Non-transgenic guinea pig strains exhibit divergent age-related changes in hippocampal mitochondrial respiration.

AIM: Alzheimer's disease (AD) is the most common form of dementia. However, while 150+ animal models of AD exist, drug translation from preclinical models to humans for treatment usually fails. One factor contributing to low translation is likely the absence of neurodegenerative models that also encompass the multi-morbidities of human aging. We previously demonstrated that, in comparison to the PigmEnTed (PET) guinea pig strain which models "typical" brain aging, the Hartley strain develops hallmarks of AD like aging humans. Hartleys also exhibit age-related impairments in cartilage and skeletal muscle. Impaired mitochondrial respiration is one driver of both cellular aging and AD. In humans with cognitive decline, diminished skeletal muscle and brain respiratory control occurs in parallel. We previously reported age-related declines in skeletal muscle mitochondrial respiration in Hartleys. It is unknown if there is concomitant mitochondrial dysfunction in the brain. METHODS: Therefore, we assessed hippocampal mitochondrial respiration in 5- and 12-month Hartley and PET guinea pigs using high-resolution respirometry. RESULTS: At 12 months, PETs had higher complex I supported mitochondrial respiration paralleling their increase in body mass compared to 5 months PETs. Hartleys were also heavier at 12 months compared to 5 months but did not have higher complex I respiration. Compared to 5 months Hartleys, 12 months Hartleys had lower complex I mitochondrial efficiency and compensatory increases in mitochondrial proteins collectively suggesting mitochondrial dysfunction with age. CONCLUSIONS: Therefore, Hartleys might be a relevant model to test promising therapies targeting mitochondria to slow brain aging and AD progression.

Treatment of an Impending Pathologic Sacral Fracture with a Novel Iliosacral Fusion Construct: A Case Report.

CASE: A 49-year-old woman presented with left leg radiculopathy and posterior pelvic pain. Subsequent evaluation demonstrated metastatic multiple myeloma with an impending left S1 sacral fracture. Immediate posterior pelvic ring stabilization was recommended to prevent fracture and disruption of her oncologic recovery. This was performed percutaneously with computer-assisted navigation using a novel cannulated screw design. CONCLUSION: The patient was treated with prophylactic percutaneous posterior pelvic ring fixation with a novel cannulated screw design that provided a durable construct for immediate weight-bearing. The fixation prevented a pathologic fracture and allowed immediate return to activity.

Skeletal muscle mitochondria demonstrate similar respiration per cristae surface area independent of training status and sex in healthy humans.

The impact of training status and sex on intrinsic skeletal muscle mitochondrial respiratory capacity remains unclear. We examined this by analysing human skeletal muscle mitochondrial respiration relative to mitochondrial volume and cristae density across training statuses and sexes. Mitochondrial cristae density was estimated in skeletal muscle biopsies originating from previous independent studies. Participants included females (n = 12) and males (n = 41) across training statuses ranging from untrained (UT, n = 8), recreationally active (RA, n = 9), active-to-elite runners (RUN, n = 27) and cross-country skiers (XC, n = 9). The XC and RUN groups demonstrated higher mitochondrial volume density than the RA and UT groups while all active groups (RA, RUN and XC) displayed higher mass-specific capacity of oxidative phosphorylation (OXPHOS) and mitochondrial cristae density than UT. Differences in OXPHOS diminished between active groups and UT when normalising to mitochondrial volume density and were lost when normalising to muscle cristae surface area density. Moreover, active females (n = 6-9) and males (n = 15-18) did not differ in mitochondrial volume and cristae density, OXPHOS, or when normalising OXPHOS to mitochondrial volume density and muscle cristae surface area density. These findings demonstrate: (1) differences in OXPHOS between active and untrained individuals may be explained by both higher mitochondrial volume and cristae density in active individuals, with no difference in intrinsic mitochondrial respiratory capacity (OXPHOS per muscle cristae surface area density); and (2) no sex differences in mitochondrial volume and cristae density or mass-specific and normalised OXPHOS. This highlights the importance of normalising OXPHOS to muscle cristae surface area density when studying skeletal muscle mitochondrial biology. KEY POINTS: Oxidative phosphorylation is the mitochondrial process by which ATP is produced, governed by the electrochemical gradient across the inner mitochondrial membrane with infoldings named cristae. In human skeletal muscle, the mass-specific capacity of oxidative phosphorylation (OXPHOS) can change independently of shifts in mitochondrial volume density, which may be attributed to variations in cristae density. We demonstrate that differences in skeletal muscle OXPHOS between healthy females and males, ranging from untrained to elite endurance athletes, are matched by differences in cristae density. This suggests that higher OXPHOS in skeletal muscles of active individuals is attributable to an increase in the density of cristae. These findings broaden our understanding of the variability in human skeletal muscle OXPHOS and highlight the significance of cristae, specific to mitochondrial respiration.

