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TGF-β1 is an important suppressive mediator of inflammation, but it can also drive fibrosis and remodeling in the lung. In response to intratracheal LPS, neutrophils migrate into the lung, and TGF-β1 was suggested to protect against the ensuing injury. However, the mechanisms for this protective role remain unknown. Using a model of acute lung injury, we demonstrate that TGF-β1 decreases neutrophil numbers during the onset of injury. This was due to increased apoptosis rather than reduced migration. We demonstrate that TGF-β1 does not directly regulate neutrophil apoptosis but instead functions through IL-6 to promote neutrophil clearance. rIL-6 is sufficient to promote neutrophil apoptosis and reduce neutrophilia in bronchoalveolar lavage fluid, while IL-6 increases rapidly following LPS-induced injury. Mast cells are a critical source of IL-6, because mast cell–deficient mice exhibit increased neutrophil numbers that are reduced by reconstitution with wild-type, but not IL-6−/−, mast cells. Although IL-6 diminishes neutrophilia in mast cell–deficient mice, TGF-β1 is ineffective, suggesting that these effects were mast cell dependent. Taken together, our findings establish a novel pathway through which TGF-β1, likely derived from resident regulatory T cells, controls the severity and magnitude of early innate inflammation by promoting IL-6 from mast cells.

Atopic asthma is a chronic inflammatory disease of the lungs generally marked by excessive Th2 inflammation. The role of allergen-specific IgG in asthma is still controversial; however, a receptor of IgG–immune complexes (IgG-ICs), FcγRIII, has been shown to promote Th2 responses through an unknown mechanism. Herein, we demonstrate that allergen-specific IgG-ICs, formed upon reexposure to allergen, promoted Th2 responses in two different models of IC-mediated inflammation that were independent of a preformed T cell memory response. Development of Th2-type airway inflammation was shown to be both FcγRIII and TLR4 dependent, and T cells were necessary and sufficient for this process to occur, even in the absence of type 2 innate lymphoid cells. We sought to identify downstream targets of FcγRIII signaling that could contribute to this process and demonstrated that bone marrow–derived DCs, alveolar macrophages, and respiratory DCs significantly upregulated IL-33 when activated through FcγRIII and TLR4. Importantly, IC-induced Th2 inflammation was dependent on the ST2/IL-33 pathway. Our results suggest that allergen-specific IgG can enhance secondary responses by ligating FcγRIII on antigen-presenting cells to augment development of Th2-mediated responses in the lungs via an IL-33–dependent mechanism.

Objective The aim of this study was to determine if a single preoperative B-type natriuretic peptide (BNP) level correlated with perioperative cardiac events, cardiac death, and all-cause mortality in elective open abdominal aortic aneurysm (AAA) repair in the short term, intermediate term, and long term. Methods A prospective, 2-year multicenter observational cohort study in the three vascular units in Glasgow was performed. All patients who were admitted for elective open AAA repair were recruited. Preoperative BNP levels were performed and batch analyzed at the end of the study. Postoperative screening for cardiac events (nonfatal myocardial infarction and cardiac death) was performed at 2, 5, and 30 days. Follow-up for all-cause mortality was sustained to a minimum of 3 years, where possible. Results A total of 106 of 111 patients were recruited. Median BNP concentrations were higher in the 16 patients (15%) with immediate postoperative cardiac events ( P = .001) and the five with cardiac death ( P = .043). Area under the receiver-operating characteristic (AUC) curve analysis indicated BNP concentrations of 99.5 pg/mL best predicted cardiac events (AUC, 0.927), and 448 pg/mL predicted cardiac death (AUC, 0.963). BNP also predicted all-cause mortality in the short-term ( P = .028), intermediate-term ( P P Conclusions Preoperative serum BNP concentration predicted postoperative cardiac events, cardiac death, and all-cause mortality in patients undergoing elective open AAA repair on short-term, intermediate-term, and long-term follow-up on an individual basis with greater accuracy than currently available risk prediction tools.

Mast cells and basophils are developmentally related cells whose activation is a hallmark of allergy. Functionally, mast cells and basophils overlap in their ability to produce several mediators, including histamine and granule proteases, but studies have increasingly demonstrated nonredundant roles. To characterize the transcriptional heterogeneity of mast cells and basophils upon their activation, we performed large-scale comparative microarrays of murine bone marrow–derived mast cells and bone marrow–derived basophils (BMBs) at rest, upon an adaptive-type activation (IgE cross-linking), or upon an innate-type activation (IL-33 stimulation). Hierarchical clustering demonstrated that bone marrow–derived mast cells and BMBs shared specific activation-associated transcriptional signatures but differed in other signatures both between cell type and between activation mode. In bone marrow–derived mast cells, IgE cross-linking upregulated 785 genes, including Egr2, Ccl1, and Fxyd6, whereas IL-33 stimulation induced 823 genes, including Ccl1, Egr2, and Il1b. Focused bioinformatics pathway analysis demonstrated that IgE activation aligned with processes such as oxidative phosphorylation, angiogenesis, and the p53 pathway. The IL-33–activated transcriptome was enriched in genes commonly altered by NF-κB in response to TNF, by IL-6 via STAT3, and in response to IFN-γ. Furthermore, BMBs activated via IgE cross-linking selectively induced immune response genes Ccl1, Il3, and Il2 compared with IL-33–stimulated BMBs. Principal-component analysis revealed key cell- and activation-specific clustering. Overall, our data demonstrate that mast cells and basophils have cell- and activation-specific transcriptional responses and suggest that context-specific gene networks and pathways may shape how the immune system responds to allergens and innate cytokines.

