Cellular senescence is a hallmark of aging and a promising target for therapeutic approaches. The identification of senescent cells requires multiple biomarkers and complex experimental procedures, ...resulting in increased variability and reduced sensitivity. Here, we propose a simple and broadly applicable imaging flow cytometry (IFC) method. This method is based on measuring autofluorescence and morphological parameters and on applying recent artificial intelligence (AI) and machine learning (ML) tools. We show that the results of this method are superior to those obtained measuring the classical senescence marker, senescence-associated beta-galactosidase (SA-β-Gal). We provide evidence that this method has the potential for diagnostic or prognostic applications as it was able to detect senescence in cardiac pericytes isolated from the hearts of patients affected by end-stage heart failure. We additionally demonstrate that it can be used to quantify senescence “in vivo” and can be used to evaluate the effects of senolytic compounds. We conclude that this method can be used as a simple and fast senescence assay independently of the origin of the cells and the procedure to induce senescence.
The coronavirus disease 2019 (COVID-19) pandemic has caused more than 2.3 million casualties worldwide and the lack of effective treatments is a major health concern. The development of targeted ...drugs is held back due to a limited understanding of the molecular mechanisms underlying the perturbation of cell physiology observed after viral infection. Recently, several approaches, aimed at identifying cellular proteins that may contribute to COVID-19 pathology, have been reported. Albeit valuable, this information offers limited mechanistic insight as these efforts have produced long lists of cellular proteins, the majority of which are not annotated to any cellular pathway. We have embarked in a project aimed at bridging this mechanistic gap by developing a new bioinformatic approach to estimate the functional distance between a subset of proteins and a list of pathways. A comprehensive literature search allowed us to annotate, in the SIGNOR 2.0 resource, causal information underlying the main molecular mechanisms through which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and related coronaviruses affect the host-cell physiology. Next, we developed a new strategy that enabled us to link SARS-CoV-2 interacting proteins to cellular phenotypes via paths of causal relationships. Remarkably, the extensive information about inhibitors of signaling proteins annotated in SIGNOR 2.0 makes it possible to formulate new potential therapeutic strategies. The proposed approach, which is generally applicable, generated a literature-based causal network that can be used as a framework to formulate informed mechanistic hypotheses on COVID-19 etiology and pathology.
Senescent cells may have a prominent role in driving inflammation and frailty. The impact of cellular senescence on frailty varies depending on the assessment tool used, as it is influenced by the ...criteria or items predominantly affected by senescent cells and the varying weights assigned to these items across different health domains. To address this challenge, we undertook a thorough review of all available studies involving gain- or loss-of-function experiments as well as interventions targeting senescent cells, focusing our attention on those studies that examined outcomes based on the individual frailty phenotype criteria or specific items used to calculate two humans (35 and 70 items) and one mouse (31 items) frailty indexes. Based on the calculation of a simple “evidence score,” we found that the burden of senescent cells related to musculoskeletal and cerebral health has the strongest causal link to frailty. We deem that insight into these mechanisms may not only contribute to clarifying the role of cellular senescence in frailty but could additionally provide multiple therapeutic opportunities to help the future development of a desirable personalized therapy in these extremely heterogeneous patients.
Frailty is an age-related condition characterized by a multisystem functional decline, increased vulnerability to stressors, and adverse health outcomes. Quantifying the degree of frailty in humans ...and animals is a health measure useful for translational geroscience research. Two frailty measurements, namely the frailty phenotype (FP) and the clinical frailty index (CFI), have been validated in mice and are frequently applied in preclinical research. However, these two tools are based on different concepts and do not necessarily identify the same mice as frail. In particular, the FP is based on a dichotomous classification that suffers from high sample size requirements and misclassification problems. Based on the monthly longitudinal non-invasive assessment of frailty in a large cohort of mice, here we develop an alternative scoring method, which we called physical function score (PFS), proposed as a continuous variable that resumes into a unique function, the five criteria included in the FP. This score would not only reduce misclassification of frailty but it also makes the two tools, PFS and CFI, integrable to provide an overall measurement of health, named vitality score (VS) in aging mice. VS displays a higher association with mortality than PFS or CFI and correlates with biomarkers related to the accumulation of senescent cells and the epigenetic clock. This longitudinal non-invasive assessment strategy and the VS may help to overcome the different sensitivity in frailty identification, reduce the sample size in longitudinal experiments, and establish the effectiveness of therapeutic/preventive interventions for frailty or other age-related diseases in geriatric animals.
Peptide-based antibiotics might help containing the rising tide of antimicrobial resistance. We developed SB056, a semi-synthetic peptide with a dimeric dendrimer scaffold, active against both ...Gram-negative and Gram-positive bacteria. Being the mechanism of SB056 attributed to disruption of bacterial membranes, we enhanced the amphiphilic profile of the original, empirically derived sequence WKKIRVRLSA-NH₂ by interchanging the first two residues KWKIRVRLSA-NH₂, and explored the effects of this modification on the interaction of peptide, both in linear and dimeric forms, with model membranes and on antimicrobial activity. Results obtained against Escherichia coli and Staphylococcus aureus planktonic strains, with or without salts at physiological concentrations, confirmed the added value of dendrimeric structure over the linear one, especially at physiological ionic strength, and the impact of the higher amphipathicity obtained through sequence modification on enhancing peptide performances. SB056 peptides also displayed intriguing antibiofilm properties. Staphylococcus epidermidis was the most susceptible strain in sessile form, notably to optimized linear analog lin-SB056-1 and the wild-type dendrimer den-SB056. Membrane affinity of all peptides increased with the percentage of negatively charged lipids and was less influenced by the presence of salt in the case of dendrimeric peptides. The analog lin-SB056-1 displayed the highest overall affinity, even for zwitterionic PC bilayers. Thus, in addition to electrostatics, distribution of charged/polar and hydrophobic residues along the sequence might have a significant role in driving peptide–lipid interaction. Supporting this view, dendrimeric analog den-SB056-1 retained greater membrane affinity in the presence of salt than den-SB056, despite the fact that they bear exactly the same net positive charge.
Purpose
Early on in the COVID-19 pandemic, the scientific community highlighted a potential risk of epidemics occurring inside prisons. Consequently, specific operational guidelines were promptly ...released, and containment measures were quickly implemented in prisons. This paper aims to describe the spread of COVID-19 in detention facilities within the Lombardy region of Italy during March to July 2020, and the impact of the prevention and control measures implemented.
Design/methodology/approach
A descriptive retrospective analysis of case distribution was performed for all COVID-19 cases identified among people in detention (PiD) and prison officers (POs). A comparison of the epidemic burden affecting different populations and a correlation analysis between the number of cases that occurred and prevention measures implemented were also carried out.
Findings
From this study, it emerged that POs were at a high risk of contracting COVID-19. This study observed a delay in the occurrence of cases among PiD and substantial heterogeneity in the size of outbreaks across different prisons. Correlation between reported cases among PiD and registered sick leave taken by POs suggested the latter contributed to introducing the infection into prison settings. Finally, number of cases among PiD inversely correlated with the capacity of each prison to identify and set up dedicated areas for medical isolation.
Originality/value
Prevention and control measures when adopted in a timely manner were effective in protecting PiD. According to the findings, POs are a population at high risk for acquiring and transmitting COVID-19 and should be prioritized for testing, active case finding and vaccination. This study highlights the critical importance of including prison settings within emergency preparedness plans.
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