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The stability of monolithic glass beams is reasonably well defined; as an elastic material it behaves in a similar manner to other elastic materials such as steel, for which there are many equations of different forms which give similar results. Special care is required for continuous restraint to the tension flange. Equations presented in Australian Standard AS1288 Glass in Buildings – Selection and Installation have been used successfully for many years for monolithic fins when used with the strength model of AS1288 but require a more comprehensive approach when using laminated fins and/or strength models that allow higher levels of stress. A review of equations for cantilevers results in a wider range of approaches with significant variance between the outcomes of various published steel and glass standards. AS1288 has been used as the default standard for stability of glass fins, however for cantilevers it appears to have a misprint which has existed for decades. This paper presents strategies for determining the moment capacity of beams and cantilevers made of laminated glass with continuous flexible buckling restraints, such as structural silicone, which have initial imperfections and a known design strength capacity. Where multiple wave lengths form, the warping stiffness may contribute and formulations for rectangles are presented. The accuracy and validity of the approach is also assessed by means of comparisons with the outcomes of Finite Element numerical analyses.

Other than limited special cases, there is a lack of standards providing guidance on the design of structural glass in the United States and much of the world. This has resulted in an ad-hoc approach by cities (authorities having jurisdiction), architects, and engineers. This paper outlines the key aspects of designing with glass in a manner that has reliability and robustness consistent with other structural materials while recognizing the unique aspects of glass. This voluntary design manual is aimed at providing 4 consistent levels of risk in applications that allow Architects, Owners and Engineers to have an informed decision-making process for selecting levels of robustness, which may or may not be otherwise required by code. The document aims at developing consistent practices to facilitate confident design in glass while also addressing a number of technical challenges.

Glass handrail loading and design in the United States lags behind best practice in other parts of the world. Improvements are possible for the design load, residual capacity and damage-event loading, each of which could be based on occupancy. Neither static loading nor impactor testing accounts for the dynamic effects of sustained loading to handrails during crowd load events. Alternate configurations for improved robustness at similar size and cost are presented.

The collection and annotation of bioacoustic data present several challenges to researchers. Bioacoustic monitoring of rare (sparse) or cryptic species generally encounter two main issues. The cost of collecting and processing field data and a lack of labelled datasets for the target species. The detection of invasive species incursions and probability of absence testing is especially challenging due to these species having population densities at or close to zero. We present a methodology specifically designed to aid in the analysis of rare acoustic events within long-term field recordings. This approach combines a wavelet-based segmentation method that automatically extracts transient features from within-field recordings. A few-shot active learning recommender system in a human-in-the-loop process prioritises the annotation of low-certainty samples. This process combines the accuracy of human classification and the speed of computational tools to greatly reduce the presence of non-target features in field recordings. We evaluate this approach using an invasive species identification case study. This methodology achieves a test accuracy of 98.4% as well as 81.2% test accuracy using 2-shot, 2-way prototypical learning without fine-tuning, demonstrating high performance at varying data availability contexts. Active learning using low-certainty samples achieves >90% test accuracy using only 20 training samples compared to 80 samples without active learning. This approach allows users to train custom audio classification models for any application with rare features. The model can be easily exported for use in the field making real-time bioacoustic monitoring of less-vocal species a possibility. All code and data are available at https://github.com/Listening-Lab/Annotator.

We present the rest-frame ultraviolet−optical spectral properties of 65 broad absorption line (BAL) quasars from the Gemini Near Infrared Spectrograph−Distant Quasar Survey (GNIRS-DQS). These properties are compared with those of 195 non-BAL quasars from GNIRS-DQS in order to identify the drivers for the appearance of BALs in quasar spectra. In particular, we compare equivalent widths and velocity widths, as well as velocity offsets from systemic redshifts, of principal emission lines. In spite of the differences between their rest-frame ultraviolet spectra, we find that luminous BAL quasars are generally indistinguishable from their non-BAL counterparts in the rest-frame optical band at redshifts 1.55 ≲ z ≲ 3.50. We do not find any correlation between BAL trough properties and the H β -based supermassive black hole masses and normalized accretion rates in our sample. Considering the Sloan Digital Sky Survey quasar sample, which includes the GNIRS-DQS sample, we find that a monochromatic luminosity at rest-frame 2500 Å of ≳10 ^45 erg s ^−1 is a necessary condition for launching BAL outflows in quasars. We compare our findings with other BAL quasar samples and discuss the roles that accretion rate and orientation play in the appearance of BAL troughs in quasar spectra.

