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BackgroundCOPD (chronic obstructive pulmonary disease) and bronchiectasis are common, and exacerbations contribute to their morbidity and mortality. Predictive factors for the frequency of future exacerbations include previous exacerbation frequency and airway colonization. Earlier treatment of exacerbations is likely to reduce severity. ObjectiveThis study tested the hypothesis that, in a population with bronchiectasis, COPD, or both who have frequent exacerbations and airway colonization, changes in symptom scores or physiological variables within 10 days prior to an exacerbation would allow the prediction of the event. MethodsWe performed a 6-month, longitudinal, observational, cohort study among 30 participants with bronchiectasis, COPD, or both; at least 2 exacerbations per year; and colonization with Pseudomonas aeruginosa or Haemophilus influenzae. Daily symptom and physiological data were collected, comprising pulse rate, blood pressure, oxygen saturation, peak flow rate, step count, weight, and temperature. Exacerbations (defined as the onset of new antibiotic use for respiratory symptoms) were collected, and predictive values for abnormal values in the 10 days prior to an exacerbation were calculated. ResultsA total of 30 participants were recruited, collecting a total of 39,534 physiological and 25,334 symptom data points across 5358 participant-days; these included 78 exacerbations across 27 participants, with the remaining 3 participants not having exacerbations within the 6-month observation period. Peak flow rate, oxygen saturation, and weight were significantly different at the point of exacerbation (all P

PurposeFemale carriers of X-linked inherited retinal diseases (IRDs) can show highly variable phenotypes and disease progression. Vascular reactivity, a potential disease biomarker, has not been investigated in female IRD carriers. In this study, functional optical coherence tomography angiography (OCT-A) was used to dynamically assess the retinal microvasculature of X-linked IRD carriers.MethodsGenetically confirmed female carriers of IRDs (choroideremia or X-linked retinitis pigmentosa), and healthy women were recruited. Macular angiograms (3x3mm, Zeiss Plex Elite 9000) were obtained in 36 eyes of 15 X-linked IRD female carriers and 21 age-matched control women. Two tests were applied to test vascular reactivity: (i) mild hypoxia and (ii) handgrip test, to induce a vasodilatory or vasoconstrictive response, respectively. Changes to vessel density (VD) and vessel length density (VLD) were independently evaluated during each of the tests for both the superficial and deep capillary plexuses.ResultsIn the control group, the superficial and deep VD decreased during the handgrip test (p0.05).ConclusionsFunctional OCT-A is a useful tool to assess dynamic retinal microvascular changes. Subclinical impairment of the physiological vascular responses seen in carriers of X-linked IRDs may serve as a valuable clinical biomarker.

Objectives The Modern Innovative Solutions to Improve Outcomes in Asthma, Breathlessness and Chronic Obstructive Pulmonary Disease (COPD) (MABC) service aimed to enhance disease management for chronic respiratory conditions through specialist multidisciplinary clinics, predominantly in the community. This study assesses the outcomes of these clinics.Design This study used a prospective, longitudinal, participatory action research approach.Setting The study was conducted in primary care practices across Hampshire, UK.Participants Adults aged 16 years and above with poorly controlled asthma or COPD, as well as those with undifferentiated breathlessness not under specialist care, were included.Interventions Participants received care through the multidisciplinary, specialist-led MABC clinics.Primary and secondary outcome measures Primary outcomes included disease activity, quality of life and healthcare utilisation. Secondary outcomes encompassed clinic attendance, diagnostic changes, patient activation, participant and healthcare professional experiences and cost-effectiveness.Results A total of 441 participants from 11 general practitioner practices were recruited. Ninety-six per cent of participants would recommend MABC clinics. MABC assessments led to diagnosis changes for 64 (17%) participants with asthma and COPD and treatment adjustments for 252 participants (57%). Exacerbations decreased significantly from 236 to 30 after attending the clinics (p

IntroductionFoot-and–mouth disease (FMD) is a highly contagious viral disease that is endemic in East Africa. FMD virus infection incurs significant control costs and reduces animal productivity through weight loss, lowered milk yield, and potentially death but how household’s respond to these losses may differentially affect household income and food consumption.MethodologyTo address this, we use unique data from a FMD outbreak to assess how household production and consumption activities change from before to during the outbreak. Data came from a 2018 survey of 254 households in selected Tanzanian wards and sub-counties in Uganda. The data includes household recall of before and during an outbreak in the past year on livestock and livestock product sales, milk and beef consumption, as well as related changes in market prices. We apply both difference-in-difference and change in difference ordinary least squares regressions with fixed effects to evaluate the impact of FMD on household production and consumption.Results and discussionWe find that households reported the largest reductions in livestock and livestock product sales, followed by reduced milk consumption and animal market prices. The changes in household income from livestock sales appears to be driven by FMD virus infection within the household herd while changes in market prices of substitute protein sources are primary associated with changes in milk and beef consumption. The role of widespread market price effects across both infected and uninfected herds and countries, tends to suggest that stabilizing prices will likely have a large impact on household nutritional security and income generation. We also propose that promoting diversity in market activity may mitigate differing impacts on households in FMD endemic regions.

Introduction Reconstruction of critical bone defects is challenging. In a substantial subgroup of patients, conventional reconstructive techniques are insufficient. Biodegradable scaffolds have emerged as a novel tissue engineering strategy for critical-sized bone defect reconstruction. A corticoperiosteal flap integrates the hosts’ ability to regenerate bone and permits the creation of a vascular axis for scaffold neo-vascularisation (regenerative matching axial vascularisation—RMAV). This phase IIa study evaluates the application of the RMAV approach alongside a custom medical-grade polycaprolactone-tricalcium phosphate (mPCL-TCP) scaffold (Osteopore) to regenerate bone sufficient to heal critical size defects in lower limb defects.Methods and analysis This open-label, single-arm feasibility trial will be jointly coordinated by the Complex Lower Limb Clinic (CLLC) at the Princess Alexandra Hospital in Woolloongabba (Queensland, Australia), the Australian Centre for Complex Integrated Surgical Solutions (Queensland, Australia) and the Faculty of Engineering, Queensland University of Technology in Kelvin Grove (Queensland, Australia). Aiming for limb salvage, the study population (n=10) includes any patient referred to the CLLC with a critical-sized bone defect not amenable to conventional reconstructive approaches, after discussion by the interdisciplinary team. All patients will receive treatment using the RMAV approach using a custom mPCL-TCP implant. The primary study endpoint will be safety and tolerability of the reconstruction. Secondary end points include time to bone union and weight-bearing status on the treated limb. Results of this trial will help shape the role of scaffold-guided bone regenerative approaches in complex lower limb reconstruction where current options remain limited.Ethics and dissemination Approval was obtained from the Human Research Ethics Committee at the participating centre. Results will be submitted for publication in a peer-reviewed journal.Trial registration number ACTRN12620001007921.