In the first of two papers we described the development in the field of allergy mechanisms as described by Clinical and Experimental Allergy in 2015. Experimental models of allergic disease, basic mechanisms, clinical mechanisms and allergens are all covered. A second paper will cover clinical aspects.

The current understanding of how chronic stress impacts hippocampal dendritic arbor complexity and the subsequent relationship to hippocampal-dependent spatial memory is reviewed. A surge in reports investigating hippocampal dendritic morphology is occurring, but with wide variations in methodological detail being reported. Consequently, this review systematically outlines the basic neuroanatomy of relevant hippocampal features to help clarify how chronic stress or glucocorticoids impact hippocampal dendritic complexity and how these changes occur in parallel with spatial cognition. Chronic stress often leads to hippocampal CA3 apical dendritic retraction first with other hippocampal regions (CA3 basal dendrites, CA1, dentate gyrus, DG) showing dendritic retraction when chronic stress is sufficiently robust or long lasting. The stress-induced reduction in hippocampal CA3 apical dendritic arbor complexity often coincides with impaired hippocampal function, such as spatial learning and memory. Yet, when chronic stress ends and a post-stress recovery period ensues, the atrophied dendritic arbors and poor spatial abilities often improve. However, this process differs from a simple reversal of chronic stress-induced deficits. Recent reports suggest that this return to baseline-like functioning is uniquely different from non-stressed controls, emphasizing the need for further studies to enhance our understanding of how a history of stress subsequently alters an organism's spatial abilities. To provide a consistent framework for future studies, this review concludes with an outline for a quick and easy reference on points to consider when planning chronic stress studies with the goal of measuring hippocampal dendritic complexity and spatial ability.

The differential equation $f''' + Q[Aff'' - (f')^2 ] = \beta (0 \leqq A 0,\beta {\text{ real}})$$(' = {d /{dx}})$ for $0 \leqq x \leqq 1$ with boundary conditions $f(0) = f(1) = 0$, $f''(1) = f''(0) + 1 = 0$ is considered. Existence of at least one solution of this two-point boundary-value problem is proved under various hypotheses, and some qualitative properties of this solution are established. The main tools used are shooting arguments and the Schauder fixed point theorem.

Acellular dermal matrices (ADMs) serve as a regenerative framework for host cell integration and collagen deposition to augment the soft tissue envelope in ADM-assisted breast reconstruction-a process dependent on vascular ingrowth. To date noninvasive intra-operative imaging techniques have been inadequate to evaluate the revascularization of ADM.We investigated the safety, feasibility, and efficacy of sidestream darkfield (SDF) microscopy to assess the status of ADM microvascular architecture in 8 patients at the time of tissue expander to permanent implant exchange during 2-stage ADM-assisted breast reconstruction. The SDF microscopy is a handheld device, which can be used intraoperatively for the real-time assessment of ADM blood flow, vessel density, vessel size, and branching pattern. The SDF microscopy was used to assess the microvascular architecture in the center and border zone of the ADM and to compare the native, non-ADM-associated capsule in each patient as a within-subject control.No incidences of periprosthetic infection, explantation, or adverse events were reported after SDF image acquisition. Native capsules demonstrate a complex, layered architecture with an average vessel area density of 14.9 mm/mm and total vessel length density of 12.3 mm/mm. In contrast to native periprosthetic capsules, ADM-associated capsules are not uniformly vascularized structures and demonstrate 2 zones of microvascular architecture. The ADM and native capsule border zone demonstrates palisading peripheral vascular arcades with continuous antegrade flow. The central zone of the ADM demonstrates punctate perforating vascular plexi with intermittent, sluggish flow, and intervening 2- to 3-cm watershed zones.Sidestream darkfield microscopy allows for real-time intraoperative assessment of ADM revascularization and serves as a potential methodology to compare revascularization parameters among commercially available ADMs. Thr SDF microscopy demonstrates that the periprosthetic capsule in ADM-assisted implant-based breast reconstruction is not a uniformly vascularized structure.

