as highly active antiretroviral therapy (HAART), consists of drugs that target various enzymes important for viral life cycle. A major fraction of these compounds, which target RT, can be classified into nucleoside (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). One prevailing issue with NRTIs is that administration of these drugs may cause off-target toxicity within patients, affecting adherence to treatment regimens. This off-target toxicity can be attributed to the incorporation of NRTIs by host polymerases, such as the mitochondrial polymerase γ (Polγ). To this end, I investigated the possibility of PrimPol, a recently characterized polymerase, in mediating the mitochondrial toxicity effects seen in HIV+ patients taking tenofovir (TFV)-containing treatments. Using gel-based kinetic assays, I validated that the active metabolite form of tenofovir is a substrate for PrimPol. Cellular-based assays using overexpression and knockdown PrimPol renal cells suggests that PrimPol likely plays a protective role against tenofovir-induced toxicity through its repriming activity, despite the in vitro incorporation evidence. Given this potential role of PrimPol in TFV toxicity, I biochemically assessed a PrimPol active site mutant in an HIV+ patient taking TFV. The mutant appears to have drastically reduced polymerase activity and complete loss of priming activity, which may predispose this patient to TFV toxicity. With NNRTIs, there are continuous development efforts to improve pharmacokinetic properties and combat drug resistance. To this end, a series of 2-naphthyl phenyl ether compounds were developed to target the Y181C mutation of RT. Interestingly, early structures of RT with these class of compounds showed two different binding modes that affected potency against the mutant. By solving structures of 2-naphthyl phenyl ether derivatives with WT and Y181C RT, we determined that the compounds that interact with W229 retain potency against the mutant. These studies will be important to consider in the development process of next generation NNRTIs. Polα, in complex with Primase, is similar to PrimPol by possessing the ability to carry out de novo synthesis of nucleic acid primers. The primary role of the Polα-Pri complex in the primosome is to produce Okazaki fragments during DNA replication in a coordinated manner. Where primase initiates the primer with ribonucleotides, Polα continues the initial primer with deoxyribonucleotides. Interestingly, recent evidence shows that after replication mutations are left over from Polα, which is low-fidelity and lacks a proofreading mechanism. To gain insight on Polα’s activity during replication, we solved the structure of Polα with two replication-like substrates (Polα:dNTP:RNA/DNA or DNA/DNA) and kinetically characterized its activity with these substrates. We observed that with the RNA/DNA structure, a kink in n-4 sugar on the RNA primer correlated to a decrease in activity of the enzyme. Our kinetic characterization also revealed that with the DNA/DNA strand, Polα had increased incorporation efficiency but lower processivity. Our studies provide evidence of how different nucleotide substrates may regulate polymerase activity during replication. Taken together, the studies of three different polymerases presented here provide a mechanistic and functional understanding of these polymerases in diseases and potential treatments. Ultimately, these findings will contribute to the development of therapies in diseases where polymerases play a vital role