Impact of the COVID-19 pandemic on mental health and viral suppression among persons living with HIV in western Washington.

The COVID-19 pandemic and social distancing measures elevated stress levels globally, exacerbating mental health challenges for people with HIV (PWH). We examined the effect of COVID-19-related stress on mental health among PWH in western Washington, exploring whether social support and coping self-efficacy were protective. Data on COVID-19-related stress, mental health, social support, and coping self-efficacy were collected using online surveys during the pandemic. Pre-COVID-19 mental health data were available for a subset of participants and were linked with the survey data. In the total sample (N = 373), COVID-19-stress was associated with elevated depression (PHQ-8, ß = 0.21, 95%CI [0.10, 0.32]) and anxiety (GAD-7, ß = 0.28, 95%CI [0.17, 0.39]). Among the subset of respondents with pre-pandemic mental health data (N = 103), COVID-19-related stress was associated with elevated PHQ-8 scores (ß = 0.35, 95%CI [0.15, 0.56]) and GAD-7 scores (ß = 0.35, 95%CI [0.16, 0.54]), adjusted for baseline mental health and other confounders. Coping self-efficacy was negatively associated with GAD-7 scores (ß = -0.01, 95%CI [-0.01, 0.00]), while social support was negatively associated with PHQ-8 scores (ß = -0.06, 95%CI [-0.12, -0.01]). Viral suppression before and during the pandemic did not differ among participants with available data. While COVID-19-related stress predicted elevated depression and anxiety symptoms among PWH, social support and coping self-efficacy were protective.

Sex Differences in Clustering Unhealthy Lifestyles Among Survivors of COVID-19: Latent Class Analysis.

BACKGROUND: The COVID-19 pandemic has underscored the significance of adopting healthy lifestyles to mitigate the risk of severe outcomes and long-term consequences. OBJECTIVE: This study focuses on assessing the prevalence and clustering of 5 unhealthy lifestyle behaviors among Vietnamese adults after recovering from COVID-19, with a specific emphasis on sex differences. METHODS: The cross-sectional data of 5890 survivors of COVID-19 in Vietnam were analyzed from December 2021 to October 2022. To examine the sex differences in 5 unhealthy lifestyle behaviors (smoking, drinking, unhealthy diet, physical inactivity, and sedentary behavior), the percentages were plotted along with their corresponding 95% CI for each behavior. Latent class analysis was used to identify 2 distinct classes of individuals based on the clustering of these behaviors: the "less unhealthy" group and the "more unhealthy" group. We examined the sociodemographic characteristics associated with each identified class and used logistic regression to investigate the factors related to the "more unhealthy" group. RESULTS: The majority of individuals (male participants: 2432/2447, 99.4% and female participants: 3411/3443, 99.1%) exhibited at least 1 unhealthy behavior, with male participants being more susceptible to multiple unhealthy behaviors. The male-to-female ratio for having a single behavior was 1.003, but it escalated to 25 for individuals displaying all 5 behaviors. Male participants demonstrated a higher prevalence of combining alcohol intake with sedentary behavior (949/2447, 38.8%) or an unhealthy diet (861/2447, 35.2%), whereas female participants tended to exhibit physical inactivity combined with sedentary behavior (1305/3443, 37.9%) or an unhealthy diet (1260/3443, 36.6%). Married male participants had increased odds of falling into the "more unhealthy" group compared to their single counterparts (odds ratio [OR] 1.45, 95% CI 1.14-1.85), while female participants exhibited lower odds (OR 0.65, 95% CI 0.51-0.83). Female participants who are underweight showed a higher likelihood of belonging to the "more unhealthy" group (OR 1.11, 95% CI 0.89-1.39), but this was not observed among male participants (OR 0.6, 95% CI 0.41-0.89). In both sexes, older age, dependent employment, high education, and obesity were associated with higher odds of being in the "more unhealthy" group. CONCLUSIONS: The study identified notable sex differences in unhealthy lifestyle behaviors among survivors of COVID-19. Male survivors are more likely to engage in unhealthy behaviors compared to female survivors. These findings emphasize the importance of tailored public health interventions targeting sex-specific unhealthy behaviors. Specifically, addressing unhealthy habits is crucial for promoting post-COVID-19 health and well-being.

