Flexible modelling of the dissolution performance of directly compressed tablets.

In this study, a compartmental disintegration and dissolution model is proposed for the prediction and evaluation of the dissolution performance of directly compressed tablets. This dissolution model uses three compartments (Bound, Disintegrated, and Dissolved) to describe the state of each particle of active pharmaceutical ingredient. The disintegration of the tablet is captured by three fitting parameters. Two disintegration parameters, ß0 and ßt,0, describe the initial disintegration rate and the change in disintegration rate, respectively. A third parameter, α, describes the effect of the volume of dissolved drug on the disintegration process. As the tablet disintegrates, particles become available for dissolution. The dissolution rate is determined by the Nernst-Brunner equation, whilst taking into account the hydrodynamic effects within the vessel of a USP II (paddle) apparatus. This model uses the raw material properties of the active pharmaceutical ingredient (solubility, particle size distribution, true density), lending it towards early development activities during which time the amount of drug substance available may be limited. Additionally, the strong correlations between the fitting parameters and the tablet porosity indicate the potential to isolate the manufacturing effects and thus implement the model as part of a real-time release testing strategy for a continuous direct compression line.

Long-term fertilization and cultivation impacts on nematode abundance and community structure in tall fescue turfgrass.

Impacts of long-term fertilization and cultivation were evaluated on nematode communities associated with tall fescue turfgrass following 11 years of treatment applications. Fertilizer treatments of biosolid, synthetic, and plant-based fertilizers and cultivation treatments of 0×, 1×, and 2× aerification passes were applied to randomized and replicated tall fescue plots at the University of Maryland Paint Branch Turfgrass facility in College Park, Maryland. Free-living and plant-parasitic nematodes were identified, enumerated, and categorized into functional groups. Nematode count data were compared using generalized linear mixed modeling with negative binomial distribution and two-way ANOVA was used to compare nematode ecological indices. Biosolid treatments resulted in lower omnivore-predator densities than plant-based fertilizer treatments (p ≤ .001) and significantly greater Hoplolaimus densities than plant-based fertilizer plots (p ≤ .05). Synthetic fertilizer applications resulted in the greatest Eucephalobus (p ≤ .05) and total bacterivore densities (p ≤ .001) of all fertilizer treatments. Plant-based fertilizer-treated plots had the largest Maturity Index cp 2-5 and Structure Index (p ≤ .05). Cultivation of 1× resulted in fewer total bacterivore densities than 2× (p ≤ .01) while omnivore-predator densities were greater in 1× than 0× (p ≤ .001). Plant health, as measured by NDVI, was lowest in biosolid-treated turfgrass (p ≤ .05). These findings suggest that long-term turfgrass management practices can have variable impacts on nematode abundance and community structure in tall fescue and provide insights into ecological impacts of turfgrass management practices.

Polymyxin B and ethylenediaminetetraacetic acid act synergistically against Pseudomonas aeruginosa and Staphylococcus aureus.

Polymyxin B and ethylenediaminetetraacetic acid are antimicrobials possessing antibiofilm activity. They act by displacement and chelation, respectively, of divalent cations in bacterial membranes and may therefore act synergistically when applied in combination. If so, this combination of agents may be useful for the treatment of diseases like cystic fibrosis (CF), in which biofilms are present on the respiratory epithelium. We used checkerboard assays to investigate the synergy between these agents using reference strains Pseudomonas aeruginosa ATCC 27853 and Staphylococcus aureus ATCC 6538 in planktonic form. We then determined the efficacy of each agent against biofilms of both species grown on 96-pin lids and proceeded to combination testing against the P. aeruginosa reference strain and 10 clinical isolates from patients with CF. Synergism was observed for planktonic forms of both species and for biofilms of P. aeruginosa. The susceptibility of biofilms of P. aeruginosa clinical isolates to these agents was variable compared to the laboratory reference strain. This combination of agents may be useful in the management of biofilm-associated conditions, particularly those amenable to topical therapies. These results provide a basis upon which the antimicrobial and antibiofilm efficacy of preparations containing these agents may be enhanced.IMPORTANCEBacteria living in biofilms produce a protective matrix which makes them difficult to kill. Patients with severe respiratory disease often have biofilms. Polymyxin B is an antibiotic commonly used in topical medications, such as eye drops and nasal sprays. Ethylenediaminetetraacetic acid (EDTA) is used widely as a preservative in medication but also has antimicrobial properties. It has been hypothesized that Polymyxin B and EDTA could have a synergistic relationship: when used in combination their antimicrobial effect is enhanced. Here, we evaluated the levels at which Polymyxin B and EDTA work together to kill common pathogens Pseudomonas aeruginosa and Staphylococcus aureus. We found that Polymyxin B and EDTA were synergistic. This synergy may be useful in the management of planktonic infection with P. aeruginosa and S. aureus, or biofilm infection with P. aeruginosa. This synergy may be beneficial in the treatment of respiratory biofilms, in which P. aeruginosa biofilms are common.