Objectives Hospital-acquired pressure injuries (PIs) are a source of morbidity and mortality, and many are potentially preventable.Design This study prospectively evaluated the prevalence and the associated factors of PIs in adult critical care patients admitted to intensive care units (ICU) in the UK.Setting This service evaluation was part of a larger, international, single-day point prevalence study of PIs in adult ICU patients. Training was provided to healthcare givers using an electronic platform to ensure standardised recognition and staging of PIs across all sites.Participants The characteristics of the ICUs were recorded before the survey; deidentified patient data were collected using a case report form and uploaded onto a secure online platform.Primary and secondary outcome measures Factors associated with ICU-acquired PIs in the UK were analysed descriptively and using mixed multiple logistic regression analysis.Results Data from 1312 adult patients admitted to 94 UK ICUs were collected. The proportion of individuals with at least one PI was 16% (211 out of 1312 patients), of whom 8.8% (n=115/1312) acquired one or more PIs in the ICU and 7.3% (n=96/1312) prior to ICU admission. The total number of PIs was 311, of which 148 (47.6%) were acquired in the ICU. The location of majority of these PIs was the sacral area, followed by the heels. Braden score and prior length of ICU stay were associated with PI development.Conclusions The prevalence and the stage of severity of PIs were generally low in adult critically ill patients admitted to participating UK ICUs during the study period. However, PIs are a problem in an important minority of patients. Lower Braden score and longer length of ICU stay were associated with the development of injuries; most ICUs assess risk using tools which do not account for this.Trial registration number NCT03270345.

Abstract Cam morphology describes an asphericity of the femoral head that develops during adolescence, is highly prevalent in athletes, and predisposes individuals to future osteoarthritis. However, it’s aetiology remains poorly understood. The aim of this study was to perform 3-year longitudinal follow-up of a control population and football club academy cohort to compare the change in hip and growth plate anatomy between athletes and controls. MRI and questionnaires were used to characterise change in hip and growth plate anatomy and quantify activity levels. 121 male academy footballers and 107 male and female controls participated at baseline. Footballers experienced significantly greater increases in femoral head asphericity (4.83 degrees (95% CI: 2.84 to 6.82), p

YouTube is the dominant online video-sharing platform and offers zoos an opportunity to engage a vast audience with conservation content. As there is limited research evaluating how zoos currently utilize YouTube, we cataloged and evaluated the content of 20 zoological organizations (focusing on the top 1000 most viewed videos from each channel) from 2006 to 2019. Separately, educational content in a subsample of the most viewed and recently produced videos from three zoo-YouTube channels was catalogued and evaluated for the period 2016 to 2019. We found that channels are becoming more focused on producing entertainment, rather than education-based content and not reflecting the taxonomic diversity of their animals. Videos containing conservation content may not be the most popular with the YouTube audience (making up only 3% of the most viewed videos), but there is evidence that outputs are becoming more conservation orientated, with more conservation-focused videos being produced over time. Zoos may be engaging with large audiences via YouTube, but should carefully consider how they represent different taxonomic classes and how they can create educational material in interesting and accessible forms.

Degree of luminal stenosis is generally considered to be an important indicator for judging the risk of atherosclerosis burden. However, patients with the same or similar degree of stenosis may have significant differences in plaque morphology and biomechanical factors. This study investigated three patients with carotid atherosclerosis within a similar range of stenosis. Using our developed fluid–structure interaction (FSI) modelling method, this study analyzed and compared the morphological and biomechanical parameters of the three patients. Although their degrees of carotid stenosis were similar, the plaque components showed a significant difference. The distribution range of time-averaged wall shear stress (TAWSS) of patient 2 was wider than that of patient 1 and patient 3. Patient 2 also had a much smaller plaque stress compared to the other two patients. There were significant differences in TAWSS and plaque stresses among three patients. This study suggests that plaque vulnerability is not determined by a single morphological factor, but rather by the combined structure. It is necessary to transform the morphological assessment into a structural assessment of the risk of plaque rupture.

Abstract Introduction Lung cancer (LC) is the most common cause of cancer death in the world and associated with significant economic burden. We conducted a review of published literature to identify prognostic factors associated with LC survival and determine which may be modifiable and could be targeted to improve outcomes. Methods The exceptionally large volume of LC prognostic research required a new staged approach to reviewing the literature. This comprised an initial mapping review of existing reviews or meta-analyses, based on titles and abstracts, followed by an overview of systematic reviews evaluating factors that independently contribute to lung cancer survival. The overview of reviews was based on full text papers and incorporated a more in-depth assessment of reviews evaluating modifiable factors. Results A large volume of published systematic reviews and meta-analyses were identified, but very few focused on modifiable factors for LC survival. Several modifiable factors were identified, which are potential candidates for targeted interventions aiming to improve cancer outcomes. The mapping review included 398 reviews, of which 207 investigated the independent effect of prognostic factors on lung cancer survival. The most frequently evaluated factors were novel biomarkers (86 biomarkers in 138 reviews). Only 15 modifiable factors were investigated in 20 reviews. Those associated with significant survival improvement included normal BMI/less weight loss, good performance status, not smoking/quitting after diagnosis, good pre-treatment quality of life, small gross volume tumour, early-stage tumour, lung resection undertaken by a thoracic/cardiothoracic surgeon, care being discussed by a multidisciplinary team, and timeliness of care. Conclusions The study utilised a novel approach for reviewing an extensive and complicated body of research evidence. It enabled us to address a broad research question and focus on a specific area of priority. The staged approach ensured the review remained relevant to the stakeholders throughout, whilst maintaining the use of objective and transparent methods. It also provided important information on the needs of future research. However, it required extensive planning, management, and ongoing reviewer training.

