Notes

Decontamination, combining and also dereplication of the 678 samples of the actual Sea Microbial Eukaryote Transcriptome Sequencing Undertaking.
Glycine transporters (GlyTs) are Na+/Cl--dependent neurotransmitter transporters, responsible for l-glycine uptake into the central nervous system. GlyTs are members of the solute carrier family 6 (SLC6) and comprise glycine transporter type 1 (SLC6A9; GlyT1) and glycine transporter type 2 (SLC6A5; Glyt2). GlyT1 and GlyT2 are expressed on both astrocytes and neurons, but their expression pattern in brain tissue is foremost related to neurotransmission. GlyT2 is markedly expressed in brainstem, spinal cord and cerebellum, where it is responsible for glycine uptake into glycinergic and GABAergic terminals. GlyT1 is abundant in neocortex, thalamus and hippocampus, where it is expressed in astrocytes, and involved in glutamatergic neurotransmission. Consequently, inhibition of GlyT1 transporters can modulate glutamatergic neurotransmission through NMDA receptors, suggesting an alternative therapeutic strategy. In this review, we focus on recent progress in the understanding of GlyTs role in brain function and in various diseases, such as epilepsy, hyperekplexia, neuropathic pain, drug addiction, schizophrenia and stroke, as well as in neurodegenerative disorders.The circadian system is an endogenous biological network responsible for coordinating near-24-h cycles in behavior and physiology with daily timing cues from the external environment. In this review, we explore how the circadian system regulates memory formation, retention, and recall. Circadian rhythms in these memory processes may arise through several endogenous pathways, and recent work highlights the importance of genetic timekeepers found locally within tissues, called local clocks. We evaluate the circadian memory literature for evidence of local clock involvement in memory, identifying potential nodes for direct interactions between local clock components and mechanisms of synaptic plasticity. Our discussion illustrates how local clocks may pervasively modulate neuronal plastic capacity, a phenomenon that we designate here as circadian metaplasticity. We suggest that this function of local clocks supports the temporal optimization of memory processes, illuminating the potential for circadian therapeutic strategies in the prevention and treatment of memory impairment.Cholesterol plays vital roles in many central physiological and pathological processes. As a key component in the cell membrane, cholesterol can regulate a variety of ion channels, including ligand-gated ion channels (LGICs). However, relatively little is known about the molecular detail and in vivo consequence of cholesterol-LGIC interaction. Here, we reveal that membrane cholesterol depletion significantly inhibits the potentiating effects of dehydroxylcannabidiol (DH-CBD) on glycine-activated currents (IGly) in HEK 293T cells expressing α1/α3 glycine receptors (GlyRs). Simvastatin considerably decreases cholesterol levels and DH-CBD-induced potentiation of IGly in the spinal cord of mice. Simvastatin also significantly decreases DH-CBD analgesia in acute and chronic pain of mice. The cholesterol levels in the dorsal horn of spinal cord, measured by mass spectrometry imaging, are specifically correlated with cannabinoid potentiation of spinal GlyRs and cannabinoid-induced analgesia. These findings suggest that spinal cholesterol is critical for the efficacy of glycinergic cannabinoid-induced analgesia.Sulfur dioxide (SO2) can be endogenously generated from sulfur-containing amino acids in animals and humans. Increasing evidence shows that endogenous SO2 may act as a gaseous molecule to participate in many physiological and pathological processes. However, the role of SO2 and its derivatives in the central nervous system remains poorly understood. The present study explored the protective effects of exogenous SO2 derivatives (Na2SO3NaHSO3, 31 M/M) on cellular injury in vitro by using the cell proliferation assay (MTS), cell counting kit 8 assay (CCK-8), and cyto-flow assay in the corticosterone (CORT)-induced PC12 cell injury model. We also examined the antidepressant and anxiolytic effects of SO2 derivatives on the chronic mild stress (CMS)-induced depression mouse model by using the open field test, novelty suppressed feeding test, forced swimming test, tail suspension test, and sucrose preference test. In the MTS and CCK-8 assays, we found that preexposure of SO2 derivatives significantly blocked CORT-induced decrease of cellular survival without causing any negative effects. Results from the cyto-flow assay indicated that treatment with SO2 derivatives could reverse CORT-induced early and late apoptosis of PC12 cells. Systemic treatment with SO2 derivatives produced markedly antidepressant- and anxiolytic-like activities in mice under normal condition and rapidly reversed CMS-induced depressive- and anxiety-like behaviors. In conclusion, these findings indicate that exogenous SO2 derivatives show protective properties against the detrimental effects of stress and exert antidepressant- and anxiolytic-like actions. The present study suggests that exogenous SO2 derivatives are potential therapeutic agents for the treatment of depression, anxiety, and other stress-related diseases.N-methyl-d-aspartate receptors (NMDARs) mediate a slow component of excitatory synaptic transmission that plays important roles in normal brain function and development. A large number of disease-associated variants in the GRIN gene family encoding NMDAR GluN subunits have been identified in patients with various neurological and neuropsychiatric disorders. Many of these variants reduce the function of NMDARs by a range of different mechanisms, including reduced glutamate potency, reduced glycine potency, accelerated deactivation time course, decreased surface