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Mitoxantrone dihydrochloride, an FDA approved drug, binds with SARS-CoV-2 NSP1 C-terminal.
One of the major virulence factors of SARS-CoV-2, NSP1, is a vital drug target due to its role in host immune evasion through multiple pathways. NSP1 protein is associated with inhibiting host mRNA translation by binding to the small subunit of ribosome through its C-terminal region. Previously, we have shown the structural dynamics of the NSP1 C-terminal region (NSP1-CTR) in different physiological environments. So, it would be very interesting to investigate the druggable compounds that could bind with NSP1-CTR. Here, in this article, we have performed different spectroscopic technique-based binding assays of an anticancer drug mitoxantrone dihydrochloride (MTX) against the NSP1-CTR. We have also performed molecular dynamics simulations of the docked complex with two different force fields up to one microsecond. Overall, our results have suggested good binding between NSP1-CTR and MTX and may have implications in developing therapeutic strategies targeting the NSP1 protein of SARS-CoV-2.
Detection of neuronal OFF periods as low amplitude neural activity segments
Abstract Background During non-rapid eye movement sleep (NREM), alternating periods of synchronised high (ON period) and low (OFF period) neuronal activity are associated with high amplitude delta band (0.5–4 Hz) oscillations in neocortical electrophysiological signals termed slow waves. As this oscillation is dependent crucially on hyperpolarisation of cortical cells, there is an interest in understanding how neuronal silencing during OFF periods leads to the generation of slow waves and whether this relationship changes between cortical layers. A formal, widely adopted definition of OFF periods is absent, complicating their detection. Here, we grouped segments of high frequency neural activity containing spikes, recorded as multiunit activity from the neocortex of freely behaving mice, on the basis of amplitude and asked whether the population of low amplitude (LA) segments displayed the expected characteristics of OFF periods. Results Average LA segment length was comparable to previous reports for OFF periods but varied considerably, from as short as 8 ms to > 1 s. LA segments were longer and occurred more frequently in NREM but shorter LA segments also occurred in half of rapid eye movement sleep (REM) epochs and occasionally during wakefulness. LA segments in all states were associated with a local field potential (LFP) slow wave that increased in amplitude with LA segment duration. We found that LA segments > 50 ms displayed a homeostatic rebound in incidence following sleep deprivation whereas short LA segments (< 50 ms) did not. The temporal organisation of LA segments was more coherent between channels located at a similar cortical depth. Conclusion We corroborate previous studies showing neural activity signals contain uniquely identifiable periods of low amplitude with distinct characteristics from the surrounding signal known as OFF periods and attribute the new characteristics of vigilance-state-dependent duration and duration-dependent homeostatic response to this phenomenon. This suggests that ON/OFF periods are currently underdefined and that their appearance is less binary than previously considered, instead representing a continuum.
Autophagy preserves hematopoietic stem cells by restraining mTORC1-mediated cellular anabolism
Adult stem cells are long-lived and quiescent with unique metabolic requirements. Macroautophagy/autophagy is a fundamental survival mechanism that allows cells to adapt to metabolic changes by degrading and recycling intracellular components. Here we address why autophagy depletion leads to a drastic loss of the stem cell compartment. Using inducible deletion of autophagy specifically in adult hematopoietic stem cells (HSCs) and in mice chimeric for autophagy-deficient and normal HSCs, we demonstrate that the stem cell loss is cell-intrinsic. Mechanistically, autophagy-deficient HSCs showed higher expression of several amino acid transporters (AAT) when compared to autophagy-competent cells, resulting in increased amino acid (AA) uptake. This was followed by sustained mTOR (mammalian target of rapamycin) activation, with enlarged cell size, glucose uptake and translation, which is detrimental to the quiescent HSCs. mTOR inhibition by rapamycin treatment in vivo was able to rescue autophagy-deficient HSC loss and bone marrow failure and resulted in better reconstitution after transplantation. Our results suggest that targeting mTOR may improve aged stem cell function, promote reprogramming and stem cell transplantation.
Explaining paranoia: cognitive and social processes in the occurrence of extreme mistrust.
