The nuclear pore is the gatekeeper of nucleocytoplasmic transport and signaling through which a vast flux of information is continuously exchanged between the nuclear and cytoplasmic compartments to ...maintain cellular homeostasis. A unifying and organizing principle has recently emerged that cements the notion that several forms of amyotrophic lateral sclerosis (ALS), and growing number of other neurodegenerative diseases, co-opt the dysregulation of nucleocytoplasmic transport and that this impairment is a pathogenic driver of neurodegeneration. The understanding of shared pathomechanisms that underpin neurodegenerative diseases with impairments in nucleocytoplasmic transport and how these interface with current concepts of nucleocytoplasmic transport is bound to illuminate this fundamental biological process in a yet more physiological context. Here, I summarize unresolved questions and evidence and extend basic and critical concepts and challenges of nucleocytoplasmic transport and its role in the pathogenesis of neurodegenerative diseases, such as ALS. These principles will help to appreciate the roles of nucleocytoplasmic transport in the pathogenesis of ALS and other neurodegenerative diseases, and generate a framework for new ideas of the susceptibility of motoneurons, and possibly other neurons, to degeneration by dysregulation of nucleocytoplasmic transport.
Nucleocytoplasmic transport comprises the multistep assembly, transport, and disassembly of protein and RNA cargoes entering and exiting nuclear pores. Accruing evidence supports that impairments to ...nucleocytoplasmic transport are a hallmark of neurodegenerative diseases. These impairments cause dysregulations in nucleocytoplasmic partitioning and proteostasis of nuclear transport receptors and client substrates that promote intracellular deposits – another hallmark of neurodegeneration. Disturbances in liquid–liquid phase separation (LLPS) between dense and dilute phases of biomolecules implicated in nucleocytoplasmic transport promote micrometer‐scale coacervates, leading to proteinaceous aggregates. This Review provides historical and emerging principles of LLPS at the interface of nucleocytoplasmic transport, proteostasis, aging and noxious insults, whose dysregulations promote intracellular aggregates. E3 SUMO‐protein ligase Ranbp2 constitutes the cytoplasmic filaments of nuclear pores, where it acts as a molecular hub for rate‐limiting steps of nucleocytoplasmic transport. A vignette is provided on the roles of Ranbp2 in nucleocytoplasmic transport and at the intersection of proteostasis in the survival of photoreceptor and motor neurons under homeostatic and pathophysiological environments. Current unmet clinical needs are highlighted, including therapeutics aiming to manipulate aggregation‐dissolution models of purported neurotoxicity in neurodegeneration.
In order to evaluate the biodegradability of the cellulose acetate (CA) films plasticized with different concentrations of glycerol (GLY) or triethyl citrate (TEC), analysis of scanning electron ...microscopy (SEM), Fourier transfer infrared spectroscopy (FTIR), and thermogravimetric analyses (TGA) were conducted through 180 days. Throughout the analysis, indicators of plasticizer exudation were observed, including changes in visual appearance and mass loss, ranging from 39.141% and 20.663% (first day) up to 0.524% and 0.488% (last day) for TEC and GLY plasticizer based films, respectively. Changes were also noted in the infrared spectrum, and TGA plots with polymer degradation peaks from 332.09 to 400.96 cm−1 for both plasticizers based films (TEC and GLY, respectively), regardless of the day of analysis. All assays revealed plasticizer losses, but there was no evidence of films' biodegradation during the experimental time. In perspective, this systematic approach can be extended to study other polymers and other biodegradation conditions.
Preparation of cellulose acetate substrates with varying concentrations and types of plasticizers and their effects on polymer biodegradation.
The neurogenetics and vision community recently mourned William L. Pak, PhD, whose pioneering work spearheaded the genetic, electrophysiological, and molecular bases of biological processes ...underpinning vision. This essay provides a historical background to the daunting challenges and personal experiences that carved the path to seminal findings. It also reflects on the intellectual framework, mentoring philosophy, and inspirational legacy of Bill Pak's research. An emphasis and perspectives are placed on the discoveries and implications to date of the phosphatidylinositol-specific phospholipase C (PI-PLC), NorpA, and the cyclophilin, NinaA of the fruit fly, Drosophila melanogaster, and their respective mammalian homologues, PI-PLCβ4, and cyclophilin-related protein, Ran-binding protein 2 (Ranbp2) in critical biological processes and diseases of photoreceptors and other neurons.The neurogenetics and vision community recently mourned William L. Pak, PhD, whose pioneering work spearheaded the genetic, electrophysiological, and molecular bases of biological processes underpinning vision. This essay provides a historical background to the daunting challenges and personal experiences that carved the path to seminal findings. It also reflects on the intellectual framework, mentoring philosophy, and inspirational legacy of Bill Pak's research. An emphasis and perspectives are placed on the discoveries and implications to date of the phosphatidylinositol-specific phospholipase C (PI-PLC), NorpA, and the cyclophilin, NinaA of the fruit fly, Drosophila melanogaster, and their respective mammalian homologues, PI-PLCβ4, and cyclophilin-related protein, Ran-binding protein 2 (Ranbp2) in critical biological processes and diseases of photoreceptors and other neurons.
