Abstract Since 1987, only a few neuroanatomical studies have been conducted to identify the origin of innervation for the immune system. These studies demonstrated that all primary and secondary ...immune organs receive a substantial sympathetic innervation from sympathetic postganglionic neurons. Neither the thymus nor spleen receive any sensory neural innervation; however, there is evidence that lymph nodes and bone marrow may be innervated by sensory neurons located in dorsal root ganglia. There is no neuroanatomical evidence for a parasympathetic or vagal nerve supply to any immune organ. Thus, the primary pathway for the neural regulation of immune function is provided by the sympathetic nervous system (SNS) and its main neurotransmitter, norepinephrine (NE). Activation of the SNS primarily inhibits the activity of cells associated with the innate immune system, while it either enhances or inhibits the activity of cells associated with the acquired/adaptive immune system. Innate immune cells express both alpha and beta-adrenergic receptor subtypes, while T and B lymphocytes express adrenergic receptors of the beta2 subtype exclusively, except for murine Th2 cells that lack expression of any subtype. Via these adrenergic receptors, NE is able to regulate the level of immune cell activity by initiating a change in the level of cellular activity, which often involves a change in the level of gene expression for cytokines and antibodies.
Hematopoietic stem cell transplantation is a potential curative therapy for malignant and nonmalignant diseases. Improving the efficiency of stem cell collection and the quality of the cells acquired ...can broaden the donor pool and improve patient outcomes. We developed a rapid stem cell mobilization regimen utilizing a unique CXCR2 agonist, GROβ, and the CXCR4 antagonist AMD3100. A single injection of both agents resulted in stem cell mobilization peaking within 15 min that was equivalent in magnitude to a standard multi-day regimen of granulocyte colony-stimulating factor (G-CSF). Mechanistic studies determined that rapid mobilization results from synergistic signaling on neutrophils, resulting in enhanced MMP-9 release, and unexpectedly revealed genetic polymorphisms in MMP-9 that alter activity. This mobilization regimen results in preferential trafficking of stem cells that demonstrate a higher engraftment efficiency than those mobilized by G-CSF. Our studies suggest a potential new strategy for the rapid collection of an improved hematopoietic graft.
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•GROβ is well tolerated and induces mobilization in a first in-human study•Combination treatment with GROβ+AMD3100 results in rapid stem cell mobilization•Mouse strain nucleotide polymorphisms in MMP-9 alter biologic activity•Rapid mobilization releases a highly engraftable hematopoietic stem cell
A new strategy for stem cell mobilization enables rapid collection of an improved hematopoietic graft in humans.
Three-phase bone scan was performed for evaluation of possible sinus tarsi syndrome in a 52-year-old man with chronic left ankle pain. MRI was initially read as unremarkable, and there was little ...symptomatic improvement after intra-articular anesthetic injection. The primary finding that appreciated only delayed bone SPECT/CT images was focal increased uptake associated with a well-corticated 8-mm bony fragment adjacent to the left calcaneus, thought to represent an accessory ossicle within the left sinus tarsi. The increased uptake suggested fracture or severe degenerative change of the ossicle, likely contributing to the patient's chronic pain.
Lambl excrescences are fibrinous connective tissue strands found predominantly on left-sided cardiac valves. These valvular strands are typically benign, but have been implicated as a potential ...etiology of embolic strokes in adult patients. The significance of Lambl excrescences in pediatric stroke cases is unclear and not previously reported in the literature. In this study, we describe a 10-year-old boy who presented with acute-onset right-sided hemiplegia, found to have multifocal embolic strokes of various ages. Extensive stroke workup was unrevealing, aside from the presence of small, filamentous, strand-like densities associated with the mitral and aortic valves noted on a transesophageal echocardiogram consistent with Lambl excrescences. In this case report, we review Lambl excrescences and their significance in acute stroke and management options for the prevention of future ischemia in these patients.
The extracellular matrix (ECM) microenvironment is increasingly implicated in the instruction of pathologically relevant cell behaviors, from aberrant transdifferentation to invasion and beyond. ...Indeed, pathologic ECMs possess a panoply of alterations that provide deleterious instructions to resident cells. Here we demonstrate the precise manner in which the ECM protein fibronectin (FN) undergoes the posttranslational modification citrullination in response to peptidyl-arginine deiminase (PAD), an enzyme associated with innate immune cell activity and implicated in systemic ECM-centric diseases, like cancer, fibrosis and rheumatoid arthritis. FN can be citrullinated in at least 24 locations, 5 of which reside in FN's primary cell-binding domain. Citrullination of FN alters integrin clustering and focal adhesion stability with a concomitant enhancement in force-triggered integrin signaling along the FAK-Src and ILK-Parvin pathways within fibroblasts. In vitro migration and in vivo wound healing studies demonstrate the ability of citrullinated FN to support a more migratory/invasive phenotype that enables more rapid wound closure. These findings highlight the potential of ECM, particularly FN, to “record” inflammatory insults via post-translational modification by inflammation-associated enzymes that are subsequently “read” by resident tissue fibroblasts, establishing a direct link between inflammation and tissue homeostasis and pathogenesis through the matrix.