Assessing exogenous carbohydrate intake needed to optimize human endurance performance across sex: insights from modeling runners pursuing a sub-2-h marathon.

Carbohydrate (CHO) availability sustains high metabolic demands during prolonged exercise. The adequacy of current CHO intake recommendations, 30-90 g·h-1 dependent on CHO mixture and tolerability, to support elite marathon performance is unclear. We sought to scrutinize the current upper limit recommendation for exogenous CHO intake to support modeled sub-2-h marathon (S2M) attempts across elite male and female runners. Male and female runners (n = 120 each) were modeled from published literature with reference characteristics necessary to complete a S2M (e.g., body mass and running economy). Completion of a S2M was considered across a range of respiratory exchange rates, with maximal starting skeletal muscle and liver glycogen content predicted for elite male and female runners. Modeled exogenous CHO bioavailability needed for male and female runners were 93 ± 26 and 108 ± 22 g·h-1, respectively (P < 0.0001, d = 0.61). Without exogenous CHO, males were modeled to deplete glycogen in 84 ± 7 min, females in 71 ± 5 min (P < 0.0001, d = 2.21) despite higher estimated CHO oxidation rates in males (5.1 ± 0.5 g·h-1) than females (4.4 ± 0.5 g·h-1; P < 0.0001, d = 1.47). Exogenous CHO intakes ≤ 90 g·h-1 are insufficient for 65% of modeled runners attempting a S2M. Current recommendations to support marathon performance appear inadequate for elite marathon runners but may be more suitable for male runners in pursuit of a S2M (56 of 120) than female runners (28 of 120).NEW & NOTEWORTHY This study scrutinizes the upper limit of exogenous carbohydrate (CHO) recommendations for elite male and female marathoners by modeling sex-specific needs across an extreme metabolic challenge lasting ∼2 h, a sub-2-h marathon. Contemporary nutritional guidelines to optimize marathon performance appear inadequate for most elite marathon runners but appear more appropriate for males over their female counterparts. Future research examining possible benefits of exogenous CHO intakes > 90 g·h-1 should prioritize female athlete study inclusion.

Implications of capacity-limited, generative models for human vision.

Although discriminative deep neural networks are currently dominant in cognitive modeling, we suggest that capacity-limited, generative models are a promising avenue for future work. Generative models tend to learn both local and global features of stimuli and, when properly constrained, can learn componential representations and response biases found in people's behaviors.

A practical perspective on how to develop, implement, execute, and reproduce high-resolution respirometry experiments: The physiologist's guide to an Oroboros O2k.

The development of high-resolution respirometry (HRR) has greatly expanded the analytical scope to study mitochondrial respiratory control relative to specific tissue/cell types across various metabolic states. Specifically, the Oroboros Oxygraph 2000 (O2k) is a common tool for measuring rates of mitochondrial respiration and is the focus of this perspective. The O2k platform is amenable for answering numerous bioenergetic questions. However, inherent variability with HRR-derived data, both within and amongst users, can impede progress in bioenergetics research. Therefore, we advocate for several vital considerations when planning and conducting O2k experiments to ultimately enhance transparency and reproducibility across laboratories. In this perspective, we offer guidance for best practices of mitochondrial preparation, protocol selection, and measures to increase reproducibility. The goal of this perspective is to propagate the use of the O2k, enhance reliability and validity for both new and experienced O2k users, and provide a reference for peer reviewers.

