Modelling Visual Neglect: Computational Insights into Conscious Perception

Background

Visual neglect is an attentional deficit typically resulting from parietal cortex lesion and sometimes frontal lesion. Patients fail to attend to objects and events in the visual hemifield contralateral to their lesion during visual search.

Methodology/Principal Finding

The aim of this work was to examine the effects of parietal and frontal lesion in an existing computational model of visual attention and search and simulate visual search behaviour under lesion conditions. We find that unilateral parietal lesion in this model leads to symptoms of visual neglect in simulated search scan paths, including an inhibition of return (IOR) deficit, while frontal lesion leads to milder neglect and to more severe deficits in IOR and perseveration in the scan path. During simulations of search under unilateral parietal lesion, the model''s extrastriate ventral stream area exhibits lower activity for stimuli in the neglected hemifield compared to that for stimuli in the normally perceived hemifield. This could represent a computational correlate of differences observed in neuroimaging for unconscious versus conscious perception following parietal lesion.

Conclusions/Significance

Our results lead to the prediction, supported by effective connectivity evidence, that connections between the dorsal and ventral visual streams may be an important factor in the explanation of perceptual deficits in parietal lesion patients and of conscious perception in general.     

The Mechanics of Metastasis: Insights from a Computational Model

Although it may seem obvious that mechanical forces are required to drive metastatic cell movements, understanding of the mechanical aspects of metastasis has lagged far behind genetic and biochemical knowledge. The goal of this study is to learn about the mechanics of metastasis using a cell-based finite element model that proved useful for advancing knowledge about the forces that drive embryonic cell and tissue movements. Metastasis, the predominant cause of cancer-related deaths, involves a series of mechanical events in which one or more cells dissociate from a primary tumour, migrate through normal tissue, traverse in and out of a multi-layer circulatory system vessel and resettle. The present work focuses on the dissemination steps, from dissociation to circulation. The model shows that certain surface tension relationships must be satisfied for cancerous cells to dissociate from a primary tumour and that these equations are analogous to those that govern dissociation of embryonic cells. For a dissociated cell to then migrate by invadopodium extension and contraction and exhibit the shapes seen in experiments, the invadopodium must generate a contraction equal to approximately twice that produced by the interfacial tension associated with surrounding cells. Intravasation through the wall of a vessel is governed by relationships akin to those in the previous two steps, while release from the vessel wall is governed by equations that involve surface and interfacial tensions. The model raises a number of potential research questions. It also identifies how specific mechanical properties and the sub-cellular structural components that give rise to them might be changed so as to thwart particular metastatic steps and thereby block the spread of cancer.     

The ADAM family: Insights into Notch proteolysis

Notch signaling is integral to a large number of developmental and homeostasis events, and either gain or loss of Notch signaling results in a wide range of defects. Notch must be processed by several proteases, including a member of the ADAM (a disintegrin and metalloprotease) family to mediate downstream signaling. Until recently, interactions of Notch with specific ADAMs in different contexts were unclear. ADAM10 is now known to be specifically essential for development and homeostasis of mouse epidermis and cardiovascular structures, and ADAM17 may not be able to fully replace ADAM10 in these contexts. However, Notch from T-cell acute lymphoblastic leukemia (T-ALL) patients can be cleaved by both ADAMs 10 and 17. Studies have revealed that ADAM10 is necessary for Notch processing when Notch is activated by a ligand, while ADAM17 is the major protease for processing Notch that is activated independently of ligand in both flies and mammals.     

New Insights into Measurement Variability in Glaucomatous Visual Fields from Computer Modelling

Objective

To develop a model to simulate visual fields (VFs) in glaucoma patients, and to characterize variability of the Mean Deviation (MD) VF summary measurement using real VFs and simulations.

Methods

Pointwise VF variability was previously approximated using longitudinal VF data (24–2 SITA Standard, Humphrey Field Analyzer) from 2,736 patients; these data were used to build a non-parametric model to simulate VFs. One million VF simulations were generated from 1,000 VFs (1,000 simulations per ‘ground-truth’ VF), and the variability of simulated MDs was characterized as a function of ground-truth MD and Pattern Standard Deviation (PSD).