Mammographic density (MD) is a strong and independent factor for breast cancer (BC) risk and is increasingly associated with BC progression. We have previously shown in mice that high MD, which is characterized by the preponderance of a fibrous stroma, facilitates BC xenograft growth and metastasis. This stroma is rich in extracellular matrix (ECM) factors, including heparan sulfate proteoglycans (HSPGs), such as the BC-associated syndecan-1 (SDC1). These proteoglycans tether growth factors, which are released by heparanase (HPSE). MD is positively associated with estrogen exposure and, in cell models, estrogen has been implicated in the upregulation of HPSE, the activity of which promotes SDC expression. Herein we describe a novel measurement approach (single-sided NMR) using a patient-derived explant (PDE) model of normal human (female) mammary tissue cultured ex vivo to investigate the role(s) of HPSE and SDC1 on MD. Relative HSPG gene and protein analyses determined in patient-paired high vs. low MD tissues identified SDC1 and SDC4 as potential mediators of MD. Using the PDE model we demonstrate that HPSE promotes SDC1 rather than SDC4 expression and cleavage, leading to increased MD. In this model system, synstatin (SSTN), an SDC1 inhibitory peptide designed to decouple SDC1-ITGαvβ3 parallel collagen alignment, reduced the abundance of fibrillar collagen as assessed by picrosirius red viewed under polarized light, and reduced MD. Our results reveal a potential role for HPSE in maintaining MD via its direct regulation of SDC1, which in turn physically tethers collagen into aligned fibers characteristic of MD. We propose that inhibitors of HPSE and/or SDC1 may afford an opportunity to reduce MD in high BC risk individuals and reduce MD-associated BC progression in conjunction with established BC therapies.

Atherosclerotic plaque rupture is a catastrophic event that contributes to mortality and long-term disability. A better understanding of the plaque mechanical behavior is essential for the identification of vulnerable plaques pre-rupture. Plaque is subjected to a natural dynamic mechanical environment under hemodynamic loading. Therefore, it is important to understand the mechanical response of plaque tissue under cyclic loading conditions. Moreover, experimental data of such mechanical properties are fundamental for more clinically relevant biomechanical modeling and numerical simulations for risk stratification. This study aims to experimentally and numerically characterize the stress-relaxation and cyclic mechanical behavior of carotid plaque tissue. Instron microtester equipped with a custom-developed setup was used for the experiments. Carotid plaque samples excised at endarterectomy were subjected to uniaxial tensile, stress-relaxation, and cyclic loading protocols. Thirty percent of the underlying load level obtained from the uniaxial tensile test results was used to determine the change in mechanical properties of the tissue over time under a controlled testing environment (Control tests). The stress-relaxation test data was used to calibrate the hyperelastic (neo-Hookean, Ogden, Yeoh) and linear viscoelastic (Prony series) material parameters. The normalized relaxation force increased initially and slowly stabilized toward the end of relaxation phase, highlighting the viscoelastic behavior. During the cyclic tests, there was a decrease in the peak force as a function of the cycle number indicating mechanical distension due to repeated loading that varied with different frequencies. The material also accumulated residual deformation, which increased with the cycle number. This trend showed softening behavior of the samples. The results of this preliminary study provide an enhanced understanding of in vivo stress-relaxation and cyclic behavior of the human atherosclerotic plaque tissue.

Abstract Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a newly described and rare T-cell lymphoma of the breast. Since 2007, there have been 56 cases of confirmed BIA-ALCL in Australia and New Zealand. The incidence is believed to be on the rise as the prevalence of elective breast implantation increases. In 2016, the World Health Organization (WHO) classified BIA-ALCL as a recognised entity and emphasised the importance of surgical management of the disease. BIA-ALCL typically presents as a delayed, non-infective fluid collection around a textured breast implant or residual fibrous scar capsule. The mean age of presentation is 47 years, with an average time frame of 7.5 years following breast implantation. Although rare, BIA-ALCL is increasing in incidence. To avoid delays in diagnosis, radiologists should consider this form of lymphoma in the differential of any non-acute peri- or post-prosthetic effusion, and suggest cytological evaluation, so as not to miss this rare but important diagnosis. Teaching Points • BIA-ALCL is a newly described and rare T-cell lymphoma of the breast. • Since 2007, there have been 56 cases of confirmed BIA-ALCL in Australia and New Zealand. • BIA-ALCL presents as a delayed, non-infective fluid collection. • The effusion typically accumulates around a textured breast implant or residual fibrous capsule.

Inflow turbulence is relevant for many engineering applications relating to noise generation, including aircraft wings, landing gears, and non-cavitating marine propellers. While modelling of this phenomenon is well-established for higher Mach number aerospace problems, lower Mach number applications, which include marine propellers, still lack validated numerical tools. For this purpose, simplified cases for which extensive measurement data are available can be used. This paper investigates the effect of inflow turbulence on a circular cylinder at a Reynolds number of 14,700, a Mach number of 0.029, and with inflow turbulence intensities ranging between 0% and 22%. In the present work focus is put on the hydrodynamics aspect, with the aim of addressing radiated noise in a later study. The flow is simulated using the partially averaged Navier Stokes equations, with turbulence inserted using a synthetic inflow turbulence generator. Results show that the proposed method can successfully replicate nearfield pressure variations and relevant flow features in the wake of the body. In agreement with the literature, increasing inflow turbulence intensity adds broadband frequency content to all the presented fluctuating flow quantities. In addition, the applied variations in inflow turbulence intensity result in a major shift in flow dynamics around a turbulence intensity of 15%, when the dominant effect of von Kármán vortices on the dominant flow dynamics becomes superseded by freestream turbulence.

A patient-specific carotid bifurcation with tandem stenosis found at both internal carotid artery (ICA) and common carotid artery (CCA) was studied. The in vivo pre-carotid endarterectomy (pre-CEA) multi-spectral magnetic resonance imaging (MRI) were performed and in vitro post-CEA carotid plaque tissue sample was collected. MR imaging data and tissue sample staining histology were used to recognize the plaque components. Further, the computational fluid dynamics (CFD) were performed on four MR-based reconstructed 3D carotid bifurcation models (the patient-specific geometry with tandem stenosis and three presumptive geometries by removing the stenosis part). The flow and shear stress behavior affected by the tandem stenosis was analyzed. From the results of MR segmentation and histology analysis, plaque lipid pool and calcification were found at both ICA and CCA. From the result of CFD simulation, the flow shear stress behavior suggested the tandem stenosis as a more “dangerous” situation than a single-stenosis artery. Besides, the CFD results deduced that the stenosis at the CCA location formed initially and led to the subsequent formation of stenosis at ICA. This study suggests that when planning CEA, CFD simulation on the presumptive models could help clinicians to estimate the blood flow behavior after surgery. Particular attention should be paid to the case of tandem stenosis, as the local hemodynamic environment is more complex and treatment of one stenosis may lead to a variation in the hemodynamic loading on the second plaque, which may result in either a higher risk of plaque rupture or restenosis.