IL-33 is an IL-1 family cytokine that displays dual functions: a cytokine via its receptor, T1/ST2, or a chromatin-binding factor within the nucleus. Functionally, it promotes Th2-associated immunity by enhancing the activation and survival of several cell types. However, the pathways regulating IL-33 expression are still unclear. Although several cells display constitutive expression of IL-33, we showed previously that mast cells expressed low levels of IL-33 constitutively but that IL-33 was induced upon IgE-mediated activation. This was mediated via a calcium-dependent mechanism. In this study, we define the pathway through which this inducible IL-33 is regulated. Importantly, this pathway does not alter expression in cells with high constitutive IL-33 expression, such as epithelial cells or fibroblasts. Our data show that, upstream of calcium, inhibition of PI3K and Sphk activity decreases inducible IL-33 expression to IgE/Ag activation. Additionally, expression of Sphk1 short hairpin RNA prevents upregulation of IL-33 expression. Downstream of calcium, NFAT activity is necessary and sufficient for inducible IL-33 expression. We also demonstrate calcium-dependent transcription from two regions of the IL-33 gene that contain putative NFAT-binding sites, one upstream of exon 1 and one upstream of the start site. Interestingly, we show that blocking other calcium pathways, including inositol triphosphate receptor, or NF-κB inhibits IgE-driven IL-1β, another IL-1 family cytokine, but it has no influence on inducible IL-33 expression. In summary, our data demonstrate cell-specific differences in the regulation of IL-33 expression and define a pathway critical for the expression of inducible IL-33 by mast cells upon their activation.

The repair protein trefoil factor 2 promotes Th2 responses to helminth infection and allergens in part by inducing IL-33., The molecular mechanisms that drive mucosal T helper type 2 (TH2) responses against parasitic helminths and allergens remain unclear. In this study, we demonstrate in mice that TFF2 (trefoil factor 2), an epithelial cell–derived repair molecule, is needed for the control of lung injury caused by the hookworm parasite Nippostrongylus brasiliensis and for type 2 immunity after infection. TFF2 is also necessary for the rapid production of IL-33, a TH2-promoting cytokine, by lung epithelia, alveolar macrophages, and inflammatory dendritic cells in infected mice. TFF2 also increases the severity of allergic lung disease caused by house dust mite antigens or IL-13. Moreover, TFF2 messenger RNA expression is significantly increased in nasal mucosal brushings during asthma exacerbations in children. These experiments extend the biological functions of TFF2 from tissue repair to the initiation and maintenance of mucosal TH2 responses.

Chronic stress has detrimental effects on hippocampal integrity, while environmental enrichment (EE) has beneficial effects when initiated early in development. In this study, we investigated whether EE initiated in adulthood would mitigate chronic stress effects on cognitive function and hippocampal neuronal architecture, when EE started one week before chronic stress began, or two weeks after chronic stress onset. Adult male Sprague Dawley rats were chronically restrained (6 h/d) or assigned as non-stressed controls and subdivided into EE or non-EE housing. After restraint ended, rats were tested on a radial arm water maze (RAWM) for 2-d to assess spatial learning and memory. The first study showed that when EE began prior to 3-weeks of chronic stress, EE attenuated chronic stress-induced impairments in acquisition, which corresponded with the prevention of chronic stress-induced reductions in CA3 apical dendritic length. A second study showed that when EE began 2-weeks after the onset of a 5-week stress regimen, EE blocked chronic stress-induced impairments in acquisition and retention at 1-h and 24-h delays. RAWM performance corresponded with CA3 apical dendritic complexity. Moreover, rats in EE housing (control or stress) exhibited similar corticosterone profiles across weeks, which differed from the muted corticosterone response to restraint by the chronically stressed pair-housed rats. These data support the interpretation that chronic stress and EE may act on similar mechanisms within the hippocampus, and that manipulation of these factors may yield new directions for optimizing brain integrity and resilience under chronic stress or stress related neuropsychological disorders in the adult.

Mast cell degranulation is a hallmark of allergic reactions, but mast cells can also produce many cytokines that modulate immunity. Recently, CD25+ regulatory T cells (Tregs) have been shown to inhibit mast cell degranulation and anaphylaxis, but their influence on cytokine production remained unknown. In this study, we show that, rather than inhibit, Tregs actually enhance mast cell production of IL-6. We demonstrate that, whereas inhibition of degranulation was OX40/OX40 ligand dependent, enhancement of IL-6 was due to TGF-β. Interestingly, our data demonstrate that the Treg-derived TGF-β was surface-bound, because the interaction was contact dependent, and no TGF-β was detectable in the supernatant. Soluble TGF-β1 alone was sufficient to enhance mast cell IL-6 production, and these supernatants were sufficient to promote Th17 skewing, but those from Treg–mast cell cultures were not, supporting this being surface-bound TGF-β from the Tregs. Interestingly, the augmentation of IL-6 production occurred basally or in response to innate stimuli (LPS or peptidoglycan), adaptive stimuli (IgE cross-linking by specific Ag), and cytokine activation (IL-33). We demonstrate that TGF-β led to enhanced transcription and de novo synthesis of IL-6 upon activation without affecting IL-6 storage or mRNA stability. In vivo, the adoptive transfer of Tregs inhibited mast cell-dependent anaphylaxis in a model of food allergy but promoted intestinal IL-6 and IL-17 production. Consequently, our findings establish that Tregs can exert divergent influences upon mast cells, inhibiting degranulation via OX40/OX40 ligand interactions while promoting IL-6 via TGF-β.