Capturing outdoor visual-inertial datasets is a challenging yet vital aspect of developing robust visual-inertial odometry (VIO) algorithms. A significant hurdle is that high-accuracy-ground-truth systems (e.g., motion capture) are not practical for outdoor use. One solution is to use a “semi-synthetic” approach that combines rendered images with real IMU data. This approach can produce sequences containing challenging imagery and accurate ground truth but with less simulated data than a fully synthetic sequence. Existing methods (used by popular tools/datasets) record IMU measurements from a visual-inertial system while measuring its trajectory using motion capture, then rendering images along that trajectory. This work identifies a major flaw in that approach, specifically that using motion capture alone to estimate the pose of the robot/system results in the generation of inconsistent visual-inertial data that is not suitable for evaluating VIO algorithms. However, we show that it is possible to generate high-quality semi-synthetic data for VIO algorithm evaluation. We do so using an open-source full-batch optimisation tool to incorporate both mocap and IMU measurements when estimating the IMU’s trajectory. We demonstrate that this improved trajectory results in better consistency between the IMU data and rendered images and that the resulting data improves VIO trajectory error by 79% compared to existing methods. Furthermore, we examine the effect of visual-inertial data inconsistency (as a result of trajectory noise) on VIO performance to provide a foundation for future work targeting real-time applications.

Soy leghemoglobin (LegH) protein derived from soy (Glycine max) produced in Pichia pastoris (reclassified as Komagataella phaffii) as LegH Prep is a novel food ingredient that provides meat-like flavor and aroma to plant-derived food products. The safety of LegH Prep has been previously assessed in a battery of in vivo and in vitro testing and found no adverse effects under the conditions tested. In this new work, we present the results of new in vivo and in vitro tests evaluating the safety of LegH Prep. LegH Prep was nonmutagenic in a bacterial reverse mutation assay and nonclastogenic in an in vitro micronucleus assay in human lymphocytes. Systemic toxicity was evaluated in the 90 day dietary study in male and female Sprague–Dawley® rats that included a 28 day recovery period. The study resulted in no animal deaths associated with the administration of LegH Prep at the highest dose (90,000 ppm). There were no significant adverse clinical or physical changes attributed to LegH Prep administration, and no observed adverse effects on either male or female rats over the course of the 28 day recovery phase study. The new 90 day dietary toxicity study established a no observed adverse effect level (NOAEL) of 4798.3 and 5761.5 mg/kg/day, the maximum level tested for male and female rats, respectively. Thus, the results of the studies demonstrate that under the conditions tested, LegH Prep is not toxic for consumption in meat analog products.

IMPORTANCE:. Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak. OBJECTIVES:. To assess the role of ANGPTL4 in COVID-19–related outcomes. DESIGN, SETTING, AND PARTICIPANTS:. Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University. MAIN OUTCOMES AND MEASURES:. Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4. RESULTS:. Higher plasma ANGPTL4 concentrations were significantly associated with worse hospital mortality (adjusted odds ratio per log2 increase, 1.53; 95% CI, 1.17–2.00; p = 0.002). Higher ANGPTL4 concentrations were also associated with higher proportions of venous thromboembolism and acute respiratory distress syndrome. Longitudinal ANGPTL4 concentrations were significantly different during the first 2 weeks of hospitalization in patients who subsequently died compared with survivors (p for interaction = 8.1 × 10–5). Proteomics analysis demonstrated abundance of ANGPTL4 in lung tissue compared with other organs in COVID-19. ANGPTL4 single-nuclear RNA gene expression was significantly increased in pulmonary alveolar type 2 epithelial cells and fibroblasts in COVID-19 lung tissue compared with controls. CONCLUSIONS AND RELEVANCE:. ANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients.

