The African spiny mouse (Acomys spp.) can heal full thickness excisional skin wounds in a scar-free manner with regeneration of all dermal components including hair and associated structures. ...Comparing Acomys scar-free healing from Mus scarring identifies gene expression differences that discriminate these processes. We have performed an extensive comparison of gene expression profiles in response to 8mm full-thickness excisional wounds at days 3, 5, 7 and 14 post-wounding between Acomys and Mus to characterize differences in wound healing, and identify mechanisms involved in scar-free healing. We also identify similarities with scar-free healing observed in fetal wounds. While wounding in Mus elicits a strong inflammatory response, wounding in Acomys produces a moderated immune response and little to no increase in expression for most cytokines and chemokines assayed. We also identified differences in the ECM profiles of the Acomys wounds, which appear to have a collagen profile more similar to fetal wounds, with larger increases in expression of collagen types III and V. In contrast, Mus wounds have very high levels of collagen XII. This data suggests that an overall lack of induction of cytokines and chemokines, coupled with an ECM profile more similar to fetal wounds, may underlie scar-free wound healing in Acomys skin. These data identify candidate genes for further testing in order to elucidate the causal mechanisms of scar-free healing.
Abstract
When solving the performance‐based earthquake engineering (PBEE) integral, the engineering demand parameters (EDPs) are assumed to be independent of the “upstream” parameters used in ground ...motion models (e.g., magnitude and source‐to‐site distance) after conditioning on the intensity measure (IM). This paper formulates a methodology for evaluating this conditional independence assumption through the lens of causal inference (CI). From a causal perspective, the effect of an upstream parameter on the EDP of interest is partially mediated by the IM with the remainder having a direct influence on the EDP. An IM is judged to be desirable (from a conditional independence standpoint) if the mediated effect of the upstream parameter is maximized, which implies that the direct effect is minimized. In the language of causal inference (CI), the IM, EDP and upstream parameters are described as the “treatment”, “outcome” and “confounding” variables, respectively. It then follows that the best performing IM is the one that maximizes the effect on the EDP after controlling for the upstream parameters. A semi‐parametric model that employs double machine learning is used to estimate the causal effect. The methodology is demonstrated through a case study application utilizing the responses from five special steel moment frames analyzed using 240 site‐agnostic ground motions. Compared to sufficiency‐based assessments, the casual inference method produces findings that are more explainable using structural dynamics principles and invariant to the number of ground motions used in the evaluation.
Sepsis is an increasingly significant challenge throughout the world as one of the major causes of patient morbidity and mortality. Central to the host immunologic response to sepsis is the increase ...in circulating myeloid-derived suppressor cells (MDSCs), which have been demonstrated to be present and independently associated with poor long-term clinical outcomes. MDSCs are plastic cells and potentially modifiable, particularly through epigenetic interventions. The objective of this study was to determine how the suppressive phenotype of MDSCs evolves after sepsis in surgical ICU patients, as well as to identify epigenetic differences in MDSCs that may explain these changes.
Circulating MDSCs from 267 survivors of surgical sepsis were phenotyped at various intervals over 6 weeks, and highly enriched MDSCs from 23 of these samples were co-cultured with CD3/CD28-stimulated autologous T cells. microRNA expression from enriched MDSCs was also identified.
We observed that MDSC numbers remain significantly elevated in hospitalized sepsis survivors for at least 6 weeks after their infection. However, only MDSCs obtained at and beyond 14 days post-sepsis significantly suppressed T lymphocyte proliferation and IL-2 production. These same MDSCs displayed unique epigenetic (miRNA) expression patterns compared to earlier time points.
We conclude that in sepsis survivors, immature myeloid cell numbers are increased but the immune suppressive function specific to MDSCs develops over time, and this is associated with a specific epigenome. These findings may explain the chronic and persistent immune suppression seen in these subjects.
