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Science Advances Jul 2023Cytokinetic abscission, the last step of cell division, is regulated by the ESCRT machinery. In response to mitotic errors, ESCRT proteins, namely, ALIX, CHMP4B, and...
Cytokinetic abscission, the last step of cell division, is regulated by the ESCRT machinery. In response to mitotic errors, ESCRT proteins, namely, ALIX, CHMP4B, and CHMP4C, accumulate in the cytosolic compartments termed "abscission checkpoint bodies" (ACBs) to delay abscission and prevent tumorigenesis. ALIX contributes to the biogenesis and stability of ACBs via an unknown mechanism. We show that ALIX phase separates into nondynamic condensates in vitro and in vivo, mediated by the amyloidogenic portion of its proline-rich domain. ALIX condensates confined CHMP4 paralogs in vitro. These condensates dissolved and reformed upon reversible tyrosine phosphorylation of ALIX, mediated by Src kinase and PTP1B, and sequestration of CHMP4C altered their Src-mediated dissolution. NMR analysis revealed how ALIX triggers the activation of CHMP4 proteins, which is required for successful abscission. These results implicate ALIX's phase separation in the modulation of ACBs. This study also highlights how posttranslational modifications can control protein phase separation.
Topics: Phosphorylation; Cell Cycle Proteins; Protein Processing, Post-Translational; Endosomal Sorting Complexes Required for Transport; Tyrosine
PubMed: 37450591
DOI: 10.1126/sciadv.adg3913 -
Frontiers in Molecular Neuroscience 2023Liquid-liquid phase separation results in the formation of dynamic biomolecular condensates, also known as membrane-less organelles, that allow for the assembly of... (Review)
Review
Phase separation and pathologic transitions of RNP condensates in neurons: implications for amyotrophic lateral sclerosis, frontotemporal dementia and other neurodegenerative disorders.
Liquid-liquid phase separation results in the formation of dynamic biomolecular condensates, also known as membrane-less organelles, that allow for the assembly of functional compartments and higher order structures within cells. Multivalent, reversible interactions between RNA-binding proteins (RBPs), including FUS, TDP-43, and hnRNPA1, and/or RNA (e.g., RBP-RBP, RBP-RNA, RNA-RNA), result in the formation of ribonucleoprotein (RNP) condensates, which are critical for RNA processing, mRNA transport, stability, stress granule assembly, and translation. Stress granules, neuronal transport granules, and processing bodies are examples of cytoplasmic RNP condensates, while the nucleolus and Cajal bodies are representative nuclear RNP condensates. In neurons, RNP condensates promote long-range mRNA transport and local translation in the dendrites and axon, and are essential for spatiotemporal regulation of gene expression, axonal integrity and synaptic function. Mutations of RBPs and/or pathologic mislocalization and aggregation of RBPs are hallmarks of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease. ALS/FTD-linked mutations of RBPs alter the strength and reversibility of multivalent interactions with other RBPs and RNAs, resulting in aberrant phase transitions. These aberrant RNP condensates have detrimental functional consequences on mRNA stability, localization, and translation, and ultimately lead to compromised axonal integrity and synaptic function in disease. Pathogenic protein aggregation is dependent on various factors, and aberrant dynamically arrested RNP condensates may serve as an initial nucleation step for pathologic aggregate formation. Recent studies have focused on identifying mechanisms by which neurons resolve phase transitioned condensates to prevent the formation of pathogenic inclusions/aggregates. The present review focuses on the phase separation of neurodegenerative disease-linked RBPs, physiological functions of RNP condensates, and the pathologic role of aberrant phase transitions in neurodegenerative disease, particularly ALS/FTD. We also examine cellular mechanisms that contribute to the resolution of aberrant condensates in neurons, and potential therapeutic approaches to resolve aberrantly phase transitioned condensates at a molecular level.