We determine the off-shell symmetry algebra and representations of Type IIB superstring theory on AdS3×S3×T4 with mixed R–R and NS–NS three-form flux. We use these to derive the non-perturbative worldsheet S matrix of fundamental excitations of the superstring theory. Our analysis includes both massive and massless modes and shows how turning on mixed three-form flux results in an integrable deformation of the S matrix of the pure R–R theory.

Rab GTPases are key regulators of membrane trafficking. When GTP-bound, or "active," Rabs are anchored to membranes and recruit effector proteins that mediate vesicle formation, transport, and fusion. Rabs are inactivated by GTPase-activating proteins (Rab-GAPs), which catalyze GTP hydrolysis, rendering Rabs cytosolic. In vivo, C-terminal prenylation modifications link activated Rabs to organelle and vesicle membranes, yet historically, in vitro Rab-GAP activity assays have been performed in the absence of membranes. We have developed a method for assaying Rab-GAP activity in a physiological context, with dissociation of the Rab from the membrane serving as a readout for Rab-GAP activity. Given that membrane-binding status is a key consequence of Rab activation state, this assay will be useful for the study of a wide range of Rab/Rab-GAP pairs., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Limited information is available on lysine requirement estimates of modern, high-producing gestating sows Therefore, the objective of this study was to evaluate the effects of increasing standardized ileal digestible (SID) lysine during gestation on piglet birthweight and reproductive performance of gilts and sows. A total of 936 females (498 gilts, 438 sows; Camborough®, PIC, Hendersonville, TN) were group-housed (approximately 275 females per pen) and individually fed with electronic sow feeders. Females were moved from the breeding stall to pens on d 4 of gestation and allotted to one of four dietary treatments on d 5. Dietary treatments included increasing SID lysine intake (11.0, 13.5, 16.0, and 18.5 g/d). Gilts (parity 1) and sows (parity 2+) received 2.1 and 2.3 kg (22.2 and 24.3 MJ net energy per day) of feed throughout the entire gestation period, respectively. Dietary treatments were achieved by different blends of low (0.48% SID lysine) and high (0.88% SID lysine) lysine diets, prepared by changing the amount of corn and soybean meal in these two diets. Female weight and backfat were recorded on d 4 and 111 of gestation. Individual piglet weight was obtained within 12 h of birth on litters from 895 females. Final weight, and calculated maternal BW, body lipid, and body lean at d 111 of gestation increased (linear, P < 0.01) for gilts and sows as SID lysine increased. There was no evidence for differences in final backfat depth. Average total born for gilts and sows was 15.3 and 16.0 pigs with no evidence for differences among treatments. The percentage of pigs born alive increased (P = 0.01) with increasing SID lysine intake for sows, but not in gilts as a result of a treatment by parity group interaction (P = 0.04) for percentage of stillborn pigs. Increasing SID lysine intake during gestation did not affect the percentage of mummified fetuses, total born, or birthweight of piglets born alive in this study. In addition, increasing SID lysine intake during gestation did not affect subsequent reproductive performance. In conclusion, increasing dietary SID lysine intake in gestation increased female BW, without changing backfat depth. The minimal effects on female reproductive performance and piglet birthweight suggest that 11 g/day of SID lysine intake appears to be adequate for gestating gilts and sows; however, providing sows with 18.5 g/d SID lysine reduced (P = 0.01) stillbirth rate by 2.3 percentage points., (Published by Elsevier B.V.)

Rab family GTPases are key organizers of membrane trafficking and function as markers of organelle identity. Accordingly, Rab GTPases often occupy specific membrane domains, and mechanisms exist to prevent the inappropriate mixing of distinct Rab domains. The yeast Golgi complex can be divided into two broad Rab domains: Ypt1 (Rab1) and Ypt6 (Rab6) are present at the early/medial Golgi and sharply transition to Ypt31/32 (Rab11) at the late Golgi/ trans -Golgi network (TGN). This Rab conversion has been attributed to GTPase-activating protein (GAP) cascades in which Ypt31/32 recruits the Rab-GAPs Gyp1 and Gyp6 to inactivate Ypt1 and Ypt6, respectively. Here we report that Rab transition at the TGN involves additional layers of regulation. We provide new evidence confirming the TRAPPII complex as an important regulator of Ypt6 inactivation and uncover an unexpected role of the Arf1 GTPase in recruiting Gyp1 to drive Ypt1 inactivation at the TGN. Given its established role in directly recruiting TRAPPII to the TGN, Arf1 is therefore a master regulator of Rab conversion on maturing Golgi compartments.

Periodontal disease (PD) is a chronic destructive inflammatory disease of the tooth-supporting structures that leads to tooth loss at its advanced stages. Although the disease is initiated by a complex organization of oral microorganisms in the form of a plaque biofilm, it is the uncontrolled immune response to periodontal pathogens that fuels periodontal tissue destruction. IL-17A has been identified as a key cytokine in the pathogenesis of PD. Despite its well documented role in host defense against invading pathogens at oral barrier sites, IL-17A-mediated signaling can also lead to a detrimental inflammatory response, causing periodontal bone destruction. In this study, we developed a local sustained delivery system that restrains IL-17A hyperactivity in periodontal tissues by incorporating neutralizing anti-IL-17A Abs in poly(lactic-coglycolic) acid microparticles (MP). This formulation allowed for controlled release of anti-IL-17A in the periodontium of mice with ligature-induced PD. Local delivery of anti-IL-17A MP after murine PD induction inhibited alveolar bone loss and osteoclastic activity. The anti-IL-17A MP formulation also decreased expression of IL-6, an IL-17A target gene known to induce bone resorption in periodontal tissues. This study demonstrates proof of concept that local and sustained release of IL-17A Abs constitutes a promising therapeutic strategy for PD and may be applicable to other osteolytic bone diseases mediated by IL-17A-driven inflammation., (Copyright © 2021 by The American Association of Immunologists, Inc.)

