G protein-coupled receptors (GPCRs) are a large family of integral membrane proteins responsible for cellular signal transductions. Identification of therapeutic compounds to regulate physiological ...processes is an important first step of drug discovery. We proposed MAGELLAN, a novel hierarchical virtual-screening (VS) pipeline, which starts with low-resolution protein structure prediction and structure-based binding-site identification, followed by homologous GPCR detections through structure and orthosteric binding-site comparisons. Ligand profiles constructed from the homologous ligand–GPCR complexes are then used to thread through compound databases for VS. The pipeline was first tested in a large-scale retrospective screening experiment against 224 human Class A GPCRs, where MAGELLAN achieved a median enrichment factor (EF) of 14.38, significantly higher than that using individual ligand profiles. Next, MAGELLAN was examined on 5 and 20 GPCRs from two public VS databases (DUD-E and GPCR-Bench) and resulted in an average EF of 9.75 and 13.70, respectively, which compare favorably with other state-of-the-art docking- and ligand-based methods, including AutoDock Vina (with EF = 1.48/3.16 in DUD-E and GPCR-Bench), DOCK 6 (2.12/3.47 in DUD-E and GPCR-Bench), PoLi (2.2 in DUD-E), and FINDSITECcomb2.0 (2.90 in DUD-E). Detailed data analyses show that the major advantage of MAGELLAN is attributed to the power of ligand profiling, which integrates complementary methods for ligand–GPCR interaction recognition and thus significantly improves the coverage and sensitivity of VS models. Finally, cases studies on opioid and motilin receptors show that new connections between functionally related GPCRs can be visualized in the minimum spanning tree built on the similarities of predicted ligand-binding ensembles, suggesting a novel use of MAGELLAN for GPCR deorphanization.
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•Developed a new pipeline for Class-A GPCR virtual screening•Proposed a novel concept to improve virtual screening based on ligand profiling•A novel approach to GPCR deorphanization through ligand-binding ensembles•Integrating composite pipelines improves ligand–GPCR interaction recognition•Stringent tests of pipelines on three large-scale virtual screening experiments
In this study, we target the main protease (Mpro) of the SARS-CoV-2 virus as it is a crucial enzyme for viral replication. Herein, we report three plausible allosteric sites on Mpro that can expand ...structure-based drug discovery efforts for new Mpro inhibitors. To find these sites, we used mixed-solvent molecular dynamics (MixMD) simulations, an efficient computational protocol that finds binding hotspots through mapping the surface of unbound proteins with 5% cosolvents in water. We have used normal mode analysis to support our claim of allosteric control for these sites. Further, we have performed virtual screening against the sites with 361 hits from Mpro screenings available through the National Center for Advancing Translational Sciences (NCATS). We have identified the NCATS inhibitors that bind to the remote sites better than the active site of Mpro, and we propose these molecules may be allosteric regulators of the system. After identifying our sites, new X-ray crystal structures were released that show fragment molecules in the sites we found, supporting the notion that these sites are accurate and druggable.
Background. It is unclear if higher-dose oseltamivir provides benefit beyond the standard dose in influenza patients who require hospitalization. Methods. A prospective intervention study was ...performed in 2 acute care general hospitals in Hong Kong over 4 seasonal peaks (2010–2012). Adults (≥18 years) with laboratory-confirmed influenza (85 A/H3N2, 34 A/H1N1pdm09, 36 B) infections who presented within 96 hours were recruited. Study regimen of either 150 mg or 75 mg oseltamivir twice daily for 5 days was allocated by site, which was switched after 2 seasons. Subjects with preexisting renal impairment (creatinine clearance, 40–60 mL/minute) received 75 mg oseltamivir twice daily. Viral clearance by day 5 and clinical responses were compared between groups. Plasma steady-state trough oseltamivir carboxylate (OC) concentration was measured by high-performance liquid chromatography–tandem mass spectrometry. Results. Altogether, 41 and 114 patients received 150 mg and 75 mg twice-daily oseltamivir, respectively; their enrollment characteristics (mean age, 61 ± 18 vs 66 ± 16 years) and illness severity were comparable. Trough OC levels were higher in the 150-mg group (501.0 ± 237.0 vs 342.6 ± 192.7 ng/mL). There were no significant differences in day 5 viral RNA (44.7% vs 40.2%) or culture negativity (100.0% vs 98.1%), RNA decline rate, and durations of fever, oxygen supplementation, and hospitalization. Results were similar when analyzed by study arm (all cases and among those without renal impairment). Subanalysis of influenza B patients showed faster RNA decline rate (analysis of variance, F = 4.14; P = .05) and clearance (day 5, 80.0% vs 57.1%) with higher-dose treatment. No oseltamivir resistance was found. Treatments were generally well tolerated. Conclusions. We found no additional benefit of higher-dose oseltamivir treatment in adults hospitalized with influenza A, but an improved virologic response in influenza B. Clinical Trials Registration. ClinicalTrials.gov, NCT01052961.