In systemic lupus erythematosus, defective clearance of apoptotic debris and activation of innate cells result in a chronically activated type 1 IFN response, which can be measured in PBMCs of most ...patients. Metformin, a widely used prescription drug for Type 2 diabetes, has a therapeutic effect in several mouse models of lupus through mechanisms involving inhibition of oxidative phosphorylation and a decrease in CD4
T cell activation. In this study, we report that in CD4
T cells from human healthy controls and human systemic lupus erythematosus patients, metformin inhibits the transcription of IFN-stimulated genes (ISGs) after IFN-α treatment. Accordingly, metformin inhibited the phosphorylation of pSTAT1 (Y701) and its binding to IFN-stimulated response elements that control ISG expression. These effects were independent of AMPK activation or mTORC1 inhibition but were replicated using inhibitors of the electron transport chain respiratory complexes I, III, and IV. This indicates that mitochondrial respiration is required for ISG expression in CD4
T cells and provides a novel mechanism by which metformin may exert a therapeutic effect in autoimmune diseases.
MicroRNAs (miRNAs) are 19 to 23 nucleotide-long RNAs that post-transcriptionally regulate gene expression. Human cells express several hundred miRNAs which regulate important biological pathways such ...as development, proliferation, and apoptosis. Recently, 12 miRNA genes have been identified within the genome of Kaposi sarcoma-associated herpesvirus; however, their functions are still unknown. To identify host cellular genes that may be targeted by these novel viral regulators, we performed gene expression profiling in cells stably expressing KSHV-encoded miRNAs. Data analysis revealed a set of 81 genes whose expression was significantly changed in the presence of miRNAs. While the majority of changes were below 2-fold, eight genes were down-regulated between 4- and 20-fold. We confirmed miRNA-dependent regulation for three of these genes and found that protein levels of thrombospondin 1 (THBS1) were decreased >10-fold. THBS1 has previously been reported to be down-regulated in Kaposi sarcoma lesions and has known activity as a strong tumor suppressor and anti-angiogenic factor, exerting its anti-angiogenic effect in part by activating the latent form of TGF-beta. We show that reduced THBS1 expression in the presence of viral miRNAs translates into decreased TGF-beta activity. These data suggest that KSHV-encoded miRNAs may contribute directly to pathogenesis by down-regulation of THBS1, a major regulator of cell adhesion, migration, and angiogenesis.
Sepsis is a major cause of morbidity and mortality, especially at the extremes of age. To understand the human age-specific transcriptomic response to sepsis, a multi-cohort, pooled analysis was ...conducted on adults, children, infants, and neonates with and without sepsis. Nine public whole-blood gene expression datasets (636 patients) were employed. Age impacted the transcriptomic host response to sepsis. Gene expression from septic neonates and adults was more dissimilar whereas infants and children were more similar. Neonates showed reductions in inflammatory recognition and signaling pathways compared to all other age groups. Likewise, adults demonstrated decreased pathogen sensing, inflammation, and myeloid cell function, as compared to children. This may help to explain the increased incidence of sepsis-related organ failure and death in adults. The number of dysregulated genes in septic patients was proportional to age and significantly differed among septic adults, children, infants, and neonates. Overall, children manifested a greater transcriptomic intensity to sepsis as compared to the other age groups. The transcriptomic magnitude for adults and neonates was dramatically reduced as compared to children and infants. These findings suggest that the transcriptomic response to sepsis is age-dependent, and diagnostic and therapeutic efforts to identify and treat sepsis will have to consider age as an important variable.