The TripleTOF 5600 System, a hybrid quadrupole time-of-flight mass spectrometer, was evaluated to explore the key figures of merit in generating peptide and protein identifications that included spectral acquisition rates, data quality, proteome coverage, and biological depth. Employing a Saccharomyces cerevisiae tryptic digest, careful consideration of several performance features demonstrated that the speed of the TripleTOF contributed most to the resultant data. The TripleTOF system was operated with 8, 20, and 50 MS/MS events in an effort to compare with other MS technologies and to demonstrate the abilities of the instrument platform.

Introduction Pathologic accumulation and over-activation of mast cells and eosinophils have been implicated in certain allergic and inflammatory diseases. Siglec-8 is an inhibitory receptor selectively expressed on human eosinophils, mast cells, and, to a significantly lesser extent, basophils. Antibodies to Siglec-8 have the potential to be broadly anti-inflammatory by inducing apoptosis of eosinophils and inhibiting mast cell activation. AK002 is a novel, humanized, non-fucosylated IgG1 monoclonal antibody to Siglec-8. This study examines the ex vivo activity of AK002 on blood and tissue eosinophils and in vivo activity against human mast cells. Methods The apoptosis and antibody-dependent cell-mediated cytotoxicity (ADCC) activity of AK002 or an isotype-matched control antibody was assessed using human blood and tissue eosinophils by flow cytometry. In addition, the activity of a mouse AK002 precursor (mAK002) was tested in a model of IgE-induced systemic and cutaneous anaphylaxis in humanized mice. Results In the presence of peripheral blood NK cells, AK002 demonstrated potent ADCC activity against blood eosinophils. AK002 also directly induced apoptosis of cytokine-activated blood eosinophils. In ex vivo human lung tissue, Siglec-8 expression was found on all tissue eosinophils and AK002 significantly reduced these cells compared to an isotype control. Lastly, mAK002 inhibited passive systemic and cutaneous anaphylaxis in humanized mice, consistent with mast cell inhibition (Figure 1). Conclusions AK002 selectively depletes blood and tissue eosinophils and inhibits IgE-mediated anaphylaxis. AK002 may represent a novel therapeutic agent for patients with eosinophil and mast cell driven inflammatory diseases.

Histamine and the histamine receptors are important regulators of a plethora of biological processes, including immediate hypersensitivity reactions and acid secretion in the stomach. In these roles, antihistamines have found widespread therapeutic applications, while the last receptor to be discovered, the H4 histamine receptor, has become a major target of novel therapeutics. Recent studies involving human genetic variance and the development of mice lacking specific receptors or the ability to generate histamine have shown roles for the histamine pathway that extend well beyond the established roles. These include identification of previously unappreciated mechanisms through which histamine regulates inflammation in allergy, as well as roles in autoimmunity, infection, and pain. As a result, antihistamines may have wider applications in the future than previously predicted.

Background: MRA and CTA are both used to evaluate perforator anatomy in preparation for autologous breast reconstruction. While CTA is most commonly performed, prone liver phase MRA (PLP-MRA) can be performed concomitantly with breast MRI to assess arterial and venous anatomy while providing superior discrimination of vascular anatomy. Methods: Consecutive patients with planned free autologous abdominally-based breast reconstruction were prospectively randomized to undergo preoperative perforator mapping with CTA or PLP-MRA. Imaging was used to predict whether a deep inferior epigastric artery perforator flap (DIEP) or muscle-sparing-2-TRAM (MS2-TRAM) would be performed. Paired radiographic and blinded intra-operative measurements of perforator location relative to the umbilicus, intramuscular pedicle length and pedicle position relative to the semilunar line were compared by paired Wilcoxon rank sum test. Results: The type of flap performed was accurately predicted in all cases from PLP-MRA or CTA. Both PLP-MRA and CTA accurately predicted perforator location (48 hemi-abdomens) and distance from semi-lunar line (30 hemi-abdomens). PLP-MRA was superior to CTA in accurately predicting intra-muscular pedicle length (P 2 mm in diameter. Conclusions: PLP-MRA offers superior accuracy in predicting intramuscular pedicle length compared to CTA while maintaining accuracy in determining perforator location and pedicle position to assist with flap design. This PLP-MRA protocol can be performed concomitantly with pre-operative breast MRI in select patients to avoid multiple imaging modalities and avoid radiation exposure.

Correction to: Mucosal Immunology (2017); advance online publication, 28 June 2017; doi: 10.1038/mi.2017.61 The advance online publication version of this article included a spelling error in the title. The corrected title appears above and in the issue version of the article. The publisher regrets the error.