Sublethal effects of imidacloprid-contaminated honey stores on colony performance, queens, and worker activities in fall and early winter colonies.

Neonicotinoid-contaminated sugar stores can have both near term and long term effects on honey bees due to their persistence in honey stores. Effects of imidacloprid food stores contaminants were examined in subtropical colonies that experience reduced brood rearing and foraging during overwintering. Colonies were given treatment sugar syrup containing 0 ppb (control), 20 ppb (field relevant), or 100 ppb (above field relevant) imidacloprid over six weeks to simulate contaminated fall nectar. Colonies were evaluated immediately (post-treatment) and 10 weeks (mid-winter) after treatment to compare proximal and latent effects. Post-treatment 0 ppb and 20 ppb colonies had more workers than 100 ppb colonies while 0 ppb colonies more brood than 20 ppb or 100 ppb colonies. Mid-winter 0 ppb and 20 ppb colonies had more workers than 100 ppb colonies and 0 ppb colonies more brood than 100 ppb colonies. Colonies experienced seasonal declines in stored pollen but no treatment effects. Lower 100 ppb colony performance was associated with reduced effort rather than lifespan. RFID (Radio Frequency Identification) tracking revealed that workers had similar adult lifespans across treatments; however, 100 ppb workers engaged in activities outside the colony for less time than 0 ppb workers. Imidacloprid exposure affected queen but not worker nutritional physiology. Nurses retained well-developed hypopharyngeal glands (as indicated by head protein) across treatments. Mid-winter queens from 0 ppb colonies had marginally higher ovary protein than queens from 100 ppb colonies and more ovary lipids than queens from 20 ppb colonies. However, queen nutrient stores in non-reproductive tissues (fat bodies) did not differ across treatments. Queens from different treatments were attended by comparable numbers of retinue workers and had similar gland contents of four QMP (Queen Mandibular Pheromone) components essential to queen care. High levels of imidacloprid in sugar stores can negatively affect colony performance months after initial storage.

Honey bee retinue workers respond similarly to queens despite seasonal differences in Queen Mandibular Pheromone (QMP) signaling.

Honey bee colonies maintain viable queens in part through communication with Queen Mandibular Pheromone (QMP), a mixture that signals the queen's presence and reproductive quality to workers. In turn, workers are thought to provide retinue queen care or replace queens partially based on QMP profiles. We examined the effects of seasonal dearth (overwintering in a warm subtropical location) on queen-worker interactions. Retinue worker responses to continuously ovipositing queens were considered in view of QMP signaling and queen reproductive quality. QMP signaling was estimated from QMP residues recovered from nest worker bodies, which is the primary mode of QMP transfer from the queen to the colony at large. QMP residues varied seasonally but not at all with queen reproductive quality (spermatheca sperm storage, ovary protein and lipid contents). 9-HDA and 9-ODA were lower in January than other months. HOB decreased from July to January, while HVA, a component associated with mated queens, increased sharply in January. Despite these seasonal signaling differences, retinue workers attended queens at similar levels through the months. In terms of reproductive quality, queens did not differ over the months in matedness (spermatheca sperm storage) or physiological age (protein carbonyl content), but varied in nutrient allocation to reproductive and non-reproductive tissues. Queen ovaries contained more protein in September than in November, and more lipid in July and September than in November and January. Queen fat bodies had more protein in July than September or November, but less lipid in July and September than November or January. Retinue worker responses did not vary with seasonal QMP changes, but reflected overall continuous brood rearing efforts and queen matedness throughout the year. The absence of seasonal differences in worker responses to QMP should be considered in the broader context of continuous reproductive efforts in warm subtropical colonies.

