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Muscle tissue drives nearly all movement in the animal kingdom, providing power, mobility, and dexterity. Technologies for measuring muscle tissue motion, such as sonomicrometry, fluoromicrometry, and ultrasound, have significantly advanced our understanding of biomechanics. Yet, the field lacks the ability to monitor muscle tissue motion for animal behavior outside the lab. Towards addressing this issue, we previously introduced magnetomicrometry, a method that uses magnetic beads to wirelessly monitor muscle tissue length changes, and we validated magnetomicrometry via tightly-controlled in situ testing. In this study we validate the accuracy of magnetomicrometry against fluoromicrometry during untethered running in an in vivo turkey model. We demonstrate real-time muscle tissue length tracking of the freely-moving turkeys executing various motor activities, including ramp ascent and descent, vertical ascent and descent, and free roaming movement. Given the demonstrated capacity of magnetomicrometry to track muscle movement in untethered animals, we feel that this technique will enable new scientific explorations and an improved understanding of muscle function.

Human movement is accomplished through muscle contraction, yet there does not exist a portable system capable of monitoring muscle length changes in real time. To address this limitation, we previously introduced magnetomicrometry, a minimally-invasive tracking technique comprising two implanted magnetic beads in muscle and a magnetic field sensor array positioned on the body’s surface adjacent the implanted beads. The implant system comprises a pair of spherical magnetic beads, each with a first coating of nickel-copper-nickel and an outer coating of Parylene C. In parallel work, we demonstrate submillimeter accuracy of magnetic bead tracking for muscle contractions in an untethered freely-roaming avian model. Here, we address the clinical viability of magnetomicrometry. Using a specialized device to insert magnetic beads into muscle in avian and lagomorph models, we collect data to assess gait metrics, bead migration, and bead biocompatibility. For these animal models, we find no gait differences post-versus pre-implantation, and bead migration towards one another within muscle does not occur for initial bead separation distances greater than 3 cm. Further, using extensive biocompatibility testing, the implants are shown to be non-irritant, non-cytotoxic, non-allergenic, and non-irritating. Our cumulative results lend support for the viability of these magnetic bead implants for implantation in human muscle. We thus anticipate their imminent use in human-machine interfaces, such as in control of prostheses and exoskeletons and in closed-loop neuroprosthetics to aid recovery from neurological disorders.

Interleukin-1β (IL-1β) is a potent proinflammatory cytokine that plays a vital role in the innate immune system. To observe the innate immune response in vivo, several transgenic zebrafish lines have been developed to model IL-1β-induced inflammation and to visualize immune cell migration and proliferation in real time. However, our understanding of the IL-1β response in zebrafish is limited due to an incomplete genome annotation and a lack of functional data for the cytokine receptors involved in the inflammatory process. Here, we use a combination of database mining, genetic analyses, and functional assays to identify zebrafish Interleukin-1 receptor, type 1 (Il1r1). We identified putative zebrafish il1r1 candidate genes that encode proteins with predicted structures similar to human IL1R1. To examine functionality of these candidates, we designed highly effective morpholinos to disrupt gene expression in a zebrafish model of embryonic Il-1β-induced systemic inflammation. In this double transgenic model, ubb:Gal4-EcR, uas:il1βmat, the zebrafish ubiquitin b (ubb) promoter drives expression of the modified Gal4 transcription factor fused to the ecdysone receptor (EcR), which in turn drives the tightly-regulated expression and secretion of mature Il-1β only in the presence of the ecdysone analog tebufenozide (Teb). Application of Teb to ubb:Gal4-EcR, uas:il1βmat embryos causes premature death, fin degradation, substantial neutrophil expansion, and generation of reactive oxygen species (ROS). To rescue these deleterious phenotypes, we injected ubb:Gal4-EcR, uas:il1βmat embryos with putative il1r1 morpholinos and found that knockdown of only one candidate gene prevented the adverse effects caused by Il-1β. Mosaic knockout of il1r1 using the CRISPR/Cas9 system phenocopied these results. Taken together, our study identifies the functional zebrafish Il1r1 utilizing a genetic model of Il-1β-induced inflammation and provides valuable new insights to study inflammatory conditions specifically driven by Il-1β or related to Il1r1 function in zebrafish.

Cataract surgery is a safe, effective and common elective procedure in Australia but access is inequitable. True waiting times for cataract care are undisclosed or inconsistently reported by governments. Estimates of true waiting times range from 4 to 30 months and have been extended during the coronavirus disease 2019 (COVID-19) pandemic. Comparative analysis revealed that reducing waiting periods from 12 to 3 months would result in estimated public health system cost savings of $6.6 million by preventing 50 679 falls. Investment in public cataract services to address current unmet needs would prevent avoidable vision impairment and associated negative consequences.

Adolescent idiopathic scoliosis (AIS) is a prevalent musculoskeletal disorder that causes abnormal spinal deformities. The early screening of children and adolescents is crucial to identify and prevent the further progression of AIS. In clinical examinations, scoliometers are often used to noninvasively estimate the primary Cobb angle, and optical 3D scanning systems have also emerged as alternative noninvasive approaches for this purpose. The recent advances in low-cost 3D scanners have led to their use in several studies to estimate the primary Cobb angle or even internal spinal alignment. However, none of these studies demonstrate whether such a low-cost scanner satisfies the minimal requirements for capturing the relevant deformities of the human back. To practically quantify the minimal required spatial resolution and camera resolution to capture the geometry and shape of the deformities of the human back, we used multiple 3D scanning methodologies and systems. The results from an evaluation of 30 captures of AIS patients and 76 captures of healthy subjects showed that the minimal required spatial resolution is between 2 mm and 5 mm, depending on the chosen error tolerance. Therefore, a minimal camera resolution of 640 × 480 pixels is recommended for use in future studies.

Primaquine is an important antimalarial drug for malaria transmission blocking and radical cure, but it is not currently available in child-friendly formulations in appropriate doses. Adult-strength tablets are often crushed and dissolved in water to obtain the required dose, which exposes the drug’s bitter taste. As part of the developing paediatric primaquine (DPP) project, this study adopted a responsive sensory pharmaceutics approach by integrating real-time formulation development and pre-clinical taste assessment to develop palatable, flavour-infused primaquine tablets. A design of experiment (DoE) approach was used to screen different taste-masking agents and excipient blends with trained, expert sensory assessors, with quinine hydrochloride as a model bitter tastant. The taste-masking efficacy of selected prototype formulation blends was validated with naïve assessors using the highest 15 mg primaquine dose. The mean bitterness intensity rating, measured on a discrete 11-point scale, was halved from 7.04 for the unflavoured control to 2.74–3.70 for the formulation blends. Sucralose had the biggest impact on bitterness suppression and improving palatability. Two different flavouring systems have been developed, and their acceptability in paediatric patients will be assessed as part of upcoming validation field clinical trials in Africa.

Abstract Turfgrasses are perennial components of urban greenspaces found in parks, recreational areas, golf courses, sports fields, and lawns that confer many ecosystem services. A copious seed producer, Poa annua is the most troublesome weed of turfgrass and continually threatens the ecosystem services provided by urban greenspaces. Field research was conducted in Knoxville, TN to better understand environmental conditions triggering P. annua seedling emergence patterns to assist managers with optimally timing interventions—both chemical and non-chemical—for control. Fluctuations in cooling degree day (CDD21C) accumulation accounted for 82% of the variance in yearly cumulative P. annua emergence data collected in a single irrigated sward of hybrid bermudagrass [C. dactylon (L.) Pers. x. C. transvaalensis Burtt-Davy]. However, non-linear models using CDD21C data developed ex post were not able to accurately predict P. annua emergence patterns ex ante. In both years, P. annua emergence changed most rapidly between the 40th and 43rd week of the year when seven-day mean soil temperature and rainfall were 18.9 °C and 12.7 mm, respectively. Future research should explore the efficacy of herbicide mixtures applied when P. annua emergence is most rapidly changing in lieu of developing models to predict when specific emergence thresholds occur.