Objective Recent guidelines recommend more aggressive lipid-lowering in secondary prevention protocols. We examined whether this resulted in improved endothelial function. Methods We studied saphenous vein specimens of patients undergoing surgical coronary revascularisation in 2007 and compared results with those of patients examined in 2003. Endothelium-dependent vasodilation was assessed by relaxation to calcium ionophore A23187, and vascular superoxide production by lucigenin enhanced chemiluminescence. Results Statin dose increased from 26 ± 16 mg/d in 2003 to 37 ± 17 mg/d in 2007 (P

Measuring the physical properties of galaxies such as redshift frequently requires the use of Spectral Energy Distributions (SEDs). SED template sets are, however, often small in number and cover limited portions of photometric color space. Here we present a new method to estimate SEDs as a function of color from a small training set of template SEDs. We first cover the mathematical background behind the technique before demonstrating our ability to reconstruct spectra based upon colors and then compare to other common interpolation and extrapolation methods. When the photometric filters and spectra overlap we show reduction of error in the estimated spectra of over 65% compared to the more commonly used techniques. We also show an expansion of the method to wavelengths beyond the range of the photometric filters. Finally, we demonstrate the usefulness of our technique by generating 50 additional SED templates from an original set of 10 and applying the new set to photometric redshift estimation. We are able to reduce the photometric redshifts standard deviation by at least 22.0% and the outlier rejected bias by over 86.2% compared to original set for z $\leq$ 3., Comment: 23 pages, 9 figures, accepted to AJ

This article develops a theoretical rationale for the role of the rising number of nongovernmental organizations (NGOs), acting as independent agents, in influencing the risk exposure of governments to the loss of trust. In this article, trust is based on government performance consistent with citizen expectations. This performance-expectation connection is a concept in theories of democracy, trust, responsive government, and good governance. A role of the NGO in influencing trust in government is proposed centered on bringing government performance and citizen expectations into alignment.

For empirical work in the resource-based view of the firm, characterizing the resources that are responsible for firm growth is difficult because valuable resources are often tacit, ambiguous, or difficult to identify. This is a particular problem for empirical assessments that rely upon the concept of relatedness between resources to characterize the direction of growth of the firm. We tackle the problem for the general case by developing a general interindustry relatedness index. The index harnesses the relatedness information embedded in the multiproduct organization decisions of every diversified firm in the U.S. manufacturing economy. The index is general in that it can be used across industry contexts without requiring explicit identification of resources and it provides a percentile relatedness rank for every possible pair of four-digit Standard Industrial Classification manufacturing industries. The general index is tested for predictive validity and found to perform as expected. Applications of the index in strategy research are suggested.

We demonstrate a strategy of maximizing the performance of reversed-phase (RP) liquid chromatography (LC) tandem mass spectrometry (MS/MS) for efficient shotgun proteome analysis by optimizing the sample loading to the instrument in an off-line two-dimensional (2D) LC tandem MS platform. To determine the quantity of peptides present in a proteome digest or fractionated peptides from strong-cation exchange (SCX) separation, an automated system based on RPLC with a rapid step solvent gradient for peptide elution and ultraviolet (UV) detection was developed. This system also allowed the purification of the peptides by removing salts and other impurities present in a sample. It was found that controlling the amount of peptides injected into a RPLC MS/MS system was critical to achieve the maximum efficiency in peptide and protein identification. With the use of off-line 2D-LC-MS/MS, peptide fractions from the first dimension of separation were desalted and quantified, followed by injecting the optimal amount of the sample into RPLC-MS/MS for peptide sequencing. The application of this strategy was demonstrated in the proteome profiling of breast cancer MCF-7 cells. From the analysis of 28 SCX fractions with each injecting 1 microg of sample into a 75 mum x 100 mm C18 column interfaced to a quadrupole/time-of-flight mass spectrometer, a total of 2362 unique proteins or protein groups were identified with a false positive peptide identification rate of 0.19%, as determined by target-decoy proteome sequence searches. Replicate 2 h runs of individual fractions with the exclusion of precursor ions of peptides already identified in the first runs resulted in the identification of an additional 549 unique proteins or protein groups with a false positive identification rate of 0.60%. This example illustrated that off-line 2D-LC-MS/MS, with maximal sample injection to the RPLC-MS, is an effective method for shotgun proteome analysis. Finally, the advantages and limitations of this method, compared to other methods, are discussed.

This paper examines the role that gender, occupational status, and family status play in moderating the effect of industrial activity on the psychological well-being of nearby residents. Using a unique spatial assessment of industrial activity and an environmental risk/social stressor framework in conjunction with individual-level data from the Detroit Area Study (DAS) and demographic data from the U.S. census, we find that residents of neighborhoods in close proximity to industrial activity report elevated levels of psychological distress compared to residents of neighborhoods removed from this type of activity. These influences are more pronounced among women but gender differences are also contingent upon occupational and family statuses. We show that specific combinations of work and family statuses make persons particularly vulnerable to the influence of this environmental stressor and women are two and a half times more likely than men to have these vulnerable statuses. This study makes an important contribution to the environmental health literature because it reminds researchers of the fundamental influence of social roles when examining the link between environmental risks and mental health.

Intracellular transport in eukarya is attributed to motor proteins that transduce chemical energy into directed mechanical motion. Nanoscale motors like kinesins tow organelles and other cargo on microtubules or filaments, have a role separating the mitotic spindle during the cell cycle, and perform many other functions. The simplest description gives rise to a weakly coupled system of evolution equations. The transport process, to the mind's eye, is analogous to a biased coin toss. We describe how this intuition may be confirmed by a careful analysis of the cooperative effect among the conformational changes and potentials present in the equations.

