Unlocking the Complex Cell Biology of Coral-Dinoflagellate Symbiosis: A Model Systems Approach.

Symbiotic interactions occur in all domains of life, providing organisms with resources to adapt to new habitats. A prime example is the endosymbiosis between corals and photosynthetic dinoflagellates. Eukaryotic dinoflagellate symbionts reside inside coral cells and transfer essential nutrients to their hosts, driving the productivity of the most biodiverse marine ecosystem. Recent advances in molecular and genomic characterization have revealed symbiosis-specific genes and mechanisms shared among symbiotic cnidarians. In this review, we focus on the cellular and molecular processes that underpin the interaction between symbiont and host. We discuss symbiont acquisition via phagocytosis, modulation of host innate immunity, symbiont integration into host cell metabolism, and nutrient exchange as a fundamental aspect of stable symbiotic associations. We emphasize the importance of using model systems to dissect the cellular complexity of endosymbiosis, which ultimately serves as the basis for understanding its ecology and capacity to adapt in the face of climate change.

Ultrafast sound production mechanism in one of the smallest vertebrates.

Motion is the basis of nearly all animal behavior. Evolution has led to some extraordinary specializations of propulsion mechanisms among invertebrates, including the mandibles of the dracula ant and the claw of the pistol shrimp. In contrast, vertebrate skeletal movement is considered to be limited by the speed of muscle, saturating around 250 Hz. Here, we describe the unique propulsion mechanism by which Danionella cerebrum, a miniature cyprinid fish of only 12 mm length, produces high amplitude sounds exceeding 140 dB (re. 1 µPa, at a distance of one body length). Using a combination of high-speed video, micro-computed tomography (micro-CT), RNA profiling, and finite difference simulations, we found that D. cerebrum employ a unique sound production mechanism that involves a drumming cartilage, a specialized rib, and a dedicated muscle adapted for low fatigue. This apparatus accelerates the drumming cartilage at over 2,000 g, shooting it at the swim bladder to generate a rapid, loud pulse. These pulses are chained together to make calls with either bilaterally alternating or unilateral muscle contractions. D. cerebrum use this remarkable mechanism for acoustic communication with conspecifics.

Omadacycline pharmacokinetics/pharmacodynamics and efficacy against multidrug-resistant Mycobacterium tuberculosis in the hollow fiber system model.

Seventy-five years ago, first-generation tetracyclines demonstrated limited efficacy in the treatment of tuberculosis but were more toxic than efficacious. We performed a series of pharmacokinetic/pharmacodynamic (PK/PD) experiments with a potentially safer third-generation tetracycline, omadacycline, for the treatment of multidrug-resistant tuberculosis (MDR-TB). Mycobacterium tuberculosis (Mtb) H37Rv and an MDR-TB clinical strain (16D) were used in the minimum inhibitory concentration (MIC) and static concentration-response studies in test tubes, followed by a PK/PD study using the hollow fiber system model of TB (HFS-TB) that examined six human-like omadacycline doses. The inhibitory sigmoid maximal effect (Emax) model and Monte Carlo experiments (MCEs) were used for data analysis and clinical dose-finding, respectively. The omadacycline MIC for both Mtb H37Rv and MDR-TB clinical strain was 16 mg/L but dropped to 4 mg/L with daily drug supplementation to account for omadacycline degradation. The Mycobacteria Growth Indicator Tube MIC was 2 mg/L. In the test tubes, omadacycline killed 4.39 log10 CFU/mL in 7 days. On Day 28 of the HFS-TB study, the Emax was 4.64 log10 CFU/mL, while exposure mediating 50% of Emax (EC50) was an area under the concentration-time curve to MIC (AUC0-24/MIC) ratio of 22.86. This translates to PK/PD optimal exposure or EC80 as AUC0-24/MIC of 26.93. The target attainment probability of the 300-mg daily oral dose was 90% but fell at MIC ≧4 mg/L. Omadacycline demonstrated efficacy and potency against both drug-susceptible and MDR-TB. Further studies are needed to identify the omadacycline effect in combination therapy for the treatment of both drug-susceptible and MDR-TB.

