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Nature Genetics Jan 2024Chromatin accessibility is a hallmark of active transcription and entails ATP-dependent nucleosome remodeling, which is carried out by complexes such as...
Chromatin accessibility is a hallmark of active transcription and entails ATP-dependent nucleosome remodeling, which is carried out by complexes such as Brahma-associated factor (BAF). However, the mechanistic links between transcription, nucleosome remodeling and chromatin accessibility are unclear. Here, we used a chemical-genetic approach coupled with time-resolved chromatin profiling to dissect the interplay between RNA Polymerase II (RNAPII), BAF and DNA-sequence-specific transcription factors in mouse embryonic stem cells. We show that BAF dynamically unwraps and evicts nucleosomes at accessible chromatin regions, while RNAPII promoter-proximal pausing stabilizes BAF chromatin occupancy and enhances ATP-dependent nucleosome eviction by BAF. We find that although RNAPII and BAF dynamically probe both transcriptionally active and Polycomb-repressed genomic regions, pluripotency transcription factor chromatin binding confers locus specificity for productive chromatin remodeling and nucleosome eviction by BAF. Our study suggests a paradigm for how functional synergy between dynamically acting chromatin factors regulates locus-specific nucleosome organization and chromatin accessibility.
Topics: Animals; Mice; Transcription Factors; Nucleosomes; Chromatin; RNA Polymerase II; Chromatin Assembly and Disassembly; Adenosine Triphosphate
PubMed: 38049663
DOI: 10.1038/s41588-023-01603-8 -
Heart (British Cardiac Society) Dec 2023Resistant hypertension is a condition where blood pressure levels remain elevated above target despite changes in lifestyle and concurrent use of at least three...
Resistant hypertension is a condition where blood pressure levels remain elevated above target despite changes in lifestyle and concurrent use of at least three antihypertensive agents, including a long-acting calcium channel blocker (CCB), a blocker of the renin-angiotensin system (ACE inhibitor or angiotensin receptor blocker) and a diuretic. To be diagnosed as resistant hypertension, maintaining adherence to therapy is required along with confirmation of blood pressure levels above target by out-of-office blood pressure measurements and exclusion of secondary causes of hypertension. The key management points of this condition include lifestyle changes such as reduced sodium and alcohol intake, regular physical activity, weight loss and discontinuation of substances that can interfere with blood pressure control. It is also recommended that current treatment be rationalised, including single pill combination treatment where antihypertensive drugs should be provided at the maximum tolerated dose. It is further recommended that current drugs be replaced with a more appropriate and less difficult treatment regimen based on the patient's age, ethnicity, comorbidities and risk of drug-drug interactions. The fourth line of treatment for patients with resistant hypertension should include mineralocorticoid receptor antagonists such as spironolactone, as demonstrated in the PATHWAY-2 trial and meta-analyses. Alternatives to spironolactone include amiloride, doxazosin, eplerenone, clonidine and beta-blockers, as well as any other antihypertensive drugs not already in use. New approaches under research are selective non-steroidal mineralocorticoid receptor antagonists such as finerenone, esaxerenone and ocedurenone, selective aldosterone synthase inhibitors such as baxdrostat, and dual endothelin antagonist aprocitentan.
PubMed: 38135468
DOI: 10.1136/heartjnl-2022-321730 -
Neoplasia (New York, N.Y.) Dec 2023This study aimed to investigate the causal relationship between mitochondrial biological function and lung cancer, including its subtypes, via MR.
OBJECTIVE
This study aimed to investigate the causal relationship between mitochondrial biological function and lung cancer, including its subtypes, via MR.
METHODS
SNPs significantly associated with lung cancer and its subtypes were employed as instrumental variables. MR-Egger regression, simple mode, weighted mode, simple median, and weighted median, were utilized to determine the causal relationship between the exposure factor and the occurrence of lung cancer and its subtypes.