Virtually all transport events at the Golgi complex are regulated by Arf and Rab family GTPases. Recent work has advanced our knowledge regarding the mechanisms controlling GTPase activity, and it has become clear that GTPases do not act in isolation but rather function in complex networks of crosstalk and feedback. Together with earlier findings, these recent studies indicate that communication between GTPases, their regulatory proteins, effectors, and lipids plays a pivotal role in Golgi transport and cisternal maturation., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Five experiments were conducted to determine the standardized total tract digestibility (STTD) of P, digestible energy (DE), metabolizable energy (ME), and standardized ileal digestibility (SID) of amino acids (AA) in three sorghum varieties compared with corn and to determine the effects of sorghum varieties on nursery pig growth. In exp. 1, 48 barrows (initially 18.6 kg) were housed individually in metabolism crates. Treatments were arranged in a 2 × 4 factorial evaluating two levels of microbial phytase (0 or 500 units/kg) and four grain sources (corn, high-lysine, red, or white sorghum). Added phytase improved (P < 0.05) STTD of P in all ingredients, but was not different among the grains. In exp. 2, the DE and ME in the three sorghum varieties were not different from corn. In exp. 3, 10 growing barrows (initially 25.9 kg) with a T-cannula in the terminal ileum were used. Standardized ileal digestible Lys, Met, Thr, and Val were greater (P < 0.05) in corn than in the sorghum-based diets with no differences among the sorghum varieties. In exp. 4, 160 pigs (initially 6.3 kg) were randomly allotted to one of four dietary treatments with five pigs per pen and eight replicate pens per treatment in a 20-d experiment. Dietary treatments included corn or the three sorghum varieties, where the varieties of sorghum replaced corn on an SID Lys basis. No differences among treatments were observed in any growth performance parameters. In exp. 5, treatments consisted of a corn-based diet, a diet based on conventional sorghum (a mixture of red and white sorghum), and four diets with high-lysine sorghum containing increasing amounts of feed-grade AA, replacing soybean meal. Overall, pigs fed the high-lysine sorghum diet with the greatest amount of added feed-grade AA had the poorest gain:feed ratio (G:F; P < 0.05) compared with pigs fed all the other experimental diets. Within those fed the high-lysine sorghum and feed-grade AA, average daily gain, final body weight (linear, P < 0.10), and G:F (linear, P < 0.01) decreased as feed-grade AA increased. In summary, no differences in STTD of P or in DE and ME were observed among the grain sources. The SID AA values for the three sorghum varieties were not different; however, they were all lower than for corn. These results indicate that these varieties of sorghum can successfully replace corn in nursery pig diets if diets are formulated to account for differences in AA digestibility., (Published by Oxford University Press on behalf of the American Society of Animal Science 2020.)

A total of 710 pigs (Line 400 × 200, DNA, Columbus, net energy (NE)) were used in two experiments (Exp. 1: initially, 6.3 ± 0.05 kg; Exp. 2: initially, 6.8 ± 0.05 kg) to evaluate the effects of two medium-chain fatty acid (MCFA) based products on nursery pig growth performance. Following their arrival at the nursery facility, pigs were randomized to pens (five pigs per pen) and allowed a 4-d acclimation period. Thereafter, pens of pigs were blocked by initial weight and randomized to dietary treatment. In Exp. 1, the dietary treatments were a dose titration of: 0%, 0.5%, 1.0%, or 2.0% MCFA-based additive, as well as a diet including 1.0% MCFA from a 1:1:1 blend of C6:0, C8:0, and C10:0. In Exp.2, dietary treatments consisted of a basal diet containing no MCFA (control), the control diet with a 1.0% inclusion of four different blends of MCFA, lactic acid, and monolaurin or a diet with 1.0% added MCFA (a 1:1:1 blend of C6:0, C8:0, and C10:0). The four blends consisted of 50% C6:0, 20% lactic acid, and increasing levels of monolaurin (0%, 10%, 20%, and 30%) at the expense of C12:0 (30%, 20%, 10%, and 0%). Treatment diets were formulated and manufactured in two dietary phases. Data were analyzed as a randomized complete block design with pen as the experimental unit. In Exp. 1, overall (days 0-34), increasing CaptiSURE increased (linear, P ≤ 0.014) average daily gain (ADG) and average daily feed intake (ADFI). Feed efficiency improved (quadratic, P = 0.002) with increasing CaptiSURE up to 1.0% of the diet with no benefit thereafter. There was no evidence for differences between pigs fed 1.0% CaptiSURE and pigs fed the 1.0% MCFA blend of C6:0, C8:0, and C10:0. In Exp. 2, overall (days 0-35), pigs fed the 1.0% 1:1:1 MCFA blend had increased ( P < 0.034) ADFI and ADG resulting in 0.9 kg greater final weight ( P = 0.014) compared with the control group. There was no evidence that the mean performance of pigs fed the four blends of MCFA, lactic acid, and monolaurin were different from the pigs fed the control diet. In summary, the addition of a 1.0% 1:1:1 blend of C6:0, C8:0, and C10:0 in nursery pig diets improved ADG, ADFI, and gain to feed ratio (G:F) compared with pigs fed the control diet. In addition, providing nursery pigs with the MCFA product CaptiSURE, up to 2% of the diet, resulted in linear improvements in ADG and ADFI. Altering the C12:0 to monolaurin ratio and adding lactic acid did not improve growth performance compared with pigs fed the control diet., (Published by Oxford University Press on behalf of the American Society of Animal Science 2020.)

