Nanomedicine platform for targeting activated neutrophils and neutrophil-platelet complexes using an α1-antitrypsin-derived peptide motif.

Targeted drug delivery to disease-associated activated neutrophils can provide novel therapeutic opportunities while avoiding systemic effects on immune functions. We created a nanomedicine platform that uniquely utilizes an α1-antitrypsin-derived peptide to confer binding specificity to neutrophil elastase on activated neutrophils. Surface decoration with this peptide enabled specific anchorage of nanoparticles to activated neutrophils and platelet-neutrophil aggregates, in vitro and in vivo. Nanoparticle delivery of a model drug, hydroxychloroquine, demonstrated significant reduction of neutrophil activities in vitro and a therapeutic effect on murine venous thrombosis in vivo. This innovative approach of cell-specific and activation-state-specific targeting can be applied to several neutrophil-driven pathologies.

Statistical Learning and Uncommon Soil Microbiota Explain Biogeochemical Responses after Wildfire.

Wildfires are a perennial event globally, and the biogeochemical underpinnings of soil responses at relevant spatial and temporal scales are unclear. Soil biogeochemical processes regulate plant growth and nutrient losses that affect water quality, yet the response of soil after variable intensity fire is difficult to explain and predict. To address this issue, we examined two wildfires in Colorado, United States, across the first and second postfire years and leveraged statistical learning (SL) to predict and explain biogeochemical responses. We found that SL predicts biogeochemical responses in soil after wildfire with surprising accuracy. Of the 13 biogeochemical analytes analyzed in this study, 9 are best explained with a hybrid microbiome + biogeochemical SL model. Biogeochemical-only models best explain 3 features, and 1 feature is explained equally well with the hybrid and biogeochemical-only models. In some cases, microbiome-only SL models are also effective (such as predicting NH4+). Whenever a microbiome component is employed, selected features always involve uncommon soil microbiota (i.e., the "rare biosphere" [existing at <1% mean relative abundance]). Here, we demonstrate that SL paired with DNA sequence and biogeochemical data predicts environmental features in postfire soils, although this approach could likely be applied to any biogeochemical system. IMPORTANCE Soil biogeochemical processes are critical to plant growth and water quality and are substantially disturbed by wildfire. However, soil responses to fire are difficult to predict. To address this issue, we developed a large environmental data set that tracks postfire changes in soil and used statistical learning (SL) to build models that exploit complex data to make predictions about biogeochemical responses. Here, we show that SL depends upon uncommon microbiota in soil (the "rare biosphere") to make surprisingly accurate predictions about soil biogeochemical responses to wildfire. Using SL to explain variation in a natively chaotic environmental system is mechanism independent. Likely, the approach that we describe for combining SL with microbiome and biogeochemical parameters has practical applications across a range of issues in the environmental sciences where predicting responses would be useful.

An "occlusive thrombosis-on-a-chip" microfluidic device for investigating the effect of anti-thrombotic drugs.

Cardiovascular disease remains one of the world's leading causes of death. Myocardial infarction (heart attack) is triggered by occlusion of coronary arteries by platelet-rich thrombi (clots). The development of new anti-platelet drugs to prevent myocardial infarction continues to be an active area of research and is dependent on accurately modelling the process of clot formation. Occlusive thrombi can be generated in vivo in a range of species, but these models are limited by variability and lack of relevance to human disease. Although in vitro models using human blood can overcome species-specific differences and improve translatability, many models do not generate occlusive thrombi. In those models that do achieve occlusion, time to occlusion is difficult to measure in an unbiased and objective manner. In this study we developed a simple and robust approach to determine occlusion time of a novel in vitro microfluidic assay. This highlighted the potential for occlusion to occur in thrombosis microfluidic devices through off-site coagulation, obscuring the effect of anti-platelet drugs. We therefore designed a novel occlusive thrombosis-on-a-chip microfluidic device that reliably generates occlusive thrombi at arterial shear rates by quenching downstream coagulation. We further validated our device and methods by using the approved anti-platelet drug, eptifibatide, recording a significant difference in the "time to occlude" in treated devices compared to control conditions. These results demonstrate that this device can be used to monitor the effect of antithrombotic drugs on time to occlude, and, for the first time, delivers this essential data in an unbiased and objective manner.

Cardiovascular reactions to psychological stress and abuse history: the role of occurrence, frequency, and type of abuse.

BACKGROUND AND OBJECTIVES: Extreme cardiovascular reactions to psychological stress have been associated with traumatic life experiences. Previous studies have focused on the occurrence or frequency of abuse rather than type of abuse. We examined how occurrence, frequency, and the type of abuse history are related to cardiovascular reactivity (CVR) to acute psychological stress. DESIGN: The study consisted of between group and continuous analyses to examine the association between occurrence, type, and frequency of abuse with cardiovascular reactions to acute psychological stress. METHODS: Data from 64 participants were collected. Heart rate, systolic blood pressure, and diastolic blood pressure were measured at baseline and during a standard mental arithmetic stress task. RESULTS: Individuals who experienced abuse showed diminished CVR to acute psychological stress; this was driven specifically by the history of sexual abuse. Frequency of abuse did not relate to stress reactions. CONCLUSIONS: These findings accord with previous work suggesting a relationship between traumatic life experience and hypoarousal in physiological reactivity and extend previous findings by suggesting the relationship may be driven by sexual abuse.