Results

The median (interquartile range, IQR) patient age and MD was 66 (56 to 75) years and −3.5 (−8.3 to −1.1) decibels, respectively. The inferred variability as a function of ground-truth MD and PSD indicated that variability, on average, increased rapidly as glaucoma worsened. However, the pattern of VF damage significantly affects the level of MD variability, with more than three-fold differences between patients with approximately the same levels of MD but different patterns of loss.

Conclusions

A novel approach for simulating VFs is introduced. A better understanding of VF variability will help clinicians to differentiate real VF progression from measurement variability. This study highlights that, overall, MD variability increases as the level of damage increases, but variability is highly dependent on the pattern of VF damage. Future research, using VF simulations, could be employed to provide benchmarks for measuring the performance of VF progression detection algorithms and developing new strategies for measuring VF progression.     

Phonological Units in Spoken Word Production: Insights from Cantonese

Evidence from previous psycholinguistic research suggests that phonological units such as phonemes have a privileged role during phonological planning in Dutch and English (aka the segment-retrieval hypothesis). However, the syllable-retrieval hypothesis previously proposed for Mandarin assumes that only the entire syllable unit (without the tone) can be prepared in advance in speech planning. Using Cantonese Chinese as a test case, the present study was conducted to investigate whether the syllable-retrieval hypothesis can be applied to other Chinese spoken languages. In four implicit priming (form-preparation) experiments, participants were asked to learn various sets of prompt-response di-syllabic word pairs and to utter the corresponding response word upon seeing each prompt. The response words in a block were either phonologically related (homogeneous) or unrelated (heterogeneous). Participants'' naming responses were significantly faster in the homogeneous than in the heterogeneous conditions when the response words shared the same word-initial syllable (without the tone) (Exps.1 and 4) or body (Exps.3 and 4), but not when they shared merely the same word-initial phoneme (Exp.2). Furthermore, the priming effect observed in the syllable-related condition was significantly larger than that in the body-related condition (Exp. 4). Although the observed syllable priming effects and the null effect of word-initial phoneme are consistent with the syllable-retrieval hypothesis, the body-related (sub-syllabic) priming effects obtained in this Cantonese study are not. These results suggest that the syllable-retrieval hypothesis is not generalizable to all Chinese spoken languages and that both syllable and sub-syllabic constituents are legitimate planning units in Cantonese speech production.     

Computational Modeling and Molecular Physiology Experiments Reveal New Insights into Shoot Branching in Pea

Bud outgrowth is regulated by the interplay of multiple hormones, including auxin, cytokinin, strigolactones, and an unidentified long-distance feedback signal that moves from shoot to root. The model of bud outgrowth regulation in pea (Pisum sativum) includes these signals and a network of five RAMOSUS (RMS) genes that operate in a shoot-root-shoot loop to regulate the synthesis of, and response to, strigolactones. The number of components in this network renders the integration of new and existing hypotheses both complex and cumbersome. A hypothesis-driven computational model was therefore developed to help understand regulation of shoot branching. The model evolved in parallel with stepwise laboratory research, helping to define and test key hypotheses. The computational model was used to verify new mechanisms involved in the regulation of shoot branching by confirming that the new hypotheses captured all relevant biological data sets. Based on cytokinin and RMS1 expression analyses, this model is extended to include subtle but important differences in the function of RMS3 and RMS4 genes in the shoot and rootstock. Additionally, this research indicates that a branch-derived signal upregulates RMS1 expression independent of the other feedback signal. Furthermore, we propose xylem-sap cytokinin promotes sustained bud outgrowth, rather than acting at the earlier stage of bud release.     