Suillus: an emerging model for the study of ectomycorrhizal ecology and evolution.

Research on mycorrhizal symbiosis has been slowed by a lack of established study systems. To address this challenge, we have been developing Suillus, a widespread ecologically and economically relevant fungal genus primarily associated with the plant family Pinaceae, into a model system for studying ectomycorrhizal (ECM) associations. Over the last decade, we have compiled extensive genomic resources, culture libraries, a phenotype database, and protocols for manipulating Suillus fungi with and without their tree partners. Our efforts have already resulted in a large number of publicly available genomes, transcriptomes, and respective annotations, as well as advances in our understanding of mycorrhizal partner specificity and host communication, fungal and plant nutrition, environmental adaptation, soil nutrient cycling, interspecific competition, and biological invasions. Here, we highlight the most significant recent findings enabled by Suillus, present a suite of protocols for working with the genus, and discuss how Suillus is emerging as an important model to elucidate the ecology and evolution of ECM interactions.

De novo assembly of transcriptomes and differential gene expression analysis using short-read data from emerging model organisms - a brief guide.

Many questions in biology benefit greatly from the use of a variety of model systems. High-throughput sequencing methods have been a triumph in the democratization of diverse model systems. They allow for the economical sequencing of an entire genome or transcriptome of interest, and with technical variations can even provide insight into genome organization and the expression and regulation of genes. The analysis and biological interpretation of such large datasets can present significant challenges that depend on the 'scientific status' of the model system. While high-quality genome and transcriptome references are readily available for well-established model systems, the establishment of such references for an emerging model system often requires extensive resources such as finances, expertise and computation capabilities. The de novo assembly of a transcriptome represents an excellent entry point for genetic and molecular studies in emerging model systems as it can efficiently assess gene content while also serving as a reference for differential gene expression studies. However, the process of de novo transcriptome assembly is non-trivial, and as a rule must be empirically optimized for every dataset. For the researcher working with an emerging model system, and with little to no experience with assembling and quantifying short-read data from the Illumina platform, these processes can be daunting. In this guide we outline the major challenges faced when establishing a reference transcriptome de novo and we provide advice on how to approach such an endeavor. We describe the major experimental and bioinformatic steps, provide some broad recommendations and cautions for the newcomer to de novo transcriptome assembly and differential gene expression analyses. Moreover, we provide an initial selection of tools that can assist in the journey from raw short-read data to assembled transcriptome and lists of differentially expressed genes.

A Prediction Model for the Efficacy of Transvaginal Repair in Patients With Cesarean Scar Defect: An Evidence-Based Proposal for Patient Selection.

STUDY OBJECTIVE: To establish a prediction model to help doctors determine which patients with cesarean scar defect are more suitable for transvaginal repair. DESIGN: Retrospective analysis. SETTING: Xinhua Hospital and Shanghai First Maternity & Infant Hospital between June 2014 and May 2021. PATIENTS: 1015 women who underwent transvaginal repair of cesarean scar defect (CSD). INTERVENTIONS: All enrolled patients underwent CSD repair performed by the same gynecologist and his team. And followed up a clinic visit at 6 months to record their menstruation and measure multiple parameters of the CSD by Magnetic Resonance Imaging. MAIN OUTCOMES AND MEASURES: CSD patients are categorized as optimal healing group when the menstruation duration is no more than 7 days, meanwhile the thickness of residual myometrium is no less than 5.39 mm after vaginal repair. The final nomogram is constructed to predict surgical outcomes based on preoperative variables. RESULTS: The key factors that determine optimal healing are the timing of cesarean section (elective or emergency), menstrual cycle, CSD length, width, depth, and the thickness of the lower uterine segment. With the prediction model, scores are given to each parameter according to the statistics. Total scores range from 0 to 25 points, with a cutoff point of 16.5. When a score is greater than 16.5, the transvaginal repair can achieve optimal healing. Uterine position (anteflexion or retroflexion) and preoperative thickness of residual myometrium are the key factors affecting postoperative thickness of residual myometrium. The width of the CSD and the thickness of the lower uterine segment are the key factors affecting abnormal uterine bleeding symptoms (p < 0.01). CONCLUSIONS: For the first time, we established a prediction model system that may predict the repair effect of CSD and can potentially be useful in future clinical trials to determine which patients are more suitable for surgery or other treatment options.

