An Overview of Environmental Risk Factors for Food Allergy

IgE-mediated food allergy is an increasing public health concern in many regions around the world. Although genetics play a role in the development of food allergy, the reported increase has occurred largely within a single generation and therefore it is unlikely that this can be accounted for by changes in the human genome. Environmental factors must play a key role. While there is strong evidence to support the early introduction of allergenic solids to prevent food allergy, this is unlikely to be sufficient to prevent all food allergy. The purpose of this review is to summarize the evidence on risk factors for food allergy with a focus the outdoor physical environment. We discuss emerging evidence of mechanisms that could explain a role for vitamin D, air pollution, environmental greenness, and pollen exposure in the development of food allergy. We also describe the recent extension of the dual allergen exposure hypothesis to potentially include the respiratory epithelial barrier in addition to the skin. Few existing studies have examined the relationship between these environmental factors with objective measures of IgE-mediated food allergy and further research in this area is needed. Future research also needs to consider the complex interplay between multiple environmental factors

PAR1 Agonists Stimulate APC-Like Endothelial Cytoprotection and Confer Resistance to Thromboinflammatory Injury

Stimulation of protease-activated receptor 1 (PAR1) on endothelium by activated protein C (APC) is protective in several animal models of disease, and APC has been used clinically in severe sepsis and wound healing. Clinical use of APC, however, is limited by its immunogenicity and its anticoagulant activity. We show that a class of small molecules termed “parmodulins” that act at the cytosolic face of PAR1 stimulates APC-like cytoprotective signaling in endothelium. Parmodulins block thrombin generation in response to inflammatory mediators and inhibit platelet accumulation on endothelium cultured under flow. Evaluation of the antithrombotic mechanism showed that parmodulins induce cytoprotective signaling through Gβγ, activating a PI3K/Akt pathway and eliciting a genetic program that includes suppression of NF-κB–mediated transcriptional activation and up-regulation of select cytoprotective transcripts. STC1 is among the up-regulated transcripts, and knockdown of stanniocalin-1 blocks the protective effects of both parmodulins and APC. Induction of this signaling pathway in vivo protects against thromboinflammatory injury in blood vessels. Small-molecule activation of endothelial cytoprotection through PAR1 represents an approach for treatment of thromboinflammatory disease and provides proof-of-principle for the strategy of targeting the cytoplasmic surface of GPCRs to achieve pathway selective signaling

The cost of procuring deceased donor kidneys: Evidence from OPO cost reports 2013-2017

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154616/1/ajt15669_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154616/2/ajt15669.pd

Final Report: Predicting Effects of Climate Change on Riparian Obligate Species in the Southwestern United States

The Lower Colorado River and Rio Grande Basins are home to many riparian vertebrate species with different degrees of rarity. In our study, we focused on two species of birds and two species of gartersnakes that are associated with riparian areas: the Yellow-breasted Chat (Icteria virens), the Yellow Warbler (Setophaga petechia), the Northern Mexican Gartersnake (Thamnophis eques megalops) and the Narrow-headed Gartersnake (T. rufipunctatus). While the extent of distributions of these species is relatively large, they are often patchily distributed in populations that are small; in addition, both gartersnake species are listed as threatened under the Endangered Species Act. Aside from detrimental effects of direct habitat loss and degradation throughout the southwestern United States, future changes in water availability might threaten the long-term persistence of populations of any one of these species. To evaluate this vulnerability at a landscape scale, we built species distribution models under current and future projected climates for each species. For modeling, we relied on climatic and hydrological predictions (downscaled CMIP3 climate and hydrology projections) developed by the Bureau of Reclamation and its partners as part of the West-Wide Climate Risk Assessments within the WATERSmart initiative. We also relied on NASAs Moderate-Resolution Imaging Spectroradiometer (MODIS) to derive a spatially explicit index that quantifies riparian vegetation in space and time. Using downscaled climate projections and other landscape data, we were able to project these riparian vegetation metric forward in time. The projected changes in water availability by end of the century will directly affect the availability of permanent water and riparian vegetation creating the habitats of our study species. Our results suggest significant and negative changes in future landscape suitability for all species (up to 64% loss of suitable area), which are in addition to already identified threats facing these species. Best models included the index of riparian vegetation (linked to water availability) as an important component of the predictions, but we also note that finer scale examination of hydrology and climate effects on habitats would be much more useful for effective management.\u2

Differentiation of primate primordial germ cell-like cells following transplantation into the adult gonadal niche.

