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The COVID-19 pandemic caused by SARS-CoV-2 continues to pose a major challenge to global health. Targeting the main protease of the virus (Mpro), which is essential for viral replication and transcription, offers a promising approach for therapeutic intervention. In this study, advanced computational techniques such as molecular docking and molecular dynamics simulations were used to screen a series of antiviral compounds for their potential inhibitory effect on the SARS-CoV-2 Mpro. A comprehensive analysis of compounds from the ChemDiv and PubChem databases was performed. The physicochemical properties, pharmacokinetics, and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiles were evaluated to determine drug similarity and safety. Compound 4896 − 4038 proved to be the most promising candidate. It exhibited a favorable balance between molecular weight (491.06) and lipophilicity (logP 3.957), high intestinal absorption (92.119%), and broad tissue distribution (VDss of 0.529), indicating good oral bioavailability and therapeutic potential. Molecular docking studies showed that 4896 − 4038 has a strong binding affinity to the active site of Mpro and forms key interactions, such as hydrogen bonds, carbon-hydrogen bonds, pi-sulfur, and multiple van der Waals and pi-pi stacked bonds. The binding energy was comparable to that of the reference drug X77, indicating potential efficacy. Molecular dynamics simulations over 300 ns confirmed the stability of the Mpro/4896 − 4038 complex of protein-ligand. Free energy landscape mapping and MM/PBSA calculations further substantiated the favorable binding and stability of the complex. Importantly, 4896 − 4038 exhibited a comparatively favorable safety profile. In summary, compound 4896 − 4038 shows significant potential as a potent SARS-CoV-2 Mpro inhibitor, combining potent inhibitory activity with favorable pharmacokinetic and safety profiles. These results support the further development of 4896 − 4038 as a promising therapeutic agent in the fight against COVID-19 that warrants experimental validation and clinical investigation.

In fear conditioning with time intervals between the conditioned (CS) and unconditioned (US) stimuli, a neural representation of the CS must be maintained over time to be associated with the later US. Usually, temporal associations are studied by investigating individual brain regions. It remains unknown, however, the effect of the interval at the network level, uncovering functional connections cooperating for the CS transient memory and its fear association. We investigated the functional network supporting temporal associations using a task in which a 5-s interval separates the contextual CS from the US (CFC-5s). We quantified c-Fos expression in forty-nine brain regions of male rats following the CFC-5s training, used c-Fos correlations to generate functional networks, and analyzed them by graph theory. Control groups were trained in contextual fear conditioning, in which CS and US overlap. The CFC-5s training additionally activated subdivisions of the basolateral, lateral, and medial amygdala; prelimbic, infralimbic, perirhinal, postrhinal, and intermediate entorhinal cortices; ventral CA1 and subiculum. The CFC-5s network had increased amygdala centrality and higher amygdala internal and external connectivity with the retrosplenial cortex, thalamus, and hippocampus. Amygdala and thalamic nuclei were network hubs. Functional connectivity among these brain regions could support CS transient memories and their association.

Melatonin receptors MT 1 and MT 2 are G protein-coupled receptors that mediate the effects of melatonin, a hormone involved in circadian rhythms and other physiological functions. Understanding the molecular interactions between these receptors and their ligands is crucial for developing novel therapeutic agents. In this study, we used molecular docking, molecular dynamics simulations, and quantum mechanics calculation to investigate the binding modes and affinities of three ligands: melatonin (MLT), ramelteon (RMT), and 2-phenylmelatonin (2-PMT) with both receptors. Based on the results, we identified key amino acids that contributed to the receptor-ligand interactions, such as Gln181/194, Phe179/192, and Asn162/175, which are conserved in both receptors. Additionally, we described new meaningful interactions with Gly108/Gly121, Val111/Val124, and Val191/Val204. Our results provide insights into receptor-ligand recognition’s structural and energetic determinants and suggest potential strategies for designing more optimized molecules. This study enhances our understanding of receptor-ligand interactions and offers implications for future drug development.

