Community Health Benefits Through a Student-Run Nonprofit Pediatric Wellness Clinic.

Purpose Community screening programs have been in effect since they were utilized in the 19th century at county fairs. A free pediatric health screening program was created by an osteopathic medical school in South Carolina in collaboration with a pediatric dental outreach organization to engage the local underserved community and train community-minded medical professionals. This study sought to demonstrate the efficacy and need for a student-run monthly pediatric health screening program in an underserved pediatric demographic. Methods A retrospective study of preexisting de-identified data obtained from a student-run health screening program was analyzed to determine the efficacy of the screening program in detecting chronic health risk factors in children in an underserved population. Patients were recruited through a partnership with a free dental clinic for underserved and uninsured children. Patients who attended the clinic were offered the opportunity to have a free, comprehensive health assessment following their dental visit. The function of this program was unique in that uninsured, underserved patients were provided free dental care and a free health assessment. Pediatric patients were screened for basic health information such as weight, height, BMI, vision, cardiovascular health, hypertension, asthma (reported via questionnaire by either the parent or child when applicable), nutrition, and lead poisoning (via questionnaire). The program also offered families additional support by connecting them to local resources and answering any questions they had about their children's health. Data from 14 health screening events was collected for quality improvement and efficacy monitoring. Descriptive analyses were performed. Results and analysis The health screening program assessed 124 children between October 2021 and March 2023 over 14 health screening events. The patients ranged from one year old to 26 years old, with a mean age of 9.65 years. Patients were predominantly Hispanic (79.67%). About one-third (27.64%) of children who were screened had positive findings associated with increased risk for chronic disease. Nearly half (43.90%) of families that were screened requested further information on ways to obtain health insurance and regular primary care services (utilized Access Health). Of the one-third of children with positive risk factors, 12.20% reported positive findings associated with asthma. Of the patients with positive risk factors, 8.94% had vision abnormalities, most of whom had not been seen by an ophthalmologist. This preliminary analysis will be followed by a secondary analysis that further investigates patient demographics (primarily Hispanic) as well as age distribution across various risk factors. Conclusion This pediatric health screening program has demonstrated a basic level of efficacy by successfully identifying increased risk for chronic disease in the underserved pediatric population. The need for these screening events was highlighted by the identification of untreated positive findings.

Novel formylpeptide receptor 1/2 agonist limits hypertension-induced cardiovascular damage.

AIMS: Formylpeptide receptors (FPRs) play a critical role in the regulation of inflammation, an important driver of hypertension-induced end-organ damage. We have previously reported that the biased FPR small-molecule agonist, compound17b (Cmpd17b), is cardioprotective against acute, severe inflammatory insults. Here, we reveal the first compelling evidence of the therapeutic potential of this novel FPR agonist against a longer-term, sustained inflammatory insult, i.e. hypertension-induced end-organ damage. The parallels between the murine and human hypertensive proteome were also investigated. METHODS AND RESULTS: The hypertensive response to angiotensin II (Ang II, 0.7 mg/kg/day, s.c.) was attenuated by Cmpd17b (50 mg/kg/day, i.p.). Impairments in cardiac and vascular function assessed via echocardiography were improved by Cmpd17b in hypertensive mice. This functional improvement was accompanied by reduced cardiac and aortic fibrosis and vascular calcification. Cmpd17b also attenuated Ang II-induced increased cardiac mitochondrial complex 2 respiration. Proteomic profiling of cardiac and aortic tissues and cells, using label-free nano-liquid chromatography with high-sensitivity mass spectrometry, detected and quantified ∼6000 proteins. We report hypertension-impacted protein clusters associated with dysregulation of inflammatory, mitochondrial, and calcium responses, as well as modified networks associated with cardiovascular remodelling, contractility, and structural/cytoskeletal organization. Cmpd17b attenuated hypertension-induced dysregulation of multiple proteins in mice, and of these, ∼110 proteins were identified as similarly dysregulated in humans suffering from adverse aortic remodelling and cardiac hypertrophy. CONCLUSION: We have demonstrated, for the first time, that the FPR agonist Cmpd17b powerfully limits hypertension-induced end-organ damage, consistent with proteome networks, supporting development of pro-resolution FPR-based therapeutics for treatment of systemic hypertension complications.

Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Formyl peptide receptor 1 mitigates colon inflammation and maintains mucosal homeostasis through the inhibition of CREB-C/EBPß-S100a8 signaling.

Excessive inflammatory responses are the main characteristic of ulcerative colitis (UC). Activation of formyl peptide receptor 1 (FPR1) has been found to promote the proliferation and migration of epithelial cells, but its role and therapeutic potential in UC remain unclear. This study observed an increased expression of FPR1 in a mouse model of colitis. Interestingly, FPR1 deficiency exacerbated UC and increased the secretion of the proinflammatory mediator from immune cells (e.g. macrophages), S100a8, a member of the damage-associated molecular patterns. Notably, the administration of the FPR agonist Cmpd43 ameliorated colon injury in a preclinical mice model of UC, likely via inhibiting phosphorylation of cyclic adenosine monophosphate-response element-binding protein and expression of CCAAT/enhancer-binding protein ß, which in turn suppressed the secretion of S100a8. In conclusion, these findings discovered a novel role of FPR1 in the development of colitis and will facilitate the development of FPR1-based pharmacotherapy to treat UC.

Pollutant profile complexity governs wastewater removal of recalcitrant pharmaceuticals.

Organic pollutants are an increasing threat for wildlife and humans. Managing their removal is however complicated by the difficulties in predicting degradation rates. In this work, we demonstrate that the complexity of the pollutant profile, the set of co-existing contaminants, is a major driver of biodegradation in wastewater. We built representative assemblages out of one to five common pharmaceuticals (caffeine, atenolol, paracetamol, ibuprofen, and enalapril) selected along a gradient of biodegradability. We followed their individual removal by wastewater microbial communities. The presence of multichemical background pollution was essential for the removal of recalcitrant molecules such as ibuprofen. High-order interactions between multiple pollutants drove removal efficiency. We explain these interactions by shifts in the microbiome, with degradable molecules such as paracetamol enriching species and pathways involved in the removal of several organic pollutants. We conclude that pollutants should be treated as part of a complex system, with emerging pollutants potentially showing cascading effects and offering leverage to promote bioremediation.

A retrospective observational cohort study on the postoperative respiratory complications and their risk factors in brachycephalic dogs undergoing BOAS surgery: 199 cases (2019-2021).

OBJECTIVES: To observe the occurrence of postanaesthetic respiratory complications and to determine their prevalence and risk factors in dogs undergoing brachycephalic obstructive airway syndrome surgery. MATERIALS AND METHODS: Data from 199 clinical records were retrospectively analysed. Univariable logistic regression followed by multivariable logistic regression was used to identify associations between the dependent variables (set as the postoperative respiratory complications observed in the study dogs) and various independent covariates. The quality of model-fit was assessed using the likelihood ratio test. P≤0.05 was considered statistically significant. RESULTS: Four postoperative respiratory complications were observed: hypoxaemia (n=10/199; 5%), dyspnoea requiring tracheal re-intubation (n=13/199, 7%), dyspnoea requiring tracheostomy (n=10/199, 5%) and aspiration pneumonia (n=12/199, 6%). Univariable logistic regression showed an association between postoperative aspiration pneumonia and increasing body condition score and American Society of Anaesthesiology classification; however, when these covariates were evaluated in the multivariable model significance was not maintained. Risk factors for tracheostomy were preoperative and postoperative aspiration pneumonia (odds ratio: 9.52, 95% confidence interval: 1.56 to 57.93) and increasing brachycephalic obstructive airway syndrome grade (odds ratio: 4.65, 95% confidence interval: 0.79 to 27.50). CLINICAL SIGNIFICANCE: High brachycephalic obstructive airway syndrome grade and aspiration pneumonia, either developing peri-operatively or as pre-existing condition, may represent risk factors for postoperative tracheostomy. Preoperative diagnosis of aspiration pneumonia may further increase the risk of postoperative complications.

The pro-resolving mediator, annexin A1 regulates blood pressure, and age-associated changes in cardiovascular function and remodeling.