Cholangiocarcinoma (CCA) has poor prognosis due to late‐stage, symptomatic presentation. Altered DNA methylation markers may improve diagnosis of CCA. Reduced‐representation bisulfite sequencing was performed on DNA extracted from frozen CCA tissues and matched to adjacent benign biliary epithelia or liver parenchyma. Methylated DNA markers (MDMs) identified from sequenced differentially methylated regions were selected for biological validation on DNA from independent formalin‐fixed, paraffin‐embedded CCA tumors and adjacent hepatobiliary control tissues using methylation‐specific polymerase chain reaction. Selected MDMs were then blindly assayed on DNA extracted from independent archival biliary brushing specimens, including 12 perihilar cholangiocarcinoma, 4 distal cholangiocarcinoma cases, and 18 controls. Next, MDMs were blindly assayed on plasma DNA from patients with extrahepatic CCA (eCCA), including 54 perihilar CCA and 5 distal CCA cases and 95 healthy and 22 primary sclerosing cholangitis controls, balanced for age and sex. From more than 3,600 MDMs discovered in frozen tissues, 39 were tested in independent samples. In the clinical pilot of 16 MDMs on cytology brushings, methylated EMX1 (empty spiracles homeobox 1) had an area under the curve (AUC) of 0.98 (95% confidence interval [CI], 0.95‐1.0). In the clinical pilot on plasma, a cross‐validated recursive partitioning tree prediction model from nine MDMs was accurate for de novo eCCA (AUC, 0.88 [0.81‐0.95]) but not for primary sclerosing cholangitis–associated eCCA (AUC, 0.54 [0.35‐0.73]). Conclusion: Next‐generation DNA sequencing yielded highly discriminant methylation markers for CCA. Confirmation of these findings in independent tissues, cytology brushings, and plasma supports further development of DNA methylation to augment diagnosis of CCA.

Ecosystems limited in phosphorous (P) are widespread, yet there is limited understanding of how these ecosystems may respond to anthropogenic deposition of nitrogen (N) and the interconnected effects on the biogeochemical cycling of carbon (C), N, and P. Here, we investigate the consequences of enhanced N addition for the C–N–P pools of two P-limited grasslands, one acidic and one limestone, occurring on contrasting soils, and we explore their responses to a long-term nutrient-manipulation experiment. We do this by combining data with an integrated C–N–P cycling model (N14CP). We explore the role of P-access mechanisms by allowing these to vary in the modelling framework and comparing model plant–soil C–N–P outputs to empirical data. Combinations of organic P access and inorganic P availability most closely representing empirical data were used to simulate the grasslands and quantify their temporal response to nutrient manipulation. The model suggested that access to organic P is a key determinant of grassland nutrient limitation and responses to experimental N and P manipulation. A high rate of organic P access allowed the acidic grassland to overcome N-induced P limitation, increasing biomass C input to soil and promoting soil organic carbon (SOC) sequestration in response to N addition. Conversely, poor accessibility of organic P for the limestone grassland meant N provision exacerbated P limitation and reduced biomass input to the soil, reducing soil carbon storage. Plant acquisition of organic P may therefore play an important role in reducing P limitation and determining responses to anthropogenic changes in nutrient availability. We conclude that grasslands differing in their access to organic P may respond to N deposition in contrasting ways, and where access is limited, soil organic carbon stocks could decline.

Abstract Genetic association studies have identified multiple variants at the SPI1 locus that modify risk and age of onset for Alzheimer’s Disease (AD). Reports linking risk variants to gene expression suggest that variants denoting higher SPI1 expression are likely to have an earlier AD onset, and several other AD risk genes contain PU.1 binding sites in the promoter region. Overall, this suggests the level of SPI1 may alter microglial phenotype potentially impacting AD. This study determined how the microglial transcriptome was altered following modest changes to Spi1 expression in primary mouse microglia. RNA-sequencing was performed on microglia with reduced or increased Spi1/PU.1 expression to provide an unbiased approach to determine transcriptomic changes affected by Spi1. In summary, a reduction in microglial Spi1 resulted in the dysregulation of transcripts encoding proteins involved in DNA replication pathways while an increased Spi1 results in an upregulation of genes associated with immune response pathways. Additionally, a subset of 194 Spi1 dose-sensitive genes was identified and pathway analysis suggests that several innate immune and interferon response pathways are impacted by the concentration of Spi1. Together these results suggest Spi1 levels can alter the microglial transcriptome and suggests interferon pathways may be altered in individuals with AD related Spi1 risk SNPs.

Potassium ion (K+) plays a critical role as an essential electrolyte in all biological systems. Genetically-encoded fluorescent K+ biosensors are promising tools to further improve our understanding of K+-dependent processes under normal and pathological conditions. Here, we report the crystal structure of a previously reported genetically-encoded fluorescent K+ biosensor, GINKO1, in the K+-bound state. Using structure-guided optimization and directed evolution, we have engineered an improved K+ biosensor, designated GINKO2, with higher sensitivity and specificity. We have demonstrated the utility of GINKO2 for in vivo detection and imaging of K+ dynamics in multiple model organisms, including bacteria, plants, and mice.

Inflammatory physiology has been linked to behavioral and emotional symptoms in a variety of contexts and experimental paradigms. Hematopoietic cell transplantation (HCT) represents an intersection of significant immune dysregulation and psychosocial stress, and this biobehavioral relationship can influence important clinical outcomes. For those undergoing HCT with inflammation-related neuropsychiatric symptoms, using targeted agents such as the IL-6 receptor antagonist tocilizumab may be an effective therapeutic approach. We conducted an observational cohort study to explore patient reported outcomes (PROs) and inflammatory biomarkers among allogeneic HCT recipients who received tocilizumab compared to those who did not. Individuals on a larger trial of tocilizumab for prevention of graft-versus-host disease received a single dose of tocilizumab 24 h prior to stem cell infusion. Measures of anxiety, depression, pain, fatigue, and sleep quality and parallel blood samples for inflammatory cytokines were collected from participants and an analogous comparison cohort at baseline and Day 28 after stem cell infusion. Demographic and medical characteristics were reported; an analysis of covariance regression model was fitted to evaluate differences in PROs and distance correlation t-tests assessed for associations between biomarkers and PRO measures. For n = 18 tocilizumab-treated and n = 22 comparison patients, there were no significant differences between patient demographics, but the tocilizumab cohort had a different distribution of primary diagnoses (p = 0.009) with more patients with leukemias and a higher proportion of patients in their first remission (64% vs 28%, p = 0.024). Depression was higher at Day 28 compared to baseline in both groups (comparison group: +5.1 [95% CI 0.14–10, p = 0.045], tocilizumab: +8.6 [95% CI 2.3–15, p = 0.011]), though the difference between groups did not reach statistical significance. The tocilizumab group had significantly increased circulating IL-6 and decreased CRP at Day 28 (all p