The varied clinical presentations of SARS-CoV-2 infection have raised concerns about long-term consequences, especially \"long-COVID\" or \"post-COVID-19 syndrome.\" In this context, the cardiorespiratory optimal point (COP) within the Cardiopulmonary Exercise Test (CPET) emerges as a crucial metric for evaluating functional capacities and detecting cardiovascular and pulmonary anomalies post-COVID-19. This study aimed to assess COP values among post-COVID-19 patients and categorized them based on the initial severity of their disease. In this cross-sectional study conducted in the Northeast Brazil, 80 patients (26 females and 54 males) previously infected with SARS-CoV-2 underwent CPET. We clinically stratified patients into mild, moderate, or severe COVID-19 categories and assessed COP values and other cardiorespiratory metrics. We found differences in the predicted COP between patients with mild and severe COVID-19 (p=0.042). Additionally, patients with moderate and severe COVID-19 record had an average COP value exceeding 22. Other parameters, including respiratory exchange ratio, heart rate, and oxygen uptake efficiency slope, did not differ across the groups. Patients with a history of severe COVID-19 showed altered COP values, suggesting potential discrepancies in cardiovascular and respiratory system integration. The outcomes emphasize the importance of continuous monitoring and assessment of the cardiorespiratory domain for post-COVID-19 patients. Further research is needed to understand the relationship between elevated COP in post-severe COVID-19 and its long-term prognostic implications.

This systematic review examined the existing literature to determine the evidence supporting the efficacy of online group treatments for anxiety-, obsessive-compulsive- and trauma-related disorders (AOTDs). A systematic review using the PUBMED, PsycInfo, Web of Science, and ClinicalTrials databases with no language, date, or study design filters was performed. The inclusion criteria comprised studies that examined individuals who had received a formal diagnosis of AOTDs, were aged 18 years or older, and had baseline and endpoint assessments of symptom severity using formal tools. Five studies on social anxiety disorder (SAD), four on post-traumatic stress disorder (PTSD) and one on tic disorders (TDs) were found. The studies were open-label ( = 2) and randomized controlled trials (RCTs) ( = 8), with five of the RCTs being non-inferiority trials. Most studies were conducted in the US and investigated psychological CBT based interventions via internet-based therapies (IBT: = 4), video teleconferencing (VTC: = 5) or a combination of both ( = 1). In SAD, IBT studies associated with a clinician assisted web-based forum (here termed \"forum-enhanced\" studies) were superior to waiting lists and not inferior to similar versions that were also \"forum enhanced\" but self-guided, \"telephone enhanced\" by a contact with a non-specialist, and \"email enhanced\" by a contact with a clinician individually. Studies involving VTC have shown comparable effectiveness to in-person interventions across some online group CBT based treatments for PTSD. Two open trials also demonstrated symptoms reductions of social anxiety and tics through VTC. There is evidence supporting the effectiveness of online group treatments for SAD and PTSD. Further studies from different research groups may be needed to replicate the use of these and other forms of online treatments in individuals with SAD, PTSD, and other clinical populations, such as OCD, panic disorder, agoraphobia and specific phobias. https://www.crd.york.ac.uk/prospero/, identifier CRD42023408491.

Ayahuasca is a hallucinogenic beverage that combines the action of the 5-HT2A/2C agonist N,N-dimethyltryptamine (DMT) from Psychotria viridis with the monoamine oxidase inhibitors (MAOIs) induced by beta-carbonyls from Banisteriopsis caapi. Previous investigations have highlighted the involvement of ayahuasca with the activation of brain regions known to be involved with episodic memory, contextual associations and emotional processing after ayahuasca ingestion. Moreover long term users show better performance in neuropsychological tests when tested in off-drug condition. This study evaluated the effects of long-term administration of ayahuasca on Morris water maze (MWM), fear conditioning and elevated plus maze (EPM) performance in rats. Behavior tests started 48h after the end of treatment. Freeze-dried ayahuasca doses of 120, 240 and 480 mg/kg were used, with water as the control. Long-term administration consisted of a daily oral dose for 30 days by gavage. The behavioral data indicated that long-term ayahuasca administration did not affect the performance of animals in MWM and EPM tasks. However the dose of 120 mg/kg increased the contextual conditioned fear response for both background and foreground fear conditioning. The tone conditioned response was not affected after long-term administration. In addition, the increase in the contextual fear response was maintained during the repeated sessions several weeks after training. Taken together, these data showed that long-term ayahuasca administration in rats can interfere with the contextual association of emotional events, which is in agreement with the fact that the beverage activates brain areas related to these processes.