FXR regulates bile acid metabolism, and FXR null (Fxr−/−) mice have elevated bile acid levels and progressive liver injury. The inositol-requiring enzyme 1α/X-box binding protein 1 (XBP1) pathway is a protective unfolded protein response pathway activated in response to endoplasmic reticulum stress. Here, we sought to determine the role of the inositol-requiring enzyme 1α/XBP1 pathway in hepatic bile acid toxicity using the Fxr−/− mouse model. Western blotting and quantitative PCR analysis demonstrated that hepatic XBP1 and other unfolded protein response pathways were activated in 24-week-old Fxr−/− compared with 10-week-old Fxr−/− mice but not in WT mice. To further determine the role of the liver XBP1 activation in older Fxr−/− mice, we generated mice with whole-body FXR and liver-specific XBP1 double KO (DKO, Fxr−/−Xbp1LKO) and Fxr−/−Xbp1fl/fl single KO (SKO) mice and characterized the role of hepatic XBP1 in cholestatic liver injury. Histologic staining demonstrated increased liver injury and fibrosis in DKO compared with SKO mice. RNA sequencing revealed increased gene expression in apoptosis, inflammation, and cell proliferation pathways in DKO mice. The proapoptotic C/EBP-homologous protein pathway and cell cycle marker cyclin D1 were also activated in DKO mice. Furthermore, we found that total hepatic bile acid levels were similar between the two genotypes. At age 60 weeks, all DKO mice and no SKO mice spontaneously developed liver tumors. In conclusion, the hepatic XBP1 pathway is activated in older Fxr−/− mice and has a protective role. The potential interaction between XBP1 and FXR signaling may be important in modulating the hepatocellular cholestatic stress responses.

Background: Surgical resection remains the primary curative treatment for intra-cavity cancer. Low physical fitness and psychological factors such as depression are predictive of post–operative morbidity, mortality and length of hospital stay. Prolonged post-operative morbidity is associated with persistently elevated risk of premature death. We aim to investigate whether a structured, responsive exercise training programme, a psychological support programme or combined exercise and psychological support, delivered between treatment decision and major intra-cavity surgery for cancer, can reduce length of hospital stay, compared with standard care. Methods: WesFit is a pragmatic, 2x2 factorial-design, multi-centre, randomised-controlled trial, with planned recruitment of N=1560. Participants will be randomised to one of four groups. Group 1 (control) will receive usual pre-operative care, Group 2 (exercise) patients will undergo 2/3 aerobic, high-intensity interval training sessions per week supervised by personal trainers. Group 3 (psychological support) patients are offered 1 session per week at a local cancer support centre. Group 4 will receive both exercise and psychological support. All patients undergo baseline and pre-operative cardiopulmonary exercise testing, complete self-report questionnaires and will be followed up at 30 days, 12 weeks and 12 months post-operatively. Primary outcome is post-operative length-of-stay. Secondary outcomes include disability-adjusted survival at 1-year postoperatively, post-operative morbidity, and health-related quality of life. Exploratory investigations include objectively measured changes in physical fitness assessed by cardiopulmonary exercise test, disease-free and overall mortality at 1-year postoperatively, longer-term physical activity behaviour change, pre-operative radiological tumour regression, pathological tumour regression, pre and post-operative body composition analysis, health economics analysis and nutritional characterisation and its relationship to post-operative outcome. Conclusions: The WesFit trial will be a randomised controlled study investigating whether a high-intensity exercise training programme +/- psychological intervention results in improvements in clinical and patient reported outcomes in patients undergoing major inter-cavity resection of cancer. ClinicalTrials.gov registration: NCT03509428 (26/04/2018)