Recovery‐based design links building‐level engineering and broader community resilience objectives. However, the relationship between above‐code engineering improvements and recovery performance is ...highly nonlinear and varies on a building‐ and site‐specific basis, presenting a challenge to both individual owners and code developers. In addition, downtime simulations are computationally expensive and hinder exploration of the full design space. In this paper, we present an optimization framework to identify optimal above‐code design improvements to achieve building‐specific recovery objectives. We supplement the optimization with a workflow to develop surrogate models that (i) rapidly estimate recovery performance under a range of user‐defined improvements, and (ii) enable complex and informative optimization techniques that can be repeated for different stakeholder priorities. We explore the implementation of the framework using a case study office building, with a 50th percentile baseline functional recovery time of 155 days at the 475‐year ground‐motion return period. To optimally achieve a target recovery time of 21 days, we find that nonstructural component enhancements are required, and that increasing structural strength (through increase of the importance factor) can be detrimental. However, for less ambitious target recovery times, we find that the use of larger importance factors eliminates the need for nonstructural component improvements. Such results demonstrate that the relative efficacy of a given recovery‐based design strategy will depend strongly on the design criteria set by the user.
Regulatory T cells (Tregs) play a central role in counteracting inflammation and autoimmunity. A more complete understanding of cellular heterogeneity and the potential for lineage plasticity in ...human Treg subsets may identify markers of disease pathogenesis and facilitate the development of optimized cellular therapeutics. To better elucidate human Treg subsets, we conducted direct transcriptional profiling of CD4(+)FOXP3(+)Helios(+) thymic-derived Tregs and CD4(+)FOXP3(+)Helios(-) T cells, followed by comparison with CD4(+)FOXP3(-)Helios(-) T conventional cells. These analyses revealed that the coinhibitory receptor T cell Ig and ITIM domain (TIGIT) was highly expressed on thymic-derived Tregs. TIGIT and the costimulatory factor CD226 bind the common ligand CD155. Thus, we analyzed the cellular distribution and suppressive activity of isolated subsets of CD4(+)CD25(+)CD127(lo/-) T cells expressing CD226 and/or TIGIT. We observed TIGIT is highly expressed and upregulated on Tregs after activation and in vitro expansion, and is associated with lineage stability and suppressive capacity. Conversely, the CD226(+)TIGIT(-) population was associated with reduced Treg purity and suppressive capacity after expansion, along with a marked increase in IL-10 and effector cytokine production. These studies provide additional markers to delineate functionally distinct Treg subsets that may help direct cellular therapies and provide important phenotypic markers for assessing the role of Tregs in health and disease.
To determine the incidence and risk factors of chronic critical illness after severe blunt trauma.
Prospective observational cohort study (NCT01810328).
Two level-one trauma centers in the United ...States.
One hundred thirty-five adult blunt trauma patients with hemorrhagic shock who survived beyond 48 hours after injury.
None.
Chronic critical illness was defined as an ICU stay lasting 14 days or more with evidence of persistent organ dysfunction. Three subjects (2%) died within the first 7 days, 107 (79%) exhibited rapid recovery and 25 (19%) progressed to chronic critical illness. Patients who developed chronic critical illness were older (55 vs 44-year-old; p = 0.01), had more severe shock (base deficit, -9.2 vs -5.5; p = 0.005), greater organ failure severity (Denver multiple organ failure score, 3.5 ± 2.4 vs 0.8 ± 1.1; p < 0.0001) and developed more infectious complications (84% vs 35%; p < 0.0001). Chronic critical illness patients were more likely to be discharged to a long-term care setting (56% vs 34%; p = 0.008) than to a rehabilitation facility/home. At 4 months, chronic critical illness patients had higher mortality (16.0% vs 1.9%; p < 0.05), with survivors scoring lower in general health measures (p < 0.005). Multivariate analysis revealed age greater than or equal to 55 years, systolic hypotension less than or equal to 70 mm Hg, transfusion greater than or equal to 5 units packed red blood cells within 24 hours, and Denver multiple organ failure score at 72 hours as independent predictors of chronic critical illness (area under the receiver operating curve, 0.87; 95% CI, 0.75-0.95).
Although early mortality is low after severe trauma, chronic critical illness is a common trajectory in survivors and is associated with poor long-term outcomes. Advancing age, shock severity, and persistent organ dysfunction are predictive of chronic critical illness. Early identification may facilitate targeted interventions to change the trajectory of this morbid phenotype.
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