Self-adaptive context aware audio localization for robots using parallel cerebellar models

An audio sensor system is presented that uses multiple cerebellar models to determine the acoustic environment in which a robot is operating, allowing the robot to select appropriate models to calibrate its audio-motor map for the detected environment. The use of the adaptive filter model of the cerebellum in a variety of robotics applications has demonstrated the utility of the so-called cerebellar chip. This paper combines the notion of cerebellar calibration of a distorted audio-motor map with the use of multiple parallel models to predict the context (acoustic environment) within which the robot is operating. The system was able to correctly predict seven different acoustic contexts in almost 70% of cases tested

Feed-forward selection of cerebellar models for calibration of robot sound source localization

We present a responsibility predictor, based on the adaptive filter model of the cerebellum, to provide feed-forward selection of cerebellar calibration models for robot Sound Source Localization (SSL), based on audio features extracted from the received audio stream. In previous work we described a system that selects the models based on sensory feedback, however, a drawback of that system is that it is only able to select a set of calibrators a-posteriori, after action (e.g. orienting a camera toward the sound source after a position estimate is made). The responsibility predictor improved the system performance compared to that without responsibility prediction. We show that a trained responsibility predictor is able to use contextual signals in the absence of ground truth to successfully select models with a performance approaching that of a system with full access to the ground truth through sensory feedback

The autism-linked UBE3A T485A mutant E3 ubiquitin ligase activates the Wnt/β-catenin pathway by inhibiting the proteasome

UBE3A is a HECT domain E3 ubiquitin ligase whose dysfunction is linked to autism, Angelman syndrome, and cancer. Recently, we characterized a de novo autism-linked UBE3A mutant (UBE3AT485A) that disrupts phosphorylation control of UBE3A activity. Through quantitative proteomics and reporter assays, we found that the UBE3AT485A protein ubiquitinates multiple proteasome subunits, reduces proteasome subunit abundance and activity, stabilizes nuclear β-catenin, and stimulates canonical Wnt signaling more effectively than wild-type UBE3A. We also found that UBE3AT485A activates Wnt signaling to a greater extent in cells with low levels of ongoing Wnt signaling, suggesting that cells with low basal Wnt activity are particularly vulnerable to UBE3AT485A mutation. Ligase-dead UBE3A did not stimulate Wnt pathway activation. Overexpression of several proteasome subunits reversed the effect of UBE3AT485A on Wnt signaling. We also observed that subunits that interact with UBE3A and affect Wnt signaling are located along one side of the 19S regulatory particle, indicating a previously unrecognized spatial organization to the proteasome. Altogether, our findings indicate that UBE3A regulates Wnt signaling in a cell context-dependent manner and that an autism-linked mutation exacerbates these signaling effects. Our study has broad implications for human disorders associated with UBE3A gain or loss of function and suggests that dysfunctional UBE3A might affect additional proteins and pathways that are sensitive to proteasome activity

FOXM1 Deubiquitination by USP21 Regulates Cell Cycle Progression and Paclitaxel Sensitivity in Basal-like Breast Cancer

The cell cycle transcription factor FOXM1 is activated in basal-like breast cancer (BLBC) and associated with therapeutic resistance and poor patient outcomes. Arceci et al. show USP21 antagonizes FOXM1 degradation, thereby promoting proliferation and paclitaxel resistance. USP21 is catalytically active and recurrently overexpressed in BLBC, representing a potential therapeutic target. © 2019 The Author(s)The transcription factor FOXM1 contributes to cell cycle progression and is significantly upregulated in basal-like breast cancer (BLBC). Despite its importance in normal and cancer cell cycles, we lack a complete understanding of mechanisms that regulate FOXM1. We identified USP21 in an RNAi-based screen for deubiquitinases that control FOXM1 abundance. USP21 increases the stability of FOXM1, and USP21 binds and deubiquitinates FOXM1 in vivo and in vitro, indicating a direct enzyme-substrate relationship. Depleting USP21 downregulates the FOXM1 transcriptional network and causes a significant delay in cell cycle progression. Significantly, USP21 depletion sensitized BLBC cell lines and mouse xenograft tumors to paclitaxel, an anti-mitotic, frontline therapy in BLBC treatment. USP21 is the most frequently amplified deubiquitinase in BLBC patient tumors, and its amplification co-occurs with the upregulation of FOXM1 protein. Altogether, these data suggest a role for USP21 in the proliferation and potentially treatment of FOXM1-high, USP21-high BLBC