In response to skeletal muscle contraction during exercise, paracrine factors coordinate tissue remodeling, which underlies this healthy adaptation. Here we describe a pH-sensing metabolite signal ...that initiates muscle remodeling upon exercise. In mice and humans, exercising skeletal muscle releases the mitochondrial metabolite succinate into the local interstitium and circulation. Selective secretion of succinate is facilitated by its transient protonation, which occurs upon muscle cell acidification. In the protonated monocarboxylic form, succinate is rendered a transport substrate for monocarboxylate transporter 1, which facilitates pH-gated release. Upon secretion, succinate signals via its cognate receptor SUCNR1 in non-myofibrillar cells in muscle tissue to control muscle-remodeling transcriptional programs. This succinate-SUCNR1 signaling is required for paracrine regulation of muscle innervation, muscle matrix remodeling, and muscle strength in response to exercise training. In sum, we define a bioenergetic sensor in muscle that utilizes intracellular pH and succinate to coordinate tissue adaptation to exercise.
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•Mouse and human muscle selectively release succinate during exercise•Muscle cells release succinate by pH-gated secretion via MCT1•Extracellular succinate regulates paracrine responses to exercise through SUCNR1•SUCNR1 signaling mediates muscle remodeling responses to exercise training
Reddy et al. identify a bioenergetic sensor that uses pH and succinate to regulate muscle tissue adaptation to exercise.
Academic and business interests in the product-service system have risen significantly in recent years. The product-service system represents a competitive opportunity for many companies as they seek ...to reduce consumption by altering how their products are used by providing services. To further establish this field, the objective of this paper is to present a literature review on the product-service system, including 149 papers published from 2006 to 2010. The review discusses specific features of the product-service system as well as the benefits and drawbacks that the literature has addressed in recent years. Positive and negative issues of the product-service system are also covered. It is evident that the research in this area is still dominated by theoretical work, and additional empirical research is required. Selected research perspectives are identified that encourage future research.
► Articles about PSS have evolved over the years in diversified academic journals. ► Terms considered synonyms of PSS should be explored in literature. ► Usually the sustainability economic aspect is the principal goal of PSS. ► The concept and empirical applications of the PSS have not evolved.
Understanding the evolution of local adaptations is a central aim of evolutionary biology and key for the identification of unique populations and lineages of conservation relevance. By combining RAD ...sequencing and whole‐genome sequencing, we identify genetic signatures of local adaptation in mountain hares (Lepus timidus) from isolated and distinctive habitats of its wide distribution: Ireland, the Alps and Fennoscandia. Demographic modelling suggested that the split of these mountain hares occurred around 20 thousand years ago, providing the opportunity to study adaptive evolution over a short timescale. Using genome‐wide scans, we identified signatures of extreme differentiation among hares from distinct geographic areas that overlap with area‐specific selective sweeps, suggesting targets for local adaptation. Several identified candidate genes are associated with traits related to the uniqueness of the different environments inhabited by the three groups of mountain hares, including coat colour, ability to live at high altitudes and variation in body size. In Irish mountain hares, a variant of ASIP, a gene previously implicated in introgression‐driven winter coat colour variation in mountain and snowshoe hares (L. americanus), may underlie brown winter coats, reinforcing the repeated nature of evolution at ASIP moulding adaptive seasonal colouration. Comparative genomic analyses across several hare species suggested that mountain hares’ adaptive variants appear predominantly species‐specific. However, using coalescent simulations, we also show instances where the candidate adaptive variants have been introduced via introgressive hybridization. Our study shows that standing adaptive variation, including that introgressed from other species, was a crucial component of the post‐glacial dynamics of species.
Aim
As a step towards providing support for an ecological approach to strengthening marine protected areas (MPAs) and meeting international commitments, this study combines cumulative impact ...assessment and conservation planning approach to undertake a large‐scale spatial prioritization.
Location
Exclusive Economic Zone (EEZ) of Brazil, Southwest Atlantic Ocean.
Methods
We developed a prioritization approach to protecting different habitat types, threatened species ranges and ecological connectivity, while also mitigating the impacts of multiple threats on biodiversity. When identifying priorities for conservation, we accounted for the co‐occurrence of 24 human threats and the distribution of 161 marine habitats and 143 threatened species, as well as their associated vulnerabilities. Additionally, we compared our conservation priorities with MPAs proposed by local stakeholders.
Results
We show that impacts to habitats and species are widespread and identify hot spots of cumulative impacts on inshore and offshore areas. Industrial fisheries, climate change and land‐based activities were the most severe threats to biodiversity. The highest priorities were mostly found towards the coast due to the high cumulative impacts found in nearshore areas. As expected, our systematic approach showed a better performance on selecting priority sites when compared to the MPAs proposed by local stakeholders without a typical conservation planning exercise, increasing the existing coverage of MPAs by only 7.9%. However, we found that proposed MPAs still provide some opportunities to protect areas facing high levels of threats.
Main conclusions
The study presents a blueprint of how to embrace a comprehensive ecological approach when identifying strategic priorities for conservation. We advocate protecting these crucial areas from degradation in emerging conservation efforts is key to maintain their biodiversity value.
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