Investigating Antiprotozoal Chemotherapies with Novel Proteomic Tools-Chances and Limitations: A Critical Review.

Identification of drug targets and biochemical investigations on mechanisms of action are major issues in modern drug development. The present article is a critical review of the classical "one drug"-"one target" paradigm. In fact, novel methods for target deconvolution and for investigation of resistant strains based on protein mass spectrometry have shown that multiple gene products and adaptation mechanisms are involved in the responses of pathogens to xenobiotics rather than one single gene or gene product. Resistance to drugs may be linked to differential expression of other proteins than those interacting with the drug in protein binding studies and result in complex cell physiological adaptation. Consequently, the unraveling of mechanisms of action needs approaches beyond proteomics. This review is focused on protozoan pathogens. The conclusions can, however, be extended to chemotherapies against other pathogens or cancer.

Do astigmatid teeth matter: a tribological review of cheliceral chelae in co-occuring mites from UK beehives.

The dentition of the chelal moveable digit in cohabiting astigmatids from UK beehives (i.e., Carpoglyphus lactis (Linnaeus), Glycyphagus domesticus (DeGeer), and Tyrophagus putrescentiae (Schrank)) is characterised for the first time using quantitative tribological measures within a 2D mechanical model. The trophic function of astigmatid chelae are reviewed in terms of macroscopic tools used by humans including hooking devices, pliers, shears, rasps and saws. Comparisons to oribatid claws and isopod dactyli are made. The overall pattern of the moveable digit form of T. putrescentiae is not just a uniformly shrunken/swollen version between the other two taxa at either the macro- or micro-scale. Mastication surface macro-roughness values are in the range of international Roughness Grade Numbers N5-N6. The moveable digit of C. lactis has low rugosity values compared to the glycyphagid and acarid (which are topographically more similar and match that roughness typical of some coral reef surfaces). C. lactis has the most plesiomorphic moveable digit form. The mastication surface of all three species as a chewing tool is distinctly ornamented despite the moveable digit of C. lactis looking like a bar-like beam. The latter has more opportunities to be a multifunctional tool behaviourally than the other two species. Little evidence of any differences in the 'spikiness' of any 'toothiness' is found. Some differences with laboratory cultured specimens are found in C. lactis and possibly T. putrescentiae suggesting where selection on the digit may be able to occur. The chelal surface of T. putrescentiae has been deformed morphologically during evolution the most, that of C. lactis the least. Repeated localised surface differentiation is a feature of the moveable digit in G. domesticus compared to the likely more concerted changes over certain nearby locations in T. putrescentiae. An impactful chelal teeth design is present in G. domesticus but this is more equivocal in T. putrescentiae. Pockets within the mastication surface of the glycyphagid (and to some extent for the acarid) may produce foodstuff crunch forces of the scale of the chelal tips of oribatids. The moveable digit dentition of G. domesticus is adapted to shred foodstuff (like a ripsaw) more than that of the grazing/shearing dentition of T. putrescentiae. The collecting 'picker' design of C. lactis posterior teeth matches the size of Bettsia alvei hyphae which attacks hive-stored pollen. Detritus accumulated in chelal digit gullets through a sawing action matches the smallest observed ingested material. The dentition of C. lactis should produce less friction when moving through food material than G. domesticus. C. lactis is the most hypocarnivorous and may 'skim' through fluids when feeding. Astigmatid teeth do matter. The three commensal species can avoid direct competition. Future work is proposed in detail.

Protein O-mannosylation: one sugar, several pathways, many functions.