Summary: Integrating data across heterogeneous research environments is a key challenge in multi-site, collaborative research projects. While it is important to allow for natural variation in data collection protocols across research sites, it is also important to achieve interoperability between datasets in order to reap the full benefits of collaborative work. However, there are few standards to guide the data coordination process from project conception to completion. In this paper, we describe the experiences of the Clinical Sequence Evidence-Generating Research (CSER) consortium Data Coordinating Center (DCC), which coordinated harmonized survey and genomic sequencing data from seven clinical research sites from 2020 to 2022. Using input from multiple consortium working groups and from CSER leadership, we first identify 14 lessons learned from CSER in the categories of communication, harmonization, informatics, compliance, and analytics. We then distill these lessons learned into 11 recommendations for future research consortia in the areas of planning, communication, informatics, and analytics. We recommend that planning and budgeting for data coordination activities occur as early as possible during consortium conceptualization and development to minimize downstream complications. We also find that clear, reciprocal, and continuous communication between consortium stakeholders and the DCC is equally important to maintaining a secure and centralized informatics ecosystem for pooling data. Finally, we discuss the importance of actively interrogating current approaches to data governance, particularly for research studies that straddle the research-clinical divide.

Background: As elective services resumed in the aftermath of the first wave of the SARS-CoV-2 pandemic, the British Rhinology Society and Juniors Committees carried out a national prospective study in order to assess and optimise safety and efficacy of surgery. Methodology: Data from 1063 cases was collected from 111 centres in the United Kingdom (excluding Northern Ireland) within the study period (1st June – 14th August 2020), and a three week follow-up period to assess whether there were any cases of SARS-CoV-2 amongst patients and staff. Results: 89.2% of procedures took place in England. 90.6% of patients had minimal comorbidities (ASA Grade 1 or 2). 98.4% of patients were known to have a COVID negative status prior to surgery, with the majority (99.8%) investigated through Viral PCR alone. The most common form of pre-operative shielding was to self-isolate for 14 days (82.5% of cases). 32.6% of cases were performed in an alternative theatre environment, and in 5.3% the private sector was used for NHS patients. In 21.6% of procedures, unfamiliar anaesthetic teams were used, and in 19.2% unfamiliar theatre teams. There was a higher probability of unfamiliar theatre staff or anaesthetist, when operating in an alternative theatre environment. Trainees were not present in theatre in 24.2% of cases. Full PPE (Personal Protective Equipment) was worn by the operating surgeon in 64.1% of cases. No patients or staff were reported to have developed SARS-CoV-2 in the three week period following surgery. Intra-operative challenges were reported in 19.7% of cases and were primarily associated with impaired communication (8.8%) or impaired vision (6.9%). There was a higher chance of challenges reported when unfamiliar theatre teams were present. Conclusions: This data suggests that overall, the resumption of rhinological elective services has been performed safely with no cases of SARS-CoV-2 reported in patients or staff. We must consider the challenges of operating in unfamiliar environments together with surgical and/or anaesthetic teams, as well as the impact on training.

NAFLD is an important public health issue closely associated with the pervasive epidemics of diabetes and obesity. Yet, despite NAFLD being among the most common of chronic liver diseases, the biological factors responsible for its transition from benign nonalcoholic fatty liver (NAFL) to NASH remain unclear. This lack of knowledge leads to a decreased ability to find relevant animal models, predict disease progression, or develop clinical treatments. In the current study, we used multiple mouse models of NAFLD, human correlation data, and selective gene overexpression of steroidogenic acute regulatory protein (StarD1) in mice to elucidate a plausible mechanistic pathway for promoting the transition from NAFL to NASH. We show that oxysterol 7α-hydroxylase (CYP7B1) controls the levels of intracellular regulatory oxysterols generated by the “acidic/alternative” pathway of cholesterol metabolism. Specifically, we report data showing that an inability to upregulate CYP7B1, in the setting of insulin resistance, results in the accumulation of toxic intracellular cholesterol metabolites that promote inflammation and hepatocyte injury. This metabolic pathway, initiated and exacerbated by insulin resistance, offers insight into approaches for the treatment of NAFLD.