Rapid runtime learning by curating small datasets of high-quality items obtained from memory.

We propose the "runtime learning" hypothesis which states that people quickly learn to perform unfamiliar tasks as the tasks arise by using task-relevant instances of concepts stored in memory during mental training. To make learning rapid, the hypothesis claims that only a few class instances are used, but these instances are especially valuable for training. The paper motivates the hypothesis by describing related ideas from the cognitive science and machine learning literatures. Using computer simulation, we show that deep neural networks (DNNs) can learn effectively from small, curated training sets, and that valuable training items tend to lie toward the centers of data item clusters in an abstract feature space. In a series of three behavioral experiments, we show that people can also learn effectively from small, curated training sets. Critically, we find that participant reaction times and fitted drift rates are best accounted for by the confidences of DNNs trained on small datasets of highly valuable items. We conclude that the runtime learning hypothesis is a novel conjecture about the relationship between learning and memory with the potential for explaining a wide variety of cognitive phenomena.

Iliac dysmorphism: defining radiographic characteristics and association with pelvic osseous corridor size.

INTRODUCTION: Insertion of iliac wing implants requires understanding of the curvilinear shape of the ilium. This study serves to quantitatively identify the area of iliac inner-outer table convergence (IOTC), characterize the iliac wing osseous corridor, and define the gluteal pillar osseous corridor. METHODS: Computed tomography scans of 100 male and 100 female hemipelves were evaluated. The iliac wing was studied using manual best-fit analysis of the bounds of the inner and outer cortices. The IOTC was defined as the location of the iliac wing with an intercortical width less than 5 mm. The shortest distance from the apex of the iliac crest to the superior border of the IOTC was defined as the iliac wing osseous corridor. Finally, the width of the gluteal pillar corridor from the gluteus medius tubercle to the ischial tuberosity was measured. RESULTS: The IOTC is an elliptical area measuring 22.3 cm2. All ilia had an area where the inner and outer cortices converged to an intercortical width of less than 5 mm; 48% converged to a single cortex. The shortest mean distance from the superior edge of the iliac crest to the beginning of the IOTC was 20.3 mm in men and 13.8 mm in women (p < 0.001). The gluteal pillar diameter averaged 5.3 mm in men and 4.3 mm in women (p < 0.001). DISCUSSION: All ilia converge to a thin and frequently unicortical central region. A 4.5 mm iliac wing lag screw will not breach the cortex if it remains within 20 mm or 14 mm distal to the cranial aspect of the iliac crest in males and females, respectively. Not only is the gluteal pillar smaller than previously thought, in 41% of males and 73% of females, it is not be large enough for 5 mm implants. CONCLUSION: This study quantitatively assesses the dimensions of the IOTC, the iliac crest osseous corridor, and the gluteal pillar. Overall, our findings provide improved understanding of the limits for implant use in the iliac wing as well as better appreciation of the complex osteology of the ilium. This will help surgeons to identify safe areas for implant placement and avoid inadvertent cortical penetration.

Intramedullary Nail and Plate Combination Technique for Peri-Implant Both-Bone Forearm Fractures.

A 35-year-old female patient with cerebellar ataxia presented with a right periprosthetic both-bone forearm fracture after a ground-level fall. Her surgical history was significant for multiple both-bone forearm fractures treated by open reduction and internal fixation. Subsequent treatment with a combination of intramedullary nailing and plate fixation for each bone provided successful fracture union while allowing immediate return to weight-bearing and range of motion. This case report demonstrates that intramedullary nailing and plate fixation of both-bone forearm fractures provides complete protection of the radius and ulna in recurrent, peri-implant both-bone forearm fractures. This technique is a valuable treatment option in the setting of a patient at risk for recurrent injury of the forearm.

Metabolomic Profiles in Starved Light Breed Horses during the Refeeding Process.