Aging is associated with chronic, low-level inflammation which may contribute to cardiovascular pathologies such as hypertension and atherosclerosis. This chronic inflammation may be opposed by endogenous mechanisms to limit inflammation, for example, by the actions of annexin A1 (ANXA1), an endogenous glucocorticoid-regulated protein that has anti-inflammatory and pro-resolving activity. We hypothesized the pro-resolving mediator ANXA1 protects against age-induced changes in blood pressure (BP), cardiovascular structure and function, and cardiac senescence. BP was measured monthly in conscious mature (4-month) and middle-aged (12-month) ANXA1-deficient (ANXA1-/- ) and wild-type C57BL/6 mice. Body composition was measured using EchoMRI, and both cardiac and vascular function using ultrasound imaging. Cardiac hypertrophy, fibrosis and senescence, vascular fibrosis, elastin, and calcification were assessed histologically. Gene expression relevant to structural remodeling, inflammation, and cardiomyocyte senescence were also quantified. In C57BL/6 mice, progression from 4 to 12 months of age did not affect the majority of cardiovascular parameters measured, with the exception of mild cardiac hypertrophy, vascular calcium, and collagen deposition. Interestingly, ANXA1-/- mice exhibited higher BP, regardless of age. Additionally, age progression had a marked impact in ANXA1-/- mice, with markedly augmented vascular remodeling, impaired vascular distensibility, and body composition. Consistent with vascular dysfunction, cardiac dysfunction, and hypertrophy were also evident, together with markers of senescence and inflammation. These findings suggest that endogenous ANXA1 plays a critical role in regulating BP, cardiovascular function, and remodeling and delays cardiac senescence. Our findings support the development of novel ANXA1-based therapies to prevent age-related cardiovascular pathologies.

The small-molecule formyl peptide receptor biased agonist, compound 17b, is a vasodilator and anti-inflammatory in mouse precision-cut lung slices.

BACKGROUND AND PURPOSE: Pulmonary arterial hypertension (PAH), a rare fatal disorder characterised by inflammation, vascular remodelling and vasoconstriction. Current vasodilator therapies reduce pulmonary arterial pressure but not mortality. The G-protein coupled formyl peptide receptors (FPRs) mediates vasodilatation and resolution of inflammation, actions possibly beneficial in PAH. We investigated dilator and anti-inflammatory effects of the FPR biased agonist compound 17b in pulmonary vasculature using mouse precision-cut lung slices (PCLS). EXPERIMENTAL APPROACH: PCLS from 8-week-old male and female C57BL/6 mice, intrapulmonary arteries were pre-contracted with 5-HT for concentration-response curves to compound 17b and 43, and standard-of-care drugs, sildenafil, iloprost and riociguat. Compound 17b-mediated relaxation was assessed with FPR antagonists or inhibitors and in PCLS treated with TNF-α or LPS. Cytokine release from TNF-α- or LPS-treated PCLS ± compound 17b was measured. KEY RESULTS: Compound 17b elicited concentration-dependent vasodilation, with potencies of iloprost > compound 17b = riociguat > compound 43 = sildenafil. Compound 17b was inhibited by the FPR1 antagonist cyclosporin H but not by soluble guanylate cyclase, nitric oxide synthase or cyclooxygenase inhibitors. Under inflammatory conditions, the efficacy and potency of compound 17b were maintained, while iloprost and sildenafil were less effective. Additionally, compound 17b inhibited secretion of PAH-relevant cytokines via FPR2. CONCLUSIONS AND IMPLICATIONS: Vasodilation to compound 17b but not standard-of-care vasodilators, is maintained under inflammatory conditions, with additional inhibition of PAH-relevant cytokine release. This provides the first evidence that targeting FPR, with biased agonist, simultaneously targets vascular function and inflammation, supporting the development of FPR-based pharmacotherapy to treat PAH.

Critical Hypophosphatemia in a Special Operations Combat Dive Candidate: A Case Report.

In contrast to shallow water (hypoxic) blackout and swimming-induced pulmonary edema (SIPE), acute electrolyte disturbance secondary to acute respiratory alkalosis is not considered a common Combat Swimmer injury but has the potential to be life-threatening. We present the case of a 28-year-old Special Operations Dive Candidate who presented to the Emergency Department after a near-drowning incident with altered mental status, generalized weakness, respiratory distress, and tetany. He was found to have severe symptomatic hypophosphatemia (1.00mg/dL) and mild hypocalcemia secondary to intentional hyperventilation between subsurface "cross-overs," causing subsequent acute respiratory alkalosis. This is a unique presentation of a common electrolyte abnormality in a highly specialized population that is self-limiting when caused by acute respiratory alkalosis but poses a significant danger to Combat Swimmers if rescue personnel are not able to respond quickly.

