Sound changes that lead to seeing longer-lasting shapes

Published online: 29 January 2018To survive, people must construct an accurate representation of the world around them. There is a body of research on visual scene analysis, and a largely separate literature on auditory scene analysis. The current study follows up research from the smaller literature on audiovisual scene analysis. Prior work demonstrated that when there is an abrupt size change to a moving object, observers tend to see two objects rather than one—the abrupt visual change enhances visible persistence of the briefly presented different-sized object. Moreover, if a sequence of tones accompanies the moving object, visible persistence is enhanced if the tone frequency suddenly changes at the same time that the object’s size changes. Here, we show that although a sound change must occur at roughly the same time as a visual change to enhance visible persistence, there is a fairly wide time frame during which the sound change can occur. In addition, the impact of a sound change on visible persistence is not simply matter of the physical pattern: The same pattern of sound can enhance visible persistence or not, depending on how the pattern is itself perceived. Specifically, a change in a tone’s frequency can enhance visible persistence when it accompanies a visual size change, but the same frequency change will not do so if the shift is embedded in a larger pattern that makes the change merely a continuation of alternating frequencies. The current study supports a scene analysis process that is both multimodal and actively constructive.Support was provided by Ministerio de Ciencia E Innovacion, Grant PSI-2014-53277, Centro de Excelencia Severo Ochoa, Grant SEV-2015-0490, and by the National Science Foundation under Grant IBSS-1519908

Resistance mechanisms to targeted therapy in BRAF-mutant melanoma - A mini review

Background The introduction of targeted therapies for the treatment of BRAF-mutant melanomas have improved survival rates in a significant proportion of patients. Nonetheless, the emergence of resistance to treatment remains inevitable in most patients. Scope of review Here, we review known and emerging molecular mechanisms that underlay the development of resistance to MAPK inhibition in melanoma cells and the potential strategies to overcome these mechanisms. Major conclusions Multiple genetic and non-genetic mechanisms contribute to treatment failure, commonly leading to the reactivation of the MAPK pathway. A variety of resistance mechanisms are enabled by the underlying heterogeneity and plasticity of melanoma cells. Moreover, it has become apparent that resistance to targeted therapy is underpinned by early functional adaptations involving the rewiring of cell states and metabolic pathways. General significance The evidence presented suggest that the use of a combinatorial treatment approach would delay the emergence of resistance and improve patient outcomes

Identification and characterisation of putative drug binding sites in human ATP-binding cassette B5 (ABCB5) transporter.

The human ATP-binding cassette B5 (ABCB5) transporter, a member of the ABC transporter superfamily, is linked to chemoresistance in tumour cells by drug effluxion. However, little is known about its structure and drug-binding sites. In this study, we generated an atomistic model of the full-length human ABCB5 transporter with the highest quality using the X-ray crystal structure of mouse ABCB1 (Pgp1), a close homologue of ABCB5 and a well-studied member of the ABC family. Molecular dynamics simulations were used to validate the atomistic model of ABCB5 and characterise its structural properties in model cell membranes. Molecular docking simulations of known ABCB5 substrates such as taxanes, anthracyclines, camptothecin and etoposide were then used to identify at least three putative binding sites for chemotherapeutic drugs transported by ABCB5. The location of these three binding sites is predicted to overlap with the corresponding binding sites in Pgp1. These findings will serve as the basis for future in vitro studies to validate the nature of the identified substrate-binding sites in the full-length ABCB5 transporter

Identification and characterisation of putative drug binding sites in human ATP-binding cassette B5 (ABCB5) transporter

© 2020 The Author(s) The human ATP-binding cassette B5 (ABCB5) transporter, a member of the ABC transporter superfamily, is linked to chemoresistance in tumour cells by drug effluxion. However, little is known about its structure and drug-binding sites. In this study, we generated an atomistic model of the full-length human ABCB5 transporter with the highest quality using the X-ray crystal structure of mouse ABCB1 (Pgp1), a close homologue of ABCB5 and a well-studied member of the ABC family. Molecular dynamics simulations were used to validate the atomistic model of ABCB5 and characterise its structural properties in model cell membranes. Molecular docking simulations of known ABCB5 substrates such as taxanes, anthracyclines, camptothecin and etoposide were then used to identify at least three putative binding sites for chemotherapeutic drugs transported by ABCB5. The location of these three binding sites is predicted to overlap with the corresponding binding sites in Pgp1. These findings will serve as the basis for future in vitro studies to validate the nature of the identified substrate-binding sites in the full-length ABCB5 transporter

Anti-inflammatory, anti-nociceptive and antipyretic activity of young and old leaves of Vernonia amygdalina

Background Both young and old leaves of Vernonia amygdalina (VA) are traditionally used to treat inflammation, pain and fever. However, the efficacy of young and old leaves for treating these ailments have not been compared till date. Aim To ascertain the effect of young and old leaves of VA in managing inflammation, pain and fever. Methods Both quantitative and qualitative phytochemical screening of ethanol extracts of young (EthYL) and old (EthOL) leaves of VA were performed. The anti-inflammatory activity of orally administered EthYL and EthOL (50–200 mg/kg) and Diclofenac (10 mg/kg) were evaluated in carrageenan-induced inflammation model in rats. Antipyretic activity of EthYL, EthOL and Aspirin (25 mg/kg) were assessed in the Baker’s yeast-induced pyrexia model. Anti-allodynic effect of both extracts were evaluated by inserting inflamed paws of rats in cold water. Antinociceptive property of the extracts were assessed using tail withdrawal and formalin-induced nociception test. Histopathological examination of the paws was performed, in addition to formalin test to understand the possible mechanism of action of the extracts. Negative control rats received 2 ml/kg normal saline in all tests. Results The amount of flavonoids, alkaloids, tannins, and phenolics were significantly (p \u3c 0.05) higher in EthOL than EthYL, while saponins were significantly higher (p \u3c 0.05) in EthYL than EthOL. The antioxidant ability and total antioxidant capacity were significantly (p \u3c 0.05) higher in EthYL than EthOL. However, this was significantly (p \u3c 0.05) lower than the anti-oxidant activity of Ascorbic acid. A dose-dependent increase in anti-inflammatory, antipyretic and antinociceptive properties were observed in both EthYL and EthOL, similar to the standard drugs. Mast cell degranulation accompanied by vasodilatation and high leukocytosis were observed in the negative control, but were markedly low in extract treated groups. Both extracts mediated their analgesic effect through opioidergic and nitric oxide pathways with EthYL additionally implicating the muscarinic cholinergic system. Conclusion Although both EthYL and EthOL alleviate inflammation, pyrexia and nociception, EthYL of VA was found to be more potent than EthOL

