The ability to replace organs and tissues on demand could save or improve millions of lives each year globally and create public health benefits on par with curing cancer. Unmet needs for organ and ...tissue preservation place enormous logistical limitations on transplantation, regenerative medicine, drug discovery, and a variety of rapidly advancing areas spanning biomedicine. A growing coalition of researchers, clinicians, advocacy organizations, academic institutions, and other stakeholders has assembled to address the unmet need for preservation advances, outlining remaining challenges and identifying areas of underinvestment and untapped opportunities. Meanwhile, recent discoveries provide proofs of principle for breakthroughs in a family of research areas surrounding biopreservation. These developments indicate that a new paradigm, integrating multiple existing preservation approaches and new technologies that have flourished in the past 10 years, could transform preservation research. Capitalizing on these opportunities will require engagement across many research areas and stakeholder groups. A coordinated effort is needed to expedite preservation advances that can transform several areas of medicine and medical science.
Eph/Ephrin Signaling in Injury and Inflammation Coulthard, Mark G; Morgan, Michael; Woodruff, Trent M ...
The American journal of pathology,
11/2012, Letnik:
181, Številka:
5
Journal Article
Recenzirano
Odprti dostop
The Eph/ephrin receptor–ligand system plays an important role in embryogenesis and adult life, principally by influencing cell behavior through signaling pathways, resulting in modification of the ...cell cytoskeleton and cell adhesion. There are 10 EphA receptors, and six EphB receptors, distinguished on sequence difference and binding preferences, that interact with the six glycosylphosphatidylinositol-linked ephrin-A ligands and the three transmembrane ephrin-B ligands, respectively. The Eph/ephrin proteins, originally described as developmental regulators that are expressed at low levels postembryonically, are re-expressed after injury to the optic nerve, spinal cord, and brain in fish, amphibians, rodents, and humans. In rodent spinal cord injury, the up-regulation of EphA4 prevents recovery by inhibiting axons from crossing the injury site. Eph/ephrin proteins may be partly responsible for the phenotypic changes to the vascular endothelium in inflammation, which allows fluid and inflammatory cells to pass from the vascular space into the interstitial tissues. Specifically, EphA2/ephrin-A1 signaling in the lung may be responsible for pulmonary inflammation in acute lung injury. A role in T-cell maturation and chronic inflammation (heart failure, inflammatory bowel disease, and rheumatoid arthritis) is also reported. Although there remains much to learn about Eph/ephrin signaling in human disease, and specifically in injury and inflammation, this area of research raises the exciting prospect that novel therapies will be developed that precisely target these pathways.
The miR-15/16 family targets a large network of genes in T cells to restrict their cell cycle, memory formation, and survival. Upon T cell activation, miR-15/16 are downregulated, allowing rapid ...expansion of differentiated effector T cells to mediate a sustained response. Here, we used conditional deletion of miR-15/16 in regulatory T cells (Tregs) to identify immune functions of the miR-15/16 family in T cells. miR-15/16 are indispensable to maintain peripheral tolerance by securing efficient suppression by a limited number of Tregs. miR-15/16 deficiency alters expression of critical Treg proteins and results in accumulation of functionally impaired FOXP3loCD25loCD127hi Tregs. Excessive proliferation in the absence of miR-15/16 shifts Treg fate and produces an effector Treg phenotype. These Tregs fail to control immune activation, leading to spontaneous multi-organ inflammation and increased allergic inflammation in a mouse model of asthma. Together, our results demonstrate that miR-15/16 expression in Tregs is essential to maintain immune tolerance.
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•Treg-specific miR-15/16 expression is essential to prevent systemic tissue inflammation•miR-15/16 restrict Treg proliferation and regulate expression of key functional molecules•miR-15/16 limit formation of effector Tregs and are necessary for high suppressive capacity
Tregs are essential suppressors of autoimmunity and allergy. Johansson et al. demonstrate that the miR-15/16 family of microRNAs control core Treg function by limiting their proliferation and expression of the key functional molecules FOXP3, IL-2Rα, CTLA4, PD-1, and IL-7Rα.
Sepsis is a life-threatening disease caused by a dysregulated host response to infection, resulting in 11 million deaths globally each year. Vascular endothelial cell dysfunction results in the loss ...of endothelial barrier integrity, which contributes to sepsis-induced multiple organ failure and mortality. Erythropoietin-producing hepatocellular carcinoma (Eph) receptors and their ephrin ligands play a key role in vascular endothelial barrier disruption but are currently not a therapeutic target in sepsis. Using a cecal ligation and puncture (CLP) mouse model of sepsis, we showed that prophylactic or therapeutic treatment of mice with EphA4-Fc, a decoy receptor and pan-ephrin inhibitor, resulted in improved survival and a reduction in vascular leak, lung injury, and endothelial cell dysfunction.
mice also exhibited reduced mortality and pathology after CLP compared with wild-type mice. Proteomics of plasma samples from mice with sepsis after CLP revealed dysregulation of a number of Eph/ephrins, including EphA2/ephrin A1. Administration of EphA4-Fc to cultured human endothelial cells pretreated with TNF-α or ephrin-A1 prevented loss of endothelial junction proteins, specifically VE-cadherin, with maintenance of endothelial barrier integrity. In children admitted to hospital with fever and suspected infection, we observed that changes in EphA2/ephrin A1 in serum samples correlated with endothelial and organ dysfunction. Targeting Eph/ephrin signaling may be a potential therapeutic strategy to reduce sepsis-induced endothelial dysfunction and mortality.