Pore-scale Modeling of Viscous Flow and Induced Forces in Dense Sphere Packings

We propose a method for effectively upscaling incompressible viscous flow in large random polydispersed sphere packings: the emphasis of this method is on the determination of the forces applied on the solid particles by the fluid. Pore bodies and their connections are defined locally through a regular Delaunay triangulation of the packings. Viscous flow equations are upscaled at the pore level, and approximated with a finite volume numerical scheme. We compare numerical simulations of the proposed method to detailed finite element (FEM) simulations of the Stokes equations for assemblies of 8 to 200 spheres. A good agreement is found both in terms of forces exerted on the solid particles and effective permeability coefficients

Thiopeptides Induce Proteasome-Independent Activation of Cellular Mitophagy

Thiopeptide antibiotics are emerging clinical candidates that exhibit potent antibacterial activity against a variety of intracellular pathogens, including Mycobacterium tuberculosis (Mtb). Many thiopeptides directly inhibit bacterial growth by disrupting protein synthesis. However, recent work has shown that one thiopeptide, thiostrepton (TSR), can also induce autophagy in infected macrophages, which has the potential to be exploited for host-directed therapies against intracellular pathogens, such as Mtb. To better define the therapeutic potential of this class of antibiotics, we studied the host-directed effects of a suite of natural thiopeptides that spans five structurally diverse thiopeptide classes, as well as several analogs. We discovered that thiopeptides as a class induce selective autophagic removal of mitochondria, known as mitophagy. This activity is independent of other biological activities, such as proteasome inhibition or antibiotic activity. We also find that many thiopeptides exhibit potent activity against intracellular Mtb in macrophage infection models. However, the thiopeptide-induced mitophagy occurs outside of pathogen-containing autophagosomes and does not appear to contribute to thiopeptide control of intracellular Mtb. These results expand basic understanding of thiopeptide biology and provide key guidance for the development of new thiopeptide antibiotics and host-directed therapeutics

Inhibition of CDK1 by RO-3306 Exhibits Anti-Tumorigenic Effects in Ovarian Cancer Cells and a Transgenic Mouse Model of Ovarian Cancer

Ovarian cancer is the deadliest gynecological malignancy of the reproductive organs in the United States. Cyclin-dependent kinase 1 (CDK1) is an important cell cycle regulatory protein that specifically controls the G2/M phase transition of the cell cycle. RO-3306 is a selective, ATP-competitive, and cell-permeable CDK1 inhibitor that shows potent anti-tumor activity in multiple pre-clinical models. In this study, we investigated the effect of CDK1 expression on the prognosis of patients with ovarian cancer and the anti-tumorigenic effect of RO-3306 in both ovarian cancer cell lines and a genetically engineered mouse model of high-grade serous ovarian cancer (KpB model). In 147 patients with epithelial ovarian cancer, the overexpression of CDK1 was significantly associated with poor prognosis compared with a low expression group. RO-3306 significantly inhibited cellular proliferation, induced apoptosis, caused cellular stress, and reduced cell migration. The treatment of KpB mice with RO-3306 for four weeks showed a significant decrease in tumor weight under obese and lean conditions without obvious side effects. Overall, our results demonstrate that the inhibition of CDK1 activity by RO-3306 effectively reduces cell proliferation and tumor growth, providing biological evidence for future clinical trials of CDK1 inhibitors in ovarian cancer

In silico APC/C substrate discovery reveals cell cycle-dependent degradation of UHRF1 and other chromatin regulators

The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase and critical regulator of cell cycle progression. Despite its vital role, it has remained challenging to globally map APC/C substrates. By combining orthogonal features of known substrates, we predicted APC/C substrates in silico. This analysis identified many known substrates and suggested numerous candidates. Unexpectedly, chromatin regulatory proteins are enriched among putative substrates, and we show experimentally that several chromatin proteins bind APC/C, oscillate during the cell cycle, and are degraded following APC/C activation, consistent with being direct APC/C substrates. Additional analysis revealed detailed mechanisms of ubiquitylation for UHRF1, a key chromatin regulator involved in histone ubiquitylation and DNA methylation maintenance. Disrupting UHRF1 degradation at mitotic exit accelerates G1-phase cell cycle progression and perturbs global DNA methylation patterning in the genome. We conclude that APC/C coordinates crosstalk between cell cycle and chromatin regulatory proteins. This has potential consequences in normal cell physiology, where the chromatin environment changes depending on proliferative state, as well as in disease

