Reading in many alphabetic writing systems depends on both item-specific knowledge used to read irregular words (sew, yacht) and generative spelling-sound knowledge used to read pseudowords (tew, ...yash). Research into the neural basis of these abilities has been directed largely by cognitive accounts proposed by the dual-route cascaded and triangle models of reading. We develop a framework that enables predictions for neural activity to be derived from cognitive models of reading using 2 principles: (a) the extent to which a model component or brain region is engaged by a stimulus and (b) how much effort is exerted in processing that stimulus. To evaluate the derived predictions, we conducted a meta-analysis of 36 neuroimaging studies of reading using the quantitative activation likelihood estimation technique. Reliable clusters of activity are localized during word versus pseudoword and irregular versus regular word reading and demonstrate a great deal of convergence between the functional organization of the reading system put forward by cognitive models and the neural systems activated during reading tasks. Specifically, left-hemisphere activation clusters are revealed reflecting orthographic analysis (occipitotemporal cortex), lexical and/or semantic processing (anterior fusiform, middle temporal gyrus), spelling-sound conversion (inferior parietal cortex), and phonological output resolution (inferior frontal gyrus). Our framework and results establish that cognitive models of reading are relevant for interpreting neuroimaging studies and that neuroscientific studies can provide data relevant for advancing cognitive models. This article thus provides a firm empirical foundation from which to improve integration between cognitive and neural accounts of the reading process.
The molecular processes that contribute to degenerative diseases are not well understood. Recent observations suggest that some degenerative diseases are promoted by the accumulation of nuclear or ...cytoplasmic RNA-protein (RNP) aggregates, which can be related to endogenous RNP granules. RNP aggregates arise commonly in degenerative diseases because RNA-binding proteins commonly self-assemble, in part through prion-like domains, which can form self-propagating amyloids. RNP aggregates may be toxic due to multiple perturbations of posttranscriptional control, thereby disrupting the normal “ribostasis” of the cell. This suggests that understanding and modulating RNP assembly or clearance may be effective approaches to developing therapies for these diseases.
Over the past decade, phase transitions have emerged as a fundamental mechanism of cellular organization. In parallel, a wealth of evidence has accrued indicating that aberrations in phase ...transitions are early events in the pathogenesis of several neurodegenerative diseases. We review the key evidence of defects at multiple levels, from phase transition of individual proteins to the dynamic behavior of complex, multicomponent condensates in neurodegeneration. We also highlight two concepts, dynamical arrest and heterotypic buffering, that are key to understanding how pathological phase transitions relate to pleiotropic defects in cellular functions and the accrual of proteinaceous deposits at end-stage disease. These insights not only illuminate disease etiology but also are likely to guide the development of therapeutic interventions to restore homeostasis.
Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by degeneration of upper and lower motor neurons in the brain and spinal cord. The hallmark ...pathological feature in most cases of ALS is nuclear depletion and cytoplasmic accumulation of the protein TDP-43 in degenerating neurons. Consistent with this pattern of intracellular protein redistribution, impaired nucleocytoplasmic trafficking has emerged as a mechanism contributing to ALS pathology. Dysfunction in nucleocytoplasmic transport is also an emerging theme in physiological aging and other related neurodegenerative diseases, such as Huntington’s and Alzheimer’s diseases. Here we review transport through the nuclear pore complex, pointing out vulnerabilities that may underlie ALS and potentially contribute to this and other age-related neurodegenerative diseases.
Kim and Taylor provide an overview of transport through the nuclear pore complex, and they review the evidence suggesting that defects in nucleocytoplasmic transport contribute to ALS and perhaps other age-related neurodegenerative diseases.
Stress granules and P bodies are conserved cytoplasmic aggregates of nontranslating messenger ribonucleoprotein complexes (mRNPs) implicated in the regulation of mRNA translation and decay and are ...related to RNP granules in embryos, neurons, and pathological inclusions in some degenerative diseases. Using baker’s yeast, 125 genes were identified in a genetic screen that affected the dynamics of P bodies and/or stress granules. Analyses of such mutants, including CDC48 alleles, provide evidence that stress granules can be targeted to the vacuole by autophagy, in a process termed granulophagy. Moreover, stress granule clearance in mammalian cells is reduced by inhibition of autophagy or by depletion or pathogenic mutations in valosin-containing protein (VCP), the human ortholog of CDC48. Because mutations in VCP predispose humans to amyotrophic lateral sclerosis, frontotemporal lobar degeneration, inclusion body myopathy, and multisystem proteinopathy, this work suggests that autophagic clearance of stress granule related and pathogenic RNP granules that arise in degenerative diseases may be important in reducing their pathology.