Post-acute COVID-19 syndrome, or long COVID, presents with persistent symptoms, including cough, dyspnea, and fatigue, extending beyond one month after SARS-CoV-2 infection. Cardiac complications such as chest pain and arrhythmias have raised concerns, with chronotropic incompetence (CI), an inadequate heart rate increase during exercise, emerging as a significant condition contributing to diminished exercise tolerance and quality of life. This study estimated the prevalence of CI and explored its association with aerobic capacity and physical activity levels in long COVID patients. A cross-sectional study was conducted at a private hospital in Sergipe, Brazil, involving 93 patients over 18 years old with persistent post-COVID-19 symptoms after confirmed SARS-CoV-2 infections. Exclusion criteria included beta-blocker use, inadequate respiratory exchange ratio, and inability to complete cardiopulmonary exercise testing (CPET). Clinical histories, CPET results, and chronotropic index calculation were used to identify CI, with logistic regression analyzing associated factors. Of the participants (mean age 45 years; average duration since COVID-19 diagnosis 120 days), 20.4% were diagnosed with CI. Logistic regression identified a strong association between CI and sedentary behavior (OR 11.80; 95% CI 2.54 to 54.78; p=0.001). Patients with CI showed lower predicted peak heart rates and maximal oxygen uptake. The prevalence of CI among long COVID patients in this study was approximately 20%, associated with decreased aerobic capacity and increased sedentary behavior. These findings highlight the need for timely diagnosis and therapeutic interventions, including cardiopulmonary rehabilitation, to enhance the quality of life in post-COVID patients with CI. The study's cross-sectional design and its specific context have limited causality inference and generalizability, underscoring the importance of further research in diverse settings.

Obsessive-compulsive disorder (OCD) is a prevalent condition with multifactorial etiology involving genetic and environmental factors. The present study aims to summarize the correlates of stressful life events (SLEs) in OCD by reviewing studies comparing OCD associated or not with SLEs before its onset. To do so, a systematic review was performed by searching PubMed, Web of Science, Scopus, and PsycINFO databases for studies published between the database’s inception and November 27, 2023. Studies including individuals whose OCD was precipitated or not by SLEs (SLEs OCD and NSLEs OCD, respectively) were assessed. Effect sizes or odds ratios were then calculated to identify the strength of association between SLEs and clinical characteristics, such as gender, age of onset, family history of OCD, severity of OCD symptoms, depressive symptoms, and mood comorbidities among patients with OCD. Out of the 4083 records initially identified, 5 studies met the inclusion criteria and 3 were comparable through a meta-analysis. Notably, the analyses were limited by the small number of studies available in the literature. The meta-analysis demonstrated SLEs OCD to be associated with female gender, later OCD onset, and increased comorbidity rates with mood disorders. Despite the cross-sectional nature of the reviewed studies, women may be more vulnerable to develop a later onset of OCD following SLEs, which may also lead to mood disorders. Caution is needed to avoid prematurely classifying this presentation as a distinct subtype of OCD.

Zika virus (ZIKV) has re-emerged in recent decades, leading to outbreaks of Zika fever in Africa, Asia, and Central and South America. Despite its drastic re-emergence and clinical impact, no vaccines or antiviral compounds are available to prevent or control ZIKV infection. This study evaluated the potential antiviral activity of quercetin hydrate against ZIKV infection and demonstrated that this substance inhibits virus particle production in A549 and Vero cells under different treatment conditions. In vitro antiviral activity was long-lasting (still observed 72 h post-infection), suggesting that quercetin hydrate affects multiple rounds of ZIKV replication. Molecular docking indicates that quercetin hydrate can efficiently interact with the specific allosteric binding site cavity of the NS2B-NS3 proteases and NS1-dimer. These results identify quercetin as a potential compound to combat ZIKV infection in vitro.