Recent research has unveiled numerous important functions of protein glycosylation in development, homeostasis, and diseases. A type of glycosylation taking the center stage is protein O-mannosylation, a posttranslational modification conserved in a wide range of organisms, from yeast to humans. In animals, protein O-mannosylation plays a crucial role in the nervous system, whereas protein O-mannosylation defects cause severe neurological abnormalities and congenital muscular dystrophies. However, the molecular and cellular mechanisms underlying protein O-mannosylation functions and biosynthesis remain not well understood. This review outlines recent studies on protein O-mannosylation while focusing on the functions in the nervous system, summarizes the current knowledge about protein O-mannosylation biosynthesis, and discusses the pathologies associated with protein O-mannosylation defects. The evolutionary perspective revealed by studies in the Drosophila model system are also highlighted. Finally, the review touches upon important knowledge gaps in the field and discusses critical questions for future research on the molecular and cellular mechanisms associated with protein O-mannosylation functions.

Deficient autophagy in epithelial stem cells drives aging in the freshwater cnidarian Hydra.

Hydra possesses three distinct stem cell populations that continuously self-renew and prevent aging in Hydra vulgaris However, sexual animals from the H. oligactis cold-sensitive strain Ho_CS develop an aging phenotype upon gametogenesis induction, initiated by the loss of interstitial stem cells. Animals stop regenerating, lose their active behaviors and die within 3 months. This phenotype is not observed in the cold-resistant strain Ho_CR To dissect the mechanisms of Hydra aging, we compared the self-renewal of epithelial stem cells in these two strains and found it to be irreversibly reduced in aging Ho_CS but sustained in non-aging Ho_CR We also identified a deficient autophagy in Ho_CS epithelial cells, with a constitutive deficiency in autophagosome formation as detected with the mCherry-eGFP-LC3A/B autophagy sensor, an inefficient response to starvation as evidenced by the accumulation of the autophagosome cargo protein p62/SQSTM1, and a poorly inducible autophagy flux upon proteasome inhibition. In the non-aging H. vulgaris animals, the blockade of autophagy by knocking down WIPI2 suffices to induce aging. This study highlights the essential role of a dynamic autophagy flux to maintain epithelial stem cell renewal and prevent aging.

An Evolved 5' Untranslated Region of Alfalfa Mosaic Virus Allows the RNA Transport of Movement-Defective Variants.

Although the coat protein (CP) has a relevant role in the long-distance movement of alfalfa mosaic virus (AMV) and brome mosaic virus (BMV), its precise function is not fully understood. Previous results showed that a specific interaction between the C termini of the movement protein (MP) and the cognate CP is required for systemic transport. Thus, we have performed a compensatory evolution experiment using an AMV RNA3 derivative defective in long-distance transport that carries a BMV MP lacking the C-terminal 48 residues and unable to interact with the AMV CP. After several passages, five independent evolution lineages were able to move long distance. The analysis of the viral RNA of these lineages showed the presence of three different modifications located exclusively at the 5' untranslated region (5' UTR). The three evolved 5' UTR variants accumulated comparable levels of viral RNA and CP but reduced the accumulation of virus particles and the affinity between the 5' UTR and the AMV CP. In addition, the evolved 5' UTR increased cell-to-cell transport for both the AMV RNA3 carrying the BMV MP and that carrying the AMV MP. Finally, the evolved 5' UTRs allowed the systemic transport of an AMV RNA3 carrying a CP mutant defective in virus particles and increased the systemic transport of several AMV RNA3 derivatives carrying different viral MPs associated with the 30K superfamily. Altogether, our findings indicate that virus particles are not required for the systemic transport of AMV but also that BMV MP is competent for the short- and long-distance transport without the interaction with the CP. IMPORTANCE The results obtained in the present work could challenge the view of the role of the virus particle in the systemic transport of plant viruses. In this sense, we show that two different MPs are competent to systemically transport the AMV genome without the requirement of the virus particles, as reported for viruses lacking a CP (e.g., Umbravirus). The incapability of the viral MP to interact with the CP triggered virus variants that evolved to reduce the formation of virus particles, probably to increase the accessibility of the MP to the viral progeny. Our results point to the idea that virus particles would not be necessary for the viral systemic transport but would be necessary for vector virus transmission. This idea is reinforced by the observation that heterologous MPs also increased the systemic transport of the AMV constructs that have reduced encapsidation capabilities.

Melica as an emerging model system for comparative studies in temperate Pooideae grasses.