GraphormerDTI: A graph transformer-based approach for drug-target interaction prediction.

The application of Artificial Intelligence (AI) to screen drug molecules with potential therapeutic effects has revolutionized the drug discovery process, with significantly lower economic cost and time consumption than the traditional drug discovery pipeline. With the great power of AI, it is possible to rapidly search the vast chemical space for potential drug-target interactions (DTIs) between candidate drug molecules and disease protein targets. However, only a small proportion of molecules have labelled DTIs, consequently limiting the performance of AI-based drug screening. To solve this problem, a machine learning-based approach with great ability to generalize DTI prediction across molecules is desirable. Many existing machine learning approaches for DTI identification failed to exploit the full information with respect to the topological structures of candidate molecules. To develop a better approach for DTI prediction, we propose GraphormerDTI, which employs the powerful Graph Transformer neural network to model molecular structures. GraphormerDTI embeds molecular graphs into vector-format representations through iterative Transformer-based message passing, which encodes molecules' structural characteristics by node centrality encoding, node spatial encoding and edge encoding. With a strong structural inductive bias, the proposed GraphormerDTI approach can effectively infer informative representations for out-of-sample molecules and as such, it is capable of predicting DTIs across molecules with an exceptional performance. GraphormerDTI integrates the Graph Transformer neural network with a 1-dimensional Convolutional Neural Network (1D-CNN) to extract the drugs' and target proteins' representations and leverages an attention mechanism to model the interactions between them. To examine GraphormerDTI's performance for DTI prediction, we conduct experiments on three benchmark datasets, where GraphormerDTI achieves a superior performance than five state-of-the-art baselines for out-of-molecule DTI prediction, including GNN-CPI, GNN-PT, DeepEmbedding-DTI, MolTrans and HyperAttentionDTI, and is on a par with the best baseline for transductive DTI prediction. The source codes and datasets are publicly accessible at https://github.com/mengmeng34/GraphormerDTI.

Effects of Empagliflozin-Induced Glycosuria on Weight Gain, Food Intake and Metabolic Indicators in Mice Fed a High-Fat Diet.

BACKGROUND: Sodium glucose-linked transporter 2 (SGLT2) inhibitors promote glucose, and therefore calorie, excretion in the urine. Patients taking SGLT2 inhibitors typically experience mild weight loss, but the amount of weight loss falls short of what is expected based on caloric loss. Understanding the mechanisms responsible for this weight loss discrepancy is imperative, as strategies to improve weight loss could markedly improve type 2 diabetes management and overall metabolic health. METHODS: Two mouse models of diet-induced obesity were administered the SGLT2 inhibitor empagliflozin in the food for 3 months. Urine glucose excretion, body weight, food intake and activity levels were monitored. In addition, serum hormone measurements were taken, and gene expression analyses were conducted. RESULTS: In both mouse models, mice receiving empagliflozin gained the same amount of body weight as their diet-matched controls despite marked glucose loss in the urine. No changes in food intake, serum ghrelin concentrations or activity levels were observed, but serum levels of fibroblast growth factor 21 (FGF21) decreased after treatment. A decrease in the levels of deiodinase 2 (Dio2) was also observed in the white adipose tissue, a primary target tissue of FGF21. CONCLUSION: These findings suggest that compensatory metabolic adaptations, other than increased food intake or decreased physical activity, occur in response to SGLT2 inhibitor-induced glycosuria that combats weight loss, and that reductions in FGF21, along with subsequent reductions in peripheral Dio2, may play a role.

Development and validation of multiplex real-time PCR for simultaneous detection of six bacterial pathogens causing lower respiratory tract infections and antimicrobial resistance genes.