The Cynicism of the Seronegative.

A physician in his 60s describes his path to a diagnosis of inflammatory arthritis, which included completely normal laboratory results.

Advanced Cystic Fibrosis Lung Disease and Lung Transplantation in the Era of Cystic Fibrosis Transmembrane Conductance Regulator Modulators.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have changed the clinical landscape of cystic fibrosis (CF) by improving clinically significant outcome measures and quality of life of people with CF (pwCF). There are now long-term data showing improved 5-year survival with the use of ivacaftor, and the field continues to evolve at a rapid pace with the continued development of highly effective CFTR modulators. While the randomized controlled trials of CFTR modulators excluded patients with severe lung disease (forced expiratory volume in 1 second <40% predicted), observational data based on case reports and registry data show similar benefits in those with advanced lung disease. This has altered clinical practice particularly as it pertains to the role of lung transplantation in CF. This article describes the impact of highly effective modulator therapy (HEMT) on the natural history of CF and the influence on the timing of referral and consideration of listing for lung transplantation. CF clinicians play a pivotal role to ensure that the impetus of the CF foundation consensus guidelines to facilitate timely referral for lung transplantation is not lost among the excitement of anticipated sustained benefit from HEMT. While the widespread availability of elexacaftor/tezacaftor/ivacaftor over the past 2 years has been associated with a sharp drop in the number of people referred for consideration for lung transplantation and the number of people wait-listed for lung transplantation, it is difficult to accurately determine the true impact due to the confounding effect of the coronavirus disease 2019 pandemic. It is expected that lung transplantation will remain an important treatment for a smaller number of pwCF. Lung transplantation offers survival benefits in CF, and there remains an imperative to ensure timely consideration of lung transplantation in patients with advanced disease to further reduce the number of pwCF dying without consideration of lung transplant.

Diet and pheromones interact to shape honey bee (Apis mellifera) worker physiology.

Honey bee colony health is a function of the individuals, their interactions, and the environment. A major goal of honey bee research is to understand how colonies respond to stress. Individual-level studies of the bee stress response are tractable, but their results do not always translate to the colony level. Nutritional stress is an important factor in colony declines. Nutrition studies are typically conducted on individual nurse workers (nurses), who are primarily responsible for converting pollen into brood. Nurse physiology is sensitive to both pollen and pheromones, which communicate signals among colony members. Here, we asked whether pheromones influence nurse nutrient pathways involved in brood care, and whether diet influences colony communication. We exposed caged, nurse-aged workers to different combinations of pheromones and pollen, and measured traits related to brood care. We found that pheromones enhanced pollen-dependent processes such as hypopharyngeal gland growth and mrjp1 expression, and buffered the negative effects of starvation. Pollen also enhanced how nurse phenotypes respond to pheromones. Therefore, diet and pheromones interact to influence nurse nutritional physiology and aspects of brood care. These findings have implications for studying colony function and health in an increasingly stressful climate.

Unbalanced fatty acid diets impair discrimination ability of honey bee workers to damaged and healthy brood odors.

Nutrition supports social insect colonies by regulating both individual performance and colony growth. In honey bee colonies, task-related behaviors such as nursing and foraging are partially mediated by nutrition. Young workers (nurses) consume almost all of the pollen in the hive, while foragers consume mostly nectar. Pollen provides vital proteins and lipids, consumed by nurse bees for approximately 1 week post-eclosion. The role that lipids play in the physiology and behavior of adult bees is gaining significant attention. Recent research suggests that diets with balanced ratios of fatty acids increase olfactory learning in honey bees. Olfaction is crucial for young worker bees to perform brood care and cell cleaning behaviors, which is important for hive health and disease control. Thus, we targeted the early adult, pollen-feeding stage to examine how fatty acids affect cognition to hive-relevant odors. We fed young workers (days 0-9) diets balanced or unbalanced in their ratio of essential fatty acids (ω-6:3) sourced from pollen or cooking oils. We then measured their ability to learn healthy and damaged brood odors, as well as their ability to discriminate between the two. Workers fed balanced diets could learn and discriminate between brood odors better than workers fed unbalanced diets. Consumption of both diet types decreased with age, but their cognitive effects remained. These results suggest that diet affects young worker cognitive development, which may affect task-related behaviors and colony hygiene.