The large population of emaciated horses continues to be an issue troubling the equine industry. However, little is known regarding the collection of equine metabolites (metabolome) during a malnourished state and the changes that occur throughout nutritional rehabilitation. In this study, ten emaciated horses underwent a refeeding process, during which blood samples were collected for a blood chemistry panel and metabolomics analysis via ultrahigh performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). Significant differences among blood chemistry analytes and metabolite abundance during the critical care period (CCP; Days 1-10 of rehabilitation) and the recovery period (RP; the remainder of the rehabilitation process) were observed. Potentially toxic compounds, analytes related to liver, kidney, and muscle function, as well as energy-related metabolites were altered during the refeeding process. The combination of blood chemistry and metabolomics analyses on starved equine during rehabilitation provide vital biological insight and evidence that the refeeding process has a significant impact on the equine metabolome.

Erythropoietin receptor regulates tumor mitochondrial biogenesis through iNOS and pAKT.

Erythropoietin receptor (EPOR) is widely expressed in healthy and malignant tissues. In certain malignancies, EPOR stimulates tumor growth. In healthy tissues, EPOR controls processes other than erythropoiesis, including mitochondrial metabolism. We hypothesized that EPOR also controls the mitochondrial metabolism in cancer cells. To test this hypothesis, we generated EPOR-knockdown cancer cells to grow tumor xenografts in mice and analyzed tumor cellular respiration via high-resolution respirometry. Furthermore, we analyzed cellular respiratory control, mitochondrial content, and regulators of mitochondrial biogenesis in vivo and in vitro in different cancer cell lines. Our results show that EPOR controls tumor growth and mitochondrial biogenesis in tumors by controlling the levels of both, pAKT and inducible NO synthase (iNOS). Furthermore, we observed that the expression of EPOR is associated with the expression of the mitochondrial marker VDAC1 in tissue arrays of lung cancer patients, suggesting that EPOR indeed helps to regulate mitochondrial biogenesis in tumors of cancer patients. Thus, our data imply that EPOR not only stimulates tumor growth but also regulates tumor metabolism and is a target for direct intervention against progression.

Discovery of an orally active benzoxaborole prodrug effective in the treatment of Chagas disease in non-human primates.

Trypanosoma cruzi, the agent of Chagas disease, probably infects tens of millions of people, primarily in Latin America, causing morbidity and mortality. The options for treatment and prevention of Chagas disease are limited and underutilized. Here we describe the discovery of a series of benzoxaborole compounds with nanomolar activity against extra- and intracellular stages of T. cruzi. Leveraging both ongoing drug discovery efforts in related kinetoplastids, and the exceptional models for rapid drug screening and optimization in T. cruzi, we have identified the prodrug AN15368 that is activated by parasite carboxypeptidases to yield a compound that targets the messenger RNA processing pathway in T. cruzi. AN15368 was found to be active in vitro and in vivo against a range of genetically distinct T. cruzi lineages and was uniformly curative in non-human primates (NHPs) with long-term naturally acquired infections. Treatment in NHPs also revealed no detectable acute toxicity or long-term health or reproductive impact. Thus, AN15368 is an extensively validated and apparently safe, clinically ready candidate with promising potential for prevention and treatment of Chagas disease.

Optimized Pyridazinone Nutrient Channel Inhibitors Are Potent and Specific Antimalarial Leads.