A major challenge in stem cell differentiation is the availability of bioassays to prove cell types generated in vitro are equivalent to cells in vivo. In the mouse, differentiation of primordial germ cell-like cells (PGCLCs) from pluripotent cells was validated by transplantation, leading to the generation of spermatogenesis and to the birth of offspring. Here we report the use of xenotransplantation (monkey to mouse) and homologous transplantation (monkey to monkey) to validate our in vitro protocol for differentiating male rhesus (r) macaque PGCLCs (rPGCLCs) from induced pluripotent stem cells (riPSCs). Specifically, transplantation of aggregates containing rPGCLCs into mouse and nonhuman primate testicles overcomes a major bottleneck in rPGCLC differentiation. These findings suggest that immature rPGCLCs once transplanted into an adult gonadal niche commit to differentiate towards late rPGCs that initiate epigenetic reprogramming but do not complete the conversion into ENO2-positive spermatogonia

Non-invasive imaging reveals convergence in root and stem vulnerability to cavitation across five tree species

Root vulnerability to cavitation is challenging to measure and under-represented in current datasets. This gap limits the precision of models used to predict plant responses to drought because roots comprise the critical interface between plant and soil. In this study we measured vulnerability to drought induced cavitation in woody roots and stems of five tree species (Acacia aneura, Cedrus deodara, Eucalyptus crebra, Eucalytus saligna, and Quercus palustris) with a wide range of xylem anatomies. X-ray microtomography was used to visualize the accumulation of xylem embolism in stems and roots of intact plants that were naturally dehydrated to varying levels of water stress. Vulnerability to cavitation, defined as the water potential causing a 50% loss of hydraulic function (P50), varied broadly among the species (-4.51 to -11.93 MPa in stems and -3.13 to -9.64 MPa in roots). The P50 of roots and stems was significantly related across species, with species that had more vulnerable stems also having more vulnerable roots. While there was strong convergence in root and stem vulnerability to cavitation, the P50 of roots was significantly higher than the P50 of stems in three species. However, the difference in root and stem vulnerability for these species was small; between 1% to 31% of stem P50. Thus, while some differences existed between organs, roots were not dramatically more vulnerable to embolism than stems and the differences observed were less than those reported in previous studies. Further study is required to evaluate the vulnerability across root orders and to extend these conclusions to a greater number of species and xylem functional types

Resident alveolar macrophageâ derived vesicular SOCS3 dampens allergic airway inflammation

Resident alveolar macrophages (AMs) suppress allergic inflammation in murine asthma models. Previously we reported that resident AMs can blunt inflammatory signaling in alveolar epithelial cells (ECs) by transcellular delivery of suppressor of cytokine signaling 3 (SOCS3) within extracellular vesicles (EVs). Here we examined the role of vesicular SOCS3 secretion as a mechanism by which AMs restrain allergic inflammatory responses in airway ECs. Bronchoalveolar lavage fluid (BALF) levels of SOCS3 were reduced in asthmatics and in allergenâ challenged mice. Ex vivo SOCS3 secretion was reduced in AMs from challenged mice and this defect was mimicked by exposing normal AMs to cytokines associated with allergic inflammation. Both AMâ derived EVs and synthetic SOCS3 liposomes inhibited the activation of STAT3 and STAT6 as well as cytokine gene expression in ECs challenged with ILâ 4/ILâ 13 and house dust mite (HDM) extract. This suppressive effect of EVs was lost when they were obtained from AMs exposed to allergic inflammationâ associated cytokines. Finally, inflammatory cell recruitment and cytokine generation in the lungs of OVAâ challenged mice were attenuated by intrapulmonary pretreatment with SOCS3 liposomes. Overall, AM secretion of SOCS3 within EVs serves as a brake on airway EC responses during allergic inflammation, but is impaired in asthma. Synthetic liposomes encapsulating SOCS3 can rescue this defect and may serve as a framework for novel therapeutic approaches targeting airway inflammation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/1/fsb220322-sup-0001-FigS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/2/fsb220322.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/3/fsb220322_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/4/fsb220322-sup-0005-TableS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/5/fsb220322-sup-0003-FigS3.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/6/fsb220322-sup-0004-FigS4.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/7/fsb220322-sup-0002-FigS2.pd