The most reliable single-epoch supermassive black hole mass ( M _BH ) estimates in quasars are obtained by using the velocity widths of low-ionization emission lines, typically the H β λ 4861 line. Unfortunately, this line is redshifted out of the optical band at z ≈ 1, leaving M _BH estimates to rely on proxy rest-frame ultraviolet (UV) emission lines, such as C iv λ 1549 or Mg ii λ 2800, which contain intrinsic challenges when measuring, resulting in uncertain M _BH estimates. In this work, we aim at correcting M _BH estimates derived from the C iv and Mg ii emission lines based on estimates derived from the H β emission line. We find that employing the equivalent width of C iv in deriving M _BH estimates based on Mg ii and C iv provides values that are closest to those obtained from H β . We also provide prescriptions to estimate M _BH values when only C iv , only Mg ii , and both C iv and Mg ii are measurable. We find that utilizing both emission lines, where available, reduces the scatter of UV-based M _BH estimates by ∼15% when compared to previous studies. Lastly, we discuss the potential of our prescriptions to provide more accurate and precise estimates of M _BH given a much larger sample of quasars at 3.20 ≲ z ≲ 3.50, where both Mg ii and H β can be measured in the same near-infrared spectrum.

Quasars at z ≳ 1 most often have redshifts measured from rest-frame ultraviolet emission lines. One of the most common such lines, C iv λ 1549, shows blueshifts up to ≈5000 km s ^−1 and in rare cases even higher. This blueshifting results in highly uncertain redshifts when compared to redshift determinations from rest-frame optical emission lines, e.g., from the narrow [O iii ] λ 5007 feature. We present spectroscopic measurements for 260 sources at 1.55 ≲ z ≲ 3.50 having −28.0 ≲ M _i ≲ − 30.0 mag from the Gemini Near Infrared Spectrograph–Distant Quasar Survey (GNIRS-DQS) catalog, augmenting the previous iteration, which contained 226 of the 260 sources whose measurements are improved upon in this work. We obtain reliable systemic redshifts based on [O iii ] λ 5007 for a subset of 121 sources, which we use to calibrate prescriptions for correcting UV-based redshifts. These prescriptions are based on a regression analysis involving C iv full-width-at-half-maximum intensity and equivalent width, along with the UV continuum luminosity at a rest-frame wavelength of 1350 Å. Applying these corrections can improve the accuracy and the precision in the C iv -based redshift by up to ∼850 km s ^−1 and ∼150 km s ^−1 , respectively, which correspond to ∼8.5 and ∼1.5 Mpc in comoving distance at z = 2.5. Our prescriptions also improve the accuracy of the best available multifeature redshift determination algorithm by ∼100 km s ^−1 , indicating that the spectroscopic properties of the C iv emission line can provide robust redshift estimates for high-redshift quasars. We discuss the prospects of our prescriptions for cosmological and quasar studies utilizing upcoming large spectroscopic surveys.

Weak emission-line quasars (WLQs) are a subset of type 1 quasars that exhibit extremely weak Ly α + N v λ 1240 and/or C iv λ 1549 emission lines. We investigate the relationship between emission-line properties and accretion rate for a sample of 230 “ordinary” type 1 quasars and 18 WLQs at z < 0.5 and 1.5 < z < 3.5 that have rest-frame ultraviolet and optical spectral measurements. We apply a correction to the H β -based black hole mass ( M _BH ) estimates of these quasars using the strength of the optical Fe ii emission. We confirm previous findings that WLQs’ M _BH values are overestimated by up to an order of magnitude using the traditional broad-emission-line region size–luminosity relation. With this M _BH correction, we find a significant correlation between H β -based Eddington luminosity ratios and a combination of the rest-frame C iv equivalent width and C iv blueshift with respect to the systemic redshift. This correlation holds for both ordinary quasars and WLQs, which suggests that the two-dimensional C iv parameter space can serve as an indicator of accretion rate in all type 1 quasars across a wide range of spectral properties.

