Mast cell desensitization inhibits calcium flux and aberrantly remodels actin

Rush desensitization (DS) is a widely used and effective clinical strategy for the rapid inhibition of IgE-mediated anaphylactic responses. However, the cellular targets and underlying mechanisms behind this process remain unclear. Recent studies have implicated mast cells (MCs) as the primary target cells for DS. Here, we developed a murine model of passive anaphylaxis with demonstrated MC involvement and an in vitro assay to evaluate the effect of DS on MCs. In contrast with previous reports, we determined that functional IgE remains on the cell surface of desensitized MCs following DS. Despite notable reductions in MC degranulation following DS, the high-affinity IgE receptor FcεRI was still capable of transducing signals in desensitized MCs. Additionally, we found that displacement of the actin cytoskeleton and its continued association with FcεRI impede the capacity of desensitized MCs to evoke the calcium response that is essential for MC degranulation. Together, these findings suggest that reduced degranulation responses in desensitized MCs arise from aberrant actin remodeling, providing insights that may lead to improvement of DS treatments for anaphylactic responses

Building a robust word-level wakeword verification network

Published versio

An audio-based wakeword-independent verification system

We propose an audio-based wakeword-independent verification model to determine whether a wakeword spotting model correctly woke and should respond or incorrectly woke and should not respond. Our model works on any wakeword-initiated audio, independent of the wakeword by operating only on the audio surrounding the wakeword, yielding a wakeword agnostic model. This model is based on two key assumptions: that audio surrounding the wakeword is informative to determine if the user intended to wake the device and that this audio is independent of the wakeword itself. We show experimentally that on wakewords not included in the training set, our model trained without examples or knowledge of the wakeword is able to achieve verification performance comparable to models trained on 5,000 to 10,000 annotated examples of the new wakeword.Published versio

Diagnosis, Management, and Investigational Therapies for Food Allergies

Food allergies have increased in prevalence over the past 20 years, now becoming an important public health concern. Although there are no therapies currently available for routine clinical care, recent reports have indicated that immunotherapies targeting the mucosal immune system may be effective. Oral immunotherapy is conducted by administering small, increasing amounts of food allergen; it has shown promise for desensitizing individuals with peanut, egg, or milk allergies. Sublingual immunotherapy also desensitizes allergic patients to foods—2 major studies have examined the effects of sublingual immunotherapy in subjects with peanut allergies. We review the complex nature of IgE-mediated food allergies and the therapies being evaluated in clinical trials. We focus on the diagnosis and management of food allergies and investigational therapies

Chemical Sensors Based on Metal Oxide Nanostructures

This paper is an overview of sensor development based on metal oxide nanostructures. While nanostructures such as nanorods show significan t potential as enabling materials for chemical sensors, a number of s ignificant technical challenges remain. The major issues addressed in this work revolve around the ability to make workable sensors. This paper discusses efforts to address three technical barriers related t o the application of nanostructures into sensor systems: 1) Improving contact of the nanostructured materials with electrodes in a microse nsor structure; 2) Controling nanostructure crystallinity to allow co ntrol of the detection mechanism; and 3) Widening the range of gases that can be detected by using different nanostructured materials. It is concluded that while this work demonstrates useful tools for furt her development, these are just the beginning steps towards realizati on of repeatable, controlled sensor systems using oxide based nanostr uctures

Tick Salivary Gland Extract Induces Alpha-Gal Syndrome In Alpha-Gal Deficient Mice

Introduction: Alpha-gal syndrome (AGS) is characterized by delayed hypersensitivity to non-primate mammalian meat in people having specific immunoglobulin E (sIgE) to the oligosaccharide galactose-alpha-1,3-galactose. AGS has been linked to tick bites from Amblyomma americanum (Aa) in the U.S. A small animal model of meat allergy is needed to study the mechanism of alpha-gal sensitization, the effector phase leading to delayed allergic responses and potential therapeutics to treat AGS. Methods: Eight- to ten-weeks old mice with a targeted inactivation of alpha-1,3-galactosyltransferase (AGKO) were injected intradermally with 50 μg of Aa tick salivary gland extract (TSGE) on days 0, 7, 21, 28, 42, and 49. Total IgE and alpha-gal sIgE were quantitated on Day 56 by enzyme-linked immunosorbent assay. Mice were challenged orally with 400 mg of cooked pork kidney homogenate or pork fat. Reaction severity was assessed by measuring a drop in core body temperature and scoring allergic signs. Results: Compared to control animals, mice treated with TSGE had 190-fold higher total IgE on Day 56 (0.60 ± 0.12 ng/ml vs. 113.2 ± 24.77 ng/ml; p \u3c 0.001). Alpha-gal sIgE was also produced in AGKO mice following TSGE sensitization (undetected vs. 158.4 ± 72.43 pg/ml). Further, sensitized mice displayed moderate clinical allergic signs along with a drop in core body temperature of ≥2°C as an objective measure of a systemic allergic reaction. Interestingly, female mice had higher total IgE responses to TSGE treatment but male mice had larger declines in mean body temperature. Conclusion: TSGE-sensitized AGKO mice generate sIgE to alpha-gal and demonstrate characteristic allergic responses to pork fat and pork kidney. In keeping with the AGS responses documented in humans, mice reacted more rapidly to organ meat than to high fat pork challenge. This mouse model establishes the central role of tick bites in the development of AGS and provides a small animal model to mechanistically study mammalian meat allergy