A growing body of literature has emphasized the importance of biobehavioral processes – defined as the interaction of behavior, psychology, socioenvironmental factors, and biological processes – for clinical outcomes among transplantation and cellular therapy (TCT) patients. TCT recipients are especially vulnerable to distress associated with pandemic conditions and represent a notably immunocompromised group at greater risk for SARS-CoV-2 infection with substantially worse outcomes. The summation of both the immunologic and psychologic vulnerability of TCT patients renders them particularly susceptible to adverse biobehavioral sequelae associated with the Covid-19 pandemic. Stress and adverse psychosocial factors alter neural and endocrine pathways through sympathetic nervous system and hypothalamic-pituitary-adrenal axis signaling that ultimately affect gene regulation in immune cells. Reciprocally, global inflammation and immune dysregulation related to TCT contribute to dysregulation of neuroendocrine and central nervous system function, resulting in the symptom profile of depression, fatigue, sleep disturbance, and cognitive dysfunction. In this article, we draw upon literature on immunology, psychology, neuroscience, hematology and oncology, Covid-19 pathophysiology, and TCT processes to discuss how they may intersect to influence TCT outcomes, with the goal of providing an overview of the significance of biobehavioral factors in understanding the relationship between Covid-19 and TCT, now and for the future. We discuss the roles of depression, anxiety, fatigue, sleep, social isolation and loneliness, and neurocognitive impairment, as well as specific implications for sub-populations of interest, including pediatrics, caregivers, and TCT donors. Finally, we address protective psychological processes that may optimize biobehavioral outcomes affected by Covid-19.

In the last few decades wild boar populations have expanded northwards, colonizing boreal forests. The soil disturbances caused by wild boar rooting may have an impact on soil organisms that play a key role in organic matter turnover. However, the impact of wild boar colonization on boreal forest ecosystems and soil organisms remains largely unknown. We investigated the effect of natural and simulated rooting on decomposer and predatory soil mites (total, adult and juvenile abundances; and adult–juvenile proportion). Our simulated rooting experiment aimed to disentangle the effects of (i) bioturbation due to soil mixing and (ii) removing organic material (wild boar food resources) on soil mites. Our results showed a decline in the abundance of adult soil mites in response to both natural and artificial rooting, while juvenile abundance and the relative proportion of adults and juveniles were not affected. The expansion of wild boar northwards and into new habitats has negative effects on soil decomposer abundances in boreal forests which may cascade through the soil food web ultimately affecting ecosystem processes. Our study also suggests that a combined use of natural and controlled experimental approaches is the way forward to reveal any subtle interaction between aboveground and belowground organisms and the ecosystem functions they drive.

Abstract Background Phytophthora species are well known as important or emerging pathogens. The genus Rhododendron is of considerable importance to plant regulatory agencies because it is host to many Phytophthora species, most notably, P. ramorum and P. kernoviae. Few studies have directly contrasted the epidemiology of different Phytophthora spp. on a given host. Methods We investigated aspects of the foliar epidemiology (lesion size, sporulation and temperature responses) of P. cactorum, P. cambivora, P. cinnamomi, P. citrophthora, P. foliorum, P. kernoviae, P. lateralis, P. nemorosa, P. nicotianae, P. plurivora, P. ramorum and P. syringae on Rhododendron in detached leaf, whole plant chamber, and field studies. Results P. syringae stood out as it appeared to be a relatively weak pathogen, showing no sporulation and low levels of disease severity, except at low temperatures. P. nicotianae was consistently able to grow at higher temperatures than any of the other Phytophthora spp. and showed higher aggressiveness than any of the other species at high temperatures. P. cinnamomi and P. cactorum, typically thought of as root-infecting species, were able to cause as much foliar disease as P. syringae, a foliar pathogen. P. kernoviae was consistently among the most aggressive species with the highest sporulation. Conclusion These results provide novel insights into the comparative epidemiology of these important established and emerging Phytophthora species.

Abstract Background Blood type has been associated with the risk of gastric cancer, but few studies have examined the association with esophageal squamous cell carcinoma (ESCC). Methods We conducted a case-control study using genotyping data of Chinese individuals, including cases of 2022 ESCC, 1189 gastric cardia adenocarcinoma, 1161 gastric noncardia adenocarcinoma, and 2696 controls. Genetic blood type was imputed using three single nucleotide polymorphisms. We used logistic regression to examine the association between blood type and the risk of each cancer. Results Compared to blood type O, the risk of ESCC was significantly elevated for blood type B and AB, with the highest risk for type AB (OR, 95%CI: 1.34, 1.07–1.67). Analysis of genotype suggested that the association of ESCC was from carrying the B allele. Similarly, blood type was significantly associated with gastric noncardia adenocarcinoma (P

Attempts to use computers to aid in the detection of breast malignancies date back more than 20 years. Despite significant interest and investment, this has historically led to minimal or no significant improvement in performance and outcomes with traditional computer-aided detection. However, recent advances in artificial intelligence and machine learning are now starting to deliver on the promise of improved performance. There are at present more than 20 FDA-approved AI applications for breast imaging, but adoption and utilization are widely variable and low overall. Breast imaging is unique and has aspects that create both opportunities and challenges for AI development and implementation. Breast cancer screening programs worldwide rely on screening mammography to reduce the morbidity and mortality of breast cancer, and many of the most exciting research projects and available AI applications focus on cancer detection for mammography. There are, however, multiple additional potential applications for AI in breast imaging, including decision support, risk assessment, breast density quantitation, workflow and triage, quality evaluation, response to neoadjuvant chemotherapy assessment, and image enhancement. In this review the current status, availability, and future directions of investigation of these applications are discussed, as well as the opportunities and barriers to more widespread utilization.

Abstract Borrelia miyamotoi, a member of the tick-borne relapsing fever spirochetes, shows a serum-resistant phenotype in vitro. This ability of B. miyamotoi may contribute to bacterial evasion of the host innate immune system. To investigate the molecular mechanism of serum-resistance, we constructed a membrane protein-encoding gene library of B. miyamotoi using Borrelia garinii strain HT59G, which shows a transformable and serum-susceptible phenotype. By screening the library, we found that bom1093 and bom1515 of B. miyamotoi provided a serum-resistant phenotype to the recipient B. garinii. These B. miyamotoi genes are predicted to encode P35-like antigen genes and are conserved among relapsing fever borreliae. Functional analysis revealed that BOM1093 bound to serum vitronectin and that the C-terminal region of BOM1093 was involved in the vitronectin-binding property. Importantly, the B. garinii transformant was not serum-resistant when the C terminus-truncated BOM1093 was expressed. We also observed that the depletion of vitronectin from human serum enhances the bactericidal activity of BOM1093 expressing B. garinii, and the survival rate of BOM1093 expressing B. garinii in vitronectin-depleted serum is enhanced by the addition of purified vitronectin. Our data suggests that B. miyamotoi utilize BOM1093-mediated binding to vitronectin as a mechanism of serum resistance.