BACKGROUND: Paranoia-incorrectly thinking that others are deliberating trying to harm you-causes distress, undermines social interactions and leads to withdrawal. It presents across multiple psychiatric diagnoses. OBJECTIVE: The primary aim was to determine the extent that cognitive and social processes may explain paranoia. The secondary aim was to identify explanatory factors that distinguished paranoia and social anxiety. METHODS: 10 382 UK adults, quota sampled to match the population for age, gender, ethnicity, income and region, participated in a non-probability survey. All participants completed a paranoia measure and assessments of cognitive and social processes. Structural equation modelling was conducted. FINDINGS: 2586 (24.9%) participants described being mistrustful of other people. 1756 (16.9%) participants wanted help to trust more. 66.7% of variance in paranoia was explained by a model comprising (in descending order of importance): within-situation defence behaviours, negative images, negative self-beliefs, discrimination, dissociation, aberrant salience, anxiety sensitivity, agoraphobic distress, worry, less social support, agoraphobic avoidance, less analytical reasoning and alcohol use. All explanatory factors were associated with paranoia and social anxiety. Ten factors were more closely associated with paranoia than social anxiety, including discrimination, hallucinations, negative images, aberrant salience and alcohol use. Nine factors were more closely associated with social anxiety, including less positive self-belief, an external locus of control, worry and less analytical reasoning. CONCLUSIONS: Multiple causes are likely to be involved in paranoia. Cognitive and social processes may explain a high degree of paranoia. CLINICAL IMPLICATIONS: Multiple clear targets for intervention to reduce paranoia are identified.
The signal peptide of the amyloid precursor protein forms amyloid-like aggregates and enhances Aβ42 aggregation
Signal sequences are short peptides at the N terminus of proteins destined for the secretion pathway. Typically, after cleavage by peptidases, signal peptides are degraded by intra-membrane proteases. In some cases, however, signal peptides can be processed further and released into the endoplasmic reticulum, secretion pathways, or cytoplasm. The consequences of these processes remain unclear, in particular considering that dysregulated signal peptides could potentially aggregate and induce cytotoxicity. To investigate this problem, we study the signal peptide of the amyloid precursor protein (APP), which originates the Alzheimer's β-amyloid (Aβ) peptide. Our results show that this signal peptide (residues 1–17 of APP [APP1–17SP]) can form amyloid-like cytotoxic aggregates. We further demonstrate that APP1–17SP seeds promote aggregation of Aβ, which raises the intriguing possibility of an interplay between APP1–17SP and Aβ aggregation in disease processes.
Quantifying neutralising antibody responses against SARS-CoV-2 in dried blood spots (DBS) and paired sera.
The ongoing SARS-CoV-2 pandemic was initially managed by non-pharmaceutical interventions such as diagnostic testing, isolation of positive cases, physical distancing and lockdowns. The advent of vaccines has provided crucial protection against SARS-CoV-2. Neutralising antibody (nAb) responses are a key correlate of protection, and therefore measuring nAb responses is essential for monitoring vaccine efficacy. Fingerstick dried blood spots (DBS) are ideal for use in large-scale sero-surveillance because they are inexpensive, offer the option of self-collection and can be transported and stored at ambient temperatures. Such advantages also make DBS appealing to use in resource-limited settings and in potential future pandemics. In this study, nAb responses in sera, venous blood and fingerstick blood stored on filter paper were measured. Samples were collected from SARS-CoV-2 acutely infected individuals, SARS-CoV-2 convalescent individuals and SARS-CoV-2 vaccinated individuals. Good agreement was observed between the nAb responses measured in eluted DBS and paired sera. Stability of nAb responses was also observed in sera stored on filter paper at room temperature for 28 days. Overall, this study provides support for the use of filter paper as a viable sample collection method to study nAb responses.
Effect of selective serotonin reuptake inhibitor discontinuation on anxiety-like behaviours in mice.
BACKGROUND: Abrupt cessation of therapy with a selective serotonin reuptake inhibitor (SSRI) is associated with a discontinuation syndrome, typified by numerous disabling symptoms, including anxiety. Surprisingly, little is known of the behavioural effect of SSRI discontinuation in animals. AIM: Here, the effect of SSRI discontinuation on anxiety-like behaviour was systematically investigated in mice. METHODS: Experiments were based on a three-arm experimental design comprising saline, continued SSRI and discontinued SSRI. Mice were assessed 2 days after SSRI discontinuation over a 5-day period using the elevated plus maze (EPM) and other anxiety tests. RESULTS: An exploratory experiment found cessation of paroxetine (12 days) was associated with decreased open-arm exploration and reduced total distance travelled, in male but not female mice. Follow-up studies confirmed a discontinuation effect on the EPM in male mice after paroxetine (12 days) and also citalopram (12 days). Mice receiving continued paroxetine (but not citalopram) also showed decreased open-arm exploration but this was dissociable from the effects of discontinuation. The discontinuation response to paroxetine did not strengthen after 28 days of treatment but was absent after 7 days of treatment. A discontinuation response was not discernible in other anxiety and fear-learning tests applied 3-5 days after treatment cessation. Finally, discontinuation effects on the EPM were typically associated with decreased locomotion on the test. However, separate locomotor testing implicated anxiety-provoked behavioural inhibition rather than a general reduction in motor activity. CONCLUSION: Overall, this study provides evidence for a short-lasting behavioural discontinuation response to cessation of SSRI treatment in mice.
