Unique among leukocytes, neutrophils follow daily cycles of release from and migration back into the bone marrow, where they are eliminated. Because removal of dying cells generates homeostatic ...signals, we explored whether neutrophil elimination triggers circadian events in the steady state. Here, we report that the homeostatic clearance of neutrophils provides cues that modulate the physiology of the bone marrow. We identify a population of CD62LLO CXCR4HI neutrophils that have “aged” in the circulation and are eliminated at the end of the resting period in mice. Aged neutrophils infiltrate the bone marrow and promote reductions in the size and function of the hematopoietic niche. Modulation of the niche depends on macrophages and activation of cholesterol-sensing nuclear receptors and is essential for the rhythmic egress of hematopoietic progenitors into the circulation. Our results unveil a process that synchronizes immune and hematopoietic rhythms and expand the ascribed functions of neutrophils beyond inflammation.
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•Neutrophils undergo a process of aging during their lifetime in circulation•Neutrophil clearance reduces the size and function of the hematopoietic niche•Macrophages and LXR receptors mediate changes in the niche•Neutrophil clearance triggers rhythmic release of progenitors during homeostasis
Aged neutrophils are cleared from the circulation by macrophages in the bone marrow, which in turn activate LXR receptors to promote the systemic egress of hematopoietic precursors from their niche in a circadian manner. Neutrophil clearance is, therefore, a homeostatic mechanism linking the immune and hemapoietic systems.
This study aimed to develop risk scores based on clinical characteristics at presentation to predict intensive care unit (ICU) admission and mortality in COVID-19 patients. 641 hospitalized patients ...with laboratory-confirmed COVID-19 were selected from 4997 persons under investigation. We performed a retrospective review of medical records of demographics, comorbidities and laboratory tests at the initial presentation. Primary outcomes were ICU admission and death. Logistic regression was used to identify independent clinical variables predicting the two outcomes. The model was validated by splitting the data into 70% for training and 30% for testing. Performance accuracy was evaluated using area under the curve (AUC) of the receiver operating characteristic analysis (ROC). Five significant variables predicting ICU admission were lactate dehydrogenase, procalcitonin, pulse oxygen saturation, smoking history, and lymphocyte count. Seven significant variables predicting mortality were heart failure, procalcitonin, lactate dehydrogenase, chronic obstructive pulmonary disease, pulse oxygen saturation, heart rate, and age. The mortality group uniquely contained cardiopulmonary variables. The risk score model yielded good accuracy with an AUC of 0.74 (95% CI, 0.63-0.85, p = 0.001) for predicting ICU admission and 0.83 (95% CI, 0.73-0.92, p<0.001) for predicting mortality for the testing dataset. This study identified key independent clinical variables that predicted ICU admission and mortality associated with COVID-19. This risk score system may prove useful for frontline physicians in clinical decision-making under time-sensitive and resource-constrained environment.
Phase-change contrast agents (PCCAs) for ultrasound-based applications have resulted in novel ways of approaching diagnostic and therapeutic techniques beyond what is possible with microbubble ...contrast agents and liquid emulsions. When subjected to sufficient pressures delivered by an ultrasound transducer, stabilized droplets undergo a phase-transition to the gaseous state and a volumetric expansion occurs. This phenomenon, termed acoustic droplet vaporization, has been proposed as a means to address a number of in vivo applications at the microscale and nanoscale. In this review, the history of PCCAs, physical mechanisms involved, and proposed applications are discussed with a summary of studies demonstrated in vivo. Factors that influence the design of PCCAs are discussed, as well as the need for future studies to characterize potential bioeffects for administration in humans and optimization of ultrasound parameters.
Despite intensive efforts over many years, the United States has made limited progress in improving rates of survival from out-of-hospital cardiac arrest. Recently, national organizations, such as ...the American Heart Association, have focused on promoting bystander cardiopulmonary resuscitation, use of automated external defibrillators, and other performance improvement efforts.