Introduction The diagnosis of neurodegenerative and psychiatric disorders (NPDs) in primary care can suffer from inefficiencies resulting in misdiagnoses and delayed diagnosis, limiting effective treatment options. The development of speech and language-based profiling biomarkers could aid in achieving earlier motor diagnosis for PD for instance, or more accurate diagnosis of clinically similar or late presenting NPDs. Objectives RHAPSODY aims to investigate the feasibility of the remote administration of a battery of speech tasks in eliciting continuous narrative speech across a range of NPDs. The project also aims to determine the feasibility of using acoustic and linguistic biomarkers from speech data to support the clinical assessment and disambiguation of common NPDs Methods All participants (n=250) will take part in a single virtual telemedicine video conference with a researcher in which they are screened and complete a battery of speech tasks, in addition to cohort-specific screening measures. Over the following month, participants will be asked to complete a series of short, self-administered speech assessments via a smartphone application. Results The speech tasks will be audio-recorded and analysed on Novoic’s technology platform. Objectives will be analysed using measures including average length of speech elicitation for speech tasks, intra- and inter-subject variance, differences in linguistic patterns, and response rates to speech assessments. Conclusions The analyses could help to identify and validate speech-derived clinical biomarkers to support clinicians in detecting and disambiguating between NPDs with heterogeneous presentations. This should further support earlier intervention, improved treatment options and improved quality of life. Disclosure In terms of significant financial interest and relationships, it is emphasised that the private organisation Novoic, who aim to develop speech algorithms for diagnostic use, is the study’s sponsor and employees or former employees of this company comprise

ObjectiveExplore the influence of family history of upper gastrointestinal (UGI) cancer on UGI cancer death, based on the Linxian Dysplasia Nutrition Intervention Trial (NIT) cohort.MethodsFamily history of UGI cancer was defined as at least one first-degree relative (parent, child, or sibling) had a history of esophageal or gastric cancer. Cancer death was carried out by ICD-10 code. Family history information was collected at baseline and cancer deaths were assessed at each annual follow-up. The COX proportional risk model was used to estimate the hazard ratio (HR) and 95% confidence interval (95% CI). We compared the positive family history group with the negative to determine the risk of family history on UGI cancer death. The effect of category of relatives, number of relatives with UGI cancer, and diagnosis age of relatives on the UGI death risk were further analyzed. Interaction and stratification analyses were done to see the subgroup effects. Sensitivity analyses were also conducted by exclusion of individuals who were followed up less than three years. We considered controlling of covariates including: gender, age (continuity), community, education level, number of siblings (continuity), BMI (continuity), smoking, alcohol use, fresh fruit intake, fresh vegetable intake, hot beverage intake, edible oil intake, meat intake, and moldy staple food intake. All food intake variables were converted into categorical variables.ResultsFrom1985 to2015, we followed up total 3,318 individuals with 898 UGI cancer deaths (537 from ESCC, 77 from GNCC, and 284 from GCC). In a single factor analysis, family history of UGI cancer increased the risk of death of esophageal squamous cell carcinoma (ESCC) by 27% (HR=1.270, 95%CI1.072-1.504). No associations were observed in gastric cardia carcinoma (GCC) and gastric non-cardia carcinoma (GNCC). After adjusting for multi-factor, a family history of UGI cancer risk of death increased by 31.9% from ESCC (HR=1.319,95%CI:1.110-1.567). Subgroup analysis of different types of relatives with UGI cancers, UGI cancers in the mother (HR=1.457,95%CI:1.200-1.768), brother (HR=1.522,95%CI:1.117-2.073), and sister (HR=1.999,95%CI:1.419-2.817) were independent risk factors for ESCC death, while the father was not. In addition, 2 relatives with UGI cancer (HR=1.495, 95%, CI:1.110-2.013) and ≥3 relatives with UGI cancer (HR=2.836, 95%CI:1.842-4.367) significantly increased the risk of ESCC death, and the trend test was statistically significant (P

Understanding the sources of error is critical before models of the musculoskeletal system can be usefully translated. Using in vivo measured tibiofemoral forces, the impact of uncertainty in muscle–tendon parameters on the accuracy of knee contact force estimates of a generic musculoskeletal model was investigated following a probabilistic approach. Population variability was introduced to the routine musculoskeletal modeling framework by perturbing input parameters of the lower limb muscles around their baseline values. Using ground reaction force and skin marker trajectory data collected from six subjects performing body-weight squat, the knee contact force was calculated for the perturbed models. The combined impact of input uncertainties resulted in a considerable variation in the knee contact force estimates (up to 2.1 BW change in the predicted force), especially at larger knee flexion angles, hence explaining up to 70% of the simulation error. Although individual muscle groups exhibited different contributions to the overall error, variation in the maximum isometric force and pathway of the muscles showed the highest impacts on the model outcomes. Importantly, this study highlights parameters that should be personalized in order to achieve the best possible predictions when using generic musculoskeletal models for activities involving deep knee flexion.

Sustained complement activation is an underlying pathologic driver in many inflammatory and autoimmune diseases. Currently approved anti-complement therapies are directed at the systemic blockade of complement. Consequently, these therapies provide widespread inhibition of complement pathway activity, beyond the site of ongoing activation and the intended pharmacodynamic (PD) effects. Given the essential role for complement in both innate and adaptive immunity, there is a need for therapies that inhibit complement in diseased tissue while limiting systemic blockade. One potential approach focuses on the development of novel fusion proteins that enable tissue-targeted delivery of complement negative regulatory proteins. These therapies are expected to provide increased potency and prolonged tissue PD, decreased dosing frequency, and the potential for improved safety profiles. We created a library of bifunctional fusion proteins that direct a fragment of the complement negative regulator, complement receptor type 1 (CR1) to sites of tissue injury. Tissue targeting is accomplished through the binding of the fusion protein to complement C3 fragments that contain a surface-exposed C3d domain and which are covalently deposited on tissues where complement is being activated. To that end, we generated a fusion protein that contains an anti-C3d monoclonal antibody recombinantly linked to the first 10 consensus repeats of CR1 (CR11-10) with the intention of delivering high local concentrations of this complement negative regulatory domain to tissue-bound complement C3 fragments iC3b, C3dg and C3d. Biochemical and in vitro characterization identified several fusion proteins that inhibit complement while maintaining the C3d domain binding properties of the parent monoclonal antibody. Preclinical in vivo studies further demonstrate that anti-C3d fusion proteins effectively distribute to injured tissue and reduce C3 fragment deposition for periods beyond 14 days. The in vitro and in vivo profiles support the further evaluation of C3d mAb-CR11-10 as a novel approach to restore proper complement activation in diseased tissue in the absence of continuous systemic complement blockade.

A previously healthy 16-year-old girl presented with hemoptysis in the setting of a persistent cough for two months. Imaging identified a large mediastinal mass with cystic and solid components, calcifications and fat suggestive of a germ cell tumor. There was associated right middle lobe consolidation with an air-fluid level concerning for a necrotizing pneumonia, right upper lobe bronchiectasis, hilar lymphadenopathy, and right upper lobe and right pleural-based nodules concerning for disseminated disease. Histologic analysis of a percutaneous biopsy revealed skeletal muscle, fibroadipose tissue, skin, and keratinous debris consistent with a mature germ cell tumor. Rigid and flexible bronchoscopy were performed and identified inspissated, purulent, and fibrinous material in the right upper and middle lobe bronchi. Microbial cultures grew Staphylococcus aureus. After 3 weeks of antibiotics, complete surgical resection was performed. No malignant components were identified. Her post-operative course was uncomplicated, and she remains without evidence of disease 6 months after resection. While mediastinal teratomas are common, rupture is uncommon with fewer than 60 reported cases in the literature. Rupture can be associated with inflammation and/or infection, resulting in diagnostic and treatment challenges.

Very recently, we proposed an explanation of the discrepancy between the measured anomalous magnetic moment of the muon and the Standard Model (SM) prediction in which the dominant contribution to (g−2)μ originates in Kaluza-Klein (KK) excitations (of the lepton gauge boson) which do not mix with quarks (to lowest order) and therefore can be quite light avoiding LHC constraints. In this addendum we reexamine the bounds on 4-fermion contact interactions from precise electroweak measurements and show that the constraints on KK masses and couplings are more severe than earlier thought. However, we demonstrate that our explanation remains plausible if a few KK modes are lighter than LEP energy, because if this were the case the contribution to the 4-fermion scattering from the internal propagator would be dominated by the energy and not by the mass. To accommodate the (g−2)μ discrepancy we assume that the lepton number L does not partake in the hypercharge and propagates in one extra dimension (transverse to the SM branes): for a mass of the lowest KK excitation of 60 GeV (lower than the LEP energy), the string scale is roughly 10 TeV while the L gauge coupling is of order ∼10−1.