Lower incidence rates but thicker melanomas in Eastern Europe before 1992: A comparison with Western Europe

The objective of this study was to investigate the epidemiology of melanoma across Europe with regard to Breslow thickness and body-site distribution. Incidence data from Cancer Incidence in 5 Continents and the EUROCARE-melanoma database were used: 28 117 melanoma cases from 20 cancer registries in 12 European countries, diagnosed between 1978 and 1992. Regression analysis and general linear modelling were used to analyse the data. Melanomas in Eastern Europe were on average 1.4 mm thicker (P<0.05) than in Western Europe and appeared more often on the trunk. From 1978 to 1992, their Breslow thickness had decreased in Western but not Eastern Europe. There was a latitude gradient in incidence, with highest rates in southern regions in Eastern Europe and an inverse gradient in Western Europe, with highest rates in the North. Mortality:incidence ratios were less favourable in southern parts across Europe, especially in Eastern Europe. If Eastern European populations copy the sunbathing behaviour of the West it is likely that in the near future a higher melanoma incidence can be expected there

Strategies in the use of light energy by Genipa spruceana Steyerm seedlings subjected to flooding

In an attempt to elucidate strategies in the use of light energy by G. spruceana seedlings subjected to flooding, we investigated the capacity of light capture and use of light energy by G. spruceana in three growing conditions: 1- absence of flooding (SA), 2- partially flooded (PA) and 3- totally flooded (TA). Destructive and non-destructive measurements, such as specific leaf area, chloroplast pigment (chlorophyll and carotenoids) content and fluorescence analyses, were made at regular intervals over a period of 90 days. All parameters decreased in seedlings subjected to flooding. Plants of treatment TA dropped all of their leaves after 30 days of complete submergence. Chloroplast pigment content differed between treatments SA and TA after 30 days from the start of the experiment; whereas SA and PA plants only differed for this variable after 90 days. Plants subjected to flooding (PA and TA) exhibited high dissipation of photochemical de-excitation (DIo/ABS), indicating a limited efficiency of light energy use. This fact was proven by the performance index (PI ABS) only in analyses after 90 days, and no significant difference was verified for PI ABS among treatments up to 30 days. Therefore, considering that G. spruceana seedlings subjected to flooding reduced the chloroplast pigment content more quickly than PI ABS, we suggest that the light energetic flux in G. spruceana seedlings subjected to flooding, in the beginning, is more restricted to a decrease in the structures that captures light (reduction chlorophyll pigment content) than how the photosynthetic apparatus functions (alterations in photochemical efficiency of photosystem II).Na tentativa de elucidar estratégias de utilização da energia luminosa em plantas jovens de Genipa spruceana Steyerm submetidas ao alagamento, nós investigamos a capacidade de captura e uso de energia luminosa em G. spruceana sob três condições de crescimento1- ausência de alagamento (SA), 2- plantas parcialmente alagadas (PA) e 3- plantas totalmente alagadas (TA). Medidas de área foliar específica, teores de pigmentos cloroplastídicos e fluorescência da clorofila a foram feitas em intervalos regulares no período de 90 dias. Todos os parâmetros analisados diminuíram em condições de alagamento (PA e TA). Aos 30 dias, as plantas no tratamento TA sofreram abscisão foliar. Os teores dos pigmentos cloroplastídicos (clorofilas e carotenóides) entre os tratamentos SA e TA diferiram aos 30 dias. Ao passo que, somente foi possível verificar diferenças entre os tratamentos SA e PA aos 90 dias. As plantas submetidas ao alagamento (PA e TA) exibiram alta dissipação de energia de excitação (DIo/ABS) indicando limitada eficiência na utilização da energia luminosa. Este fato foi comprovado pelos resultados do índice de desempenho (PI ABS) somente ao fim do período experimental (90 dias). Mas, não foi verificado diferença para PI ABS entre os tratamentos aos 30 dias. Portanto, considerando que G. spruceana submetidas ao tratamento TA reduziram seus teores de clorofilas mais rapidamente do que decrescem seus PI ABS, sugere-se que o fluxo de energia luminosa em plântulas de G. spruceana sob alagamento total, no início, é mais restringido pelo decréscimo na estrutura de captura de luz (diminuição dos pigmentos cloroplastídicos) do que no funcionamento do aparato fotossintético (alterações na eficiência fotoquímica do fotossistema II)