BACKGROUND AND AIMS: Pooideae grasses contain some of the world's most important crop and forage species. Although much work has been conducted on understanding the genetic basis of trait diversification within a few annual Pooideae, comparative studies at the subfamily level are limited by a lack of perennial models outside 'core' Pooideae. We argue for development of the perennial non-core genus Melica as an additional model for Pooideae, and provide foundational data regarding the group's biogeography and history of character evolution. METHODS: Supplementing available ITS and ndhF sequence data, we built a preliminary Bayesian-based Melica phylogeny, and used it to understand how the genus has diversified in relation to geography, climate and trait variation surveyed from various floras. We also determine biomass accumulation under controlled conditions for Melica species collected across different latitudes and compare inflorescence development across two taxa for which whole genome data are forthcoming. KEY RESULTS: Our phylogenetic analyses reveal three strongly supported geographically structured Melica clades that are distinct from previously hypothesized subtribes. Despite less geographical affinity between clades, the two sister 'Ciliata' and 'Imperfecta' clades segregate from the more phylogenetically distant 'Nutans' clade in thermal climate variables and precipitation seasonality, with the 'Imperfecta' clade showing the highest levels of trait variation. Growth rates across Melica are positively correlated with latitude of origin. Variation in inflorescence morphology appears to be explained largely through differences in secondary branch distance, phyllotaxy and number of spikelets per secondary branch. CONCLUSIONS: The data presented here and in previous studies suggest that Melica possesses many of the necessary features to be developed as an additional model for Pooideae grasses, including a relatively fast generation time, perenniality, and interesting variation in physiology and morphology. The next step will be to generate a genome-based phylogeny and transformation tools for functional analyses.

Correlates of Longitudinal Trajectories of Depressive Symptoms in Adolescents With Traumatic Brain Injuries.

OBJECTIVE: Depression poses a significant threat to the health and well-being of adolescents with traumatic brain injury. Existing research has limitations in longitudinal follow-up period, consideration of sample heterogeneity, and outcome measurement modeling. This study aimed to address these gaps by applying the second-order growth mixture model (SO-GMM) to examine the 10-year post-injury depression trajectories in adolescents with TBI. METHODS: A total of 1,989 adolescents with TBI 16-21 years old from the Traumatic Brain Injury Model System National Data Bank were analyzed up to 10 years post-injury. Depressive symptoms were measured by Patient Health Questionnaire-9. Covariates included age, sex, race/ethnicity, employment, Functional Independence Measure Cognition, TBI severity, pre-injury disability, and substance use. Longitudinal measurement invariance was tested at the configural, metric, and scalar levels before SO-GMM was fit. Logistic regression was conducted for disparities in depression trajectories by covariates. RESULTS: A 2-class SO-GMM was identified with a low-stable group (85% of the sample) and a high-increasing group (15% of the sample) on depression levels. Older age, being a Native American, and having Hispanic origin was associated with a higher likelihood of being in the high-increasing class (odds ratios [ORs] = 1.165-4.989 and 1.609, respectively), while patients with higher education and being male were less likely to be in the high-increasing class (ORs = 0.735 and 0.557, respectively). CONCLUSIONS: This study examined the disparities in depression among two distinct longitudinal groups of adolescents with TBI 10 years post-injury. Findings of the study are informative for intervention development to improve long-term mental health in adolescents with TBI.

The revised reference genome of the leopard gecko (Eublepharis macularius) provides insight into the considerations of genome phasing and assembly.