Abstract Extracellular vesicles (EVs) are of growing interest due to their potential diagnostic, disease surveillance, and therapeutic applications. While several studies have evaluated EV isolation methods in various biofluids, there are few if any data on these techniques when applied to stool. The latter is an ideal biospecimen for studying EVs and colorectal cancer (CRC) because the release of tumour markers by luminal exfoliation into stool occurs earlier than vascular invasion. Since EV release is a conserved mechanism, bacteria in stool contribute to the overall EV population. In this study, we assessed five EV separation methods (ultracentrifugation [UC], precipitation [EQ‐O, EQ‐TC], size exclusion chromatography [SEC], and ultrafiltration [UF]) for total recovery, reproducibility, purity, RNA composition, and protein expression in stool supernatant. CD63, TSG101, and ompA proteins were present in EV fractions from all methods except UC. Human (18s) and bacterial (16s) rRNA was detected in stool EV preparations. Enzymatic treatment prior to extraction is necessary to avoid non‐vesicular RNA contamination. Ultrafiltration had the highest recovery, RNA, and protein yield. After assessing purity further, SEC was the isolation method of choice. These findings serve as the groundwork for future studies that use high throughput omics technologies to investigate the potential of stool‐derived EVs as a source for novel biomarkers for early CRC detection.

The nanoscale architecture of synapses has been investigated using multiple super-resolution methods, revealing a common modular structure for scaffolds, neurotransmitter receptors, and presynaptic proteins. This fundamental organization of proteins into subsynaptic domains (SSDs) is thought to be important for synaptic function and plasticity and common to many types of synapses. Using 3D super-resolution Structured Illumination Microscopy (3D-SIM), we recently showed that GABAergic inhibitory synapses exhibit this nanoscale organizational principle and are composed of SSDs of GABAA receptors (GABAARs), the inhibitory scaffold gephyrin, and the presynaptic active zone protein, RIM. Here, we have investigated the use of 3D-SIM and dSTORM to analyze the nanoscale architecture of the inhibitory synaptic adhesion molecule, neuroligin-2 (NL2). NL2 is a crucial mediator of inhibitory synapse formation and organization, associating with both GABAARs and gephyrin. However, the nanoscale sub-synaptic distribution NL2 remains unknown. We found that 3D-SIM and dSTORM provide complementary information regarding the distribution of NL2 at the inhibitory synapse, with NL2 forming nanoscale structures that have many similarities to gephyrin nanoscale architecture.

Introduction: The demand for radiation therapy services in New Zealand is growing due to an increasing and ageing population. The radiation therapist (RT) workforce is currently in a vulnerable state and this study aimed to understand RT perceptions on intent to remain in both the workplace and profession. Understanding factors that contribute to satisfaction and retention are important for the development of strategies by healthcare leaders to improve workforce sustainability. Materials and methods: All current practising RTs were invited via email link to complete an online survey. Multivariate regression models were used to investigate any impact of demographic, workplace and professional variables on intent to remain in the workplace and intent to leave the profession. Results: Three hundred and sixty two (91% response rate) RTs completed the survey. Key findings include: a) 33% are thinking of leaving their current workplace with 31% of these intending to leave within the next 12 months; b) 35% intend to change careers before they retire; and c) 25% indicated they would leave the profession if they could. Workplace satisfaction, being challenged and a lack of career development opportunities were common factors that influence intention to leave both the workplace and profession. Conclusions: Strategies to ensure the sustainability of the RT workforce in New Zealand need to focus on developing a robust framework for career development including advanced practice opportunities that challenge RTs and ensuring workplaces create an environment that promote a sense of pride, camaraderie and flexibility in how they operate.

Mapping and quantifying degree of forest modification is critical to conserve and manage forests. Here the authors propose a new quantitative metric for landscape integrity and apply it to a global forest map, showing that less than half of the world’s forest cover has high integrity, most of which is outside nationally designed protected areas.

Abstract LUX-ZEPLIN (LZ) is a second-generation direct dark matter experiment with spin-independent WIMP-nucleon scattering sensitivity above $${1.4 \times 10^{-48}}\, {\hbox {cm}}^{2}$$ 1.4 × 10 - 48 cm 2 for a WIMP mass of $${40}\, \hbox {GeV}/{\hbox {c}}^{2}$$ 40 GeV / c 2 and a $${1000}\, \hbox {days}$$ 1000 days exposure. LZ achieves this sensitivity through a combination of a large $${5.6}\, \hbox {t}$$ 5.6 t fiducial volume, active inner and outer veto systems, and radio-pure construction using materials with inherently low radioactivity content. The LZ collaboration performed an extensive radioassay campaign over a period of six years to inform material selection for construction and provide an input to the experimental background model against which any possible signal excess may be evaluated. The campaign and its results are described in this paper. We present assays of dust and radon daughters depositing on the surface of components as well as cleanliness controls necessary to maintain background expectations through detector construction and assembly. Finally, examples from the campaign to highlight fixed contaminant radioassays for the LZ photomultiplier tubes, quality control and quality assurance procedures through fabrication, radon emanation measurements of major sub-systems, and bespoke detector systems to assay scintillator are presented.

Background To investigate oral leukoplakia (OL) and risk of upper gastrointestinal (UGI) cancer deaths in the Linxian Dysplasia Nutrition Intervention Trial (NIT) cohort. Methods A total of 3318 subjects with esophageal squamous dysplasia enrolled on 1 May 1985, and were followed up until 30 September 2015. Participants with OL at baseline were treated as an exposed group, while the remainder was selected as a control group. All subjects were followed monthly and reviewed quarterly by the Linxian Cancer Registry. Cox proportional hazard model was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs). Results During the 30‐year follow‐up, a total of 902 UGI cancer deaths occurred, including 541 esophageal squamous cell carcinoma (ESCC) related, 284 gastric cardia carcinoma (GCC) related, and 77 gastric noncardia carcinoma (GNCC) related deaths. Relative to subjects without OL, the long‐term risk of ESCC mortality in participants with OL increased by 26.1% (HR = 1.26, 95% CI: 1.05–1.52). In the subgroup analyses, adverse effects of OL on ESCC mortality were observed especially in younger subjects (HR = 1.48, 95% CI: 1.11–1.97), females (HR = 1.44, 95% CI: 1.11–1.89), non‐smokers (HR = 1.44, 95% CI: 1.15–1.81), nondrinkers (HR = 1.28, 95% CI: 1.04–1.57), and individuals with a family history of cancer (HR = 1.37, 95% CI: 1.05–1.79). No associations were observed between OL and risk of GCC and GNCC mortality. Conclusions OL may increase the long‐term risk of ESCC mortality, especially in younger subjects, females, nondrinkers, non‐smokers, and subjects with a family cancer history. Future studies are needed to explore the potentially etiological mechanism.