Functional diversity can facilitate the collapse of an undesirable ecosystem state.

Biodiversity may increase ecosystem resilience. However, we have limited understanding if this holds true for ecosystems that respond to gradual environmental change with abrupt shifts to an alternative state. We used a mathematical model of anoxic-oxic regime shifts and explored how trait diversity in three groups of bacteria influences resilience. We found that trait diversity did not always increase resilience: greater diversity in two of the groups increased but in one group decreased resilience of their preferred ecosystem state. We also found that simultaneous trait diversity in multiple groups often led to reduced or erased diversity effects. Overall, our results suggest that higher diversity can increase resilience but can also promote collapse when diversity occurs in a functional group that negatively influences the state it occurs in. We propose this mechanism as a potential management approach to facilitate the recovery of a desired ecosystem state.

Endothelium-dependent relaxation is impaired in Schlager hypertensive (BPH/2J) mice by region-specific mechanisms in conductance and resistance arteries.

AIMS: Endothelial dysfunction and arterial stiffness are hallmarks of hypertension, and major risk factors for cardiovascular disease. BPH/2J (Schlager) mice are a genetic model of spontaneous hypertension, but little is known about the vascular pathophysiology of these mice and the region-specific differences between vascular beds. Therefore, this study compared the vascular function and structure of large conductance (aorta and femoral) and resistance (mesenteric) arteries of BPH/2J mice with their normotensive BPN/2J counterparts. MAIN METHODS: Blood pressure was measured in BPH/2J and BPN/3J mice via pre-implanted radiotelemetry probes. At endpoint, vascular function and passive mechanical wall properties were assessed using wire and pressure myography, qPCR and histology. KEY FINDINGS: Mean arterial blood pressure was elevated in BPH/2J mice compared to BPN/3J controls. Endothelium-dependent relaxation to acetylcholine was attenuated in both the aorta and mesenteric arteries of BPH/2J mice, but through different mechanisms. In the aorta, hypertension reduced the contribution of prostanoids. Conversely, in the mesenteric arteries, hypertension reduced the contribution of both nitric oxide and endothelium-dependent hyperpolarization. Hypertension reduced volume compliance in both femoral and mesenteric arteries, but hypertrophic inward remodelling was only observed in the mesenteric arteries of BPH/2J mice. SIGNIFICANCE: This is the first comprehensive investigation of vascular function and structural remodelling in BPH/2J mice. Overall, hypertensive BPH/2J mice exhibited endothelial dysfunction and adverse vascular remodelling in the macro- and microvasculature, underpinned by distinct region-specific mechanisms. This highlights BPH/2J mice as a highly suitable model for evaluating novel therapeutics to treat hypertension-associated vascular dysfunction.

Stochasticity causes high ß-diversity and functional divergence of bacterial assemblages in closed systems.

Stochasticity is a major cause of compositional ß-diversity in communities that develop under similar environmental conditions. Such communities may exhibit functional similarity due to sympatric taxa with equivalent metabolic capacities in the source assemblage. However, the redundancy of individual physiological traits may differ in the original source community, which in turn might lead to more or less pronounced variability of single functions among newly formed communities. We analyzed the degree of stochasticity during the primary assembly of bacterial communities originating from the same source and growing under identical conditions. We tested the links between community composition and functioning in parallel microcosms containing glucose and its dimer cellobiose. Bacteria from prefiltered lake water were diluted in artificial lake water and grown to the stationary phase. The resulting assemblages exhibited high compositional variability of taxa that were rare in the source communities. Simulations showed that the observed richness and incidence-based ß-diversity could be reproduced by dispersal limitation, or by low dispersal rates associated with the ecological drift of the colonizers. Further null model analysis supported an important influence of stochasticity, as well as a synergy between dispersal limitation and both, heterogeneous and homogeneous selection. The communities functionally differed and the magnitude of functional variability depended on the substrate: more communities consumed glucose than cellobiose. However, there was no relationship between community structure and growth kinetics or substrate consumption. Thus, both structural and functional variability may be a consequence of stochastic processes during initial colonization in closed microbial communities.