Genomic resources across squamate reptiles (lizards and snakes) have lagged behind other vertebrate systems and high-quality reference genomes remain scarce. Of the 23 chromosome-scale reference genomes across the order, only 12 of the ~60 squamate families are represented. Within geckos (infraorder Gekkota), a species-rich clade of lizards, chromosome-level genomes are exceptionally sparse representing only two of the seven extant families. Using the latest advances in genome sequencing and assembly methods, we generated one of the highest-quality squamate genomes to date for the leopard gecko, Eublepharis macularius (Eublepharidae). We compared this assembly to the previous, short-read only, E. macularius reference genome published in 2016 and examined potential factors within the assembly influencing contiguity of genome assemblies using PacBio HiFi data. Briefly, the read N50 of the PacBio HiFi reads generated for this study was equal to the contig N50 of the previous E. macularius reference genome at 20.4 kilobases. The HiFi reads were assembled into a total of 132 contigs, which was further scaffolded using HiC data into 75 total sequences representing all 19 chromosomes. We identified 9 of the 19 chromosomal scaffolds were assembled as a near-single contig, whereas the other 10 chromosomes were each scaffolded together from multiple contigs. We qualitatively identified that the percent repeat content within a chromosome broadly affects its assembly contiguity prior to scaffolding. This genome assembly signifies a new age for squamate genomics where high-quality reference genomes rivaling some of the best vertebrate genome assemblies can be generated for a fraction of previous cost estimates. This new E. macularius reference assembly is available on NCBI at JAOPLA010000000.

G × E interactions as a basis for toxicological uncertainty.

To transfer toxicological findings from model systems, e.g. animals, to humans, standardized safety factors are applied to account for intra-species and inter-species variabilities. An alternative approach would be to measure and model the actual compound-specific uncertainties. This biological concept assumes that all observed toxicities depend not only on the exposure situation (environment = E), but also on the genetic (G) background of the model (G × E). As a quantitative discipline, toxicology needs to move beyond merely qualitative G × E concepts. Research programs are required that determine the major biological variabilities affecting toxicity and categorize their relative weights and contributions. In a complementary approach, detailed case studies need to explore the role of genetic backgrounds in the adverse effects of defined chemicals. In addition, current understanding of the selection and propagation of adverse outcome pathways (AOP) in different biological environments is very limited. To improve understanding, a particular focus is required on modulatory and counter-regulatory steps. For quantitative approaches to address uncertainties, the concept of "genetic" influence needs a more precise definition. What is usually meant by this term in the context of G × E are the protein functions encoded by the genes. Besides the gene sequence, the regulation of the gene expression and function should also be accounted for. The widened concept of past and present "gene expression" influences is summarized here as Ge. Also, the concept of "environment" needs some re-consideration in situations where exposure timing (Et) is pivotal: prolonged or repeated exposure to the insult (chemical, physical, life style) affects Ge. This implies that it changes the model system. The interaction of Ge with Et might be denoted as Ge × Et. We provide here general explanations and specific examples for this concept and show how it could be applied in the context of New Approach Methodologies (NAM).

The enigmatic Placozoa part 2: Exploring evolutionary controversies and promising questions on earth and in space.

The placozoan Trichoplax adhaerens has been bridging gaps between research disciplines like no other animal. As outlined in part 1, placozoans have been subject of hot evolutionary debates and placozoans have challenged some fundamental evolutionary concepts. Here in part 2 we discuss the exceptional genetics of the phylum Placozoa and point out some challenging model system applications for the best known species, Trichoplax adhaerens.

The enigmatic Placozoa part 1: Exploring evolutionary controversies and poor ecological knowledge.

The placozoan Trichoplax adhaerens is a tiny hairy plate and more simply organized than any other living metazoan. After its original description by F.E. Schulze in 1883, it attracted attention as a potential model for the ancestral state of metazoan organization, the "Urmetazoon". Trichoplax lacks any kind of symmetry, organs, nerve cells, muscle cells, basal lamina, and extracellular matrix. Furthermore, the placozoan genome is the smallest (not secondarily reduced) genome of all metazoan genomes. It harbors a remarkably rich diversity of genes and has been considered the best living surrogate for a metazoan ancestor genome. The phylum Placozoa presently harbors three formally described species, while several dozen "cryptic" species are yet awaiting their description. The phylogenetic position of placozoans has recently become a contested arena for modern phylogenetic analyses and view-driven claims. Trichoplax offers unique prospects for understanding the minimal requirements of metazoan animal organization and their corresponding malfunctions.

Acceleration effect of galacturonic acid on acrylamide generation: evidence in model reaction systems.