This study compared the performance of the artificial neural network (ANN) model with the Acute Physiologic and Chronic Health Evaluation (APACHE) II and IV models for predicting hospital mortality ...among critically ill patients in Hong Kong.
This retrospective analysis included all patients admitted to the intensive care unit of Pamela Youde Nethersole Eastern Hospital from January 2010 to December 2019. The ANN model was constructed using parameters identical to the APACHE IV model. Discrimination performance was assessed using area under the receiver operating characteristic curve (AUROC); calibration performance was evaluated using the Brier score and Hosmer-Lemeshow statistic.
In total, 14 503 patients were included, with 10% in the validation set and 90% in the ANN model development set. The ANN model (AUROC=0.88, 95% confidence interval CI=0.86-0.90, Brier score=0.10; P in Hosmer-Lemeshow test=0.37) outperformed the APACHE II model (AUROC=0.85, 95% CI=0.80-0.85, Brier score=0.14; P<0.001 for both comparisons of AUROCs and Brier scores) but showed performance similar to the APACHE IV model (AUROC=0.87, 95% CI=0.85-0.89, Brier score=0.11; P=0.34 for comparison of AUROCs, and P=0.05 for comparison of Brier scores). The ANN model demonstrated better calibration than the APACHE II and APACHE IV models.
Our ANN model outperformed the APACHE II model but was similar to the APACHE IV model in terms of predicting hospital mortality in Hong Kong. Artificial neural networks are valuable tools that can enhance real-time prognostic prediction.
In the event of a global infectious pandemic, drastic measures may be needed that limit or require adjustment of ambulatory allergy services. However, no rationale for how to prioritize service shut ...down and patient care exists. A consensus-based ad-hoc expert panel of allergy/immunology specialists from the United States and Canada developed a service and patient prioritization schematic to temporarily triage allergy/immunology services. Recommendations and feedback were developed iteratively, using an adapted modified Delphi methodology to achieve consensus. During the ongoing pandemic while social distancing is being encouraged, most allergy/immunology care could be postponed/delayed or handled through virtual care. With the exception of many patients with primary immunodeficiency, patients on venom immunotherapy, and patients with asthma of a certain severity, there is limited need for face-to-face visits under such conditions. These suggestions are intended to help provide a logical approach to quickly adjust service to mitigate risk to both medical staff and patients. Importantly, individual community circumstances may be unique and require contextual consideration. The decision to enact any of these measures rests with the judgment of each clinician and individual health care system. Pandemics are unanticipated, and enforced social distancing/quarantining is highly unusual. This expert panel consensus document offers a prioritization rational to help guide decision making when such situations arise and an allergist/immunologist is forced to reduce services or makes the decision on his or her own to do so.
Concerns for anaphylaxis may hamper severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization efforts. We convened a multidisciplinary group of international experts in anaphylaxis ...composed of allergy, infectious disease, emergency medicine, and front-line clinicians to systematically develop recommendations regarding SARS-CoV-2 vaccine immediate allergic reactions. Medline, EMBASE, Web of Science, the World Health Organizstion (WHO) global coronavirus database, and the gray literature (inception, March 19, 2021) were systematically searched. Paired reviewers independently selected studies addressing anaphylaxis after SARS-CoV-2 vaccination, polyethylene glycol (PEG) and polysorbate allergy, and accuracy of allergy testing for SARS-CoV-2 vaccine allergy. Random effects models synthesized the data to inform recommendations based on the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach, agreed upon using a modified Delphi panel. The incidence of SARS-CoV-2 vaccine anaphylaxis is 7.91 cases per million (n = 41,000,000 vaccinations; 95% confidence interval 95% CI 4.02-15.59; 26 studies, moderate certainty), the incidence of 0.15 cases per million patient-years (95% CI 0.11-0.2), and the sensitivity for PEG skin testing is poor, although specificity is high (15 studies, very low certainty). We recommend vaccination over either no vaccination or performing SARS-CoV-2 vaccine/excipient screening allergy testing for individuals without history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient, and a shared decision-making paradigm in consultation with an allergy specialist for individuals with a history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient. We recommend further research to clarify SARS-CoV-2 vaccine/vaccine excipient testing utility in individuals potentially allergic to SARS-CoV2 vaccines or their excipients.
This paper introduces and evaluates the use of Gaussian mixture models (GMMs) for multiple limb motion classification using continuous myoelectric signals. The focus of this work is to optimize the ...configuration of this classification scheme. To that end, a complete experimental evaluation of this system is conducted on a 12 subject database. The experiments examine the GMMs algorithmic issues including the model order selection and variance limiting, the segmentation of the data, and various feature sets including time-domain features and autoregressive features. The benefits of postprocessing the results using a majority vote rule are demonstrated. The performance of the GMM is compared to three commonly used classifiers: a linear discriminant analysis, a linear perceptron network, and a multilayer perceptron neural network. The GMM-based limb motion classification system demonstrates exceptional classification accuracy and results in a robust method of motion classification with low computational load.