RESULTS
NADH dehydrogenase (ubiquinone) flavoprotein 2 and transmembrane protein 70 were found to have a causal relationship with lung adenocarcinoma, acting as protective factors. The causal relationship between mitochondrial import inner membrane translocase subunit and NADH dehydrogenase (ubiquinone) iron-sulfur protein 4 and small-cell lung cancer was established as a risk factor. NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 8 exhibited a causal relationship with small-cell lung cancer, acting as a protective factor. Furthermore, NAD-dependent protein deacylase sirtuin-5 was causally linked to lung squamous cell carcinoma, serving as a protective factor. A funnel plot demonstrated the symmetrical distribution of the SNPs. Thew pleiotroy test (P > 0.05) and "leave-one-out" test validated the relative stability of the results.
CONCLUSION
This study established a causal relationship between mitochondrial biological function and lung cancer, including its subtypes.
Topics: Humans; Lung Neoplasms; Electron Transport Complex I; Mendelian Randomization Analysis; Genome-Wide Association Study; Carcinoma, Non-Small-Cell Lung; Small Cell Lung Carcinoma; Polymorphism, Single Nucleotide
PubMed: 37976568
DOI: 10.1016/j.neo.2023.100950 -
Neuropsychopharmacology : Official... Jan 2024We begin by summarizing several examples of antidepressants whose therapeutic actions begin when they encounter their targets in the cytoplasm or in the lumen of an... (Review)
Review
We begin by summarizing several examples of antidepressants whose therapeutic actions begin when they encounter their targets in the cytoplasm or in the lumen of an organelle. These actions contrast with the prevailing view that most neuropharmacological actions begin when drugs engage their therapeutic targets at extracellular binding sites of plasma membrane targets-ion channels, receptors, and transporters. We review the chemical, pharmacokinetic, and pharmacodynamic principles underlying the movements of drugs into subcellular compartments. We note the relationship between protonation-deprotonation events and membrane permeation of antidepressant drugs. The key properties relate to charge and hydrophobicity/lipid solubility, summarized by the parameters LogP, pK and LogD. The classical metric, volume of distribution (V), is unusually large for some antidepressants and has both supracellular and subcellular components. A table gathers structures, LogP, PKa, LogD, and V data and/or calculations for most antidepressants and antidepressant candidates. The subcellular components, which can now be measured in some cases, are dominated by membrane binding and by trapping in the lumen of acidic organelles. For common antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs), the target is assumed to be the eponymous reuptake transporter(s), although in fact the compartment of target engagement is unknown. We review special aspects of the pharmacokinetics of ketamine, ketamine metabolites, and other rapidly acting antidepressants (RAADs) including methoxetamine and scopolamine, psychedelics, and neurosteroids. Therefore, the reader can assess properties that markedly affect a drug's ability to enter or cross membranes-and therefore, to interact with target sites that face the cytoplasm, the lumen of organelles, or a membrane. In the current literature, mechanisms involving intracellular targets are termed "location-biased actions" or "inside-out pharmacology". Hopefully, these general terms will eventually acquire additional mechanistic details.
Topics: Ketamine; Antidepressive Agents; Selective Serotonin Reuptake Inhibitors; Norepinephrine; Organelles
PubMed: 37783840
DOI: 10.1038/s41386-023-01725-x -
Nature Communications Oct 2023Ketamine, a rapid-acting anesthetic and acute antidepressant, carries undesirable spatial cognition side effects including out-of-body experiences and spatial memory...
Ketamine, a rapid-acting anesthetic and acute antidepressant, carries undesirable spatial cognition side effects including out-of-body experiences and spatial memory impairments. The neural substrates that underlie these alterations in spatial cognition however, remain incompletely understood. Here, we used electrophysiology and calcium imaging to examine ketamine's impacts on the medial entorhinal cortex and hippocampus, which contain neurons that encode an animal's spatial position, as mice navigated virtual reality and real world environments. Ketamine acutely increased firing rates, degraded cell-pair temporal firing-rate relationships, and altered oscillations, leading to longer-term remapping of spatial representations. In the reciprocally connected hippocampus, the activity of neurons that encode the position of the animal was suppressed after ketamine administration. Together, these findings demonstrate ketamine-induced dysfunction of the MEC-hippocampal circuit at the single cell, local-circuit population, and network levels, connecting previously demonstrated physiological effects of ketamine on spatial cognition to alterations in the spatial navigation circuit.