This article connects the impairment of the public's trust in nonprofit organizations to managerial actions in five transactions that lie at the core of the relationship between the nonprofit and the public. For each core transaction it asks: What does the public trust mean? How may that trust be impaired by managerial action? What concepts in a relationship-marketing message might help restore that trust? What are the conditions or antecedents that might materially modify the results of any of these messages? This article offers important lessons to help clarify, manage, and restore the public's trust in nonprofit organizations when that trust is impaired by managerial action.

Food allergy is a growing public health problem that is estimated to affect 4% to 8% of children and 5% of adults. In this review, we discuss our current understanding of the pathophysiology of food allergy, from oral tolerance, to sensitization, and lastly the elicitation of an allergic response. As much of the existing evidence for the mechanisms of food allergy is derived from animal models, we include these studies where relevant. In addition, whenever possible, we review similar evidence involved in human disease and provide applications for consideration in clinical practice.

Purpose Given the implications for clinical care and prevention in identifying a BRCA1 / 2 mutation, the objective of this study was to determine current BRCA1 / 2 testing practices in ovarian cancer and to identify future directions. Methods Two parallel complementary web-based surveys were sent by email to representatives of Gynecologic Cancer InterGroup (GCIG) and to referral centers in countries with and without GCIG membership. Questions posed addressed indications of BRCA1 / 2 testing for ovarian cancer; the implication of genetic counseling; and prevention strategies employed. Results Among the GCIG, 22 collaborative groups from 19 countries answered the survey. For the complementary survey, 22 referral centers replied. Findings show criteria to offer germline BRCA1 / 2 testing are mixed; 55% of GCIG members based testing decisions on histology and, among all respondents the main testing criterion remains family history. Typically, genetic counseling is scheduled prior to the genetic testing; however, if negative, results may not be communicated by the genetic counselor. Time between testing and communicating results varies widely between the groups. Lastly, recommendations to relatives regarding risk reduction surgery are inconsistent. Conclusion Our study highlights the need for collaborative efforts to devise international guidelines around BRCA1 / 2 testing in ovarian cancer to ensure consistent BRCA1 / 2 screening practices are adopted. Clinical practice is evolving rapidly and as BRCA1 / 2 testing is expected to become more widespread, new approaches are required. Coordinating BRCA 1/2 testing practices is crucial in terms of care for the patient diagnosed with ovarian cancer but also towards cancer prevention for affected family members.

Background Recent genome-wide association studies have identified single nucleotide polymorphisms in the gene encoding the protein αT-catenin (CTNNA3) that correlate with both steroid-resistant atopic asthma and asthmatic exacerbations. α-Catenins are important mediators of cell-cell adhesion, and αT-catenin is predominantly expressed in cardiomyocytes. In the lung αT-catenin appears to be exclusively expressed in cardiomyocytes surrounding the pulmonary veins (PVs), but its contribution to atopic asthma remains unknown. Objective We sought to understand the role of αT-catenin in asthma pathogenesis. Methods We used αT-catenin knockout mice and a house dust mite (HDM) extract model of atopic asthma, with assessment by means of forced oscillation, bronchoalveolar lavage, and histologic analysis. Results We found that the genetic loss of αT-catenin in mice largely attenuated HDM-induced airway inflammation and airway hyperresponsiveness to methacholine. Mice lacking αT-catenin that were exposed to HDM extract had reduced PV inflammation, specifically near the large veins surrounded by cardiac cells. The proximity of the airways to PVs correlated with the severity of airway goblet cell metaplasia, suggesting that PVs can influence the inflammatory milieu of adjacent airways. Loss of αT-catenin led to compensatory upregulation of αE-catenin, which itself has a defined anti-inflammatory function. Conclusion These data mechanistically support previous clinical and genetic associations between αT-catenin and the development of atopic asthma and suggest that PVs might have an underappreciated role in allergic airway inflammation.

Background Mast cells are a critical component of allergic responses in humans, and animal models that allow the in vivo investigation of their contribution to allergy and evaluation of new human-specific therapeutics are urgently needed. Objective To develop a new humanized mouse model that supports human mast cell engraftment and human IgE-dependent allergic responses. Methods This model is based on the NOD- scid IL2rg null SCF/GM-CSF/IL3 (NSG-SGM3) strain of mice engrafted with human thymus, liver, and hematopoietic stem cells (termed Bone marrow, Liver, Thymus [BLT]). Results Large numbers of human mast cells develop in NSG-SGM3 BLT mice and populate the immune system, peritoneal cavity, and peripheral tissues. The human mast cells in NSG-SGM3 BLT mice are phenotypically similar to primary human mast cells and express CD117, tryptase, and FceRI. These mast cells undergo degranulation in an IgE-dependent and -independent manner, and can be readily cultured in vitro for additional studies. Intradermal priming of engrafted NSG-SGM3 mice with a chimeric IgE containing human constant regions resulted in the development of a robust passive cutaneous anaphylaxis response. Moreover, we describe the first report of a human mast cell antigen-dependent passive systemic anaphylaxis response in primed mice. Conclusions NSG-SGM3 BLT mice provide a readily available source of human mast cells for investigation of mast cell biology and a preclinical model of passive cutaneous anaphylaxis and passive systemic anaphylaxis that can be used to investigate the pathogenesis of human allergic responses and to test new therapeutics before their advancement to the clinic.