G protein-coupled receptors (GPCRs) are probably the most attractive drug target membrane proteins, which constitute nearly half of drug targets in the contemporary drug discovery industry. While the ...majority of drug discovery studies employ existing GPCR and ligand interactions to identify new compounds, there remains a shortage of specific databases with precisely annotated GPCR-ligand associations.
We have developed a new database, GLASS, which aims to provide a comprehensive, manually curated resource for experimentally validated GPCR-ligand associations. A new text-mining algorithm was proposed to collect GPCR-ligand interactions from the biomedical literature, which is then crosschecked with five primary pharmacological datasets, to enhance the coverage and accuracy of GPCR-ligand association data identifications. A special architecture has been designed to allow users for making homologous ligand search with flexible bioactivity parameters. The current database contains ∼500 000 unique entries, of which the vast majority stems from ligand associations with rhodopsin- and secretin-like receptors. The GLASS database should find its most useful application in various in silico GPCR screening and functional annotation studies.
The website of GLASS database is freely available at http://zhanglab.ccmb.med.umich.edu/GLASS/.
zhng@umich.edu
Supplementary data are available at Bioinformatics online.
The aim of this study was to investigate factors affecting clinical outcomes of adults hospitalised with severe seasonal influenza.
A prospective, observational cohort study was conducted over 24 ...months (2007-2008) in two acute, general hospitals. Consecutive, hospitalised adult patients were recruited and followed once their laboratory diagnosis of influenza A/B was established (based on viral antigen detection and virus isolation from nasopharyngeal aspirates collected per protocol). Outcomes studied included in-hospital death, length of stay and duration of oxygen therapy. Factors affecting outcomes were analysed using multivariate Cox proportional hazards models. Sequencing analysis on the neuraminidase gene was performed for available H1N1 isolates.
754 patients were studied (influenza A, n=539; >75% H3N2). Their mean age was 70+/-18 years; co-morbidities and serious complications were common (61-77%). Supplemental oxygen and ventilatory support was required in 401 (53.2%) and 41 (5.4%) patients, respectively. 39 (5.2%) patients died; pneumonia, respiratory failure and sepsis were the causes. 395 (52%) patients received antiviral (oseltamivir) treatment. Omission of antiviral treatment was associated with delayed presentation or negative antigen detection results. The mortality rate was 4.56 and 7.42 per 1000 patient-days in the treated and untreated patients, respectively; among those with co-morbidities, it was 5.62 and 11.64 per 1000 patient-days, respectively. In multivariate analysis, antiviral use was associated with reduced risk of death (adjusted HR (aHR) 0.27 (95% CI 0.13 to 0.55); p<0.001). Improved survival was observed with treatment started within 4 days from onset. Earlier hospital discharge (aHR 1.28 (95% CI 1.04 to 1.57); p=0.019) and faster discontinuation of oxygen therapy (aHR 1.30 (95% CI 1.01 to 1.69); p=0.043) was associated with early treatment within 2 days. Few (n=15) H1N1 isolates in this cohort had the H275Y mutation.
Antiviral treatment for severe influenza is associated with reduced mortality and improved clinical outcomes.
Laparoscopic liver resection for hepatocellular carcinoma (HCC) in Child-Pugh A cirrhosis has been demonstrated as beneficial. However, the role of laparoscopy in Child-Pugh B cirrhosis is ...undetermined. The aim of this retrospective cohort study was to compare open and laparoscopic resection for HCC with Child-Pugh B cirrhosis.
Data on liver resections were gathered from 17 centres. A 1 : 1 propensity score matching was performed according to 17 predefined variables.
Of 382 available liver resections, 100 laparoscopic and 100 open resections were matched and analysed. The 90-day postoperative mortality rate was similar in open and laparoscopic groups (4.0 versus 2.0 per cent respectively; P = 0.687). Laparoscopy was associated with lower blood loss (median 110 ml versus 400 ml in the open group; P = 0.004), less morbidity (38.0 versus 51.0 per cent respectively; P = 0.041) and fewer major complications (7.0 versus 21.0 per cent; P = 0.010), and ascites was lower on postoperative days 1, 3 and 5. For laparoscopic resections, patients with portal hypertension developed more complications than those without (26 versus 12 per cent respectively; P = 0.002), and patients with a Child-Pugh B9 score had higher morbidity rates than those with B8 and B7 (7 of 8, 10 of 16 and 21 of 76 respectively; P < 0.001). Median hospital stay was 7.5 (range 2-243) days for laparoscopic liver resection and 18 (3-104) days for the open approach (P = 0.058). The 5-year overall survival rate was 47 per cent for open and 65 per cent for laparoscopic resection (P = 0.142). The 5-year disease-free survival rate was 32 and 37 per cent respectively (P = 0.742).
Patients without preoperative portal hypertension and Child-Pugh B7 cirrhosis may benefit most from laparoscopic liver surgery.
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