•Fibronectin can be citrullinated at five cell-binding domain sites including PHSRN.•Integrin binding preference shifts from αvβ3 to α5β1 on citrullinated fibronectin.•An αvβ3 to5β1 shift promotes focal adhesion-associated FAK, SRC, and ILK.•Exposure to citrullinated fibronectin is sufficient to stimulate fibroblast migration.
To characterize the outcomes of ABO incompatible direct antiglobulin test (DAT) positive newborns and determine the predictive ability of a sixth-hour transcutaneous bilirubin (TcB for needing ...phototherapy ≤24 hours of age.
Retrospective, cross-sectional study from May 2013 to March 2017. Of 10 942 consecutive newborns ≥35 weeks estimated gestational age, 829 were ABO incompatible and DAT positive. After excluding for antibodies other than ABO (51), missing data (4), miscategorization of blood type O (1), and duplicate record (1), 772 newborns remained. Of 772, a subsample of 346 newborns with both TcB and total serum bilirubin (TSB) tests within 1 hour of the sixth hour was analyzed to determine the predictive ability.
Phototherapy was required in 281 of 772 (36.4%); 156 (20.2%) in the first 24 hours. There were 10 (1.3%) admissions for hyperbilirubinemia to the NICU for intravenous immunoglobin. Birth weight, infant blood type B, TSB, reticulocyte count, and TcB were all significantly associated with phototherapy ≤24 hours. On multivariate analysis, significant predictors of phototherapy ≤24 hours were TSB and reticulocyte count if no TcB was done and TcB alone if no blood tests were done. TcB was highly predictive (odds ratio 3.1, 95% confidence interval: 2.4-4.0) and nearly as accurate as the TSB and reticulocyte count (area under the curve, 0.90 and 0.96, respectively). Low (<3.0 mg/dL) and high (≥5.3 mg/dL) risk TcB cutoffs demonstrated a negative predictive value of 98% and positive predictive value of 85%, respectively.
Among high-risk ABO incompatible DAT positive newborns, the sixth-hour TcB is highly predictive of the need for phototherapy ≤24 hours.
Work ethic and information security behavior Ramakrishnan, Thiagarajan; Hite, Dwight M.; Schuessler, Joseph H. ...
Information and computer security,
05/2022, Letnik:
30, Številka:
3
Journal Article
Recenzirano
Purpose
Information security is a growing issue that impacts organizations in virtually all industries, and data breaches impact millions of customers and cost organizations millions of dollars. ...Within the past several years alone, huge data breaches have been experienced by organizations such as Marriot, Equifax, eBay, JP Morgan Chase, Home Depot, Target and Yahoo, the latter of which impacted three billion users. This study aims to examine the utilization of pre-employment screening to identify potential hires that may require enhanced information security training to avoid such costs.
Design/methodology/approach
The authors hypothesize that an individual’s work ethic predicts a person’s information security behavior. The authors test this hypothesis using structural equation modeling with bootstrapping techniques.
Findings
Data analysis suggests that certain dimensions of work ethic do indeed predict information security posture, and thus, simple pre-employment screening techniques (i.e. questionnaires) can aid in identifying potential security threats.
Practical implications
The findings provide a tool for identifying problematic employee security posture prior to hiring, which may be useful in identifying training needs for new hires.
Originality/value
The findings provide a tool for identifying problematic employee security posture prior to hiring, which may be useful in identifying training needs for new hires.
Transforming growth factor-β (TGFβ) signaling through SMAD2/3 is an important driver of pathological fibrosis in multiple organ systems. TGFβ signaling and extracellular matrix (ECM) stiffness form ...an unvirtuous pathological circuit in which matrix stiffness drives activation of latent TGFβ, and TGFβ signaling then drives cellular stress and ECM synthesis. Moreover, ECM stiffness also appears to sensitize cells to exogenously activated TGFβ through unknown mechanisms. Here, using human fibroblasts, we explored the effect of ECM stiffness on a putative inner nuclear membrane protein, LEM domain–containing protein 3 (LEMD3), which is physically connected to the cell's actin cytoskeleton and inhibits TGFβ signaling. We showed that LEMD3–SMAD2/3 interactions are inversely correlated with ECM stiffness and TGFβ-driven luciferase activity and that LEMD3 expression is correlated with the mechanical response of the TGFβ-driven luciferase reporter. We found that actin polymerization but not cellular stress or LEMD3–nuclear-cytoplasmic couplings were necessary for LEMD3–SMAD2/3 interactions. Intriguingly, LEMD3 and SMAD2/3 frequently interacted in the cytosol, and we discovered LEMD3 was proteolytically cleaved into protein fragments. We confirmed that a consensus C-terminal LEMD3 fragment binds SMAD2/3 in a stiffness-dependent manner throughout the cell and is sufficient for antagonizing SMAD2/3 signaling. Using human lung biopsies, we observed that these nuclear and cytosolic interactions are also present in tissue and found that fibrotic tissues exhibit locally diminished and cytoplasmically shifted LEMD3–SMAD2/3 interactions, as noted in vitro. Our work reveals novel LEMD3 biology and stiffness-dependent regulation of TGFβ by LEMD3, providing a novel target to antagonize pathological TGFβ signaling.
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