AIM: To determine the prevalence and associations of non-retinopathy ocular conditions among older Australian adults with diabetes. METHODS: Multistage random-cluster sampling was used to select 3098 non-indigenous Australians aged 50y or older (46.4% male) and 1738 indigenous Australians aged 40y or older (41.1% male) from all levels of geographic remoteness in Australia. Participants underwent a standardised questionnaire to ascertain diabetes history, and a clinical examination to identify eye disease. We determined the prevalence of uncorrected refractive error, visually significant cataract, cataract surgery, age-related macular degeneration, glaucoma, ocular hypertension, retinal vein occlusion and epiretinal membrane among those with and without self-reported diabetes. RESULTS: Participants with self-reported diabetes had a higher prevalence of cataract surgery than those without diabetes (28.8% vs 16.9%, OR 1.78, 95%CI: 1.35-2.34 among non-indigenous Australians, and 11.3% vs 5.2%, OR 1.62, 95%CI: 1.22-2.14 among indigenous Australians). Diabetic retinopathy (DR) increased the odds of cataract surgery among self-reported diabetic indigenous and non-indigenous Australians (OR 1.89, P=0.004 and OR 2.33, P

Abstract We study two-dimensional celestial conformal field theory describing four- dimensional N $$ \mathcal{N} $$ =1 supergravity/Yang-Mills systems and show that the underlying symmetry is a supersymmetric generalization of BMS symmetry. We construct fermionic conformal primary wave functions and show how they are related via supersymmetry to their bosonic partners. We use soft and collinear theorems of supersymmetric Einstein-Yang- Mills theory to derive the OPEs of the operators associated to massless particles. The bosonic and fermionic soft theorems are shown to form a sequence under supersymmetric Ward identities. In analogy with the energy momentum tensor, the supercurrents are shadow transforms of soft gravitino operators and generate an infinite-dimensional super- symmetry algebra. The algebra of sbms 4 $$ {\mathfrak{sbms}}_4 $$ generators agrees with the expectations based on earlier work on the asymptotic symmetry group of supergravity. We also show that the supertranslation operator can be written as a product of holomorphic and anti-holomorphic supercurrents.

Abstract Conformally soft gluons are conserved currents of the Celestial Conformal Field Theory (CCFT) and generate a Kac-Moody algebra. We study celestial amplitudes of Yang-Mills theory, which are Mellin transforms of gluon amplitudes and take the double soft limit of a pair of gluons. In this manner we construct the Sugawara energy-momentum tensor of the CCFT. We verify that conformally soft gauge bosons are Virasoro primaries of the CCFT under the Sugawara energy-momentum tensor. The Sugawara tensor though does not generate the correct conformal transformations for hard states. In Einstein-Yang- Mills theory, we consider an alternative construction of the energy-momentum tensor, similar to the double copy construction which relates gauge theory amplitudes with gravity ones. This energy momentum tensor has the correct properties to generate conformal transformations for both soft and hard states. We extend this construction to supertranslations.

Abstract Background Prolonged cytotoxic concentrations of cytarabine (CA) are required for maximum cytotoxicity. DepoCyt is a human liposomal cytarabine (LC) product that lasts longer in plasma and CSF compared with free CA (FC). The use of LC has not been evaluated in dogs. Objectives To perform a LC pharmacokinetic (PK) study when administered SC in dogs. Animals Five healthy female beagles. Methods Three‐period, 3‐treatment, nonblinded, randomized, and crossover design, including a pilot study. LC was administered at 50 mg/m2 SC and FC was administered at 25 and 50 mg/m2 SC and IV. Plasma CA concentrations were measured until 240, 72, and 8 hours after SC LC, SC FC, and IV FC administration, respectively. CA plasma concentrations were quantitated by ultra‐high‐performance liquid chromatography with mass spectrometry (MS/MS) detection and concentration‐time profiles were evaluated by noncompartmental analysis. Results Subcutaneous LC administration resulted in a maximum plasma concentration of 26.3 to 59.78 ng/mL, time to reach maximum plasma concentration of 2 hours, area under the concentration‐time curve to last measurable concentration of 669.3 to 1126 h × ng/mL, and plasma bioavailability (%F) of 19.6% to 31.3%. The PK profiles of FC after SC and IV administration differed when compared with LC. Conclusions and Clinical Importance In healthy dogs, SC LC administration at 50 mg/m2 results in measurable plasma CA concentrations, is apparently safe and well tolerated, but does not result in prolonged cytotoxic plasma concentrations. Poor absorption of LC prevented establishment of a complete LC PK profile.

Abstract Background Symmetry during lifting is considered critical for allowing balanced power production and avoidance of injury. This investigation assessed the influence of elevating the heels on bilateral lower limb symmetry during loaded (50% of body weight) high-bar back squats. Methods Ten novice (mass 67.6 ± 12.4 kg, height 1.73 ± 0.10 m) and ten regular weight trainers (mass 66.0 ± 10.7 kg, height 1.71 ± 0.09 m) were assessed while standing on both the flat level floor and on an inclined board. Data collection used infra-red motion capture procedures and two force platforms to record bilateral vertical ground reaction force (GRFvert) and ankle, knee and hip joint kinematic and kinetic data. Paired t-tests and statistical parametric mapping (SPM1D) procedures were used to assess differences in discrete and continuous bilateral symmetry data across conditions. Results Although discrete joint kinematic and joint moment symmetry data were largely unaffected by raising the heels, the regular weight trainers presented greater bilateral asymmetry in these data than the novices. The one significant finding in these discrete data showed that raising the heels significantly reduced maximum knee extension moment asymmetry (P = 0.02), but in the novice group only. Time-series analyses indicated significant bilateral asymmetries in both GRFvert and knee extension moments mid-way though the eccentric phase for the novice group, with the latter unaffected by heel lift condition. There were no significant bilateral asymmetries in time series data within the regular weight training group. Conclusions This investigation highlights that although a degree of bilateral lower limb asymmetry is common in individuals performing back squats, the degree of this symmetry is largely unaffected by raising the heels. Differences in results for discrete and time-series symmetry analyses also highlight a key issue associated with relying solely on discrete data techniques to assess bilateral symmetry during tasks such as the back squat.

Background The objective of this study was to explore the association between fresh fruit consumption and long‐term risk of upper gastrointestinal cancer (UGI) in the Linxian Dysplasia Nutrition Intervention Trial (NIT) cohort. Methods A cohort of 3318 subjects with esophageal squamous dysplasia participated in the Linxian Dysplasia NIT in May 1985 and were followed up until 30 September 2015. Demographic characteristics, lifestyle, and history of diseases were collected at the baseline. The primary endpoint was death from esophageal squamous cell carcinoma (ESCC), gastric cardia carcinoma (GCC), and gastric noncardia carcinoma (GNCC). Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using the Cox proportional hazard model. Results In the 30‐year follow‐up, a total of 541 ESCC, 284 GCC, and 77 GNCC deaths occurred. Relative to those who never or rarely consumed fresh fruit, the risk of ESCC mortality in participants who consumed fresh fruit more than 12 times/year were significantly decreased by 37.3% (HR = 0.63, 95% CI: 0.49–0.81). In the subgroup analyses, significantly protective effects on ESCC mortality were observed especially in females (HR = 0.59, 95% CI: 0.40–0.89), non‐smokers (HR = 0.67, 95% CI: 0.48–0.94), and nondrinkers (HR = 0.69, 95% CI: 0.51–0.93). Conclusions Consuming fresh fruit more than 12 times/year may reduce the long‐term risk of ESCC mortality in this dysplasia population, particularly in females, non‐smokers, and nondrinkers. Future studies are needed to confirm these findings.

