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Substance Abuse and Rehabilitation 2022Recreational gamma-hydroxybutyrate (GHB) use, although less common than other substance use, is increasingly recognised and is over-represented in emergency toxicology... (Review)
Review
Recreational gamma-hydroxybutyrate (GHB) use, although less common than other substance use, is increasingly recognised and is over-represented in emergency toxicology presentations. This narrative review summarizes GHB pharmacology, current patterns of use, potential harms and management of GHB toxicity and withdrawal. There is a complex interplay between GHB and GABA as GHB is both a prodrug and metabolite of GABA and GHB activates both GHB and GABA receptors. GHB is rapidly absorbed, with effects seen within minutes of ingestion. Metabolism is non-linear at higher doses. While GHB is listed as a controlled substance, its precursor's gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are easily available as both have industrial applications. National surveys indicate low rates of GHB use, with identification of high-risk populations in men who have sex with men and polysubstance users. GHB is one of the three drugs most commonly used in chemsex. GHB is often co-ingested with other interacting psychoactive substances. Acute toxicity is dose-dependent, and management is supportive care. Withdrawal management is generally with benzodiazepines with addition of baclofen for more severe withdrawal. Barbiturates may have a role. Titration and tapering of pharmaceutical GHB is commonly used in the Netherlands. Complicated withdrawal with delirium may require intensive care and treatment with intravenous sedation. There are high rates of relapse after withdrawal and medications for longer-term management are currently being investigated. Chronic use is associated with poorer mental, physical and sexual health, social dysfunction and poor work performance. Laboratory detection is complicated as GHB is an endogenous substance with a short half-life, and therefore not often routinely assayed in the clinical setting. Future research should focus on improving GHB detection and management of GHB withdrawal and dependence. Interventions specific for high-risk groups should be developed and assessed.
PubMed: 35173515
DOI: 10.2147/SAR.S315720 -
Bioscience Reports Mar 2023RNA is a fundamental biomolecule that has many purposes within cells. Due to its single-stranded and flexible nature, RNA naturally folds into complex and dynamic... (Review)
Review
RNA is a fundamental biomolecule that has many purposes within cells. Due to its single-stranded and flexible nature, RNA naturally folds into complex and dynamic structures. Recent technological and computational advances have produced an explosion of RNA structural data. Many RNA structures have regulatory and functional properties. Studying the structure of nascent RNAs is particularly challenging due to their low abundance and long length, but their structures are important because they can influence RNA processing. Precursor RNA processing is a nexus of pathways that determines mature isoform composition and that controls gene expression. In this review, we examine what is known about human nascent RNA structure and the influence of RNA structure on processing of precursor RNAs. These known structures provide examples of how other nascent RNAs may be structured and show how novel RNA structures may influence RNA processing including splicing and polyadenylation. RNA structures can be targeted therapeutically to treat disease.
Topics: Humans; RNA Precursors; RNA Splicing; RNA; Polyadenylation; Gene Expression
PubMed: 36689327
DOI: 10.1042/BSR20220149 -
Methods (San Diego, Calif.) Jan 2008microRNAs (miRNAs) are challenging molecules to amplify by PCR because the miRNA precursor consists of a stable hairpin and the mature miRNA is roughly the size of a... (Review)
Review
microRNAs (miRNAs) are challenging molecules to amplify by PCR because the miRNA precursor consists of a stable hairpin and the mature miRNA is roughly the size of a standard PCR primer. Despite these difficulties, successful real-time RT-PCR technologies have been developed to amplify and quantify both the precursor and mature microRNA. An overview of real-time PCR technologies developed by us to detect precursor and mature microRNAs is presented here. Protocols describe presentation of the data using relative (comparative C(T)) and absolute (standard curve) quantification. Real-time PCR assays were used to measure the time course of precursor and mature miR-155 expression in monocytes stimulated by lipopolysaccharide. Protocols are provided to configure the assays as low density PCR arrays for high throughput gene expression profiling. By profiling over 200 precursor and mature miRNAs in HL60 cells induced to differentiate with 12-O-tetradecanoylphorbol-13-acetate, it was possible to identify miRNAs who's processing is regulated during differentiation. Real-time PCR has become the gold standard of nucleic acid quantification due to the specificity and sensitivity of the PCR. Technological advancements have allowed for quantification of miRNA that is of comparable quality to more traditional RNAs.