BACKGROUND: Acrylamide (AA) is a potential carcinogen formed in food rich in carbohydrate during heating. Recently, AA has been found in several fruit products, such as prune juice, sugarcane molasses and canned black olives. This study focused on the role of galacturonic acid (GalA), the main acid hydrolysis product of fruit pectin, in AA formation in three model systems - asparagine (Asn)/glucose (Glc), Asn/GalA, and Asn/Glc/GalA - during heating under different pH values (pH 3.8-7.8), Glc concentration (0-0.1 mol L-1 ), molar ratio of substrates (Asn/Glc = 1:1, 0.025-0.5 mol L-1 ) and temperature (120-180 °C) for 30 min, respectively. RESULTS: The results suggested that the addition of 0.1 mol L-1 GalA strongly accelerated AA formation in a manner dependent on pH value and temperature (P < 0.05). AA concentration under different Glc concentration and molar ratio of substrates suggested that GalA was more reactive than Glc when reacted with Asn. Furthermore, the Amadori rearrangement product/Schiff base/oxazolidine-5-one were identified as the intermediates formed in the Asn/GalA model system using ultra-performance liquid chromatography-quadrupole-time-of-flight-mass spectrometry. CONCLUSION: The results suggested that Maillard reaction between Asn and GalA might contribute to AA formation. This study is significant in elucidating the contribution of interaction between components for AA formation in fruit products. © 2022 Society of Chemical Industry.

Accounting for the spatial incidence of working from home in an integrated transport and land model system.

The COVID-19 pandemic has resulted in a seismic shift in the way in which work is conducted. Remote working or working from home is becoming a centrepiece of the next normal with strong support from both employers and employees. With reduced commuting activity associated with an expected 1 to 2 days working from home for many occupations and industries, associated with releasing commuting time to spend on other activities including changed levels and patterns on non-commuting travel, it is necessary, indeed essential, to allow for the incidence of working from home in integrated strategic transport and location model systems. In this paper we show the extent of changes in travel behaviour and the performance of the transport network before and after allowing for working from home, which is more impactful than any new infrastructure project. The differences are significant and suggest that even within the existing modelling frameworks used pre-COVID-19, we need to make adjustments in the modal activity overall and by location. Using the MetroScan platform in the Greater Sydney Metropolitan area, we present a number of outputs to illustrate the significant impacts of working from home such as modal activity (total and shares), emissions, government revenues, and generalised cost of travel.

Rifampin Pharmacokinetics/Pharmacodynamics in the Hollow-Fiber Model of Mycobacterium kansasii Infection.

There is limited high-quality evidence to guide the optimal treatment of Mycobacterium kansasii pulmonary disease. We retrospectively collected clinical data from 33 patients with M. kansasii pulmonary disease to determine the time-to-sputum culture conversion (SCC) upon treatment with a standard combination regimen consist of isoniazid-rifampin-ethambutol. Next, MIC experiments with 20 clinical isolates were performed, followed by a dose-response study with the standard laboratory strain using the hollow-fiber system model of M. kansasii infection (HFS-Mkn). The inhibitory sigmoid maximum effect (Emax) model was used to describe the relationship between the bacterial burden and rifampin concentrations. Finally, in silico clinical trial simulations were performed to determine the clinical dose to achieve the optimal rifampin exposure in patients. The SCC rate in patients treated with combination regimen containing rifampin at 10 mg/kg of body weight/day was 73%, the mean time to SSC was 108 days, and the mean duration of therapy was 382 days. The MIC of the M. kansasii laboratory strain was 0.125 mg/L, whereas the MICs of the clinical isolates ranged between 0.5 and 4 mg/L. In the HFS-Mkn model, a maximum kill (Emax) of 7.82 log10 CFU/mL was recorded on study day 21. The effective concentration mediating 80% of the Emax (EC80) was calculated as the ratio of the maximum concentration of drug in serum for the free, unbound fraction (fCmax) to MIC of 34.22. The target attainment probability of the standard 10-mg/kg/day dose fell below 90% even at the MIC of 0.0625 mg/L. Despite the initial kill, there was M. kansasii regrowth with the standard rifampin dose in the HFS-Mkn model. Doses higher than 10 mg/kg/day, in combination with other drugs, need to be evaluated for better treatment outcome.