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•Network of 125 genes identified affecting stress-granule and P body dynamics in yeast•Stress granules are cleared by autophagy in yeast and mammalian cells•Cdc48/VCP facilitates stress-granule clearance•Autophagy of related mRNP aggregates may help avoid degenerative pathology
Proteins linked to modulating stress-granule levels include key autophagy factors, and regulation of these RNP aggregates by autophagic clearance, involving VCP/Cdc48, is conserved in yeast and mammalian cells; this has implications for addressing these kinds of aggregates in neuronal pathologies.
In the current decade, the U.S. population reached historically high levels of ethnic–racial diversity and reelected the nation's first Black–White biracial President. Simultaneously, scholars also ...documented significant ethnic–racial inequities in education, increased xenophobia, and a racial climate that revealed deep‐seated ethnic–racial tensions. Given this backdrop and acknowledging the significant role that families play in youths' abilities to navigate their social contexts, the current review focused on the literature on families' ethnic–racial socialization efforts with youth from the 2010 decade. Our review of 259 empirical articles revealed that there has been an exponential increase in research on family ethnic–racial socialization in this decade. Furthermore, although it is clear that family ethnic–racial socialization is a robust predictor of youths' adjustment, the associations between socialization and adjustment must be considered with attention to specific socialization strategies, the confluence of strategies used, and the unique contexts within which families' lives are embedded.
Earth's climate affects nearly all aspects of landscape evolution, from the breakdown of rock to the delivery of sediment to the oceans. Yet quantifying climate's influence on landscapes is a major ...challenge, not only because it is difficult to know how landscapes responded to past changes in climate, but also because landscapes are shaped by various processes that respond to climate in different ways. I review the current state of efforts to quantify climate's effects on the rates of the main processes that drive landscape evolution, with a focus on unglaciated landscapes formed by bedrock erosion. Although many uncertainties remain, recent research has clarified how the processes governing hillslopes, bedrock channels, and chemical erosion depend on major climate factors such as precipitation and temperature. A few themes emerge, including the importance of climatically mediated biological processes, the role of variability, and the value of natural experiments for revealing climate's effects.
Biomolecular condensation arising through phase transitions has emerged as an essential organizational strategy that governs many aspects of cell biology. In particular, the role of phase transitions ...in the assembly of large, complex ribonucleoprotein (RNP) granules has become appreciated as an important regulator of RNA metabolism. In parallel, genetic, histopathological and cell and molecular studies have provided evidence that disturbance of phase transitions is an important driver of neurological diseases, notably amyotrophic lateral sclerosis (ALS), but most likely also other diseases. Indeed, our growing knowledge of the biophysics underlying biological phase transitions suggests that this process offers a unifying mechanism to explain the numerous and diverse disturbances in RNA metabolism that have been observed in ALS and some related diseases - specifically, that these diseases are driven by disturbances in the material properties of RNP granules. Here, we review the evidence for this hypothesis, emphasizing the reciprocal roles in which disease-related protein and disease-related RNA can lead to disturbances in the material properties of RNP granules and consequent pathogenesis. Additionally, we review evidence that implicates aberrant phase transitions as a contributing factor to a larger set of neurodegenerative diseases, including frontotemporal dementia, certain repeat expansion diseases and Alzheimer disease.
Stress granules are membrane-less organelles composed of RNA-binding proteins (RBPs) and RNA. Functional impairment of stress granules has been implicated in amyotrophic lateral sclerosis, ...frontotemporal dementia, and multisystem proteinopathy—diseases that are characterized by fibrillar inclusions of RBPs. Genetic evidence suggests a link between persistent stress granules and the accumulation of pathological inclusions. Here, we demonstrate that the disease-related RBP hnRNPA1 undergoes liquid-liquid phase separation (LLPS) into protein-rich droplets mediated by a low complexity sequence domain (LCD). While the LCD of hnRNPA1 is sufficient to mediate LLPS, the RNA recognition motifs contribute to LLPS in the presence of RNA, giving rise to several mechanisms for regulating assembly. Importantly, while not required for LLPS, fibrillization is enhanced in protein-rich droplets. We suggest that LCD-mediated LLPS contributes to the assembly of stress granules and their liquid properties and provides a mechanistic link between persistent stress granules and fibrillar protein pathology in disease.
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•hnRNPA1 undergoes spontaneous concentration-dependent liquid-liquid phase separation•Liquid-liquid phase separation is mediated by a low complexity sequence domain•Stress granules assemble in a RNA-binding protein concentration-dependent manner•Pathological fibrillization of hnRNPA1 is driven by liquid-liquid phase separation
Liquid-liquid phase separation by RNA-binding proteins harboring low complexity sequence domains is the molecular basis for stress granule assembly, and persistent stress granules promote pathological protein fibrillization.
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