Mast cells are critical in the pathogenesis of allergic disease due to the release of preformed and newly synthesized mediators, yet the mechanisms controlling mast cell activation are not well understood. Members of the tetraspanin family are recently emerging as modulators of FcεRI-mediated mast cell activation; however, mechanistic understanding of their function is currently lacking. The tetraspanin CD151 is a poorly understood member of this family and is specifically induced on mouse and human mast cells upon FcεRI aggregation but its functional effects are unknown. In this study, we show that CD151 deficiency significantly exacerbates the IgE-mediated late phase inflammation in a murine model of passive cutaneous anaphylaxis. Ex vivo, FcεRI stimulation of bone marrow–derived mast cells from CD151−/− mice resulted in significantly enhanced expression of proinflammatory cytokines IL-4, IL-13, and TNF-α compared with wild-type controls. However, FcεRI-induced mast cell degranulation was unaffected. At the molecular signaling level, CD151 selectively regulated IgE-induced activation of ERK1/2 and PI3K, associated with cytokine production, but had no effect on the phospholipase Cγ1 signaling, associated with degranulation. Collectively, our data indicate that CD151 exerts negative regulation over IgE-induced late phase responses and cytokine production in mast cells.

Chronic restraint stress alters hippocampal-dependent spatial learning and memory in a sex-dependent manner, impairing spatial performance in male rats and leaving intact or facilitating performance in female rats. Moreover, these stress-induced spatial memory deficits improve following post-stress recovery in males. The current study examined whether restraint administered in an unpredictable manner would eliminate these sex differences and impact a post-stress period on spatial ability and limbic glutamic acid decarboxylase (GAD65) expression. Male (n=30) and female (n=30) adult Sprague-Dawley rats were assigned to non-stressed control (Con), chronic stress (Str-Imm), or chronic stress given a post-stress recovery period (Str-Rec). Stressed rats were unpredictably restrained for 21 days using daily non-repeated combinations of physical context, duration, and time of day. Then, all rats were tested on the radial arm water maze (RAWM) for two days and given one retention trial on the third day, with brains removed 30 minutes later to assess GAD65 mRNA. In Str-Imm males, deficits occurred on day 1 of RAWM acquisition, an impairment that was not evident in the Str-Rec group. In contrast, females did not show significant outcomes following chronic stress or post-stress recovery. In males, amygdalar GAD65 expression negatively correlated with RAWM performance on day 1. In females, hippocampal CA1 GAD65 positively correlated with RAWM performance on day 1. These results demonstrate that GABAergic function may contribute to the sex differences observed following chronic stress. Furthermore, unpredictable restraint and a recovery period failed to eliminate the sex differences on spatial learning and memory.

This article explores a new, universal, and theoretically inclusive approach to understanding the performance and purpose of nonprofit organizations in today’s world. This approach envisions the nonprofit organization as a social capital asset and agent in a specific relationship to the public. This relationship is depicted in a principal-agent paradigm and the performance is in the public policy process. The public policy arena is the nonprofit’s analogy of the firm’s marketplace. Nonprofits do more than fill in for market or government failures. They also regulate, facilitate, assist, and modify markets and play a significant role in every aspect of public policy, that is, from determining party platforms to the implementation of policies. In the public policy process, they have a comparative advantage as agents of citizens and firms.

Histamine, signaling via the type 1 receptor (H1R), has been shown to suppress Th2 cytokine production by in vitro cultured T cells. We examined the role of H1R in allergic inflammation in vivo using a murine asthma model. Allergen-stimulated splenic T cells from sensitized H1R-/- mice exhibited enhanced Th2 cytokine production. Despite this Th2 bias, allergen-challenged H1R-/- mice exhibited diminished lung Th2 cytokine mRNA levels, airway inflammation, goblet cell metaplasia, and airway hyperresponsiveness (AHR). Restoration of pulmonary Th2 cytokines in H1R-/- mice by intranasal IL-4 or IL-13 restored inflammatory lung responses and AHR. Further investigation revealed that histamine acts as a T cell chemotactic factor and defective T cell trafficking was responsible for the absence of lung inflammation. Cultured T cells migrated in response to histamine in vitro, but this was ablated by blockade of H1R but not H2R. In vivo, allergen-specific WT but not H1R-/- CD4+ T cells were recruited to the lungs of naive recipients following inhaled allergen challenge. H1R-/- T cells failed to confer airway inflammation or AHR observed after transfer of WT T cells. Our data establish a role for histamine and H1R in promoting the migration of Th2 cells into sites of allergen exposure.