Topics: Animals; Base Sequence; Humans; MicroRNAs; Molecular Sequence Data; RNA Precursors; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 18158130
DOI: 10.1016/j.ymeth.2007.09.006 -
Cellulose (London, England) 2021Polyacrylonitrile (PAN)-based carbon precursor is a well-established and researched material for electrodes in energy storage applications due to its good physical... (Review)
Review
Polyacrylonitrile (PAN)-based carbon precursor is a well-established and researched material for electrodes in energy storage applications due to its good physical properties and excellent electrochemical performance. However, in the fight of preserving the environment and pioneering renewable energy sources, environmentally sustainable carbon precursors with superior electrochemical performance are needed. Therefore, bio-based materials are excellent candidates to replace PAN as a carbon precursor. Depending on the design requirement (e.g. carbon morphology, doping level, specific surface area, pore size and volume, and electrochemical performance), the appropriate selection of carbon precursors can be made from a variety of biomass and biowaste materials. This review provides a summary and discussion on the preparation and characterization of the emerging and recent bio-based carbon precursors that can be used as electrodes in energy storage applications. The review is outlined based on the morphology of nanostructures and the precursor's type. Furthermore, the review discusses and summarizes the excellent electrochemical performance of these recent carbon precursors in storage energy applications. Finally, a summary and outlook are also given. All this together portrays the promising role of bio-based carbon electrodes in energy storage applications.
PubMed: 33897123
DOI: 10.1007/s10570-021-03881-z -
The New Phytologist Jan 2021The gaseous plant hormone ethylene is produced by a fairly simple two-step biosynthesis route. Despite this pathway's simplicity, recent molecular and genetic studies... (Review)
Review
The gaseous plant hormone ethylene is produced by a fairly simple two-step biosynthesis route. Despite this pathway's simplicity, recent molecular and genetic studies have revealed that the regulation of ethylene biosynthesis is far more complex and occurs at different layers. Ethylene production is intimately linked with the homeostasis of its general precursor S-adenosyl-l-methionine (SAM), which experiences transcriptional and posttranslational control of its synthesising enzymes (SAM synthetase), as well as the metabolic flux through the adjacent Yang cycle. Ethylene biosynthesis continues from SAM by two dedicated enzymes: 1-aminocyclopropane-1-carboxylic (ACC) synthase (ACS) and ACC oxidase (ACO). Although the transcriptional dynamics of ACS and ACO have been well documented, the first transcription factors that control ACS and ACO expression have only recently been discovered. Both ACS and ACO display a type-specific posttranslational regulation that controls protein stability and activity. The nonproteinogenic amino acid ACC also shows a tight level of control through conjugation and translocation. Different players in ACC conjugation and transport have been identified over the years, however their molecular regulation and biological significance is unclear, yet relevant, as ACC can also signal independently of ethylene. In this review, we bring together historical reports and the latest findings on the complex regulation of the ethylene biosynthesis pathway in plants.
Topics: Amino Acid Oxidoreductases; Ethylenes; Gene Expression Regulation, Plant; Lyases; Plants
PubMed: 32790878
DOI: 10.1111/nph.16873 -
ACS Omega Sep 2018In mass spectrometry (MS)-based proteomics, protein and peptide sequences are determined by the isolation and subsequent fragmentation of precursor ions. When an...
In mass spectrometry (MS)-based proteomics, protein and peptide sequences are determined by the isolation and subsequent fragmentation of precursor ions. When an isolation window captures only part of a precursor's isotopic distribution, the isotope distributions of the fragments depend on the subset of isolated precursor isotopes. Approximation of the expected isotope distributions of these fragments prior to sequence determination enables MS2 deisotoping, monoisotopic mass calculation, charge assignment of fragment peaks, and deconvolution of chimeric spectra. However, currently such methods do not exist, and precursor isotope distributions are often used as a proxy. Here, we present methods that approximate the isotope distribution of a biomolecule's fragment given its monoisotopic mass, the monoisotopic mass of its precursor, the set of isolated precursor isotopes, and optionally sulfur atom content. Our methods use either the Averagine model or splines, the latter of which have similar accuracy to the Averagine approach, but are 20 times faster to compute. Theoretical and approximated isotope distributions are consistent for fragments of in silico digested peptides. Furthermore, mass spectrometry experiments with the angiotensin I peptide and HeLa cell lysate demonstrate that the fragment methods match isotope peaks in MS2 spectra more accurately than the precursor Averagine approach. The algorithms for the approximation of fragment isotope distributions have been added to the OpenMS software library. By providing the means for analyzing fragment isotopic distributions, these methods will improve MS2 spectra interpretation.
PubMed: 30288463
DOI: 10.1021/acsomega.8b01649 -
International Journal of Molecular... Dec 2021With few exceptions, proteins that constitute the proteome of mitochondria originate outside of this organelle in precursor forms. Such protein precursors follow... (Review)
Review
With few exceptions, proteins that constitute the proteome of mitochondria originate outside of this organelle in precursor forms. Such protein precursors follow dedicated transportation paths to reach specific parts of mitochondria, where they complete their maturation and perform their functions. Mitochondrial precursor targeting and import pathways are essential to maintain proper mitochondrial function and cell survival, thus are tightly controlled at each stage. Mechanisms that sustain protein homeostasis of the cytosol play a vital role in the quality control of proteins targeted to the organelle. Starting from their synthesis, precursors are constantly chaperoned and guided to reduce the risk of premature folding, erroneous interactions, or protein damage. The ubiquitin-proteasome system provides proteolytic control that is not restricted to defective proteins but also regulates the supply of precursors to the organelle. Recent discoveries provide evidence that stress caused by the mislocalization of mitochondrial proteins may contribute to disease development. Precursors are not only subject to regulation but also modulate cytosolic machinery. Here we provide an overview of the cellular pathways that are involved in precursor maintenance and guidance at the early cytosolic stages of mitochondrial biogenesis. Moreover, we follow the circumstances in which mitochondrial protein import deregulation disturbs the cellular balance, carefully looking for rescue paths that can restore proteostasis.