Human and animal malaria parasites increase their host erythrocyte permeability to a broad range of solutes as mediated by parasite-associated ion channels. Molecular and pharmacological studies have implicated an essential role in parasite nutrient acquisition, but inhibitors suitable for development of antimalarial drugs are missing. Here, we generated a potent and specific drug lead using Plasmodium falciparum, a virulent human pathogen, and derivatives of MBX-2366, a nanomolar affinity pyridazinone inhibitor from a high-throughput screen. As this screening hit lacks the bioavailability and stability needed for in vivo efficacy, we synthesized 315 derivatives to optimize drug-like properties, establish target specificity, and retain potent activity against the parasite-induced permeability. Using a robust, iterative pipeline, we generated MBX-4055, a derivative active against divergent human parasite strains. MBX-4055 has improved oral absorption with acceptable in vivo tolerability and pharmacokinetics. It also has no activity against a battery of 35 human channels and receptors and is refractory to acquired resistance during extended in vitro selection. Single-molecule and single-cell patch-clamp indicate direct action on the plasmodial surface anion channel, a channel linked to parasite-encoded RhopH proteins. These studies identify pyridazinones as novel and tractable antimalarial scaffolds with a defined mechanism of action. SIGNIFICANCE STATEMENT: Because antimalarial drugs are prone to evolving resistance in the virulent human P. falciparum pathogen, new therapies are needed. This study has now developed a novel drug-like series of pyridazinones that target an unexploited parasite anion channel on the host cell surface, display excellent in vitro and in vivo ADME properties, are refractory to acquired resistance, and demonstrate a well defined mechanism of action.

Conceptual knowledge shapes visual working memory for complex visual information.

Human visual working memory (VWM) is a memory store people use to maintain the visual features of objects and scenes. Although it is obvious that bottom-up information influences VWM, the extent to which top-down conceptual information influences VWM is largely unknown. We report an experiment in which groups of participants were trained in one of two different categories of geologic faults (left/right lateral, or normal/reverse faults), or received no category training. Following training, participants performed a visual change detection task in which category knowledge was irrelevant to the task. Participants were more likely to detect a change in geologic scenes when the changes crossed a trained categorical distinction (e.g., the left/right lateral fault boundary), compared to within-category changes. In addition, participants trained to distinguish left/right lateral faults were more likely to detect changes when the scenes were mirror images along the left/right dimension. Similarly, participants trained to distinguish normal/reverse faults were more likely to detect changes when scenes were mirror images along the normal/reverse dimension. Our results provide direct empirical evidence that conceptual knowledge influences VWM performance for complex visual information. An implication of our results is that cognitive scientists may need to reconceptualize VWM so that it is closer to "conceptual short-term memory".

Birch-naive, oak-allergic subjects' response to birch pollen in an environmental chamber.

Background: Oak and birch pollens are strongly cross-reactive. It is unknown how robust this cross-reactivity is in patients without natural exposure to pollen of both trees. We assessed the symptom response to birch pollen in subjects with skin-prick test (SPT) results positive to oak and birch but only naturally exposed to oak by using an allergen challenge chamber. Methods: The subjects with SPT results positive to oak and birch had their serum-specific immunoglobulin E (ssIgE) to oak and birch antigens measured. Residential historical data were obtained. The subjects were exposed to birch pollen (3500 ± 700 grains/m³) in two consecutive 3-hour challenges. Symptoms were recorded at baseline and 30-minute intervals. Results: Twenty-four subjects, 12 men; ages 20-58 years, completed the study. Sixteen subjects (66.7%) responded with high Total Symptom Scores (TSS) ≥10 of a maximum 21. Twelve subjects (50%) had ssIgE values ≥0.70 kU/L to oak, 10 of whom had ssIgE values ≥0.70 kU/L to birch. These 10 subjects had a significantly higher maximum TSS than the rest. Also, 15 subjects without a previous natural exposure to birch pollen responded with TSS equivalent to the 9 subjects with previous exposure. Conclusion: Virginia live oak ssIgE levels of patients allergic to oak and birch correlated with the symptom response to birch pollen exposure, even without previous natural exposure to birch. The subjects naive to birch pollen responded to birch pollen exposure with symptoms comparable with both those with previous sustained exposure and also those who resided in endemic areas, as reported by other researchers.

Analogy-Related Information Can Be Accessed by Simple Addition and Subtraction of fMRI Activation Patterns, Without Participants Performing any Analogy Task.