Clinical efficacy and immune regulation with peanut oral immunotherapy

Background Oral immunotherapy (OIT) has been thought to induce clinical desensitization to allergenic foods, but trials coupling the clinical response and immunologic effects of peanut OIT have not been reported. Objective The study objective was to investigate the clinical efficacy and immunologic changes associated with OIT. Methods Children with peanut allergy underwent an OIT protocol including initial day escalation, buildup, and maintenance phases, and then oral food challenge. Clinical response and immunologic changes were evaluated. Results Of 29 subjects who completed the protocol, 27 ingested 3.9 g peanut protein during food challenge. Most symptoms noted during OIT resolved spontaneously or with antihistamines. By 6 months, titrated skin prick tests and activation of basophils significantly declined. Peanut-specific IgE decreased by 12 to 18 months, whereas IgG4 increased significantly. Serum factors inhibited IgE–peanut complex formation in an IgE-facilitated allergen binding assay. Secretion of IL-10, IL-5, IFN-γ, and TNF-α from PBMCs increased over a period of 6 to 12 months. Peanut-specific forkhead box protein 3 T cells increased until 12 months and decreased thereafter. In addition, T-cell microarrays showed downregulation of genes in apoptotic pathways. Conclusion Oral immunotherapy induces clinical desensitization to peanut, with significant longer-term humoral and cellular changes. Microarray data suggest a novel role for apoptosis in OIT

Conceptual framework of public health surveillance and action and its application in health sector reform

BACKGROUND: Because both public health surveillance and action are crucial, the authors initiated meetings at regional and national levels to assess and reform surveillance and action systems. These meetings emphasized improved epidemic preparedness, epidemic response, and highlighted standardized assessment and reform. METHODS: To standardize assessments, the authors designed a conceptual framework for surveillance and action that categorized the framework into eight core and four support activities, measured with indicators. RESULTS: In application, country-level reformers measure both the presence and performance of the six core activities comprising public health surveillance (detection, registration, reporting, confirmation, analyses, and feedback) and acute (epidemic-type) and planned (management-type) responses composing the two core activities of public health action. Four support activities – communications, supervision, training, and resource provision – enable these eight core processes. National, multiple systems can then be concurrently assessed at each level for effectiveness, technical efficiency, and cost. CONCLUSIONS: This approach permits a cost analysis, highlights areas amenable to integration, and provides focused intervention. The final public health model becomes a district-focused, action-oriented integration of core and support activities with enhanced effectiveness, technical efficiency, and cost savings. This reform approach leads to sustained capacity development by an empowerment strategy defined as facilitated, process-oriented action steps transforming staff and the system

Conceptual framework of public health surveillance and action and its application in health sector reform

<p>Abstract</p> <p>Background</p> <p>Because both public health surveillance and action are crucial, the authors initiated meetings at regional and national levels to assess and reform surveillance and action systems. These meetings emphasized improved epidemic preparedness, epidemic response, and highlighted standardized assessment and reform.</p> <p>Methods</p> <p>To standardize assessments, the authors designed a conceptual framework for surveillance and action that categorized the framework into eight core and four support activities, measured with indicators.</p> <p>Results</p> <p>In application, country-level reformers measure both the presence and performance of the six core activities comprising public health surveillance (detection, registration, reporting, confirmation, analyses, and feedback) and acute (epidemic-type) and planned (management-type) responses composing the two core activities of public health action. Four support activities – communications, supervision, training, and resource provision – enable these eight core processes. National, multiple systems can then be concurrently assessed at each level for effectiveness, technical efficiency, and cost.</p> <p>Conclusions</p> <p>This approach permits a cost analysis, highlights areas amenable to integration, and provides focused intervention. The final public health model becomes a district-focused, action-oriented integration of core and support activities with enhanced effectiveness, technical efficiency, and cost savings. This reform approach leads to sustained capacity development by an empowerment strategy defined as facilitated, process-oriented action steps transforming staff and the system.</p