Correct localization of Rab GTPases in cells is critical for proper function in membrane trafficking, yet the mechanisms that target Rabs to specific subcellular compartments remain controversial. Guanine nucleotide exchange factors (GEFs) activate and consequently stabilize Rab substrates on membranes, thus implicating GEFs as the primary determinants of Rab localization. A competing hypothesis is that the Rab C-terminal hypervariable domain (HVD) serves as a subcellular targeting signal. In this study, we present a unifying mechanism in which the HVD controls targeting of certain Rabs by mediating interaction with their GEFs. We demonstrate that the TRAPP complexes, two related GEFs that use the same catalytic site to activate distinct Rabs, distinguish between Ypt1 (Rab1) and Ypt31/32 (Rab11) via their divergent HVDs. Remarkably, we find that HVD length gates Rab access to the TRAPPII complex by constraining the distance between the nucleotide-binding domain and the membrane surface., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Current models of SIRT1 enzymatic regulation primarily consider the effects of fluctuating levels of its co-substrate NAD + , which binds to the stably folded catalytic domain. By contrast, the roles of the sizeable disordered N- and C-terminal regions of SIRT1 are largely unexplored. Here we identify an insulin-responsive sensor in the SIRT1 N-terminal region (NTR), comprising an acidic cluster (AC) and a 3-helix bundle (3HB), controlling deacetylase activity. The allosteric assistor DBC1 removes a distal N-terminal shield from the 3-helix bundle, permitting PACS-2 to engage the acidic cluster and the transiently exposed helix 3 of the 3-helix bundle, disrupting its structure and inhibiting catalysis. The SIRT1 activator (STAC) SRT1720 binds and stabilizes the 3-helix bundle, protecting SIRT1 from inhibition by PACS-2. Identification of the SIRT1 insulin-responsive sensor and its engagement by the DBC1 and PACS-2 regulatory hub provides important insight into the roles of disordered regions in enzyme regulation and the mode by which STACs promote metabolic fitness., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The objective of this study was to evaluate the effect of parity and stage of gestation on predicted maternal weight gain and efficiency of feed use in gestating sows from a commercial sow farm. A total of 712 females (Camborough, PIC, Hendersonville, TN) were group-housed from days 5 to 112 of gestation and individually fed with electronic sow feeders (ESF). Feed intake and body weight (BW) were recorded daily throughout gestation via the ESF and a scale located in an alleyway just after sows exited the feeding station. Gilts (parity 1) and sows received 6,450 or 7,418 kcal ME, respectively, whereas 12 thin females received 9,675 kcal ME per day. Maternal weight gain, not including products of conceptus, and feed efficiency were predicted using a series of equations to model nutrient utilization in gestation. Data were divided into 3 parity groups: 1, 2, and 3+, and gestation was divided into 3 periods: days 5 to 39, 40 to 74, and 75 to 109. After dividing energy requirements into tissue pools for maintenance, growth (maternal protein and fat deposition), and products of conceptus, the greatest portion of the energy requirement was for maintenance and maternal growth. The predicted energy used for maternal protein and fat deposition decreased (P < 0.05) in each period of gestation, regardless of parity group. Parity 2 sows had the greatest (P < 0.05) energy use for maternal protein and fat deposition in all stages of gestation, whereas parity 1 sows had a negative energy balance during the final stage of gestation. Parity 1 sow BW increased (P < 0.05) in each period of gestation; however, parity 2 and 3+ sow BW remained static from days 75 to 109 of gestation. Parity 3+ sows had the greatest (P < 0.05) maternal BW throughout the course of gestation compared with other parity groups. Regardless of parity, maternal ADG decreased (P < 0.05) from days 40 to 74 before increasing (P < 0.05) during the final stage of gestation. Parity 1 sows had the greatest (P < 0.05) ADG in all gestation periods. Parity 1 sow G:F decreased (P < 0.05) in each sequential period of gestation. Parity 2 and 3+ sow G:F decreased (P < 0.05) from days 40 to 74 but improved (P < 0.05) during the final period of gestation. Parity 1 sow G:F was greater than parity 2 and 3+ sows in most gestation periods. Overall, this study and subsequent prediction models show how stage of gestation and parity affect the growth of different tissue pools, sow maternal BW, and feed usage throughout the course of gestation.

The effects of parity and stage of gestation on female growth criteria, and reproductive performance were evaluated on a commercial sow farm. A total of 712 females (Camborough, PIC, Hendersonville, TN) were group-housed and individually fed with electronic sow feeders. Gilts (parity 1) and sows were offered 2.0 and 2.26 kg of feed per day (4.7 and 5.3 Mcal NE per day), respectively. Females were moved from the breeding stall to pens on day 5 of gestation. A scale was located in the alleyway after sows left individual feeding stations. Feed intake and BW were recorded daily throughout gestation generating values for ADFI, ADG, and G:F for each sow. Data were divided into 3 parity groups: 1, 2, and 3+ and gestation was divided into 3 periods: day 5 to 39, 40 to 74, and 75 to 109. From day 5 to 39, ADFI was decreased (P < 0.05) for parity 3+ sows compared to the other periods of gestation. Parity 2 sows, although provided the same feed allowance, had greater (P < 0.05) ADFI during the first period of gestation than parity 3+ sows. Parity 1 and 2 sow ADG increased (P < 0.05) from day 39 to 74 of gestation, then decreased (P < 0.05) from day 74 to 109 of gestation. Parity 3+ sow ADG increased (P < 0.05) in each subsequent period of gestation. Parity 1 sows had the greatest (P < 0.05) ADG in comparison to parity 2 and 3+ sows in each period of gestation. Regardless of parity group, G:F was poorest (P < 0.05) from day 5 to 39 of gestation compared with sequential periods of gestation. Parity 1 sow G:F was greater (P < 0.05) than parity 2 and 3+ sows for all periods of gestation. Backfat gain indicated that parity 1 sows maintained backfat (approximately 18 mm) while parity 2 and 3+ sows gained (P < 0.05) approximately 1 mm backfat throughout gestation. Total born was greatest (P < 0.05) for parity 3+ sows with parity 1 sows marginally greater (P < 0.10) than parity 2 sows. Although there was statistical evidence (P < 0.001) for a positive correlation between BW gain and total born in parities 1 (r = 0.23; P = < 0.001), 2 (r = 0.15; P = 0.035), and 3+ (r = 0.29; P < 0.001), these correlations are very weak. Overall, this study indicates that parity 1 sows have the greatest G:F in gestation and that there is a lack of evidence for strong correlations between feed intake, growth, and reproductive performance.

Rab GTPases serve as molecular switches to regulate eukaryotic membrane trafficking pathways. The transport protein particle (TRAPP) complexes activate Rab GTPases by catalyzing GDP/GTP nucleotide exchange. In mammalian cells, there are two distinct TRAPP complexes, yet in budding yeast, four distinct TRAPP complexes have been reported. The apparent differences between the compositions of yeast and mammalian TRAPP complexes have prevented a clear understanding of the specific functions of TRAPP complexes in all cell types. In this study, we demonstrate that akin to mammalian cells, wild-type yeast possess only two TRAPP complexes, TRAPPII and TRAPPIII. We find that TRAPPIII plays a major role in regulating Rab activation and trafficking at the Golgi in addition to its established role in autophagy. These disparate pathways share a common regulatory GTPase Ypt1 (Rab1) that is activated by TRAPPIII. Our findings lead to a simple yet comprehensive model for TRAPPIII function in both normal and starved eukaryotic cells., (© 2018 Thomas et al.)

