Gi/o-protein coupled receptors in the aging brain

Cells translate extracellular signals to regulate processes such as differentiation, metabolism and proliferation, via transmembranar receptors. G protein-coupled receptors (GPCRs) belong to the largest family of transmembrane receptors, with over 800 members in the human species. Given the variety of key physiological functions regulated by GPCRs, these are main targets of existing drugs. During normal aging, alterations in the expression and activity of GPCRs have been observed. The central nervous system (CNS) is particularly affected by these alterations, which results in decreased brain functions, impaired neuroregeneration, and increased vulnerability to neuropathologies, such as Alzheimer's and Parkinson diseases. GPCRs signal via heterotrimeric G proteins, such as Go, the most abundant heterotrimeric G protein in CNS. We here review age-induced effects of GPCR signaling via the Gi/o subfamily at the CNS. During the aging process, a reduction in protein density is observed for almost half of the Gi/o-coupled GPCRs, particularly in age-vulnerable regions such as the frontal cortex, hippocampus, substantia nigra and striatum. Gi/o levels also tend to decrease with aging, particularly in regions such as the frontal cortex. Alterations in the expression and activity of GPCRs and coupled G proteins result from altered proteostasis, peroxidation of membranar lipids and age-associated neuronal degeneration and death, and have impact on aging hallmarks and age-related neuropathologies. Further, due to oligomerization of GPCRs at the membrane and their cooperative signaling, down-regulation of a specific Gi/o-coupled GPCR may affect signaling and drug targeting of other types/subtypes of GPCRs with which it dimerizes. Gi/o-coupled GPCRs receptorsomes are thus the focus of more effective therapeutic drugs aiming to prevent or revert the decline in brain functions and increased risk of neuropathologies at advanced ages.This work was supported by Fundação para a Ciência e Tecnologia, Centro 2020 and Portugal 2020, the COMPETE program, QREN, and the European Union (FEDER program) via the GoBack project (PTDC/CVT-CVT/32261/2017), the pAGE program (Centro-01-0145-FEDER-000003), and Institute for Biomedicine iBiMED (UID/BIM/04501/2013; UID/BIM/04501/2019).publishe

Notes for genera: basal clades of Fungi (including Aphelidiomycota, Basidiobolomycota, Blastocladiomycota, Calcarisporiellomycota, Caulochytriomycota, Chytridiomycota, Entomophthoromycota, Glomeromycota, Kickxellomycota, Monoblepharomycota, Mortierellomycota, Mucoromycota, Neocallimastigomycota, Olpidiomycota, Rozellomycota and Zoopagomycota)

Compared to the higher fungi (Dikarya), taxonomic and evolutionary studies on the basal clades of fungi are fewer in number. Thus, the generic boundaries and higher ranks in the basal clades of fungi are poorly known. Recent DNA based taxonomic studies have provided reliable and accurate information. It is therefore necessary to compile all available information since basal clades genera lack updated checklists or outlines. Recently, Tedersoo et al. (MycoKeys 13:1--20, 2016) accepted Aphelidiomycota and Rozellomycota in Fungal clade. Thus, we regard both these phyla as members in Kingdom Fungi. We accept 16 phyla in basal clades viz. Aphelidiomycota, Basidiobolomycota, Blastocladiomycota, Calcarisporiellomycota, Caulochytriomycota, Chytridiomycota, Entomophthoromycota, Glomeromycota, Kickxellomycota, Monoblepharomycota, Mortierellomycota, Mucoromycota, Neocallimastigomycota, Olpidiomycota, Rozellomycota and Zoopagomycota. Thus, 611 genera in 153 families, 43 orders and 18 classes are provided with details of classification, synonyms, life modes, distribution, recent literature and genomic data. Moreover, Catenariaceae Couch is proposed to be conserved, Cladochytriales Mozl.-Standr. is emended and the family Nephridiophagaceae is introduced

Development and Validation of a Deep Learning Classifier Using Chest Radiographs to Predict Extubation Success in Patients Undergoing Invasive Mechanical Ventilation

The decision to extubate patients on invasive mechanical ventilation is critical; however, clinician performance in identifying patients to liberate from the ventilator is poor. Machine Learning-based predictors using tabular data have been developed; however, these fail to capture the wide spectrum of data available. Here, we develop and validate a deep learning-based model using routinely collected chest X-rays to predict the outcome of attempted extubation. We included 2288 serial patients admitted to the Medical ICU at an urban academic medical center, who underwent invasive mechanical ventilation, with at least one intubated CXR, and a documented extubation attempt. The last CXR before extubation for each patient was taken and split 79/21 for training/testing sets, then transfer learning with k-fold cross-validation was used on a pre-trained ResNet50 deep learning architecture. The top three models were ensembled to form a final classifier. The Grad-CAM technique was used to visualize image regions driving predictions. The model achieved an AUC of 0.66, AUPRC of 0.94, sensitivity of 0.62, and specificity of 0.60. The model performance was improved compared to the Rapid Shallow Breathing Index (AUC 0.61) and the only identified previous study in this domain (AUC 0.55), but significant room for improvement and experimentation remains

MEWS++: Enhancing the Prediction of Clinical Deterioration in Admitted Patients through a Machine Learning Model

Early detection of patients at risk for clinical deterioration is crucial for timely intervention. Traditional detection systems rely on a limited set of variables and are unable to predict the time of decline. We describe a machine learning model called MEWS++ that enables the identification of patients at risk of escalation of care or death six hours prior to the event. A retrospective single-center cohort study was conducted from July 2011 to July 2017 of adult (age > 18) inpatients excluding psychiatric, parturient, and hospice patients. Three machine learning models were trained and tested: random forest (RF), linear support vector machine, and logistic regression. We compared the models’ performance to the traditional Modified Early Warning Score (MEWS) using sensitivity, specificity, and Area Under the Curve for Receiver Operating Characteristic (AUC-ROC) and Precision-Recall curves (AUC-PR). The primary outcome was escalation of care from a floor bed to an intensive care or step-down unit, or death, within 6 h. A total of 96,645 patients with 157,984 hospital encounters and 244,343 bed movements were included. Overall rate of escalation or death was 3.4%. The RF model had the best performance with sensitivity 81.6%, specificity 75.5%, AUC-ROC of 0.85, and AUC-PR of 0.37. Compared to traditional MEWS, sensitivity increased 37%, specificity increased 11%, and AUC-ROC increased 14%. This study found that using machine learning and readily available clinical data, clinical deterioration or death can be predicted 6 h prior to the event. The model we developed can warn of patient deterioration hours before the event, thus helping make timely clinical decisions

Risk of COVID-19 after natural infection or vaccinationResearch in context

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health