Topics: Mice; Animals; Ketamine; Entorhinal Cortex; Hippocampus; Neurons; Cognition
PubMed: 37805575
DOI: 10.1038/s41467-023-41750-4 -
European Child & Adolescent Psychiatry Oct 2023Childhood adversity is a well-established risk factor for adolescent acting-out behaviors such as self-harm, bingeing, substance abuse, and aggressive behavior. From a...
Childhood adversity is a well-established risk factor for adolescent acting-out behaviors such as self-harm, bingeing, substance abuse, and aggressive behavior. From a mentalizing perspective, acting-out behaviors are understood as resulting from a combination of impairments in mentalizing and epistemic vigilance that are a consequence of childhood adversity. Yet, few studies have investigated these assumptions. The current study investigated the potential mediating role of mentalizing impairments and epistemic vigilance in the relationship between childhood adversity and acting-out behaviors in adolescents, oversampled for risk status for psychopathology (N = 451, mean age = 15.40 years). Structural equation modeling showed a strong, direct relationship between childhood adversity and acting-out behaviors, confirming the importance of traumatic childhood experiences for adolescent acting-out behaviors. This relationship was partially mediated by both mentalizing difficulties and epistemic vigilance, explaining about 40% of the total variance. These results support the importance of focusing on strengthening mentalizing abilities and lowering epistemic hypervigilance in psychotherapeutic work with adolescents who have experienced childhood trauma.
PubMed: 37787820
DOI: 10.1007/s00787-023-02302-9 -
Current Topics in Behavioral... Nov 2023SSRIs are one of the most widely used drug therapies in primary care and psychiatry, and central to the management of the most common mental health problems in today's...
SSRIs are one of the most widely used drug therapies in primary care and psychiatry, and central to the management of the most common mental health problems in today's society. Despite this, SSRIs suffer from a slow onset of therapeutic effect and relatively poor efficacy as well as adverse effects, with recent concerns being focused on a disabling SSRI discontinuation syndrome. The mechanism underpinning their therapeutic effect has long shifted away from thinking that SSRIs act simply by increasing 5-HT in the synapse. Rather, a current popular view is that increased 5-HT is just the beginning of a series of complex downstream signalling events, which trigger changes in neural plasticity at the functional and structural level. These changes in plasticity are then thought to interact with neuropsychological processes to enhance re-learning of emotional experiences that ultimately brings about changes in mood. This compelling view of SSRI action is underpinning attempts to understand fast-acting antidepressants, such as ketamine and psychedelic drugs, and aid the development of future therapies. An important gap in the theory is evidence that changes in plasticity are causally linked to relevant behavioural effects. Also, predictions that the SSRI-induced neural plasticity might have applicability in other areas of medicine have not yet been borne out. In contrast to the sophisticated view of the antidepressant action of SSRIs, the mechanism underpinning SSRI discontinuation is little explored. Nevertheless, evidence of rebound increases in 5-HT neuron excitability immediately on cessation of SSRI treatment provide a starting point for future investigation. Indeed, this evidence allows formulation of a mechanistic explanation of SSRI discontinuation which draws on parallels with the withdrawal states of other psychotropic drugs.
PubMed: 37955823
DOI: 10.1007/7854_2023_452 -
Chembiochem : a European Journal of... Jul 2023The vast majority of RNA splicing in today's organisms is achieved by the highly regulated and precise removal of introns from pre-mRNAs via the spliceosome. Here we...
The vast majority of RNA splicing in today's organisms is achieved by the highly regulated and precise removal of introns from pre-mRNAs via the spliceosome. Here we present a model of how RNA splicing may have occurred in earlier life forms. We have designed a hairpin ribozyme derived spliceozyme that mediates two RNA cleavages and one ligation event at specific positions and thus cuts a segment (intron) out of a parent RNA and ligates the remaining fragments (exons). The cut-out intron then performs a downstream function, acting as a positive regulator of the activity of a bipartite DNAzyme. This simple scenario shows how small RNAs can perform complex RNA processing dynamics, involving the generation of new phenotypes by restructuring segments of given RNA species, as well as delivering small RNAs that may play a functional role in downstream processes.
Topics: RNA, Catalytic; RNA; RNA Splicing; RNA Precursors; Introns; Nucleic Acid Conformation
PubMed: 37184100
DOI: 10.1002/cbic.202300204