GM1 gangliosidosis (GM1) is a fatal neurodegenerative lysosomal storage disease that occurs most commonly in young children, with no effective treatment available. Long-term follow-up of GM1 cats treated by bilateral thalamic and deep cerebellar nuclei (DCN) injection of adeno-associated virus (AAV)-mediated gene therapy has increased lifespan to 8 years of age, compared with an untreated lifespan of ~8 months. Due to risks associated with cerebellar injection in humans, the lateral ventricle was tested as a replacement route to deliver an AAVrh8 vector expressing feline β-galactosidase (β-gal), the defective enzyme in GM1. Treatment via the thalamus and lateral ventricle corrected storage, myelination, astrogliosis, and neuronal morphology in areas where β-gal was effectively delivered. Oligodendrocyte number increased, but only in areas where myelination was corrected. Reduced AAV and β-gal distribution were noted in the cerebellum with subsequent increases in storage, demyelination, astrogliosis, and neuronal degeneration. These postmortem findings were correlated with endpoint MRI and magnetic resonance spectroscopy (MRS). Compared with the moderate dose with which most cats were treated, a higher AAV dose produced superior survival, currently 6.5 years. Thus, MRI and MRS can predict therapeutic efficacy of AAV gene therapy and non-invasively monitor cellular events within the GM1 brain.

Abstract Given that adverse remodeling is the leading cause of heart failure and death in the USA, there is an urgent unmet need to develop new methods in dealing with this devastating disease. Here we evaluated the efficacy of a short-course glucagon-like peptide-1 receptor agonist therapy—specifically 2-quinoxalinamine, 6,7-dichloro-N-(1,1-dimethylethyl)-3-(methylsulfonyl)-,6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB; aka Compound 2) – in attenuating adverse LV remodeling. We also examined the role, if any, of mitochondrial turnover in this process. Wild-type, Parkin knockout and MitoTimer-expressing mice were subjected to permanent coronary artery ligation, then treated briefly with DMB. LV remodeling and cardiac function were assessed by histology and echocardiography. Autophagy and mitophagy markers were examined by western blot and mitochondrial biogenesis was inferred from MitoTimer protein fluorescence and qPCR. We found that DMB given post-infarction significantly reduced adverse LV remodeling and the decline of cardiac function. This paralleled an increase in autophagy, mitophagy and mitochondrial biogenesis. The salutary effects of the drug were lost in Parkin knockout mice, implicating Parkin-mediated mitophagy as part of its mechanism of action. Our findings suggest that enhancing Parkin-associated mitophagy and mitochondrial biogenesis after infarction is a viable target for therapeutic mitigation of adverse remodeling.

Abstract Background Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer death worldwide and in China. We know miRNAs influence gene expression in tumorigenesis, but it is unclear how miRNAs affect gene expression or influence survival at the genome-wide level in ESCC. Methods We performed miRNA and mRNA expression arrays in 113 ESCC cases with tumor/normal matched tissues to identify dysregulated miRNAs, to correlate miRNA and mRNA expressions, and to relate miRNA and mRNA expression changes to survival and clinical characteristics. Results Thirty-nine miRNAs were identified whose tumor/normal tissue expression ratios showed dysregulation (28 down- and 11 up-regulated by at least two-fold with P

Abstract Background The effectiveness of a 2015–17 community intervention to reduce cardiovascular disease (CVD) and type 2 diabetes (T2DM) risk factors is assessed in a Sri Lanka adult population, using a before-and-after study design. Methods Four contiguous Public Health Midwife (PHM) areas in Kalutara district (Western Province) were exposed to a Sri Lankan designed community health promotion initiatives (without screening) to lower CVD and T2DM risk factors. Pre- and post-intervention surveys (2014, n=1,019; 2017, n=908) were of 25–64 year males (M) and females (F) from dissimilar randomly selected clusters (villages or settlements) from PHMs, with probability of selection proportional to population size, followed by household sampling, then individual selection to yield equal-probability samples. Differences in resting blood pressure (BP), fasting plasma glucose (FPG), total cholesterol, body mass index and tobacco smoking, adjusting for cluster sampling, age and socio-economic differences, were examined. Results Hypertension prevalence declined from 25% to 16% (F) (p

Abstract We elaborate on the proposal of flat holography in which four-dimensional physics is encoded in two-dimensional celestial conformal field theory (CCFT). The symmetry underlying CCFT is the extended BMS symmetry of (asymptotically) flat space­ time. We use soft and collinear theorems of Einstein-Yang-Mills theory to derive the OPEs of BMS field operators generating superrotations and supertranslations. The energy­ momentum tensor, given by a shadow transform of a soft graviton operator, implements superrotations in the Virasoro subalgebra of 𝔟𝔪𝔰4. Supertranslations can be obtained from a single translation generator along the light-cone direction by commuting it with the energy-momentum tensor. This operator also originates from a soft graviton and generates a flow of conformal dimensions. All supertranslations can be assembled into a single primary conformal field operator on celestial sphere.

Tissue-resident macrophages exhibit specialized phenotypes dependent on their in vivo physiological niche. Investigation of their function often relies upon complex whole mouse transgenic studies. While some appropriate lineage-associated promoters exist, there are no options for tissue-specific targeting of macrophages. We have developed full protocols for in vivo productive infection (defined by stable transgene expression) of tissue-resident macrophages with lentiviral vectors, enabling RNA and protein overexpression, including expression of small RNA species such as shRNA, to knock down and modulate gene expression. These approaches allow robust infection of peritoneal tissue-resident macrophages without significant infection of other cell populations. They permit rapid functional study of macrophages in homeostatic and inflammatory settings, such as thioglycolate-induced peritonitis, while maintaining the cells in their physiological context. Here we provide detailed protocols for the whole workflow: viral production, purification, and quality control; safety considerations for administration of the virus to mice; and assessment of in vivo transduction efficiency and the low background levels of inflammation induced by the virus. In summary, we present a quick and accessible protocol for the rapid assessment of gene function in peritoneal tissue-resident macrophages in vivo.

Purpose - The purpose of this paper is to provide a conceptual framework for using citizen science – defined as a data collection method through which non-professionals engage in contributing to authentic scientific inquiry – within the expedition cruise industry to contribute significantly to the collection of environmental data from hard-to-access Arctic areas. Design/methodology/approach - The authors review trends in Arctic expedition cruise tourism and current needs in Arctic research and monitoring, and clarify where the expedition cruise tourism industry could have the most impact by providing data to the scientific community. The authors also compare the regulatory context in the Antarctic to that in the Arctic and discuss how these differences could affect the widespread use of citizen science. At last, the authors describe some general principles for designing citizen science programs to be successful on board, and highlight several existing programs that are being recognized for their contributions to a greater scientific understanding of the Arctic. Findings - The authors find that citizen science data from the expedition cruise industry are underutilized as a tool for monitoring Arctic change. Numerous examples illustrate how citizen science programs on-board expedition ships can successfully collect robust scientific data and contribute to enhancing the knowledge and stewardship capacity of cruise passengers. Inclusion of citizen science data from the expedition cruise industry should be considered a critical part of international Arctic observing networks and systems. Social implications - Active participation in Arctic citizen science by tourists on expedition cruise ships has many potential benefits beyond the collection of high quality data, from increasing passengers’ knowledge and understanding of the Arctic while on board, to affecting their attitudes and behaviors after they return home. Originality/value - The potential for tourism to contribute to Arctic observing systems has been discussed previously in the scientific literature; the authors narrow the focus to citizen science programs in the expedition cruise industry, and provide concrete examples, in the hope that this will streamline acceptance and implementation of these ideas by researchers and tourism practitioners.