BACKGROUND: Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Streptococcus pneumoniae and Staphylococcus aureus are major bacterial causes of lower respiratory tract infections (LRTIs) globally, leading to substantial morbidity and mortality. The rapid increase of antimicrobial resistance (AMR) in these pathogens poses significant challenges for their effective antibiotic therapy. In low-resourced settings, patients with LRTIs are prescribed antibiotics empirically while awaiting several days for culture results. Rapid pathogen and AMR gene detection could prompt optimal antibiotic use and improve outcomes. METHODS: Here, we developed multiplex quantitative real-time PCR using EvaGreen dye and melting curve analysis to rapidly identify six major pathogens and fourteen AMR genes directly from respiratory samples. The reproducibility, linearity, limit of detection (LOD) of real-time PCR assays for pathogen detection were evaluated using DNA control mixes and spiked tracheal aspirate. The performance of RT-PCR assays was subsequently compared with the gold standard, conventional culture on 50 tracheal aspirate and sputum specimens of ICU patients. RESULTS: The sensitivity of RT-PCR assays was 100% for K. pneumoniae, A. baumannii, P. aeruginosa, E. coli and 63.6% for S. aureus and the specificity ranged from 87.5% to 97.6%. The kappa correlation values of all pathogens between the two methods varied from 0.63 to 0.95. The limit of detection of target bacteria was 1600 CFU/ml. The quantitative results from the PCR assays demonstrated 100% concordance with quantitative culture of tracheal aspirates. Compared to culture, PCR assays exhibited higher sensitivity in detecting mixed infections and S. pneumoniae. There was a high level of concordance between the detection of AMR gene and AMR phenotype in single infections. CONCLUSIONS: Our multiplex quantitative RT-PCR assays are fast and simple, but sensitive and specific in detecting six bacterial pathogens of LRTIs and their antimicrobial resistance genes and should be further evaluated for clinical utility.

Functional regulation of aquaporin dynamics by lipid bilayer composition.

With the diversity of lipid-protein interactions, any observed membrane protein dynamics or functions directly depend on the lipid bilayer selection. However, the implications of lipid bilayer choice are seldom considered unless characteristic lipid-protein interactions have been previously reported. Using molecular dynamics simulation, we characterize the effects of membrane embedding on plant aquaporin SoPIP2;1, which has no reported high-affinity lipid interactions. The regulatory impacts of a realistic lipid bilayer, and nine different homogeneous bilayers, on varying SoPIP2;1 dynamics are examined. We demonstrate that SoPIP2;1's structure, thermodynamics, kinetics, and water transport are altered as a function of each membrane construct's ensemble properties. Notably, the realistic bilayer provides stabilization of non-functional SoPIP2;1 metastable states. Hydrophobic mismatch and lipid order parameter calculations further explain how lipid ensemble properties manipulate SoPIP2;1 behavior. Our results illustrate the importance of careful bilayer selection when studying membrane proteins. To this end, we advise cautionary measures when performing membrane protein molecular dynamics simulations.

Elemental Sulfur Promoted Cyclization of Aryl Hydrazones and Aryl Isothiocyanates Yielding 2-Imino-1,3,4-thiadiazoles.

We report a method for using elemental sulfur to facilitate the cyclization of aryl hydrazones and aryl isothiocyanates, affording biorelated 2-imino-1,3,4-thiadiazoles. Reactions progressed in the presence of elemental sulfur, N-methylmorpholine base, and DMSO solvent, while were tolerant of a wide range of functionalities including halogen, nitro, cyano, methylsulfonyl, and heterocyclic groups. The method appears to offer a general pathway for using simple, cheap, and stable reagents to afford triaryl-substituted 2-imino-1,3,4-thiadiazoles under relatively mild conditions.

Synthesis of 2-benzyl benzoxazoles and benzothiazoles via elemental sulfur promoted cyclization of styrenes with 2-nitrophenols and N,N-dialkyl-3-nitroanilines.

Herein we report a method for affording 2-benzyl benzoxazoles from substituted styrenes and 2-nitrophenols. The success of this method relies on the use of simple reagents, namely elemental sulfur and DABCO. A combination of identical reagents was utilized for the annulation of styrenes with N,N-dialkyl-3-nitroanilines to afford 2-benzyl benzothiazoles. Overall, benzoxazoles and benzothiazoles bearing useful functionalities such as halogens, amines, and heterocyclic groups were isolated in moderate to good yields. Our methods are a rare example of divergent transformations of substituted nitroarenes towards 2-benzyl benzoxazoles and benzothiazoles.