A total of 405 pigs (PIC 327 × 1,050) were used in 2 experiments (Exp. 1, initially 66.1 ± 1.8 kg BW, Exp. 2 initially 60.8 ± 2.5 kg BW) to examine the effects of space allocation on finishing pig growth performance and carcass characteristics. Pigs were randomly allotted to pens on entry into the finishing facility. Pens of pigs were balanced by initial BW and randomly allotted to 1 of 3 treatments with either 7 or 8 replications per treatment (Exp.1 and 2, respectively). There were 9 pigs per pen and gates were adjusted to provide 0.84, 0.74, or 0.65 m 2 per pig. Each pen was equipped with a dry single-sided feeder with two 35.6 cm × 11.4 cm (length × width) feeder spaces and a cup waterer. In both experiments, as space allocation decreased, overall ADG and ADFI decreased (linear, P < 0.019) with no evidence for differences in G:F. In Exp. 2, there was marginal evidence for a linear improvement ( P = 0.061) in G:F as space allocation decreased from d 42 to 56. Final BW was 3.8 and 5.3 kg greater (linear, P ≤ 0.005) in Exp. 1 and 2, respectively, when comparing the 0.65 to the 0.84 m 2 per pig space allocation treatments. Using a predicted k -value of 0.0336, ADFI and, subsequently, ADG should have begun to decrease when pigs reached 121.2, 101.7, and 83.3 kg at 0.84, 0.74, or 0.65 m 2 per pig, respectively. In Exp. 1, we found marginal evidence for a reduction in ADFI as space allocation decreased starting at a mean BW of 80.3 kg (d 14; linear, P = 0.072). In Exp. 2, ADFI and consequently ADG decreased linearly ( P < 0.029) starting at a mean BW of 74 kg, as space allocation decreased, before pigs reached the k -value that should have influenced performance. It is unknown if growth performance was impacted for the 0.84 m 2 treatment group as this was the greatest space allocation treatment. Overall, these studies indicate that decreasing space allocation resulted in poorer ADG driven by a reduction in ADFI. The data suggests that the accepted k -value of 0.0336 might underestimate the impact of space restriction on finishing pig ADG and ADFI.

Rab guanosine triphosphatases (GTPases) control cellular trafficking pathways by regulating vesicle formation, transport, and tethering. Rab11 and its paralogs regulate multiple secretory and endocytic recycling pathways, yet the guanine nucleotide exchange factor (GEF) that activates Rab11 in most eukaryotic cells is unresolved. The large multisubunit transport protein particle (TRAPP) II complex has been proposed to act as a GEF for Rab11 based on genetic evidence, but conflicting biochemical experiments have created uncertainty regarding Rab11 activation. Using physiological Rab-GEF reconstitution reactions, we now provide definitive evidence that TRAPPII is a bona fide GEF for the yeast Rab11 homologues Ypt31/32. We also uncover a direct role for Arf1, a distinct GTPase, in recruiting TRAPPII to anionic membranes. Given the known role of Ypt31/32 in stimulating activation of Arf1, a bidirectional cross talk mechanism appears to drive biogenesis of secretory and endocytic recycling vesicles. By coordinating simultaneous activation of two essential GTPase pathways, this mechanism ensures recruitment of the complete set of effectors needed for vesicle formation, transport, and tethering., (© 2016 Thomas and Fromme.)

Nuclear factor kappa B (NF-κB) promotes cell survival in response to genotoxic stress by inducing the expression of anti-apoptotic proteins including Bcl-xL, which protects mitochondria from stress-induced mitochondrial outer membrane permeabilization (MOMP). Here we show that the multifunctional sorting protein Pacs-2 (phosphofurin acidic cluster sorting protein-2) is required for Bcl-xL induction following DNA damage in primary mouse thymocytes. Consequently, in response to DNA damage, Pacs-2(-/-) thymocytes exhibit a blunted induction of Bcl-xL, increased MOMP and accelerated apoptosis. Biochemical studies show that cytoplasmic PACS-2 promotes this DNA damage-induced anti-apoptotic pathway by interacting with ataxia telangiectasia mutated (ATM) to drive NF-κB activation and induction of Bcl-xL. However, Pacs-2 was not required for tumor necrosis factor-α-induced NF-κB activation, suggesting a role for PACS-2 selectively in NF-κB activation in response to DNA damage. These findings identify PACS-2 as an in vivo mediator of the ATM and NF-κB-dependent induction of Bcl-xL that promotes cell survival in response to DNA damage.

Background: Elevations in neutrophil-like low-density granulocytes (LDGs) are observed in association with disease severity in some autoimmune and other disorders. This study evaluated whether a similar association with disease severity is observed in asthma., Objective: To determine LDG levels in peripheral blood mononuclear cells of subjects with intermittent or mild persistent asthma, subjects with moderate persistent or severe persistent (SP) asthma, and control subjects without a history or allergy or asthma., Methods: A brief medical history and physical examination, spirometry, and measurement of fraction of exhaled nitric oxide were performed. The LDGs were quantified by polychromatic flow cytometry., Results: The LDGs displaying the same phenotype as those described previously for LDGs in other diseases were significantly elevated in peripheral blood mononuclear cells of subjects with moderate persistent or SP asthma. The LDGs comprised up to 39% of peripheral blood mononuclear cells, with elevated LDG levels most prevalent in subjects with SP asthma. The highest LDG levels were observed in 4 subjects with SP asthma. Fraction of exhaled nitric oxide levels and body mass were significantly increased in subjects with low LDG levels compared with control subjects, whereas fraction of exhaled nitric oxide levels and body mass were not elevated in subjects with moderate persistent or SP asthma and high LDG levels compared with control subjects., Conclusion: These findings identify a previously unrecognized association between LDG levels and asthma severity. Identification of the factor(s) responsible for the increased LDG levels in moderate persistent or SP asthma may provide a serum biomarker to aid in the identification of neutrophil-associated phenotypes of severe asthma., (Copyright © 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

SIRT1 regulates the DNA damage response by deacetylating p53, thereby repressing p53 transcriptional output. Here, we demonstrate that the sorting protein PACS-2 regulates SIRT1-mediated deacetylation of p53 to modulate the DNA damage response. PACS-2 knockdown cells failed to efficiently undergo p53-induced cell-cycle arrest in response to DNA damage. Accordingly, p53 acetylation was reduced both in PACS-2 knockdown cells and thymocytes from Pacs-2(-/-) mice, thereby blunting induction of the cyclin-dependent kinase inhibitor p21 (CDKN1A). The SIRT1 inhibitor EX-527 or SIRT1 knockdown restored p53 acetylation and p21 induction as well as p21-dependent cell-cycle arrest in PACS-2 knockdown cells. Trafficking studies revealed that cytoplasmic PACS-2 shuttled to the nucleus, where it interacted with SIRT1 and repressed SIRT1-mediated p53 deacetylation. Correspondingly, in vitro assays demonstrated that PACS-2 directly inhibited SIRT1-catalyzed p53 deacetylation. Together, these findings identify PACS-2 as an in vivo mediator of the SIRT1-p53-p21 axis that modulates the DNA damage response., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Asthma is a chronic inflammatory disease of the airways, and is associated with upregulation of phospholipase A2 (PLA2), the enzyme that hydrolyzes phosphatidylcholine, producing lysophosphatidylcholine (LPC) and free fatty acids. LPC is a lipid mediator with known pro-inflammatory and pro-atherogenic properties, and is believed to be a critical factor in cardiovascular diseases. We postulate that asthmatic subjects have an elevated content of LPC in the lung lining fluids., Methods: Eight non-asthmatic controls and seven asthmatic subjects were recruited for broncho-alveolar lavage fluids (BALF) collection for analysis of LPC by high performance liquid chromatography-tandem mass spectrometry., Results: LPC16:0 and LPC18:0 were significantly elevated in the BALF of asthmatics with impaired lung function characteristic of moderate asthma, but not mild asthma. The increased LPC content in BALF was accompanied by increased PLA2 activity. Furthermore, qRT-PCR analysis of the BALF cell fraction indicated increased secretory PLA2-X (sPLA2-X)., Conclusions: The increased LPC content in the lung lining fluids is a potential critical lipid mediator in the initiation and/or progression of airway epithelial injury in asthma.