A high-sucrose diet exacerbates the left ventricular phenotype in a high fat-fed streptozotocin rat model of diabetic cardiomyopathy.

Left ventricular (LV) dysfunction is an early, clinically detectable sign of cardiomyopathy in type 2 diabetes mellitus (T2DM) that precedes the development of symptomatic heart failure. Preclinical models of diabetic cardiomyopathy are essential to develop therapies that may prevent or delay the progression of heart failure. This study examined the molecular, structural, and functional cardiac phenotype of two rat models of T2DM induced by a high-fat diet (HFD) with a moderate- or high-sucrose content (containing 88.9 or 346 g/kg sucrose, respectively), plus administration of low-dose streptozotocin (STZ). At 8 wk of age, male Sprague-Dawley rats commenced a moderate- or high-sucrose HFD. Two weeks later, rats received low-dose STZ (35 mg/kg ip for 2 days) and remained on their respective diets. LV function was assessed by echocardiography 1 wk before end point. At 22 wk of age, blood and tissues were collected postmortem. Relative to chow-fed sham rats, diabetic rats on a moderate- or high-sucrose HFD displayed cardiac reactive oxygen species dysregulation, perivascular fibrosis, and impaired LV diastolic function. The diabetes-induced impact on LV adverse remodeling and diastolic dysfunction was more apparent when a high-sucrose HFD was superimposed on STZ. In conclusion, a high-sucrose HFD in combination with low-dose STZ produced a cardiac phenotype that more closely resembled T2DM-induced cardiomyopathy than STZ diabetic rats subjected to a moderate-sucrose HFD.NEW & NOTEWORTHY Left ventricular dysfunction and adverse remodeling were more pronounced in diabetic rats that received low-dose streptozotocin (STZ) and a high-sucrose high-fat diet (HFD) compared with those on a moderate-sucrose HFD in combination with STZ. Our findings highlight the importance of sucrose content in diet composition, particularly in preclinical studies of diabetic cardiomyopathy, and demonstrate that low-dose STZ combined with a high-sucrose HFD is an appropriate rodent model of cardiomyopathy in type 2 diabetes.

Survival of Clostridioides difficile spores in thermal and chemo-thermal laundering processes and influence of the exosporium on their adherence to cotton bed sheets.

Clostridioides difficile spores were previously demonstrated to survive industrial laundering. Understanding interactions between heat, disinfectants and soiling (e.g. bodily fluids) affecting C. difficile spore survival could inform the optimization of healthcare laundry processes. Reducing spore attachment to linen could also enhance laundering efficacy. This study aimed to compare the sensitivity of C. difficile spores to heat and detergent, with and without soiling and to investigate adherence to cotton. Survival of C. difficile spores exposed to industrial laundering temperatures (71-90°C), reference detergent and industrial detergent was quantified with and without soiling. The adherence to cotton after 0 and 24 h air drying was determined with the exosporium of C. difficile spores partially or fully removed. Clostridioides difficile spores were stable at 71°C for 20 min (≤0·37 log10 reduction) while 90°C was sporicidal (3 log10 reduction); soiling exerted a protective effect. Industrial detergent was more effective at 71°C compared to 25°C (2·81 vs 0·84 log10 reductions), however, specifications for sporicidal activity (>3 log10 reduction) were not met. Clostridioides difficile spores increasingly adhered to cotton over time, with 49% adherence after 24 h. Removal of the exosporium increased adherence by 19-23% compared to untreated spores. Further understanding of the role of the exosporium in attachment to cotton could enhance spore removal and aid decontamination of linen.

Novel strategies to promote resolution of inflammation to treat lower extremity artery disease.