Desilification of phytolith exacerbates the release of arsenic from rice straw.

Arsenic (As) turnover in rice paddy agro-ecosystems has received much attention because As can enter the food chain through its accumulation in rice, thereby affecting human health. Returning straw to soil is a common practice to retain nutrients for soil and crops, but it also cycles As within the rice paddy field ecosystems. However, there is still a lack of detailed understanding of the fate of As in rice straw, and how or to what extent it is recycled back into the soil environment. This study aims to elucidate the relationship between the microstructure of rice straw and the release of As during rice straw decomposition. The microstructure of rice straw was found to comprise both organic and silica (phytolith) components. These two constituents are inter-embedded to form a composite-like structure that contains up to 6.48 mg As Kg-1. The 30-day batch experiments revealed that the biochemical release of As simultaneously depends upon the decomposition of the organic component and the desilicification of the silica component. Accompanying the release of As was the release of other elements such as Fe, Al, P and S. These elements can further interact with As to form less mobile compounds. The introduction of either Trichoderma harzianum or Bacillus velezensis was expected to accelerate the decomposition of rice straw, and enhance the silica dissolution, hence contributing to an increase in the As release. Despite these expectations, our observations showed the opposite effects. Microorganisms presumably have facilitated the change in solution chemistry or the inclusion of As into the newly-formed precipitates. The biochemical decomposition process can reduce straw particle size, while the negatively-charge surface will involve microsized straw particles in the electrostatic interaction, thereby favoring the dispersibility state. Therefore, the co-transport of micro-sized straw particles with As under field conditions should not be neglected.

Swept under the carpet: a qualitative study of patient perspectives on Long COVID, treatments, services, and mental health.

BACKGROUND: A constellation of often disabling long-term physical symptoms enduring after an acute SARS-COV-2 infection is commonly referred to as Long COVID. Since Long COVID is a new clinical entity, research is required to clarify treatment needs and experiences of individuals affected. This qualitative descriptive study aimed to provide insight into Long COVID treatment and service experiences and preferences of individuals experiencing Long COVID and the intersections with mental health. METHODS: The study was conducted out of a tertiary care mental health hospital, with online recruitment from the community across Canada. A total of 47 individuals (average age = 44.9) participated in one of 11 focus groups between June and December 2022. Five focus groups were conducted with participants who had pre-existing mental health concerns prior to contracting SARS-CoV-2, and six were with people with Long COVID but without pre-existing mental health concerns. A semi-structured interview guide asked about service experiences and service preferences, including mental health and well-being services. Discussions were recorded, transcribed, and analyzed using codebook thematic analysis. RESULTS: When accessing services for Long COVID, patients experienced: (1) systemic barriers to accessing care, and (2) challenges navigating the unknowns of Long COVID, leading to (3) negative impacts on patient emotional well-being and recovery. Participants called for improvements in Long COVID care, with a focus on: (1) developing Long COVID-specific knowledge and services, (2) enhancing support for financial well-being, daily living, and building a Long COVID community, and (3) improving awareness and the public representation of Long COVID. CONCLUSIONS: Substantial treatment barriers generate considerable burden for individuals living with Long COVID. There is a pressing need to improve treatment, social supports, and the social representation of Long COVID to create integrated, accessible, responsive, and ongoing support systems.

The lived experience of long COVID: A qualitative study of mental health, quality of life, and coping.

The majority of people who contract COVID-19 experience a short period of symptomatic infection. However, symptoms persist for months or years following initial exposure to the virus in some cases. This has been described as long COVID. Little is known about the lived experience of this condition, as it has only recently emerged. This study aimed to explore the experiences of mental health, quality of life, and coping among people living with long COVID. A sample of 47 adults with lived experience participated in web-based focus groups. Separate focus groups were held for 24 individuals with pre-existing mental health conditions and 23 individuals without pre-existing mental health conditions. Data were analyzed using a codebook thematic analysis approach. Five themes were identified as integral to the long COVID experience: The Emotional Landscape of Long COVID, New Limits to Daily Functioning, Grief and Loss of Former Identity, Long COVID-related Stigmatization, and Learning to Cope with Persisting Symptoms. These findings illustrate the immense impact of long COVID on mental health and quality of life. Minimal differences were found between those with and those without pre-existing mental health conditions, as both groups were substantially impacted by the condition. Attention to the perspectives of people with lived experience of long COVID is necessary to inform future directions for research and clinical practice.