Between crime and colony: Interrogating (im)mobilities aboard the convict ship

Recent literature in carceral geography has attended to the importance of mobilities in interrogating the experience and control of spaces of imprisonment, detention and confinement. Scholars have explored the paradoxical nature of incarcerated experience as individuals oscillate between moments of fixity and motion as they are transported to/from carceral environments. This paper draws upon the convict ship – an example yet to gain attention within these emerging discussions – which is both an exemplar of this paradox and a lens through which to complicate understandings of carceral (im)mobilities. The ship is a space of macro-movement from point A to B, whilst simultaneously a site of apparent confinement for those aboard who are unable to move beyond its physical parameters. Yet, we contend that all manner of mobilities permeate the internal space of the ship. Accordingly, we challenge the binary thinking that separates moments of fixity from motion and explore the constituent parts that shape movement. In paying attention to movements in motion on the ship, we argue that studies of carceral mobility must attend to both methods of moving in the space between points A and B; as micro, embodied and intimate (im)mobilities are also played out within large-scale regimes of movement

Adeno-Associated Virus-Mediated Rescue of the Cognitive Defects in a Mouse Model for Angelman Syndrome

Angelman syndrome (AS), a genetic disorder occurring in approximately one in every 15,000 births, is characterized by severe mental retardation, seizures, difficulty speaking and ataxia. The gene responsible for AS was discovered to be UBE3A and encodes for E6-AP, an ubiquitin ligase. A unique feature of this gene is that it undergoes maternal imprinting in a neuron-specific manner. In the majority of AS cases, there is a mutation or deletion in the maternally inherited UBE3A gene, although other cases are the result of uniparental disomy or mismethylation of the maternal gene. While most human disorders characterized by severe mental retardation involve abnormalities in brain structure, no gross anatomical changes are associated with AS. However, we have determined that abnormal calcium/calmodulin-dependent protein kinase II (CaMKII) regulation is seen in the maternal UBE3A deletion AS mouse model and is responsible for the major phenotypes. Specifically, there is an increased αCaMKII phosphorylation at the autophosphorylation sites Thr286 and Thr305/306, resulting in an overall decrease in CaMKII activity. CaMKII is not produced until after birth, indicating that the deficits associated with AS are not the result of developmental abnormalities. The present studies are focused on exploring the potential to rescue the learning and memory deficits in the adult AS mouse model through the use of an adeno-associated virus (AAV) vector to increase neuronal UBE3A expression. These studies show that increasing the levels of E6-AP in the brain using an exogenous vector can improve the cognitive deficits associated with AS. Specifically, the associative learning deficit was ameliorated in the treated AS mice compared to the control AS mice, indicating that therapeutic intervention may be possible in older AS patients

Hepatic fibrosis and immune phenotype vary by HCV viremia in HCV/HIV co-infected subjects: A Women\u27s interagency HIV study.

HCV and HIV independently lead to immune dysregulation. The mechanisms leading to advanced liver disease progression in HCV/HIV coinfected subjects remain unclear. In this cross-sectional study, we assessed the association of HCV viremia, liver fibrosis, and immune response patterns in well-characterized HIV phenotypes: Elite controllers (Elites), HIV controlled (ARTc), and HIV uncontrolled (ARTuc) matched by age and race. Groups were stratified by HCV RNA status. Regulatory T-cell frequencies, T-cell activation (HLADR+CD38+), apoptosis (Caspase-3+), and intracellular cytokines (interferon-γ, IL-2, IL-17) were assessed using multiparametric flow-cytometry. Liver fibrosis was scored by AST to platelet ratio index (APRI). We found liver fibrosis (APRI) was 50% lower in Elites and ARTc compared to ARTuc. Higher liver fibrosis was associated with significantly low CD4+ T cell counts (P \u3c 0.001, coefficient r = −0.463). Immune activation varied by HIV phenotype but was not modified by HCV viremia. HCV viremia was associated with elevated CD8 T-cell Caspase-3 in Elites, ARTuc, and HIV− except ARTc. CD8 T-cell Caspase-3 levels were significantly higher in HCV RNA+ Elites (P = 0.04) and ARTuc (P = 0.001) and HIV− groups (P = 0.02) than ARTc. Importantly, ARTuc HCV RNA+ had significantly higher CD4 T-cell interleukin-17 levels than ARTuc HCV RNA− (P = 0.005). HIV control was associated with lower liver fibrosis in HCV/HIV co-infected women. HCV viremia is associated with an inflammatory CD4 TH-17 phenotype in absence of HIV control and higher frequency of pro-apoptosis CD8 T-cells critical to avert progression of HIV and HCV disease that is attenuated in ART controllers. Elite controllers with HCV viremia are more prone to CD8 T-cell apoptosis than ART controllers, which could have negative consequences over time, highlighting the importance of ART control in HCV/HIV coinfected individuals