Lower extremity artery disease (LEAD) is a chronic inflammatory disease that occurs when atherosclerotic plaques form in the lower extremities, which may lead to amputation if not manged properly. Given clinical standardcare (pharmacological and surgical) have limited efficacy in LEAD, developing novel strategies to manage LEAD remains an unmet clinical need. Given that active resolution of inflammation is essential to facilitate tissue healing and repair, failure to resolve inflammation may lead to chronic inflammation, dysregulated cellular homeostasis and adverse tissue remodeling. Several studies have demonstrated the importance of the balance between endogenous pro-resolving mediators and pro-inflammatory factors. There is growing evidence to suggest endogenous pro-resolving mediators engage with pro-resolving G-protein-coupled receptors to reduce the initiation and progression of inflammatory responses and to increase therapeutic angiogenesis in LEAD. Here, we highlight the mechanisms and the consequences of resolved inflammation, and the therapeutic potential of endogenous pro-resolving mediators-based strategy for this devastating disease.

Allergen-Specific IgA Antibodies Block IgE-Mediated Activation of Mast Cells and Basophils.

Mast cells and basophils have long been implicated in the pathogenesis of IgE-mediated hypersensitivity reactions. They express the high-affinity IgE receptor, FcϵRI, on their surface. Antigen-induced crosslinking of IgE antibodies bound to that receptor triggers a signaling cascade that results in activation, leading to the release of an array of preformed vasoactive mediators and rapidly synthesized lipids, as well as the de novo production of inflammatory cytokines. In addition to bearing activating receptors like FcεRI, these effector cells of allergy express inhibitory ones including FcγR2b, an IgG Fc receptor with a cytosolic inhibitory motif that activates protein tyrosine phosphatases that suppress IgE-mediated activation. We and others have shown that food allergen-specific IgG antibodies strongly induced during the course of oral immunotherapy (OIT), signal via FcγR2b to suppress IgE-mediated mast cell and basophil activation triggered by food allergen challenge. However, the potential inhibitory effects of IgA antibodies, which are also produced in response to OIT and are present at high levels at mucosal sites, including the intestine where food allergens are encountered, have not been well studied. Here we uncover an inhibitory function for IgA. We observe that IgA binds mouse bone marrow-derived mast cells (BMMCs) and peritoneal mast cells. Binding to BMMCs is dependent on calcium and sialic acid. We also found that IgA antibodies inhibit IgE-mediated mast cell degranulation in an allergen-specific fashion. Antigen-specific IgA inhibits IgE-mediated mast cell activation early in the signaling cascade, suppressing the phosphorylation of Syk, the proximal protein kinase mediating FcεRI signaling, and suppresses mast cell production of cytokines. Furthermore, using basophils from a peanut allergic donor we found that IgA binds to basophils and that activation by exposure to peanuts is effectively suppressed by IgA. We conclude that IgA serves as a regulator of mast cell and basophil degranulation, suggesting a physiologic role for IgA in the maintenance of immune homeostasis at mucosal sites.

Forecasting in the face of ecological complexity: Number and strength of species interactions determine forecast skill in ecological communities.

The potential for forecasting the dynamics of ecological systems is currently unclear, with contrasting opinions regarding its feasibility due to ecological complexity. To investigate forecast skill within and across systems, we monitored a microbial system exposed to either constant or fluctuating temperatures in a 5-month-long laboratory experiment. We tested how forecasting of species abundances depends on the number and strength of interactions and on model size (number of predictors). We also tested how greater system complexity (i.e. the fluctuating temperatures) impacted these relations. We found that the more interactions a species had, the weaker these interactions were and the better its abundance was predicted. Forecast skill increased with model size. Greater system complexity decreased forecast skill for three out of eight species. These insights into how abundance prediction depends on the connectedness of the species within the system and on overall system complexity could improve species forecasting and monitoring.

Predicting the effects of multiple global change drivers on microbial communities remains challenging.