The Fog signaling pathway: Insights into signaling in morphogenesis

Epithelia form the building blocks of many tissue and organ types. Epithelial cells often form a contiguous 2-dimensional sheet that is held together by strong adhesions. The mechanical properties conferred by these adhesions allow the cells to undergo dramatic three-dimensional morphogenetic movements while maintaining cell–cell contacts during embryogenesis and post-embryonic development. The Drosophila Folded gastrulation pathway triggers epithelial cell shape changes that drive gastrulation and tissue folding and is one of the most extensively studied examples of epithelial morphogenesis. This pathway has yielded key insights into the signaling mechanisms and cellular machinery involved in epithelial remodeling. In this review, we discuss principles of morphogenesis and signaling that have been discovered through genetic and cell biological examination of this pathway. We also consider various regulatory mechanisms and the system?s relevance to mammalian development. We propose future directions that will continue to broaden our knowledge of morphogenesis across taxa.     

Computational Modeling of the Hematopoietic Erythroid-Myeloid Switch Reveals Insights into Cooperativity, Priming, and Irreversibility

Hematopoietic stem cell lineage choices are decided by genetic networks that are turned ON/OFF in a switch-like manner. However, prior to lineage commitment, genes are primed at low expression levels. Understanding the underlying molecular circuitry in terms of how it governs both a primed state and, at the other extreme, a committed state is of relevance not only to hematopoiesis but also to developmental systems in general. We develop a computational model for the hematopoietic erythroid-myeloid lineage decision, which is determined by a genetic switch involving the genes PU.1 and GATA-1. Dynamical models based upon known interactions between these master genes, such as mutual antagonism and autoregulation, fail to make the system bistable, a desired feature for robust lineage determination. We therefore suggest a new mechanism involving a cofactor that is regulated as well as recruited by one of the master genes to bind to the antagonistic partner that is necessary for bistability and hence switch-like behavior. An interesting fallout from this architecture is that suppression of the cofactor through external means can lead to a loss of cooperativity, and hence to a primed state for PU.1 and GATA-1. The PU.1–GATA-1 switch also interacts with another mutually antagonistic pair, C/EBPα–FOG-1. The latter pair inherits the state of its upstream master genes and further reinforces the decision due to several feedback loops, thereby leading to irreversible commitment. The genetic switch, which handles the erythroid-myeloid lineage decision, is an example of a network that implements both a primed and a committed state by regulating cooperativity through recruitment of cofactors. Perturbing the feedback between the master regulators and downstream targets suggests potential reprogramming strategies. The approach points to a framework for lineage commitment studies in general and could aid the search for lineage-determining genes.     

肠道菌群与病毒性肺炎关系的研究进展

在21世纪头20年里,呼吸道病毒造成的地区性乃至世界性的流行已经发生多次,而疫情的暴发严重威胁人类健康与生存,但临床上,仍缺乏针对病毒的特异性治疗手段。随着肠道微生态相关研究的广泛开展,肠道菌群在哮喘,纤维化及细菌性感染等多种肺部疾病的发病及防治中发挥着重要作用,成为"肠-肺轴"的关键枢纽。病毒性肺炎与肠道微生态间也存在着紧密的相互联系,通过改善肠道菌群,对呼吸病毒感染具有较好的防治作用。其内在机制主要涉及到:通过增强肠道黏膜屏障功能、减少继发性细菌的感染;通过菌体成分或者代谢产物如短链脂肪酸,色氨酸代谢产物等提高固有样淋巴细胞(Innate lymphoid cells,ILC)、单核-巨噬细胞、树突状细胞、自然杀伤细胞(Natural killer,NK)、粒细胞等固有免疫细胞的抗病毒免疫功能及调节Th17/Treg平衡抑制过度的炎症反应等。本文将系统回顾已发表的文章,对肠道菌群在病毒性肺炎方面的研究作系统的阐述,以求为研究者在病毒性肺炎的机制探究和防治方面提供帮助。     