PubMed: 37720552
DOI: 10.3389/fnmol.2023.1242925 -
Journal of Environmental Management Dec 2023Several nations around the world use rice as their primary food staple because of its tremendous nutritional value. India's expanding population has sparked a... (Review)
Review
Several nations around the world use rice as their primary food staple because of its tremendous nutritional value. India's expanding population has sparked a proliferation of rice mills as a result of the country's growing rice demand. However, small and medium-scale industries lack adequate facilities for processing effluents and other waste generated. Paddy is typically processed by parboiling, which involves soaking it in water, boiling it with steam, and then drying and milling. Around 1-1.5 L of water is necessary to partially cook 1 kg of unhusked rice, with approximately half of this water being discharged as effluent. Disposal of rice mill effluent (RME) in water bodies or on the land causes severe damage to soil and water. An inclusive examination of diverse approaches for the treatment and stabilization of partially cooked rice milling effluents is provided. Moreover, the document provides a concise overview of contemporary and environmentally friendly technologies for treating RME. Adsorption, electrocoagulation, chemical coagulation, and bioremediation using microbes, plants, and microalgae are all included in these methods. This manuscript discusses the concept of a circular economy, which is focused on enhancing environmental sustainability through the recycling and repurposing of generated waste into raw materials for the creation of new products. In addition, this review aims to focus on the impact of RME on soils and water species and the status of sustainable management at the point of circular economy with RME bioenergy production (bioelectricity, biomethane, and bio-hydrogen).
Topics: Wastewater; Waste Disposal, Fluid; Oryza; Biodegradation, Environmental; Soil; Water
PubMed: 37839206
DOI: 10.1016/j.jenvman.2023.119248 -
The Ocular Surface Jul 2023Nutrients, required by human bodies to perform life-sustaining functions, are obtained from the diet. They are broadly classified into macronutrients (carbohydrates,...
Nutrients, required by human bodies to perform life-sustaining functions, are obtained from the diet. They are broadly classified into macronutrients (carbohydrates, lipids, and proteins), micronutrients (vitamins and minerals) and water. All nutrients serve as a source of energy, provide structural support to the body and/or regulate the chemical processes of the body. Food and drinks also consist of non-nutrients that may be beneficial (e.g., antioxidants) or harmful (e.g., dyes or preservatives added to processed foods) to the body and the ocular surface. There is also a complex interplay between systemic disorders and an individual's nutritional status. Changes in the gut microbiome may lead to alterations at the ocular surface. Poor nutrition may exacerbate select systemic conditions. Similarly, certain systemic conditions may affect the uptake, processing and distribution of nutrients by the body. These disorders may lead to deficiencies in micro- and macro-nutrients that are important in maintaining ocular surface health. Medications used to treat these conditions may also cause ocular surface changes. The prevalence of nutrition-related chronic diseases is climbing worldwide. This report sought to review the evidence supporting the impact of nutrition on the ocular surface, either directly or as a consequence of the chronic diseases that result. To address a key question, a systematic review investigated the effects of intentional food restriction on ocular surface health; of the 25 included studies, most investigated Ramadan fasting (56%), followed by bariatric surgery (16%), anorexia nervosa (16%), but none were judged to be of high quality, with no randomized-controlled trials.
Topics: Humans; Nutritional Status; Vitamins; Micronutrients; Diet; Life Style
PubMed: 37100346
DOI: 10.1016/j.jtos.2023.04.003 -
The Journal of Cell Biology Nov 2023The c-Jun N-terminal kinase (JNK) regulates various important physiological processes. Although the JNK pathway has been under intense investigation for over 20 yr, its...
The c-Jun N-terminal kinase (JNK) regulates various important physiological processes. Although the JNK pathway has been under intense investigation for over 20 yr, its complexity is still perplexing, with multiple protein partners underlying the diversity of its activity. We show that JNK is associated with the basal bodies in both primary and motile cilia. Loss of JNK disrupts basal body migration and docking and leads to severe ciliogenesis defects. JNK's involvement in ciliogenesis stems from a dual role in the regulation of the actin networks of multiciliated cells (MCCs) and the establishment of the intraflagellar transport-B core complex. JNK signaling is also critical for the maintenance of the actin networks and ciliary function in mature MCCs. JNK is implicated in the development of diabetes, neurodegeneration, and liver disease, all of which have been linked to ciliary dysfunction. Our work uncovers a novel role of JNK in ciliogenesis and ciliary function that could have important implications for JNK's role in the disease.
Topics: Actins; Cilia; MAP Kinase Signaling System; Phosphorylation; Protein Processing, Post-Translational; JNK Mitogen-Activated Protein Kinases
PubMed: 37851005
DOI: 10.1083/jcb.202303052 -
Nature Communications Nov 2023In the mammalian visual system, the ventral lateral geniculate nucleus (vLGN) of the thalamus receives salient visual input from the retina and sends prominent GABAergic...