Analogical reasoning, for example, inferring that teacher is to chalk as mechanic is to wrench, plays a fundamental role in human cognition. However, whether brain activity patterns of individual words are encoded in a way that could facilitate analogical reasoning is unclear. Recent advances in computational linguistics have shown that information about analogical problems can be accessed by simple addition and subtraction of word embeddings (e.g., wrench = mechanic + chalk - teacher). Critically, this property emerges in artificial neural networks that were not trained to produce analogies but instead were trained to produce general-purpose semantic representations. Here, we test whether such emergent property can be observed in representations in human brains, as well as in artificial neural networks. fMRI activation patterns were recorded while participants viewed isolated words but did not perform analogical reasoning tasks. Analogy relations were constructed from word pairs that were categorically or thematically related, and we tested whether the predicted fMRI pattern calculated with simple arithmetic was more correlated with the pattern of the target word than other words. We observed that the predicted fMRI patterns contain information about not only the identity of the target word but also its category and theme (e.g., teaching-related). In summary, this study demonstrated that information about analogy questions can be reliably accessed with the addition and subtraction of fMRI patterns, and that, similar to word embeddings, this property holds for task-general patterns elicited when participants were not explicitly told to perform analogical reasoning.

Defining the iliac wing osseous fixation pathways: anatomy and implant constriction points.

INTRODUCTION: Insertion of iliac wing implants requires understanding of the curvilinear shape of the ilium. This study serves to quantitatively identify the area of iliac inner-outer table convergence (IOTC), characterize the iliac wing osseous corridor, and define the gluteal pillar osseous corridor. METHODS: Computed tomography scans of 100 male and 100 female hemipelves were evaluated. The iliac wing was studied using manual best-fit analysis of the bounds of the inner and outer cortices. The IOTC was defined as the location of the iliac wing with an intercortical width less than 5 mm. The shortest distance from the apex of the iliac crest to the superior border of the IOTC was defined as the iliac wing osseous corridor. Finally, the width of the gluteal pillar corridor from the gluteus medius tubercle to the ischial tuberosity was measured. RESULTS: The IOTC is an elliptical area measuring 22.3 cm2. All ilia had an area where the inner and outer cortices converged to an intercortical width of less than 5 mm; 48% converged to a single cortex. The shortest mean distance from the superior edge of the iliac crest to the beginning of the IOTC was 20.3 mm in men and 13.8 mm in women (p < 0.001). The gluteal pillar diameter averaged 5.3 mm in men and 4.3 mm in women (p < 0.001). DISCUSSION: All ilia converge to a thin and frequently unicortical central region. A 4.5 mm iliac wing lag screw will not breach the cortex if it remains within 20 mm or 14 mm distal to the cranial aspect of the iliac crest in males and females, respectively. Not only is the gluteal pillar smaller than previously thought, in 41% of males and 73% of females, it is not be large enough for 5 mm implants. CONCLUSION: This study quantitatively assesses the dimensions of the IOTC, the iliac crest osseous corridor, and the gluteal pillar. Overall, our findings provide improved understanding of the limits for implant use in the iliac wing as well as better appreciation of the complex osteology of the ilium. This will help surgeons to identify safe areas for implant placement and avoid inadvertent cortical penetration.

Supraacetabular osseous corridor: defining dimensions, sex differences, and alternatives.

INTRODUCTION: The supraacetabular (SA) corridor extends from the anterior inferior iliac spine to the posterior ilium and can safely accommodate implants to stabilize pelvic and acetabular fractures. However, quantitative analysis of its dimensions and characteristics have not been thoroughly described. This study seeks to define the dimensions, common constriction points, and any alternative trajectories that would maximize the corridor diameter. METHODS: Computed tomography of 100 male and 100 female hemipelves without osseous trauma were evaluated. The corridor boundaries were determined through manual best-fit analysis. The largest intercortical cylinder within the pathway was created and measured. Alternative trajectories were tested within the SA boundaries to identify another orientation that maximized the diameter of the intercortical cylinder. RESULTS: The traditional SA corridor had a mean diameter of 8.3 mm in men and 6.2 mm in women. This difference in diameter is due to a more S-shaped ilium in women. A larger alternative SA corridor was found that had a less limited path through the ilium and measured 11.3 mm in men and 9.9 mm in women. These dimensions are significantly different compared to those of the traditional SA corridor in both men and women. CONCLUSIONS: In men, the SA corridor allows for the safe passage of most hardware used in pelvic and acetabular fractures. However, in women, the SA corridor is restricted by a more S-shaped ilium. An alternative trajectory was found that has a significantly larger mean diameter in both sexes. Ultimately, the trajectory of hardware will be dictated by the clinical scenario. When large implants are needed, especially in women, we recommend considering the alternative SA corridor.