Insights into plant immunity signaling: The bacterial competitive index angle

The interaction between a bacterial pathogen and its potential plant host develops from a complex combination of bacterial and plant elements, which determines either the establishment of resistance or the development of disease. The use of virulence assays based on competitive index in mixed infections constitutes a powerful tool for the analysis of bacterial virulence factors. In this work, we describe how the use of competitive index assays also constitutes an alternative approach for the analysis of plant immunity, to determine the contribution of different elements to bacterial recognition or immunity signaling.Key words: competitive index, mixed infections, pathogen, plant immunity, defence response, effector-triggered immunityThe type III secretion system (T3SS) allows Gram negative bacterial pathogens to deliver a set of effector proteins into the host cell. The plant pathogen Pseudomonas syringae employs a large inventory of type III-secreted effectors (T3SEs) to suppress plant immunity. Individual mutation of effector genes has traditionally failed to provide a relevant virulence phenotype, a fact generally associated to a high degree of functional redundancy between T3SEs, which also hinders the characterisation of effector activities within the plant cell. This problem has led researchers to use alternative approaches to overcome functional redundancy, including the generation of polymutants lacking several effector genes, ectopic expression of effectors in heterologous strains lacking the corresponding homolog, as well as the generation of transgenic plants expressing a given effector.¹ We have previously established that the use of competitive index in mixed infections provides an accurate and sensitive manner of establishing virulence phenotypes for single effector mutants for which other assays have failed,² thus providing an alternative to previously used approaches for the analysis of effector function within the context of the infection. This increase in sensitivity and accuracy is due to the direct comparison between growth of the co-inoculated strains within the same infection (Fig. 1), which replicate as they would in individual infections under the appropriate experimental settings.²Open in a separate windowFigure 1Basis for the increased sensitivity and acuracy of CI assays. A mixed inoculum with equal amounts of wild type and query strain is inoculated within the same plant (A), allowing a direct comparison between the replication values of both strains within the same infection (B). On the contrary, in regular individual infections, the values obtained from different plants have to be pulled first and compared afterwards (B), thus accumulating experimental and plant-to-plant variation.Plant immunity can be triggered by a group of conserved microbial molecules known as PAMPs (pathogen-associated molecular patterns). PAMP-triggered immunity (PTI) can be suppressed by effectors which in turn can be recognized by nucleotide binding-leucine rich repeat (NB-LRR) proteins, encoded by resistance genes or R genes.^3,4 Detection of such effectors by NB-LRR proteins determines effector-triggered immunity (ETI),³ an amplified version of PTI, which usually crosses the threshold inducing the hypersensitive response (HR), a localized cell death response. Furthermore, bacteria have evolved effectors that suppress ETI, some of which can in turn be recognized by the plant, thus triggering a secondary ETI.⁴ Selection favors new plant NB-LRRs that can recognize such secondary, newly acquired effectors.R-gene-mediated defences are usually associated with the accumulation of salycilic acid (SA),⁵ although SA-independent pathways such as that dependent on EDS1 (enhanced disease susceptibility-1),⁶ can also mediate ETI and trigger an HR.⁷ Although regulating independent pathways, EDS1 and SA have been recently described to function redundantly to regulate R-gene-mediated signaling.⁸     

The prion protein and its ligands: Insights into structure-function relationships

The prion protein is a multifunctional protein that exists in at least two different folding states. It is subject to diverse proteolytic processing steps that lead to prion protein fragments some of which are membrane-bound whereas others are soluble. A multitude of ligands bind to the prion protein and besides proteinaceous binding partners, interaction with metal ions and nucleic acids occurs. Although of great importance, information on structural and functional consequences of prion protein binding to its partners is limited. Here, we will reflect on the structure-function relationship of the prion protein and its binding partners considering the different folding states and prion protein fragments.     