expression, and/or reduced open probability. We have evaluated whether three positive allosteric modulators of NMDAR receptor function (24(S)-hydroxycholesterol, pregnenolone sulfate, tobramycin) and three co-agonists (d-serine, l-serine, and d-cycloserine) can mitigate the diminished function of NMDARs harboring GRIN variants. We examined the effects of these modulators on NMDARs that contained 21 different loss-of-function variants in GRIN1, GRIN2A, or GRIN2B, identified in patients with epilepsy, intellectual disability, autism, and/or movement disorders. For all variants, some aspect of the reduced function was partially restored. Moreover, some variants showed enhanced sensitivity to positive allosteric modulators compared to wild type receptors. These results raise the possibility that enhancement of NMDAR function by positive allosteric modulators may be a useful therapeutic strategy.Certain ligands slowly bind to acetylcholinesterase. As a result, there is a slow establishment of enzyme-inhibitor equilibrium characterized by a slow onset of inhibition prior reaching steady state. Three mechanisms account for slow-binding inhibition a) slow binding rate constant kon, b) slow ligand induced-fit following a fast binding step, c) slow conformational selection of an enzyme form. The slow equilibrium may be followed by a chemical step. This later that can be irreversible has been observed with certain alkylating agents and substrate transition state analogs. Slow-binding inhibitors present long residence times on target. This results in prolonged pharmacological or toxicological action. Through several well-known molecules (e.g. huperzine) and new examples (tocopherol, trifluoroacetophenone and a 6-methyluracil alkylammonium derivative), we show that slow-binding inhibitors of acetylcholinesterase are promising drugs for treatment of neurological diseases such as Alzheimer disease and myasthenia gravis. Moreover, they may be of interest for neuroprotection (prophylaxis) against organophosphorus poisoning. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors From Bench to Bedside to Battlefield'.Cocaine abuse remains a public health threat around the world. There are no pharmacological treatments approved for cocaine use disorder. Cannabis has received growing attention as a treatment for many conditions, including addiction. learn more Most cannabis-based medication development has focused on cannabinoid CB1 receptor (CB1R) antagonists (and also inverse agonists) such as rimonabant, but clinical trials with rimonabant have failed due to its significant side-effects. Here we sought to determine whether a novel and selective CB2R inverse agonist, Xie2-64, has similar therapeutic potential for cocaine use disorder. Computational modeling indicated that Xie2-64 binds to CB2R in a way similar to SR144528, another well-characterized but less selective CB2R antagonist/inverse agonist, suggesting that Xie2-64 may also have CB2R antagonist profiles. Unexpectedly, systemic administration of Xie2-64 or SR144528 dose-dependently inhibited intravenous cocaine self-administration and shifted cocaine dose-response curves downward in rats and wild-type, but not in CB2R-knockout, mice. Xie2-64 also dose-dependently attenuated cocaine-enhanced brain-stimulation reward maintained by optical stimulation of ventral tegmental area dopamine (DA) neurons in DAT-Cre mice, while Xie2-64 or SR144528 alone inhibited optical brain-stimulation reward. In vivo microdialysis revealed that systemic or local administration of Xie2-64 into the nucleus accumbens reduced extracellular dopamine levels in a dose-dependent manner in rats. Together, these results suggest that Xie2-64 has significant anti-cocaine reward effects likely through a dopamine-dependent mechanism, and therefore, deserves further study as a new pharmacotherapy for cocaine use disorder.Most outcomes of COVID-19 are associated with dysfunction of the vascular system, particularly in the lung. Inhalation of nitric oxide (NO) gas is currently being investigated as a treatment for patients with moderate to severe COVID-19. In addition to the expected vasodilation effect, it has been also suggested that NO potentially prevents infection by SARS-CoV-2. Since NO is an unstable radical molecule that is easily oxidized by multiple mechanisms in the human body, it is practically difficult to control its concentration at lesions that need NO. Inorganic nitrate and/or nitrite are known as precursors of NO that can be produced through chemical as well enzymatic reduction. It appears that this NO synthase (NOS)-independent mechanism has been overlooked in the current developing of clinical treatments. Here, I suggest the missing link between nitrate and COVID-19 in terms of hypoxic NO generation.In some countries, snakes are important protein sources in human diets, and their economic value depends predominantly on their muscle production, including in the king ratsnake (Elaphe carinata). Muscle growth in the king ratsnake clearly differs among individuals. To date, few potential molecular mechanisms underlying these differences in muscle growth and development have been reported. Here, we integrated mRNA and miRNA expression profiles to screen for genes, pathways, and predicted miRNA-mRNA networks associated with muscle growth and development in fast-growing and slow-growing King ratsnakes. Six hundred eight differentially expressed genes (DEGs) were identified, 48 of which were associated with muscle growth. The 37 genes upregulated in fast-growing individuals (FGIs) may be related to the promotion of muscle growth, whereas the 11 upregulated genes in slow-growing individuals (SGIs) may be related to the inhibition of muscle growth. Seven DEGs were enriched in the PI3K-AKT-MTOR signaling pathway, which appears to promote muscle growth in FGIs.
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