Automatic variable selection in ecological niche modeling: A case study using Cassin's Sparrow (Peucaea cassinii).

MERRA/Max provides a feature selection approach to dimensionality reduction that enables direct use of global climate model outputs in ecological niche modeling. The system accomplishes this reduction through a Monte Carlo optimization in which many independent MaxEnt runs, operating on a species occurrence file and a small set of randomly selected variables in a large collection of variables, converge on an estimate of the top contributing predictors in the larger collection. These top predictors can be viewed as potential candidates in the variable selection step of the ecological niche modeling process. MERRA/Max's Monte Carlo algorithm operates on files stored in the underlying filesystem, making it scalable to large data sets. Its software components can run as parallel processes in a high-performance cloud computing environment to yield near real-time performance. In tests using Cassin's Sparrow (Peucaea cassinii) as the target species, MERRA/Max selected a set of predictors from Worldclim's Bioclim collection of 19 environmental variables that have been shown to be important determinants of the species' bioclimatic niche. It also selected biologically and ecologically plausible predictors from a more diverse set of 86 environmental variables derived from NASA's Modern-Era Retrospective Analysis for Research and Applications Version 2 (MERRA-2) reanalysis, an output product of the Goddard Earth Observing System Version 5 (GEOS-5) modeling system. We believe these results point to a technological approach that could expand the use global climate model outputs in ecological niche modeling, foster exploratory experimentation with otherwise difficult-to-use climate data sets, streamline the modeling process, and, eventually, enable automated bioclimatic modeling as a practical, readily accessible, low-cost, commercial cloud service.

The Importance of Time and Place: Nutrient Composition and Utilization of Seasonal Pollens by European Honey Bees (Apis mellifera L.).

Honey bee colonies have a yearly cycle that is supported nutritionally by the seasonal progression of flowering plants. In the spring, colonies grow by rearing brood, but in the fall, brood rearing declines in preparation for overwintering. Depending on where colonies are located, the yearly cycle can differ especially in overwintering activities. In temperate climates of Europe and North America, colonies reduce or end brood rearing in the fall while in warmer climates bees can rear brood and forage throughout the year. To test the hypothesis that nutrients available in seasonal pollens and honey bee responses to them can differ we analyzed pollen in the spring and fall collected by colonies in environments where brood rearing either stops in the fall (Iowa) or continues through the winter (Arizona). We fed both types of pollen to worker offspring of queens that emerged and open mated in each type of environment. We measured physiological responses to test if they differed depending on the location and season when the pollen was collected and the queen line of the workers that consumed it. Specifically, we measured pollen and protein consumption, gene expression levels (hex 70, hex 110, and vg) and hypopharyngeal gland (HPG) development. We found differences in macronutrient content and amino and fatty acids between spring and fall pollens from the same location and differences in nutrient content between locations during the same season. We also detected queen type and seasonal effects in HPG size and differences in gene expression between bees consuming spring vs. fall pollen with larger HPG and higher gene expression levels in those consuming spring pollen. The effects might have emerged from the seasonal differences in nutritional content of the pollens and genetic factors associated with the queen lines we used.

Correction: Honey bees preferentially consume freshly-stored pollen.

[This corrects the article DOI: 10.1371/journal.pone.0175933.].

Toward a Monte Carlo approach to selecting climate variables in MaxEnt.