Sorption of oxytetracycline to microsized colloids under concentrated salt solution: A perspective on terrestrial-to-ocean transfer of antibiotics.

The sorption of antibiotics on soil minerals and their cotransport have been widely studied for the past few years; however, these processes in concentrated salt solutions (estuary-like conditions) are not fully understood. This study aims to determine the possible sorption of oxytetracycline (OTC) on various natural and synthesized microsized minerals (including haematite, goethite, kaolinite, bentonite, lateritic, kaolinitic and illitic soil clays) under conditions mimicking pure, fresh, brackish and sea waters. The sorption of OTC was found to decrease in surface charge (herein zeta potential), hence altering the colloidal properties of the materials used. The sorption capacities of soil clays for OTC follow the inequality illitic soil clay > kaolinitic soil clay > lateritic soil clay, and the sorption capacities were found to decrease at higher salt concentrations. Seawater can intensify the release of the sorbed OTC from soil clay surfaces while favouring the coaggregation of the remaining OTC with soil clays. This implies that the long-range transport of OTC or other similar antibiotics can be governed by the mineralogical composition/properties of the suspended particles. More importantly, increasing salt concentrations in estuaries may form a chemical barrier at which limited amounts of OTC/antibiotics can pass through, while the remaining OTC/antibiotics can be favoured to aggregate simultaneously with suspended mineral particles.

Small molecule allosteric modulation of the adenosine A1 receptor.

G protein-coupled receptors (GPCRs) represent the target for approximately a third of FDA-approved small molecule drugs. The adenosine A1 receptor (A1R), one of four adenosine GPCR subtypes, has important (patho)physiological roles in humans. A1R has well-established roles in the regulation of the cardiovascular and nervous systems, where it has been identified as a potential therapeutic target for a number of conditions, including cardiac ischemia-reperfusion injury, cognition, epilepsy, and neuropathic pain. A1R small molecule drugs, typically orthosteric ligands, have undergone clinical trials. To date, none have progressed into the clinic, predominantly due to dose-limiting unwanted effects. The development of A1R allosteric modulators that target a topographically distinct binding site represent a promising approach to overcome current limitations. Pharmacological parameters of allosteric ligands, including affinity, efficacy and cooperativity, can be optimized to regulate A1R activity with high subtype, spatial and temporal selectivity. This review aims to offer insights into the A1R as a potential therapeutic target and highlight recent advances in the structural understanding of A1R allosteric modulation.

Functional Regulation of Aquaporin Dynamics by Lipid Bilayer Composition.

With the diversity of lipid-protein interactions, any observed membrane protein dynamics or functions directly depend on the lipid bilayer selection. However, the implications of lipid bilayer choice are seldom considered unless characteristic lipid-protein interactions have been previously reported. Using molecular dynamics simulation, we characterize the effects of membrane embedding on plant aquaporin SoPIP2;1, which has no reported high-affinity lipid interactions. The regulatory impacts of a realistic lipid bilayer, and nine different homogeneous bilayers, on varying SoPIP2;1 dynamics were examined. We demonstrate that SoPIP2;1s structure, thermodynamics, kinetics, and water transport are altered as a function of each membrane construct's ensemble properties. Notably, the realistic bilayer provides stabilization of non-functional SoPIP2;1 metastable states. Hydrophobic mismatch and lipid order parameter calculations further explain how lipid ensemble properties manipulate SoPIP2;1 behavior. Our results illustrate the importance of careful bilayer selection when studying membrane proteins. To this end, we advise cautionary measures when performing membrane protein molecular dynamics simulations.

Earthworms can mobilize soil arsenic through their casts.