In the mammalian visual system, the ventral lateral geniculate nucleus (vLGN) of the thalamus receives salient visual input from the retina and sends prominent GABAergic axons to the superior colliculus (SC). However, whether and how vLGN contributes to fundamental visual information processing remains largely unclear. Here, we report in mice that vLGN facilitates visually-guided approaching behavior mediated by the lateral SC and enhances the sensitivity of visual object detection. This can be attributed to the extremely broad spatial integration of vLGN neurons, as reflected in their much lower preferred spatial frequencies and broader spatial receptive fields than SC neurons. Through GABAergic thalamocollicular projections, vLGN specifically exerts prominent surround suppression of visuospatial processing in SC, leading to a fine tuning of SC preferences to higher spatial frequencies and smaller objects in a context-dependent manner. Thus, as an essential component of the central visual processing pathway, vLGN serves to refine and contextually modulate visuospatial processing in SC-mediated visuomotor behaviors via visually-driven long-range feedforward inhibition.
Topics: Mice; Animals; Geniculate Bodies; Neurons; Thalamus; Visual Pathways; Superior Colliculi; Mammals
PubMed: 37949869
DOI: 10.1038/s41467-023-43147-9 -
Cureus Aug 2023Artificial intelligence (AI) has transformed pharmacological research through machine learning, deep learning, and natural language processing. These advancements have... (Review)
Review
Artificial intelligence (AI) has transformed pharmacological research through machine learning, deep learning, and natural language processing. These advancements have greatly influenced drug discovery, development, and precision medicine. AI algorithms analyze vast biomedical data identifying potential drug targets, predicting efficacy, and optimizing lead compounds. AI has diverse applications in pharmacological research, including target identification, drug repurposing, virtual screening, de novo drug design, toxicity prediction, and personalized medicine. AI improves patient selection, trial design, and real-time data analysis in clinical trials, leading to enhanced safety and efficacy outcomes. Post-marketing surveillance utilizes AI-based systems to monitor adverse events, detect drug interactions, and support pharmacovigilance efforts. Machine learning models extract patterns from complex datasets, enabling accurate predictions and informed decision-making, thus accelerating drug discovery. Deep learning, specifically convolutional neural networks (CNN), excels in image analysis, aiding biomarker identification and optimizing drug formulation. Natural language processing facilitates the mining and analysis of scientific literature, unlocking valuable insights and information. However, the adoption of AI in pharmacological research raises ethical considerations. Ensuring data privacy and security, addressing algorithm bias and transparency, obtaining informed consent, and maintaining human oversight in decision-making are crucial ethical concerns. The responsible deployment of AI necessitates robust frameworks and regulations. The future of AI in pharmacological research is promising, with integration with emerging technologies like genomics, proteomics, and metabolomics offering the potential for personalized medicine and targeted therapies. Collaboration among academia, industry, and regulatory bodies is essential for the ethical implementation of AI in drug discovery and development. Continuous research and development in AI techniques and comprehensive training programs will empower scientists and healthcare professionals to fully exploit AI's potential, leading to improved patient outcomes and innovative pharmacological interventions.
PubMed: 37779744
DOI: 10.7759/cureus.44359 -
BioRxiv : the Preprint Server For... Nov 2023Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the first exon of the gene encoding huntingtin. Prior reports have...
Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the first exon of the gene encoding huntingtin. Prior reports have established a correlation between CAG expanded and altered gene expression. However, the mechanisms leading to disruption of RNA processing in HD remain unclear. Here, our analysis of the reported HTT protein interactome identifies interactions with known RNA-binding proteins (RBPs). Total, long-read sequencing and targeted RASL-seq of RNAs from cortex and striatum of the HD mouse model R6/2 reveals increased exon skipping which is confirmed in Q150 and Q175 knock-in mice and in HD human brain. We identify the RBP TDP-43 and the N6-methyladenosine (m6A) writer protein methyltransferase 3 (METTL3) to be upstream regulators of exon skipping in HD. Along with this novel mechanistic insight, we observe decreased nuclear localization of TDP-43 and cytoplasmic accumulation of phosphorylated TDP-43 in HD mice and human brain. In addition, TDP-43 co-localizes with HTT in human HD brain forming novel nuclear aggregate-like bodies distinct from mutant HTT inclusions or previously observed TDP-43 pathologies. Binding of TDP-43 onto RNAs encoding HD-associated differentially expressed and aberrantly spliced genes is decreased. Finally, m6A RNA modification is reduced on RNAs abnormally expressed in striatum from HD R6/2 mouse brain, including at clustered sites adjacent to TDP-43 binding sites. Our evidence supports TDP-43 loss of function coupled with altered m6A modification as a novel mechanism underlying alternative splicing/unannotated exon usage in HD and highlights the critical nature of TDP-43 function across multiple neurodegenerative diseases.