Citrobacter rodentium is an attaching and effacing mouse pathogen that models enteropathogenic and enterohemorrhagic Escherichia coli in humans. The complement system is an important innate defense ...mechanism; however, only scant information is available about the role of complement proteins during enteric infections. In this study, we examined the impact of the lack of properdin, a positive regulator of complement, in C. rodentium-induced colitis. Following infection, properdin knockout (P(KO)) mice had increased diarrhea and exacerbated inflammation combined with defective epithelial cell-derived IL-6 and greater numbers of colonizing bacteria. The defect in the mucosal response was reversed by administering exogenous properdin to P(KO) mice. Then, using in vitro and in vivo approaches, we show that the mechanism behind the exacerbated inflammation of P(KO) mice is due to a failure to increase local C5a levels. We show that C5a directly stimulates IL-6 production from colonic epithelial cells and that inhibiting C5a in infected wild-type mice resulted in defective epithelial IL-6 production and exacerbated inflammation. These outcomes position properdin early in the response to an infectious challenge in the colon, leading to complement activation and C5a, which in turn provides protection through IL-6 expression by the epithelium. Our results unveil a previously unappreciated mechanism of intestinal homeostasis involving complement, C5a, and IL-6 during bacteria-triggered epithelial injury.
The inflammatory response is characterized by increased endothelial permeability, which permits the passage of fluid and inflammatory cells into interstitial spaces. The Eph/ephrin receptor ligand ...system plays a role in inflammation through a signaling cascade, which modifies Rho-GTPase activity. We hypothesized that blocking Eph/ephrin signaling using an EphA4-Fc would result in decreased inflammation and tissue injury in a model of ischemia/reperfusion (I/R) injury. Mice undergoing intestinal I/R pretreated with the EphA4-Fc had significantly reduced intestinal injury compared to mice injected with the control Fc. This reduction in I/R injury was accompanied by significantly reduced neutrophil infiltration, but did not affect intestinal inflammatory cytokine generation. Using microdialysis, we identified that intestinal I/R induced a marked increase in systemic vascular leakage, which was completely abrogated in EphA4-Fc-treated mice. Finally, we confirmed the direct role of Eph/ephrin signaling in endothelial leakage by demonstrating that EphA4-Fc inhibited tumor necrosis factor-α-induced vascular permeability in human umbilical vein endothelial cells. This study identifies that Eph/ephrin interaction induces proinflammatory signaling in vivo by inducing vascular leak and neutrophil infiltration, which results in tissue injury in intestinal I/R. Therefore, therapeutic targeting of Eph/ephrin interaction using inhibitors, such as EphA4-Fc, may be a novel method to prevent tissue injury in acute inflammation by influencing endothelial integrity and by controlling vascular leak.
The cartogram, or value-by-area map, is a popular technique for cartographically representing social data. Such maps visually equalize a basemap before mapping a social variable by adjusting the size ...of each enumeration unit by a second, related variable. However, to scale the basemap units according to an equalizing variable, cartograms must distort the shape and/or topology of the original geography. Such compromises reduce the effectiveness of the visualisation for elemental and general map-reading tasks. Here we describe a new kind of representation, termed a value-by-alpha map, which visually equalizes the basemap by adjusting the alpha channel, rather than the size, of each enumeration unit. Although not without its own limitations, the value-by-alpha map is able to circumvent the compromise inherent to the cartogram form, perfectly equalizing the basemap while preserving both shape and topology.
ABSTRACT
BACKGROUND
Patient hand-offs at physician shift changes have limited ability to convey the primary team’s longitudinal insight. The Patient Acuity Rating (PAR) is a previously validated, ...7-point scale that quantifies physician judgment of patient stability, where a higher score indicates a greater risk of clinical deterioration. Its impact on cross-covering physician understanding of patients is not known.
OBJECTIVE
To determine PAR contribution to sign-outs.
DESIGN
Cross-sectional survey.
SUBJECTS
Intern physicians at a university teaching hospital.
INTERVENTIONS
Subjects were surveyed using randomly chosen, de-identified patient sign-outs, previously assigned PAR scores by their primary teams. For each sign-out, subjects assigned a PAR score, then responded to hypothetical cross-cover scenarios before and after being informed of the primary team’s PAR.
MAIN MEASURE
Changes in intern assessment of the scenario before and after being informed of the primary team’s PAR were measured. In addition, responses between novice and experienced interns were compared.
KEY RESULTS
Between May and July 2008, 23 of 39 (59 %) experienced interns and 25 of 42 (60 %) novice interns responded to 480 patient scenarios from ten distinct sign-outs. The mean PAR score assigned by subjects was 4.2 ± 1.6 vs. 3.8 ± 1.8 by the primary teams (
p
< 0.001). After viewing the primary team’s PAR score, interns changed their level of concern in 47.9 % of cases, their assessment of the importance of immediate bedside evaluation in 48.7 % of cases, and confidence in their assessment in 43.2 % of cases. For all three assessments, novice interns changed their responses more frequently than experienced interns (
p
= 0.03, 0.009, and <0.001, respectively). Overall interns reported the PAR score to be theoretically helpful in 70.8 % of the cases, but this was more pronounced in novice interns (81.2 % vs 59.6 %,
p
< 0.001).
CONCLUSIONS
The PAR adds valuable information to sign-outs that could impact cross-cover decision-making and potentially benefit patients. However, correct training in its use may be required to avoid unintended consequences.
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