The mobilization of arsenic (As) in paddy soil has received much attention because it might accelerate the transfer of As from soil to rice. This study aims to elucidate whether earthworms can mobilize As through their casts. Cast samples were collected from 23 different paddy fields in the Red River delta. We first analysed different forms of As through fractionation and then performed batch experiments under reducing conditions to identify factors that govern the mobility of As in casts. Because the dissociation of casts may induce colloids that carry As, the colloidal properties of cast suspensions were also examined. The median value of As in casts (obtained from aqua regia digestion) was 5.11 mg kg-1, which was lower than that in the surrounding soil (6.7 mg kg-1). Compared with the surrounding soil, casts contain less As, possibly because cast As is more labile and more easily lost due to leaching. Various processes, including the reductive dissolution of Fe oxides, decomposition of organic matter, and sorption competition of soluble anionic substances, such as P, Si and DOC, were found to strongly correlate with the release of As from casts. We propose that earthworms, via their casts, may accelerate the As cycle in paddy soils, potentially intensifying As exposure to human health. The dissociation of cast could release colloids containing As; therefore, the cotransport of As with cast-induced colloids should also be considered in future works.

Compact, Fast Blinking Cd-Free Quantum Dots for Super-Resolution Fluorescence Imaging.

Quantum dots (QDs) can be used as fluorescent probes in single molecule localization microscopy to achieve subdiffraction limit resolution (super-resolution fluorescence imaging). However, the toxicity of Cd in the prototypical CdSe-based QDs can limit their use in biological applications. Furthermore, commercial CdSe QDs are usually modified with relatively thick shells of both inorganic and organic materials to render them in the 10-20 nm size range, which is relatively large for biological labels. In this report, we present compact (4-6 nm) CuInS2/ZnS (CIS/ZnS) and compare them to commercially sourced CdSe/ZnS QDs for their blinking behavior, localization precision and super-resolution imaging. Although commercial CdSe/ZnS QDs are brighter than the more compact Cd-free CIS/ZnS QD, both give comparable results of 4.5-5.0-fold improvement in imaging resolution over conventional TIRF imaging of actin filaments. This likely results from the fact that CIS/ZnS QDs show very short on-times and long off times which leads to less overlap in the point spread functions of emitting CIS/ZnS QD labels on the actin filaments at the same labeling density. These results demonstrate that CIS/ZnS QDs are an excellent candidate to complement and perhaps even replace the larger and more toxic CdSe-based QDs for robust single- molecule super-resolution imaging.

Sympathoinhibitory electroacupuncture (EA) interacts positively with anti-inflammatory EA alleviating blood pressure in hypertensive rats.

Elevated sympathetic activity and chronic inflammation are known contributory factors observed in hypertension. We have observed that sympathoinhibitory electroacupuncture (SI-EA) at acupoints ST36-37 alleviates sympathetic activity and hypertension. Additionally, EA at acupoints SP6-7 exerts anti-inflammatory (AI-EA) effects. However, it is not known whether simultaneous stimulation of this combination of acupoints attenuates or enhances individual effects. A 2 × 2 factorial design was used to test the hypothesis that combining SI-EA and AI-EA (cEA) leads to greater reduction of hypertension by decreasing sympathetic activity and inflammation in hypertensive rats than either set of acupoints alone. Dahl salt-sensitive hypertensive (DSSH) rats were treated with four EA regimens including cEA, SI-EA, AI-EA, and sham-EA twice weekly for five weeks. A group of normotensive (NTN) rats served as control. Systolic and diastolic BP (SBP and DBP) and heart rate (HR) were measured non-invasively by tail-cuff. Plasma norepinephrine (NE), high-sensitivity C-reactive protein (hs-CRP) and interleukin 6 (IL-6) concentrations were determined with ELISA at the completion of treatments. DSSH rats on high salt diet progressively developed moderate hypertension within five weeks. DSSH rats treated with sham-EA showed continuous increase in SBP and DBP and elevations in plasma NE, hs-CRP, and IL-6 levels relative to NTN control. Both SI-EA and cEA decreased SBP and DBP, and had corresponding changes in biomarkers (NE, hs-CRP, and IL-6) compared with sham-EA. AI-EA prevented SBP and DBP elevation and decreased IL-6 and hs-CRP relative to sham-EA. Importantly in DSSH rats that received repetitive cEA treatment, SI-EA interacted positively with AI-EA leading to greater reduction of SBP, DBP, NE, hs-CRP, and IL-6 than SI-EA or AI-EA alone. These data suggest that by targeting both elevated sympathetic activity and chronic inflammation, cEA regimen results in a greater reduction of BP effects in treating hypertension compared to using individual SI-EA or AI-EA alone.