PubMed: 37961595
DOI: 10.1101/2023.10.31.565004 -
Molecular Horticulture Aug 2023The CCCH proteins play important roles in plant growth and development, hormone response, pathogen defense and abiotic stress tolerance. However, the knowledge of their...
The CCCH proteins play important roles in plant growth and development, hormone response, pathogen defense and abiotic stress tolerance. However, the knowledge of their roles in thermotolerance are scarce. Here, we identified a heat-inducible CCCH gene LlC3H18 from lily. LlC3H18 was localized in the cytoplasm and nucleus under normal conditions, while it translocated in the cytoplasmic foci and co-located with the markers of two messenger ribonucleoprotein (mRNP) granules, processing bodies (PBs) and stress granules (SGs) under heat stress conditions, and it also exhibited RNA-binding ability. In addition, LlC3H18 exhibited transactivation activity in both yeast and plant cells. In lily and Arabidopsis, overexpression of LlC3H18 damaged their thermotolerances, and silencing of LlC3H18 in lily also impaired its thermotolerance. Similarly, Arabidopsis atc3h18 mutant also showed decreased thermotolerance. These results indicated that the appropriate expression of C3H18 was crucial for establishing thermotolerance. Further analysis found that LlC3H18 directly bound to the promoter of LlWRKY33 and activated its expression. Besides, it was found that LlMYB305 acted as an upstream factor of LlC3H18 and activated its expression. In conclusion, we demonstrated that there may be a LlMYB305-LlC3H18-LlWRKY33 regulatory module in lily that is involved in the establishment of thermotolerance and finely regulates heat stress response.
PubMed: 37789438
DOI: 10.1186/s43897-023-00064-1 -
NMR in Biomedicine Jul 2023In recent years, MRS has benefited from increased MRI field strengths, new acquisition protocols and new processing techniques. This review aims to determine how this... (Review)
Review
BACKGROUND
In recent years, MRS has benefited from increased MRI field strengths, new acquisition protocols and new processing techniques. This review aims to determine how this has altered our understanding of MRS neurometabolic markers in neurodegenerative dementias.
METHODS
Our systematic review of human in vivo MRS literature since 2002 pertains to Alzheimer's disease (AD), dementia with Lewy bodies (DLB), Parkinson's disease dementia, frontotemporal dementia (FTD), prodromal and 'at-risk' states. Studies using field strengths of 3 T or more were included.
RESULTS
Of 85 studies, AD and/or mild cognitive impairment (MCI) were the most common conditions of interest (58 papers, 68%). Only 14 (16%) studies included other dementia syndromes and 13 (15%) investigated 'at-risk' cohorts. Earlier findings of lower N-acetylaspartate and higher myo-inositol were confirmed. Additionally, lower choline and creatine in AD and MCI were reported, though inconsistently. Previously challenging-to-measure metabolites (glutathione, glutamate and gamma-aminobutyric acid) were reportedly lower in AD, FTD and DLB compared with controls.
DISCUSSION
Increasing field strength alongside targeted acquisition protocols has revealed additional metabolite changes. Most studies were small and regional metabolite differences between dementia types may not have been captured due to the predominant placement of voxels in the posterior cingulate cortex. The standard of data collection, quality control and analysis is improving due to greater consensus regarding acquisition and processing techniques. Ongoing harmonization of techniques, creation of larger and longitudinal cohorts, and placement of MRS voxels in more diverse regions will strengthen future research.
Topics: Humans; Frontotemporal Dementia; Prodromal Symptoms; Parkinson Disease; Alzheimer Disease; Magnetic Resonance Imaging
PubMed: 36624067
DOI: 10.1002/nbm.4896