Microbial communities in many ecosystems are facing a broad range of global change drivers, such as nutrient enrichment, chemical pollution, and temperature change. These drivers can cause changes in the abundance of taxa, the composition of communities, and the properties of ecosystems. While the influence of single drivers is already described in numerous studies, the effect and predictability of multiple drivers changing simultaneously is still poorly understood. In this study, we used 240 highly replicable oxic/anoxic aquatic lab microcosms and four drivers (fertilizer, glyphosate, metal pollution, antibiotics) in all possible combinations at three different temperatures (20, 24, and 28°C) to shed light into consequences of multiple drivers on different levels of organization, ranging from species abundance to community and ecosystem parameters. We found (i) that at all levels of ecological organization, combinations of drivers can change the biological consequence and direction of effect compared to single drivers, (ii) that effects of combinations are further modified by temperature, (iii) that a larger number of drivers occurring simultaneously is often quite closely related to their effect size, and (iv) that there is little evidence that any of these effects are associated with the level of ecological organization of the state variable. These findings suggest that, at least in this experimental ecosystem approximating a stratified aquatic ecosystem, there may be relatively little scope for predicting the effects of combinations of drivers from the effects of individual drivers, or by accounting for the level of ecological organization in question, though there may be some scope for prediction based on the number of drivers that are occurring simultaneous. A priority, though also a considerable challenge, is to extend such research to consider continuous variation in the magnitude of multiple drivers acting together.

Cardioprotective actions of nitroxyl donor Angeli's salt are preserved in the diabetic heart and vasculature in the face of nitric oxide resistance.

BACKGROUND AND PURPOSE: The risk of fatal cardiovascular events is increased in patients with type 2 diabetes mellitus (T2DM). A major contributor to poor prognosis is impaired nitric oxide (NO•) signalling at the level of tissue responsiveness, termed NO• resistance. This study aimed to determine if T2DM promotes NO• resistance in the heart and vasculature and whether tissue responsiveness to nitroxyl (HNO) is affected. EXPERIMENTAL APPROACH: At 8 weeks of age, male Sprague-Dawley rats commenced a high-fat diet. After 2 weeks, the rats received low-dose streptozotocin (two intraperitoneal injections, 35 mg·kg-1 , over two consecutive days) and continued on the same diet. Twelve weeks later, isolated hearts were Langendorff-perfused to assess responses to the NO• donor diethylamine NONOate (DEA/NO) and the HNO donor Angeli's salt. Isolated mesenteric arteries were utilised to measure vascular responsiveness to the NO• donors sodium nitroprusside (SNP) and DEA/NO, and the HNO donor Angeli's salt. KEY RESULTS: Inotropic, lusitropic and coronary vasodilator responses to DEA/NO were impaired in T2DM hearts, whereas responses to Angeli's salt were preserved or enhanced. Vasorelaxation to Angeli's salt was augmented in T2DM mesenteric arteries, which were hyporesponsive to the relaxant effects of SNP and DEA/NO. CONCLUSION AND IMPLICATIONS: This is the first evidence that inotropic and lusitropic responses are preserved, and NO• resistance in the coronary and mesenteric vasculature is circumvented, by the HNO donor Angeli's salt in T2DM. These findings highlight the cardiovascular therapeutic potential of HNO donors, especially in emergencies such as acute ischaemia or heart failure.

Contrasting resistance and resilience to light variation of the coupled oxic and anoxic components of an experimental microbial ecosystem.

Understanding how microbial communities of aquatic ecosystems respond to environmental change remains a critical challenge in microbial ecology. In this study, we used light-dependent oxic-anoxic micro-ecosystems to understand how the functioning and diversity of aerobic and anaerobic lake analog communities are affected by a pulse light deprivation. Continuous measurements of oxygen concentration were made and a time series of full-length 16S rRNA sequencing was used to quantify changes in alpha- and beta diversity. In the upper oxic layer, oxygen concentration decreased significantly under light reduction, but showed resilience in daily mean, minimum, and maximum after light conditions were restored to control level. Only the amplitude of diurnal fluctuations in oxygen concentrations did not recover fully, and instead tended to remain lower in treated ecosystems. Alpha diversity of the upper oxic layer communities showed a delayed increase after light conditions were restored, and was not resilient in the longer term. In contrast, alpha diversity of the anoxic lower layer communities increased during the light reduction, but was resilient in the longer term. Community composition changed significantly during light reduction, and showed resilience in the oxic layer and lack of resilience in the anoxic layer. Alpha diversity and the amplitude of daily oxygen fluctuations within and among treatments were strongly correlated, suggesting that higher diversity could lead to less variable oxygen concentrations, or vice versa. Our experiment showed that light deprivation induces multifaceted responses of community function (oxygen respiration) and structure, hence focusing on a single stability component could potentially be misleading.