The application of artificial intelligence to accelerate G protein-coupled receptor drug discovery.

The application of artificial intelligence (AI) approaches to drug discovery for G protein-coupled receptors (GPCRs) is a rapidly expanding area. Artificial intelligence can be used at multiple stages during the drug discovery process, from aiding our understanding of the fundamental actions of GPCRs to the discovery of new ligand-GPCR interactions or the prediction of clinical responses. Here, we provide an overview of the concepts behind artificial intelligence, including the subfields of machine learning and deep learning. We summarise the published applications of artificial intelligence to different stages of the GPCR drug discovery process. Finally, we reflect on the benefits and limitations of artificial intelligence and share our vision for the exciting potential for further development of applications to aid GPCR drug discovery. In addition to making the drug discovery process "faster, smarter and cheaper," we anticipate that the application of artificial intelligence will create exciting new opportunities for GPCR drug discovery.

The influence of smoking on oral neutrophils and matrix metalloproteinase-8 in periodontitis patients before and after nonsurgical treatment.

Objective: To evaluate and compare the oral neutrophil numbers (ONN) in saliva, the level of matrix metalloproteinase-8 (MMP-8) in gingival crevicular fluid (GCF) and the periodontal parameters in smokers versus non-smokers with periodontitis, before and after nonsurgical periodontal treatment (NSPT). Materials and method: 40 chronic periodontitis patients including 20 smokers and 20 non-smokers were enrolled in this quasi-experimental study. All patients were received the NSPT included instructing oral hygiene, scaling and root planing. At baseline (T0) and after NSPT 1 month (T1) and 3 months (T3), all patients were assessed for salivary ONN, GCF MMP-8, and clinical parameters like plaque index (PlI), gingival index (GI), bleeding on probing (BOP), probing pocket depth (PPD) and clinical attachment loss (CAL). The differences between the two groups were analyzed using the independent sample t-test and the Mann-Whitney U test; and the differences between T0, T1 and T3 of each group were analyzed with paired-samples t-test and Wilcoxon signed-rank test. The level of significance was set at 0.05. Results: The ONN was significantly less in smokers than in non-smokers although there was no significant difference in other parameters between the two groups at baseline (p > 0.05). All clinical periodontal parameters reduced significantly after 1 month and 3 months of NSPT in both groups (p < 0.01). PPD of non-smokers was significantly lower than those of smokers at T1 and T3. ONN and MMP-8 level showed a significant decrease in non-smoking subjects, while there was no significant difference in smoking ones after NSPT (T1 and T3). At 1 month after treatment, ONN tended to reduce in non-smokers whereas to increase in smokers significantly. Conclusion: Smoking reduced ONN, impaired treatment effect in reducing PPD, and changed the MMP-8 level in gingival crevicular fluid to NSPT. Trial registration: Identifier NCT04974502 in CLinicalTrials.gov.

Targeting G protein-coupled receptors for heart failure treatment.

Heart failure remains a leading cause of morbidity and mortality worldwide. Current treatment for patients with heart failure include drugs targeting G protein-coupled receptors such as ß-adrenoceptor antagonists (ß-blockers) and angiotensin II type 1 receptor antagonists (or angiotensin II receptor blockers). However, many patients progress to advanced heart failure with persistent symptoms, despite treatment with available therapeutics that have been shown to reduce mortality and mortality. GPCR targets currently being explored for the development of novel heart failure therapeutics include adenosine receptor, formyl peptide receptor, relaxin/insulin-like family peptide receptor, vasopressin receptor, endothelin receptor and the glucagon-like peptide 1 receptor. Many GPCR drug candidates are limited by insufficient efficacy and/or dose-limiting unwanted effects. Understanding the current challenges hindering successful clinical translation and the potential to overcome existing limitations will facilitate the future development of novel heart failure therapeutics.