Abstract Commercial fisheries yield essential foods, sustain cultural practices, and provide widespread employment around the globe. Commercially harvested species face a myriad of anthropogenic threats including degraded habitats, changing climate, overharvest, and pollution. Microplastics are pollutants of increasing concern, which are pervasive in the environment and can harbor or adsorb pollutants from surrounding waters. Aquatic organisms, including commercial species, encounter and ingest microplastics, but there is a paucity of data about those caught and cultured in North America. Additional research is needed to determine prevalence, physiological effects, and population‐level implications of microplastics in commercial species from Canada, the United States, and Mexico. Investigations into possible human health effects of microplastic exposure from seafood are also greatly needed. This synthesis summarizes current knowledge, identifies data gaps, and provides future research directions for addressing microplastics effects in commercially valuable North American fishery species.

Abstract Microplastics are of increasing concern as they are readily ingested by aquatic organisms. This study investigated microplastic trophic transfer using larval inland silversides (Menidia beryllina) (5 d posthatch) and unicellular tintinnid (Favella spp.) as a model food chain relevant to North American estuaries. Low‐density polyethylene microspheres (10–20 μm) were used to compare direct ingestion of microplastics by larval fish and trophic transfer via tintinnid prey. Dichlorodiphenyltrichloroethane (DDT)‐treated microspheres were used to determine sorbed pollutant effects on microplastic ingestion. Larval fish exposed directly to microspheres ingested significantly fewer than those exposed via contaminated prey. Larvae ingested significantly more ciliates containing DDT‐treated microspheres than ciliates containing untreated plastics but did not discriminate when exposed directly. Larvae reared for 16 d following a direct 2 h exposure had significantly lower wet weight values than unexposed controls. Our results demonstrate that trophic transfer is a significant route of microplastic exposure that can cause detrimental effects in sensitive life stages.

Following an outbreak of highly pathogenic avian influenza virus (HPAIV) in a poultry house, control measures are put in place to prevent further spread. An essential part of the control measures based on the European Commission Avian Influenza Directive 2005/94/EC is the cleansing and disinfection (C&D) of infected premises. Cleansing and disinfection includes both preliminary and secondary C&D, and the dismantling of complex equipment during secondary C&D is also required, which is costly to the owner and also delays the secondary cleansing process, hence increasing the risk for onward spread. In this study, a quantitative risk assessment is presented to assess the risk of re-infection (recrudescence) occurring in an enriched colony-caged layer poultry house on restocking with chickens after different C&D scenarios. The risk is expressed as the number of restocked poultry houses expected before recrudescence occurs. Three C&D scenarios were considered, namely (i) preliminary C&D alone, (ii) preliminary C&D plus secondary C&D without dismantling and (iii) preliminary C&D plus secondary C&D with dismantling. The source-pathway-receptor framework was used to construct the model, and parameterisation was based on the three C&D scenarios. Two key operational variables in the model are (i) the time between depopulation of infected birds and restocking with new birds (TbDR) and (ii) the proportion of infected material that bypasses C&D, enabling virus to survive the process. Probability distributions were used to describe these two parameters for which there was recognised variability between premises in TbDR or uncertainty due to lack of information in the fraction of bypass. The risk assessment estimates that the median (95% credible intervals) number of repopulated poultry houses before recrudescence are 1.2 × 104 (50 to 2.8 × 106), 1.9 × 105 (780 to 5.7 × 107) and 1.1 × 106 (4.2 × 103 to 2.9 × 108) under C&D scenarios (i), (ii) and (iii), respectively. Thus for HPAIV in caged layers, undertaking secondary C&D without dismantling reduces the risk by 16-fold compared to preliminary C&D alone. Dismantling has an additional, although smaller, impact, reducing the risk by a further 6-fold and thus around 90-fold compared to preliminary C&D alone. On the basis of the 95% credible intervals, the model demonstrates the importance of secondary C&D (with or without dismantling) over preliminary C&D alone. However, the extra protection afforded by dismantling may not be cost beneficial in the context of reduced risk of onward spread.

Dietary fiber-derived short-chain fatty acids (SCFA) act as histone deacetylase (HDAC) inhibitors on Tregs and innate immune cells, promoting immune tolerance by altering gene expression. Here the authors show that SCFA HDAC inhibitor activity impacts B cell differentiation, antibody responses and antibody-driven autoimmunity.

Abstract Background The utility of environmental DNA (eDNA) metabarcoding surveys to accurately detect species depends on the degree of DNA dispersal. Multiple marine studies have observed only minimal eDNA transport by horizontal water movement across small spatial scales, leading to the conclusion that spatially specific eDNA signals accurately resemble in‐field species assemblages along a horizontal axis. Marine communities, however, are also structured vertically according to depth. In marine environments displaying permanent water stratification, vertical zonation patterns may be more apparent and present on smaller spatial scales (i.e., meters) than horizontal community structuring. The scale at which eDNA signals differ along a vertical transect and the accuracy of eDNA metabarcoding in revealing naturally stratified communities have yet to be assessed. Methods and results In this study, we determined the ability of eDNA metabarcoding surveys to distinguish vertically localized community assemblages. To test this, we sampled three vertical transects along a steep rock wall at three depths (0 m, 4 m, 15 m), covering two distinct communities that were separated by near‐permanent water column stratification in the form of a strong halocline at ~3 m. Using three metabarcoding assays, our eDNA metabarcoding survey detected 54 taxa, across 46 families and 7 phyla, including 19 fish, 15 crustacean, and 8 echinoderm species. Ordination and cluster analyses show distinct eDNA signals across the halocline for all three replicate transects, suggesting that vertical dispersal of eDNA between communities was limited. Furthermore, eDNA signals of individual taxa were only retrieved within their observed vertical distribution, providing biological validation for the obtained results. Our results demonstrate, for the first time, the need to take into consideration oceanographic (e.g. water column stratification) and biological processes (e.g. vertical community structuring) when designing sampling strategies for marine eDNA metabarcoding surveys.

Background: Recent data suggest that acidosis alone is not a good predictor of mortality in trauma patients. Little data are currently available regarding factors associated with survival in trauma patients presenting with acidosis. Aims: The aims were to characterize the outcomes of trauma patients presenting with acidosis and to identify modifiable risk factors associated with mortality in these patients. Settings and Design: This is a retrospective observational study of University of Arkansas for Medical Sciences (UAMS) trauma patients between November 23, 2013, and May 21, 2017. Methods: Data were collected from the UAMS trauma registry. The primary outcome was hospital mortality. Analyses were performed using t-test and Pearson's Chi-squared test. Simple and multiple logistic regressions were performed to determine crude and adjusted odds ratios. Results: There were 532 patients identified and 64.7% were acidotic (pH < 7.35) on presentation: 75.9% pH 7.2–7.35; 18.5% pH 7.0–7.2; and 5.6% pH ≤ 7.0. The total hospital mortality was 23.7%. Nonsurvivors were older and more acidotic, with a base deficit >−8, Glasgow Coma Scale (GCS) ≤ 8, systolic blood pressure ≤ 90, International Normalized Ratio (INR) >1.6, and Injury Severity Score (ISS) >15. Mortality was significantly higher with a pH ≤ 7.2 but mortality with a pH 7.2–7.35 was comparable to pH > 7.35. In the adjusted model, pH ≤ 7.0, pH 7.0–7.2, INR > 1.6, GCS ≤ 8, and ISS > 15 were associated with increased mortality. For patients with a pH ≤ 7.2, only INR was associated with increase in mortality. Conclusions: A pH ≤ 7.2 is associated with increased mortality. For patients in this range, only the presence of coagulopathy is associated with increased mortality. A pH > 7.2 may be an appropriate treatment goal for acidosis. Further work is needed to identify and target potentially modifiable factors in patients with acidosis such as coagulopathy.