MaxEnt is an important aid in understanding the influence of climate change on species distributions. There is growing interest in using IPCC-class global climate model outputs as environmental predictors in this work. These models provide realistic, global representations of the climate system, projections for hundreds of variables (including Essential Climate Variables), and combine observations from an array of satellite, airborne, and in-situ sensors. Unfortunately, direct use of this important class of data in MaxEnt modeling has been limited by the large size of climate model output collections and the fact that MaxEnt can only operate on a relatively small set of predictors stored in a computer's main memory. In this study, we demonstrate the feasibility of a Monte Carlo method that overcomes this limitation by finding a useful subset of predictors in a larger, externally-stored collection of environmental variables in a reasonable amount of time. Our proposed solution takes an ensemble approach wherein many MaxEnt runs, each drawing on a small random subset of variables, converges on a global estimate of the top contributing subset of variables in the larger collection. In preliminary tests, the Monte Carlo approach selected a consistent set of top six variables within 540 runs, with the four most contributory variables of the top six accounting for approximately 93% of overall permutation importance in a final model. These results suggest that a Monte Carlo approach could offer a viable means of screening environmental predictors prior to final model construction that is amenable to parallelization and scalable to very large data sets. This points to the possibility of near-real-time multiprocessor implementations that could enable broader and more exploratory use of global climate model outputs in environmental niche modeling and aid in the discovery of viable predictors.

Thermal, Quantum Antibunching and Lasing Thresholds from Single Emitters to Macroscopic Devices.

Starting from a fully quantized Hamiltonian for an ensemble of identical emitters coupled to the modes of an optical cavity, we determine analytically regimes of thermal, collective anti-bunching and laser emission that depend explicitly on the number of emitters. The lasing regime is reached for a number of emitters above a critical number-which depends on the light-matter coupling, detuning, and the dissipation rates-via a universal transition from thermal emission to collective anti-bunching to lasing as the pump increases. Cases where the second order intensity correlation fails to predict laser action are also presented.

Hybrid reconstruction of bronchial dehiscence following lung transplant.

Surgical repair of right-sided bronchial dehiscence post lung transplant is challenging. We report a hybrid reconstruction of the bronchus using an aortic homograft patch with stenting as a novel technique of management of ischemic airway injury following lung transplantation.

Lung transplant graft salvage using aortic homograft for bronchial dehiscence.

The use of aortic homograft in infective pathology is well described. Its use in the repair of post-transplant airway complications has been seldom reported. Herein, we report our experience with the successful use of aortic homograft in the management of post-transplant large airway complications in two patients.

Lung transplant in a recipient with tracheal bronchus.

We describe the intraoperative surgical management of tracheal bronchus encountered in a lung transplant recipient.

Pollen Alters Amino Acid Levels in the Honey Bee Brain and This Relationship Changes With Age and Parasitic Stress.

Pollen nutrition is necessary for proper growth and development of adult honey bees. Yet, it is unclear how pollen affects the honey bee brain and behavior. We investigated whether pollen affects amino acids in the brains of caged, nurse-aged bees, and what the behavioral consequences might be. We also tested whether parasitic stress altered this relationship by analyzing bees infected with prevalent stressor, Nosema ceranae. Levels of 18 amino acids in individual honey bee brains were measured using Gas Chromatography - Mass Spectrometry at two different ages (Day 7 and Day 11). We then employed the proboscis extension reflex to test odor learning and memory. We found that the honey bee brain was highly responsive to pollen. Many amino acids in the brain were elevated and were present at higher concentration with age. The majority of these amino acids were non-essential. Without pollen, levels of amino acids remained consistent, or declined. Nosema-infected bees showed a different profile. Infection altered amino acid levels in a pollen-dependent manner. The majority of amino acids were lower when pollen was given, but higher when pollen was deprived. Odor learning and memory was not affected by feeding pollen to uninfected bees; but pollen did improve performance in Nosema-infected bees. These results suggest that pollen in early adulthood continues to shape amino acid levels in the brain with age, which may affect neural circuitry and behavior over time. Parasitic stress by N. ceranae modifies this relationship revealing an interaction between infection, pollen nutrition, and behavior.

Bringing Open Data to Whole Slide Imaging.

Faced with the need to support a growing number of whole slide imaging (WSI) file formats, our team has extended a long-standing community file format (OME-TIFF) for use in digital pathology. The format makes use of the core TIFF specification to store multi-resolution (or "pyramidal") representations of a single slide in a flexible, performant manner. Here we describe the structure of this format, its performance characteristics, as well as an open-source library support for reading and writing pyramidal OME-TIFFs.