AMPA Receptor Surface Expression Is Regulated by S-Nitrosylation of Thorase and Transnitrosylation of NSF

Umanah et al. show that the S-nitrosylation of Thorase and the transnitrosylation of NSF are responsible for NMDAR-activated trafficking of AMPARs underlying synaptic plasticity. © 2020 The Author(s) The regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking affects multiple brain functions, such as learning and memory. We have previously shown that Thorase plays an important role in the internalization of AMPARs from the synaptic membrane. Here, we show that N-methyl-D-aspartate receptor (NMDAR) activation leads to increased S-nitrosylation of Thorase and N-ethylmaleimide-sensitive factor (NSF). S-nitrosylation of Thorase stabilizes Thorase-AMPAR complexes and enhances the internalization of AMPAR and interaction with protein-interacting C kinase 1 (PICK1). S-nitrosylated NSF is dependent on the S-nitrosylation of Thorase via trans-nitrosylation, which modulates the surface insertion of AMPARs. In the presence of the S-nitrosylation-deficient C137L Thorase mutant, AMPAR trafficking, long-term potentiation, and long-term depression are impaired. Overall, our data suggest that both S-nitrosylation and interactions of Thorase and NSF/PICK1 are required to modulate AMPAR-mediated synaptic plasticity. This study provides critical information that elucidates the mechanism underlying Thorase and NSF-mediated trafficking of AMPAR complexes. © 2020 The Author(s)1

An investigation on role of the ATP-binding cassette B5 (ABCB5) transporter as potential mediator of melanoma resistance to BRAF inhibition

Cutaneous melanoma is a highly metastatic and drug-resistant skin cancer type, responsible for a disproportionate number of skin cancer deaths. Targeted therapies, in the form of BRAF inhibitors (BRAFis), have been effective at treating BRAFV600 mutant melanomas. However, majority of the melanoma patients fail to respond to BRAFis due to intrinsic or acquired resistance within one year of treatment commencement. Multiple mechanisms that contribute to BRAFi resistance in melanoma cells have been identified, as discussed in the review in Chapter 1. Overexpression of ATP-binding cassette (ABC) transporters has been linked to multidrug resistance in numerous cancer types. These transporters expel the anti-cancer drugs out of the cell, thereby decreasing the intracellular concentration of the drug. In melanoma, the ATP-binding cassette B5 transporter (a member of ABC superfamily) has been linked to chemoresistance by drug extrusion. Moreover, overexpression of ABCB5 has been observed in BRAFV600 melanoma cells after short-term BRAFi treatment. In this study we investigated the role of the ABCB5 transporter as potential mediators of resistance to BRAFis by drug expulsion. In Chapter 2, we showed increased ABCB5 expression in melanoma cell lines after short-term treatment with the BRAFis accompanied by an increased expression of melanocytic signature. Gene expression of fluorescent activated cell sorted melanoma cells into ABCB5high and ABCB5low populations, revealed an increased melanocytic signature in the ABCB5high population. Moreover, analysis of single-cell RNA sequencing (scRNAseq) data of two BRAFV600 melanoma cell lines, A2058 and 451Lu, revealed a strong association between ABCB5 expression and melanocytic signature. Based on these initial observations, the capacity of the ABCB5 transporter to efflux BRAFis was evaluated indirectly through an in-silico approach using molecular docking simulations (Chapter 3 and 4), and directly through in vitro experiments using an ABCB5 overexpressing melanoma BRAFV600 cell line (Chapter 5). In Chapter 3, a full-length ABCB5 model was generated, based on mouse ATP-binding cassette B1 transporter (ABCB1; Pgp1), a close homologue of ABCB5. Molecular dynamics simulations were performed in 2 model cell membranes and the dominant conformation was identified. Docking simulations of known ABCB5 substrates such as taxanes, anthracyclines, camptothecin and etoposide enabled the identification of at least three putative substrate binding sites in ABCB5. The overlap of these three binding sites with validated binding sites for these chemotherapeutic drugs in Pgp1 corroborate our findings. In Chapter 4, docking simulations revealed at least one overlapping binding site for BRAFis and chemotherapeutic drugs on ABCB5, suggesting that BRAFis could potentially act as a substrate for ABCB5. In Chapter 5, we generated an ABCB5 overexpressing BRAFV600E melanoma cell line. However, no differences in sensitivity to BRAF inhibition was observed as a result of ABCB5 overexpression. Intracellular drug accumulation analyses revealed no reduction in vemurafenib or dabrafenib concentrations, indicating that BRAFis do not act as substrates for ABCB5. Altogether, our studies suggest that ABCB5 expression is linked to the melanocytic program. However, despite the molecular docking evidence that BRAFis may be substrates of ABCB5, in vitro studies failed to demonstrate direct efflux of BRAFis by ABCB5