The human disease Hermansky-Pudlak syndrome results from defective biogenesis of lysosome-related organelles (LROs) and can be caused by mutations in subunits of the BLOC-1 complex. Here we show that C. elegans glo-2 and snpn-1, despite relatively low levels of amino acid identity, encode Pallidin and Snapin BLOC-1 subunit homologues, respectively. BLOC-1 subunit interactions involving Pallidin and Snapin were conserved for GLO-2 and SNPN-1. Mutations in glo-2 and snpn-1,or RNAi targeting 5 other BLOC-1 subunit homologues in a genetic background sensitized for glo-2 function, led to defects in the biogenesis of lysosome-related gut granules. These results indicate that the BLOC-1 complex is conserved in C. elegans. To address the function of C. elegans BLOC-1, we assessed the intracellular sorting of CDF-2::GFP, LMP-1, and PGP-2 to gut granules. We validated their utility by analyzing their mislocalization in intestinal cells lacking the function of AP-3, which participates in an evolutionarily conserved sorting pathway to LROs. BLOC-1(-) intestinal cells missorted gut granule cargo to the plasma membrane and conventional lysosomes and did not have obviously altered function or morphology of organelles composing the conventional lysosome protein sorting pathway. Double mutant analysis and comparison of AP-3(-) and BLOC-1(-) phenotypes revealed that BLOC-1 has some functions independent of the AP-3 adaptor complex in trafficking to gut granules. We discuss similarities and differences of BLOC-1 activity in the biogenesis of gut granules as compared to mammalian melanosomes, where BLOC-1 has been most extensively studied for its role in sorting to LROs. Our work opens up the opportunity to address the function of this poorly understood complex in cell and organismal physiology using the genetic approaches available in C. elegans.

P120 catenin (p120ctn) is an adherens junction protein recognized to regulate barrier function, but emerging evidence indicates that p120ctn may also exert control on other cellular functions such as transcriptional suppression of genes. We investigated the hypothesis that loss of p120ctn in human endothelial cells activates transcription of pro-inflammatory adhesion molecules. For study, siRNA targeted to p120ctn was transfected into brain microvascular (HBMECs) or pulmonary artery endothelial cells (HPAECs) for 24-120h, which depleted 50-80% of endogenous p120ctn. This loss of p120ctn resulted in increased promoter reporter activity of transcription factors, NFκB, AP-1, and Kaiso, as well as of target genes, MMP-1 and ICAM-1. Real-time RT-PCR analysis indicated that the mRNA for ICAM-1, VCAM-1, and E- and P-selectins were all upregulated during the period of 24-120h of p120ctn depletion, although the time-course and extent of the expression profiles differed. The upregulated mRNA of adhesion molecules corresponded with increased PMN adhesion to the EC surface and elevated ICAM-1 protein expression. We further explored the role of ERK1/2 as a potential signaling mechanism responsible for regulation of transcriptional activities by p120ctn. Results indicated that loss of p120ctn increased phosphorylated ERK1/2, and a MEK1 inhibitor (PD98059) prevented NFκB nuclear translocation. This implicates ERK1/2 in signaling the NFκB activation induced by p120ctn loss. The findings provide strong evidence that deficiency in p120ctn expression in endothelial cells is a potent stimulus for transcriptional upregulation of multiple adhesion molecules. We conclude that p120ctn functions to suppress transcription, which is an important and novel regulation in vascular endothelium., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: HIV-1 bound to intact neutrophils efficiently infects activated peripheral blood mononuclear cells (PBMC). Here, we evaluated the effect of the local milieu created by activated PBMC before and after HIV-1 infection on neutrophil survival and HLA-DR expression, with emphasis placed on a role for GM-CSF., Methods: PBMC of healthy adult individuals were activated by phytohemagglutinin (PHA) or anti-CD3/anti-CD28 and were subsequently cultured without (HIV-1⁻) or with HIV-1 (HIV-1+). The effects of the culture supernatants or recombinant GM-CSF on survival and HLA-DR expression by neutrophils of healthy adult individuals and of HIV-1-infected individuals were evaluated using flow cytometry., Results: Conditioned medium from PHA-activated PBMC (HIV-1⁻ and HIV-1+) increased neutrophil survival and induced HLA-DR expression by neutrophils of healthy individuals in a GM-CSF dependent fashion. HIV-1 infection variably, but consistently, increased GM-CSF production by PHA-activated PBMC but not GM-CSF production by anti-CD3/anti-CD28-activated PBMC. The latter was correlated with a loss of CD3+GMCSF+ cells after infection. Neutrophils of elite controllers exhibited a diminished HLADR response to GM-CSF in culture, whereas neutrophils of HIV-1+ subjects having a low viral load on anti-retroviral therapy or subjects with a high viral load exhibited a range of HLA-DR responses., Conclusions: GM-CSF production within the mucosa or draining lymph nodes may promote HIV-1 infection by facilitating sustained contact between viable neutrophils with bound HIV-1 and CD4 lymphocytes. The minimal effect of GM-CSF on HLA-DR expression by neutrophils of elite controllers provides indirect support for this conclusion.

The increasing prevalence of atopy and asthma remains unexplained but may be due to infection with respiratory viruses. In support of this hypothesis, we showed that experimental asthma after viral infection in mice depended on type I IFN-driven upregulation of FcεRI on conventional dendritic cells (cDCs) in the lung. In this article, we demonstrate that FcεRI expression on lung cDCs depends on an unexpected activity of a CD49d(+) subset of polymorphonuclear neutrophils (PMNs) that are found in the lungs of wild-type C57BL6 but not mice deficient in type I IFNR. Expression of FcεRI depends in part on a CD11b-dependent interaction between PMNs and cDCs. This study demonstrates a PMN-cDC interaction in the lung that is necessary for the ability of viral infection to induce atopic disease.