Glutamatergic dysfunction leads to a hyper-dopaminergic phenotype through deficits in short-term habituation: a mechanism for aberrant salience
ABSTRACTPsychosis in disorders like schizophrenia is commonly associated with aberrant salience and elevated striatal dopamine. However, the underlying cause(s) of this hyper-dopaminergic state remain elusive. Various lines of evidence point to glutamatergic dysfunction and impairments in synaptic plasticity in the aetiology of schizophrenia, including deficits associated with the GluA1 AMPAR subunit. GluA1 knockout (Gria1-/-) mice provide a model of impaired synaptic plasticity in schizophrenia and exhibit a selective deficit in a form of short-term memory which underlies short-term habituation. As such, these mice are unable to reduce attention to recently presented stimuli. In this study we used fast-scan cyclic voltammetry to measure phasic dopamine responses in the nucleus accumbens ofGria1-/-mice to determine whether this behavioral phenotype might be a key driver of a hyper-dopaminergic state. There was no effect of GluA1 deletion on electrically-evoked dopamine responses in anaesthetized mice, demonstrating normal endogenous release properties of dopamine neurons inGria1-/-mice. Furthermore, dopamine signals were initially similar inGria1-/-mice compared to controls in response to both sucrose rewards and neutral light stimuli. They were also equally sensitive to changes in the magnitude of delivered rewards. In contrast, however, these stimulus-evoked dopamine signals failed to habituate with repeated presentations inGria1-/-mice, resulting in a task-relevant, hyper-dopaminergic phenotype. Thus, here we show that GluA1 dysfunction, resulting in impaired short-term habituation, is a key driver of enhanced striatal dopamine responses, which may be an important contributor to aberrant salience and psychosis in psychiatric disorders like schizophrenia.
Distinct effects of AMPAR subunit depletion on spatial memory.
Pharmacological studies established a role for AMPARs in the mammalian forebrain in spatial memory performance. Here we generated global GluA1/3 double knockout mice (Gria1/3-/-) and conditional knockouts lacking GluA1 and GluA3 AMPAR subunits specifically from principal cells across the forebrain (Gria1/3ΔFb). In both models, loss of GluA1 and GluA3 resulted in reduced hippocampal GluA2 and increased levels of the NMDAR subunit GluN2A. Electrically-evoked AMPAR-mediated EPSPs were greatly diminished, and there was an absence of tetanus-induced LTP. Gria1/3-/- mice showed premature mortality. Gria1/3ΔFb mice were viable, and their memory performance could be analyzed. In the Morris water maze (MWM), Gria1/3ΔFb mice showed profound long-term memory deficits, in marked contrast to the normal MWM learning previously seen in single Gria1-/- and Gria3-/- knockout mice. Our results suggest a redundancy of function within the pool of available ionotropic glutamate receptors for long-term spatial memory performance.
Continuous home cage monitoring of activity and sleep in mice during repeated paroxetine treatment and discontinuation.
RATIONALE: Non-invasive home cage monitoring is emerging as a valuable tool to assess the effects of experimental interventions on mouse behaviour. A field in which these techniques may prove useful is the study of repeated selective serotonin reuptake inhibitor (SSRI) treatment and discontinuation. SSRI discontinuation syndrome is an under-researched condition that includes the emergence of sleep disturbances following treatment cessation. OBJECTIVES: We used passive infrared (PIR) monitoring to investigate changes in activity, sleep, and circadian rhythms during repeated treatment with the SSRI paroxetine and its discontinuation in mice. METHODS: Male mice received paroxetine (10 mg/kg/day, s.c.) for 12 days, then were swapped to saline injections for a 13 day discontinuation period and compared to mice that received saline injections throughout. Mice were continuously tracked using the Continuous Open Mouse Phenotyping of Activity and Sleep Status (COMPASS) system. RESULTS: Repeated paroxetine treatment reduced activity and increased behaviourally-defined sleep in the dark phase. These effects recovered to saline-control levels within 24 h of paroxetine cessation, yet there was also evidence of a lengthening of sleep bouts in the dark phase for up to a week following discontinuation. CONCLUSIONS: This study provides the first example of how continuous non-invasive home cage monitoring can be used to detect objective behavioural changes in activity and sleep during and after drug treatment in mice. These data suggest that effects of paroxetine administration reversed soon after its discontinuation but identified an emergent change in sleep bout duration, which could be used as a biomarker in future preclinical studies to prevent or minimise SSRI discontinuation symptoms.