Large-scale provocation studies identify maladaptive responses to ubiquitous aeroallergens as a correlate of severe allergic rhinoconjunctivitis and asthma.

BACKGROUND: Allergic asthma (AA) and allergic rhinoconjunctivitis (ARC) are common comorbid environmentally triggered diseases. We hypothesized that severe AA/ARC reflects a maladaptive or unrestrained response to ubiquitous aeroallergens. METHODS: We performed provocation studies wherein six separate cohorts of persons (total n = 217) with ARC, with or without AA, were challenged once or more with fixed concentrations of seasonal or perennial aeroallergens in an aeroallergen challenge chamber (ACC). RESULTS: Aeroallergen challenges elicited fully or partially restrained vs. unrestrained evoked symptom responsiveness, corresponding to the resilient and adaptive vs. maladaptive AA/ARC phenotypes, respectively. The maladaptive phenotype was evoked more commonly during challenge with a non-endemic versus endemic seasonal aeroallergen. In an AA cohort, symptom responses evoked after house dust mite (HDM) challenges vs. recorded in the natural environment were more accurate and precise predictors of asthma severity and control, lung function (FEV1), and mechanistic correlates of maladaptation. Correlates included elevated levels of peripheral blood CD4+ and CD8+ T-cells, eosinophils, and T-cell activation, as well as gene expression proxies for ineffectual epithelial injury/repair responses. Evoked symptom severity after HDM challenge appeared to be more closely related to levels of CD4+ and CD8+ T-cells than eosinophils, neutrophils, or HDM-specific IgE. CONCLUSIONS: Provocation studies support the concept that resilience, adaptation, and maladaptation to environmental disease triggers calibrate AA/ARC severity. Despite the ubiquity of aeroallergens, in response to these disease triggers in controlled settings (ie, ACC), most atopic persons manifest the resilient or adaptive phenotype. Thus, ARC/AA disease progression may reflect the failure to preserve the resilient or adaptive phenotype. The triangulation of CD8+ T-cell activation, airway epithelial injury/repair processes and maladaptation in mediating AA disease severity needs more investigation.

Switchable ß-lactoglobulin (BLG) adsorption on protein resistant oligo (ethylene glycol) (OEG) self-assembled monolayers (SAMs).

HYPOTHESIS: Although protein adsorption at an interface is very common and important in biology and biotechnology, it is still not fully understood - mainly due to the intricate balance of forces that ultimately control it. In food processing (and medicine), controlling and manipulating protein adsorption, as well as avoiding protein adsorption (biofilm formation or membrane fouling) by the production of protein-resistant surfaces is of substantial interest. A major factor conferring resistance towards protein adsorption to a surface is the presence of tightly bound water molecules, as is the case in oligo ethylene glycol (OEG)-terminated self-assembled monolayers (SAMs). Due to strong attractive protein-protein and protein-surface interactions observed in systems containing trivalent salt ions, we hypothesize that these conditions may lead to a breakdown of protein resistance in OEG SAMs. EXPERIMENTS: We studied the adsorption behavior of BLG in the presence of a lanthanum(III) chloride (LaCl3) at concentrations of 0, 0.1, 0.8 and 5.0 mM on normally protein resistant triethylene glycol-termianted (EG3) SAMs on a gold surface. We used quartz-crystal microbalance with dissipation (QCM-D) and neutron reflectivity (NR) to characterize the morphology of the interfacial region of the SAM. FINDINGS: We demonstrate that the protein resistance of the EG3 SAM breaks down beyond a threshold salt concentration c∗ and mirrors the bulk behaviour of this system, showing reduced adsorption beyond a second critical salt concentration c∗∗. These results demonstrate for the first time the controlled switching of the protein-resistant properties of this type of SAM by the addition of trivalent salt.