Stem cells: Insights into the secretome

Stem cells have been considered as possible therapeutic vehicles for different health related problems such as cardiovascular and neurodegenerative diseases and cancer. Secreted molecules are key mediators in cell–cell interactions and influence the cross talk with the surrounding tissues. There is strong evidence supporting that crucial cellular functions such as proliferation, differentiation, communication and migration are strictly regulated from the cell secretome. The investigation of stem cell secretome is accumulating continuously increasing interest given the potential use of these cells in regenerative medicine. The scope of the review is to report the main findings from the investigation of stem cell secretome by the use of contemporary proteomics methods and discuss the current status of research in the field. This article is part of a Special Issue entitled: An Updated Secretome.     

DNA Methylation: Insights into Human Evolution

A fundamental initiative for evolutionary biologists is to understand the molecular basis underlying phenotypic diversity. A long-standing hypothesis states that species-specific traits may be explained by differences in gene regulation rather than differences at the protein level. Over the past few years, evolutionary studies have shifted from mere sequence comparisons to integrative analyses in which gene regulation is key to understanding species evolution. DNA methylation is an important epigenetic modification involved in the regulation of numerous biological processes. Nevertheless, the evolution of the human methylome and the processes driving such changes are poorly understood. Here, we review the close interplay between Cytosine-phosphate-Guanine (CpG) methylation and the underlying genome sequence, as well as its evolutionary impact. We also summarize the latest advances in the field, revisiting the main literature on human and nonhuman primates. We hope to encourage the scientific community to address the many challenges posed by the field of comparative epigenomics.     

视觉中文词汇识别的整体优先效应和词内核证原则:来自ERPs的证据

目的:以视觉的汉语真假双字词为材料,用词汇判断任务考察词汇加工过程与表征的关系.方法:记录了16名被试者的行为数据和ERPs数据.结果:①真词的反应时间显著短于假词.②真词和假词均诱发了明显的N1、P2、N2、P3、N400、P600成分.③假词的N2波幅显著大于真词;假词的P3波幅、潜伏期显著小于真词.④假词的N400波幅显著小于真词,假词减真词的差异波波幅表现出显著的半球效应,左半球大于右半球.⑤假词的P600潜伏期显著长于真词.结论:N2、P3成分分别反映了词汇认知加工早期对心理表征的匹配和评价、注意的分配;N400、P600成分分别反映了词汇认知加工晚期词素之间的语义冲突和词素之间语义、句法等关系的整合.研究结果证明了中文双字词识别的整体优先效应和词内核证原则,支持了词汇后加工的观点,为假词反应时长于真词提供了电生理证据.     

Mitochondrial Oscillations and Waves in Cardiac Myocytes: Insights from Computational Models

Periodic cellwide depolarizations of mitochondrial membrane potential (Ψ_M) which are triggered by reactive oxygen species (ROS) and propagated by ROS-induced ROS release (RIRR) have been postulated to contribute to cardiac arrhythmogenesis and injury during ischemia/reperfusion. Two different modes of RIRR have been described: Ψ_M oscillations involving ROS-sensitive mitochondrial inner membrane anion channels (IMAC), and slow depolarization waves related to mitochondrial permeability transition pore (MPTP) opening. In this study, we developed a computational model of mitochondria exhibiting both IMAC-mediated RIRR and MPTP-mediated RIRR, diffusively coupled in a spatially extended network, to study the spatiotemporal dynamics of RIRR on Ψ_M. Our major findings are: 1), as the rate of ROS production increases, mitochondria can exhibit either oscillatory dynamics facilitated by IMAC opening, or bistable dynamics facilitated by MPTP opening; 2), in a diffusively-coupled mitochondrial network, the oscillatory dynamics of IMAC-mediated RIRR results in rapidly propagating (∼25 μm/s) cellwide Ψ_M oscillations, whereas the bistable dynamics of MPTP-mediated RIRR results in slow (0.1-2 μm/s) Ψ_M depolarization waves; and 3), the slow velocity of the MPTP-mediated depolarization wave is related to competition between ROS scavenging systems and ROS diffusion. Our observations provide mechanistic insights into the spatiotemporal dynamics underlying RIRR-induced Ψ_M oscillations and waves observed experimentally in cardiac myocytes.