Using the Cardiac Arrest Registry to Enhance Survival (CARES), a prospective clinical registry, we identified 70 027 U.S. patients who experienced an out-of-hospital cardiac arrest between October 2005 and December 2012. Using multilevel Poisson regression, we examined temporal trends in risk-adjusted survival. After adjusting for patient and cardiac arrest characteristics, risk-adjusted rates of out-of-hospital cardiac arrest survival increased from 5.7% in the reference period of 2005 to 2006 to 7.2% in 2008 (adjusted risk ratio, 1.27; 95% confidence interval, 1.12-1.43; P<0.001). Survival improved more modestly to 8.3% in 2012 (adjusted risk ratio, 1.47; 95% confidence interval, 1.26-1.70; P<0.001). This improvement in survival occurred in both shockable and nonshockable arrest rhythms (P for interaction=0.22) and was also accompanied by better neurological outcomes among survivors (P for trend=0.01). Improved survival was attributable to both higher rates of prehospital survival, where risk-adjusted rates increased from 14.3% in 2005 to 2006 to 20.8% in 2012 (P for trend<0.001), and in-hospital survival (P for trend=0.015). Rates of bystander cardiopulmonary resuscitation and automated external defibrillator use modestly increased during the study period and partly accounted for prehospital survival trends.
Data drawn from a large subset of U.S communities suggest that rates of survival from out-of-hospital cardiac arrest have improved among sites participating in a performance improvement registry.
Microarray technology has become a standard molecular biology tool. Experimental data have been generated on a huge number of organisms, tissue types, treatment conditions and disease states. The ...Gene Expression Omnibus (Barrett et al., 2005), developed by the National Center for Bioinformatics (NCBI) at the National Institutes of Health is a repository of nearly 140 000 gene expression experiments. The BioConductor project (Gentleman et al., 2004) is an open-source and open-development software project built in the R statistical programming environment (R Development core Team, 2005) for the analysis and comprehension of genomic data. The tools contained in the BioConductor project represent many state-of-the-art methods for the analysis of microarray and genomics data. We have developed a software tool that allows access to the wealth of information within GEO directly from BioConductor, eliminating many the formatting and parsing problems that have made such analyses labor-intensive in the past. The software, called GEOquery, effectively establishes a bridge between GEO and BioConductor. Easy access to GEO data from BioConductor will likely lead to new analyses of GEO data using novel and rigorous statistical and bioinformatic tools. Facilitating analyses and meta-analyses of microarray data will increase the efficiency with which biologically important conclusions can be drawn from published genomic data. Availability: GEOquery is available as part of the BioConductor project. Contact: sdavis2@mail.nih.gov
The novel coronavirus SARS-CoV2 causes COVID-19, a pandemic threatening millions. As protective immunity does not exist in humans and the virus is capable of escaping innate immune responses, it can ...proliferate, unhindered, in primarily infected tissues. Subsequent cell death results in the release of virus particles and intracellular components to the extracellular space, which result in immune cell recruitment, the generation of immune complexes and associated damage. Infection of monocytes/macrophages and/or recruitment of uninfected immune cells can result in massive inflammatory responses later in the disease. Uncontrolled production of pro-inflammatory mediators contributes to ARDS and cytokine storm syndrome. Antiviral agents and immune modulating treatments are currently being trialled. Understanding immune evasion strategies of SARS-CoV2 and the resulting delayed massive immune response will result in the identification of biomarkers that predict outcomes as well as phenotype and disease stage specific treatments that will likely include both antiviral and immune modulating agents.
•SARS-CoV2 can escape the immune system by suppressing innate anti-viral responses•Tissue damage and antibody dependent enhancement can promote a cytokine storm•Unfavorable outcomes associate with features of cytokine storm syndrome•Host factors, including age, affect the individual’s prognosis•Immune modulating treatment should be considered and tested prospectively
Genetic factors contribute to the risk of thrombotic diseases. Recent genome wide association studies have identified genetic loci including SLC44A2 which may regulate thrombosis. Here we show that ...Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial energetics. We find that Slc44a2 null mice (Slc44a2(KO)) have increased bleeding times and delayed thrombosis compared to wild-type (Slc44a2(WT)) controls. Platelets from Slc44a2(KO) mice have impaired activation in response to thrombin. We discover that Slc44a2 mediates choline transport into mitochondria, where choline metabolism leads to an increase in mitochondrial oxygen consumption and ATP production. Platelets lacking Slc44a2 contain less ATP at rest, release less ATP when activated, and have an activation defect that can be rescued by exogenous ADP. Taken together, our data suggest that mitochondria require choline for maximum function, demonstrate the importance of mitochondrial metabolism to platelet activation, and reveal a mechanism by which Slc44a2 influences thrombosis.
Sickle cell disease (SCD) is a severe genetic blood disorder characterized by hemolytic anemia, episodic vaso-occlusion, and progressive organ damage. Current management of the disease remains ...symptomatic or preventative. Specific treatment targeting major complications such as vaso-occlusion is still lacking. Recent studies have identified various cellular and molecular factors that contribute to the pathophysiology of SCD. Here, we review the role of these elements and discuss the opportunities for therapeutic intervention.
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