A simple and robust impulse-driven droplet deposition system was developed for off-line liquid chromatography matrix-assisted laser desorption ionization mass spectrometry (LC-MALDI MS). The system uses a solenoid operated with a pulsed voltage power supply to generate impulses that dislodge the hanging droplets from the LC outlet directly to a MALDI plate via a momentum transfer process. There is no contact between the LC outlet and the collection surface. The system is compatible with solvents of varying polarity and viscosity, and accommodates the use of hydrophobic and hydrophilic MALDI matrices. MALDI spots are produced on-line with the separation, and do not require further processing before MS analysis. It is shown that high quality MALDI spectra from 5 fmol of pyro-Glu-fibrinopeptide deposition after LC separation could be obtained using the device, indicating that there was no sample loss in the interface. To demonstrate the analytical performance of the system as a proteome analysis tool, a range of BSA digest concentrations covering about 3 orders of magnitude, from 5 fmol to 1 pmol, were analyzed by LC-MALDI quadrupole time-of-flight MS, yielding 6 and 57% amino acid sequence coverage, respectively. In addition, a complex protein mixture of an E. coli cell extract was tryptically digested and analyzed by LC-MALDI MS, resulting in the detection of a total of 409 unique peptides from 100 fractions of 15-s intervals.

We have previously reported that tumor necrosis factor receptor-associated factor 1 (TRAF1), an intracellular protein, which binds to a range of molecules, including tumor necrosis factor (TNF) receptor family members, regulates TNF-induced NF-jB and AP-1 signaling as well as TCR-triggered proliferative responses in T cells. In order to define the role of TRAF1 in Th cell differentiation, we analyzed the responses of TRAF1 � /� T cells following TCR activation. Stimulation of TRAF1 � /� Tc ells by antigen resulted in significantly increased expression of the Th2 cytokines (IL-4, IL-5 and IL-13) compared with wild-type (WT) controls. The Th2 bias of TRAF1 � /� T cells is T lymphocyte intrinsic, since naive CD4 1 CD62L 1 TRAF1 � /� T cells activated with CD3/CD28 produced elevated levels of Th2 cytokines. Consistent with these observations in cultured T cells, TRAF1 � /� T cells induced enhanced Th2 responses in vivo. Transfer of ovalbumin (OVA)-immune TRAF1 � /� T cells into naive WT recipients conferred significantly more intense pulmonary inflammation and higher airway hyperresponsiveness following inhaled OVA challenge than did transfer of OVA-immune WT T cells. Biochemical analysis of TRAF1 � /� T cells revealed that they have elevated nuclear expression of NFAT-interacting protein (NIP45), a Th2 cell-associated transcription factor known to potentiate NFATp-driven IL-4 expression. In further experiments, we demonstrated that TRAF1 associates with a fraction of NIP45 in the cytoplasm and prevents its translocation to the nucleus. Taken together these results suggest that TRAF1 may limit the induction of Th2 responses by decreasing NIP45 concentration to the nucleus and thereby down-regulating the expression of NIP45-dependent IL-4 gene transcription.

Mucosa-associated lymphoid tissue (MALT) type lymphoma has generally been thought not to show increased fluorine 18-fluorodeoxyglucose (FDG) accumulation on positron emission tomography (PET), based on previous research. Only a limited numbers of articles have been published on this topic, however, involving a small number of cases. Although positive FDG PET results might be uncommon in this entity, a case of increased FDG accumulation in a case of MALT type lymphoma of the lung is presented.

In 1983, Schoell et al. [Schoell, M., Faber, E., Coleman, M.L., 1983. Carbon and hydrogen isotopic compositions of the NBS 22 and NBS 21 stable isotope reference materials: an inter-laboratory comparison. Organic Geochemistry 5, 3–6] carried out an inter-laboratory comparison of the International Atomic Energy Agency (IAEA) reference materials NBS 21 (a graphite) and NBS 22 (an oil). At that time they found that NBS 22 in particular to be more depleted in 13C than the values published by the IAEA at that time (i.e., δ13C of −29.81‰ PDB ±0.06 as opposed to δ13C of −29.4‰ PDB). Even so, to this day, the IAEA has subsequently used a value of δ13C of −29.7‰ ± 0.2 VPDB. Following the advent of the new IAEA VPDB scale, defined by NBS 19 (a carbonate), this laboratory at the Commonwealth Scientific and Industrial Research Organisation (CSIRO) Petroleum and Exploration and Mining Divisions in North Ryde, NSW, Australia found that a number of the reference materials depleted in 13C (especially “organic” type reference materials) to be more depleted in 13C on the VPDB scale than expected. In particular, NBS 22 appears to be 0.25‰ more depleted in 13C than generally accepted values compared with a suite of carbonate standards run together. We suggest that the NBS 22 and other “organic” reference materials have probably all been calibrated to NBS 21 or 22 and should now be redefined on the VPDB scale.

A description of the relationship between Sir Hans Sloane and Johann Amman is given, particularly the latter's appointment as Professor of Botany in St Petersburg and their subsequent correspondence. In particular, Amman's description of the flora of Russia as outlined in these letters is examined, that around St Petersburg which he observed personally, that of Bashkiria collected by Heinzelmann, and that of Siberia. The plant specimens sent by Amman which have survived and are now held in the Sloane Herbarium are identified and the circumstances of their acquisition set out. The specimens are divided into two groups. The first is attributed to collections made by Amman himself in the vicinity of St Petersburg, and the second group is attributed to collections made in Siberia and Dauria by D. G. Messerschmidt, and the unique nature of these specimens is set out.