Topics: Cell Survival; Cytosol; Humans; Mitochondria; Mitochondrial Proteins; Organelle Biogenesis; Protein Precursors; Protein Transport
PubMed: 35008433
DOI: 10.3390/ijms23010007 -
Journal of Applied Behavior Analysis 2011A literature search identified 17 articles reporting data on 34 subjects who engaged in precursors to severe problem behavior, which we examined to identify... (Review)
Review
A literature search identified 17 articles reporting data on 34 subjects who engaged in precursors to severe problem behavior, which we examined to identify topographical and functional characteristics. Unintelligible vocalization was the most common precursor to aggression (27%) and property destruction (29%), whereas self- or nondirected movement was the most common precursor to SIB (32%). Unintelligible vocalization and object-directed movement were the most common precursors to behavior maintained by social-positive reinforcement (27% each), and unintelligible vocalization was the most common precursor to behavior maintained by social-negative reinforcement (29%). Only one precursor was reported for behavior maintained by automatic reinforcement.
Topics: Aggression; Humans; Mental Disorders
PubMed: 22219552
DOI: 10.1901/jaba.2011.44-993 -
Nature Reviews. Rheumatology Mar 2015Osteoclasts are cells of haematopoietic origin that are uniquely specialized to degrade bone. Under physiological conditions, the osteoclastogenesis pathway depends on... (Review)
Review
Osteoclasts are cells of haematopoietic origin that are uniquely specialized to degrade bone. Under physiological conditions, the osteoclastogenesis pathway depends on macrophage colony-stimulating factor 1 (CSF-1, also known as M-CSF) and receptor activator of nuclear factor κB ligand (RANKL). However, an emerging hypothesis is that alternative pathways of osteoclast generation might be active during inflammatory arthritis. In this Perspectives article, we summarize the physiological pathway of osteoclastogenesis and then focus on experimental findings that support the hypothesis that infiltrating inflammatory cells and the cytokine milieu provide multiple routes to bone destruction. The precise identity of osteoclast precursor(s) is not yet known. We propose that myeloid cell differentiation during inflammation could be an important contributor to the differentiation of osteoclast populations and their associated pathologies. Understanding the dynamics of osteoclast differentiation in inflammatory arthritis is crucial for the development of therapeutic strategies for inflammatory joint disease in children and adults.
Topics: Animals; Arthritis; Bone Resorption; Humans; Inflammation; Osteoclasts
PubMed: 25422000
DOI: 10.1038/nrrheum.2014.198 -
The Journal of Nutrition Sep 2020A gluconeogenic precursor is a biochemical compound acted on by a gluconeogenic pathway enabling the net synthesis of glucose. Recognized gluconeogenic precursors in...
A gluconeogenic precursor is a biochemical compound acted on by a gluconeogenic pathway enabling the net synthesis of glucose. Recognized gluconeogenic precursors in fasting placental mammals include glycerol, lactate/pyruvate, certain amino acids, and odd-chain length fatty acids. Each of these precursors is capable of contributing net amounts of carbon to glucose synthesis via the tricarboxylic acid cycle (TCA cycle) because they are anaplerotic, that is, they are able to increase the pools of TCA cycle intermediates by the contribution of more carbon than is lost via carbon dioxide. The net synthesis of glucose from even-chain length fatty acids (ECFAs) in fasting placental mammals, via the TCA cycle alone, is not possible because equal amounts of carbon are lost via carbon dioxide as is contributed from fatty acid oxidation via acetyl-CoA. Therefore, ECFAs do not meet the criteria to be recognized as a gluconeogenic precursor via the TCA cycle alone. ECFAs are gluconeogenic precursors in organisms with a functioning glyoxylate cycle, which enables the net contribution of carbon to the intermediates of the TCA cycle from ECFAs and the net synthesis of glucose. The net conversion of ECFAs to glucose in fasting placental mammals via C3 metabolism of acetone may be a competent though inefficient metabolic path by which ECFA could be considered a gluconeogenic precursor. Defining a substrate as a gluconeogenic precursor requires careful articulation of the definition, organism, and physiologic conditions under consideration.
Topics: Acetyl Coenzyme A; Carbon; Citric Acid Cycle; Fatty Acids; Gluconeogenesis; Glucose; Glyoxylates; Humans; Oxidation-Reduction
PubMed: 32652033
DOI: 10.1093/jn/nxaa166