Reward Deficiency Syndrome (RDS) is defined as a breakdown of reward neurotransmission that results in a wide range of addictive, compulsive, and impulsive behaviors. RDS is caused by a combination of environmental (epigenetic) influences and DNA-based (genetic) neurotransmission deficits that interfere with the normal satisfaction of human physiological drives (i.e., food, water, and sex). An essential feature of RDS is the lack of integration between perception, cognition, and emotions that occurs because of (1) significant dopaminergic surges in motivation, reward, and learning centers causing neuroplasticity in the striato-thalamic-frontal cortical loop; (2) hypo-functionality of the excitatory glutamatergic afferents from the amygdala–hippocampus complex. A large volume of literature regarding the known neurogenetic and psychological underpinnings of RDS has revealed a significant risk of dopaminergic gene polymorphic allele overlap between cohorts of depression and subsets of schizophrenia. The suggestion is that instead of alcohol, opioids, gambling disorders, etc. being endophenotypes, the true phenotype is RDS. Additionally, reward deficiency can result from depleted or hereditary hypodopaminergia, which can manifest as a variety of personality traits and mental/medical disorders that have been linked to genetic studies with dopamine-depleting alleles. The carrying of known DNA antecedents, including epigenetic insults, results in a life-long vulnerability to RDS conditions and addictive behaviors. Epigenetic repair of hypodopaminergia, the causative basis of addictive behaviors, may involve precision DNA-guided therapy achieved by combining the Genetic Addiction Risk Severity (GARS) test with a researched neutraceutical having a number of variant names, including KB220Z. This nutraceutical formulation with pro-dopamine regulatory capabilities has been studied and published in peer-reviewed journals, mostly from our laboratory. Finally, it is our opinion that RDS should be given an ICD code and deserves to be included in the DSM-VI because while the DSM features symptomology, it is equally important to feature etiological roots as portrayed in the RDS model.

Active Buildings that allow users to adjust their demands on the grid to the needs of the energy system could greatly assist the transition to net zero, but will not be widely adopted unless the businesses involved can make money from doing so. We describe the construction, flexibility and information supply chains of activities needed to make these buildings work. Drawing on the results of an expert workshop, we set out four possible business models deserving further investigation. Developers may find it profitable to build or upgrade energy-efficient buildings with the monitoring and control equipment needed to adjust demand and energy storage as required, selling them soon after completion. Aggregators monitor the state of the building and communicate with the energy system to adjust the building’s demand while maintaining comfort levels, in return for suitable payments. Energy service companies may sell energy-as-a-service and own the equipment instead of a consumer who wishes to minimize their upfront costs, and the idea of an active, energy-efficient, building may be attractive to the tenants of the new group of all-inclusive rental companies, and hence to those companies. Our discussion shows that each is an evolution of an existing (successful) business model, but that further work will be needed to evaluate their profitability when applied to Active Buildings.

Summary: Multi-omic profiling of human peripheral blood is increasingly utilized to identify biomarkers and pathophysiologic mechanisms of disease. The importance of these platforms in clinical and translational studies led us to investigate the impact of delayed blood processing on the numbers and state of peripheral blood mononuclear cells (PBMC) and on the plasma proteome. Similar to previous studies, we show minimal effects of delayed processing on the numbers and general phenotype of PBMC up to 18 hours. In contrast, profound changes in the single-cell transcriptome and composition of the plasma proteome become evident as early as 6 hours after blood draw. These reflect patterns of cellular activation across diverse cell types that lead to progressive distancing of the gene expression state and plasma proteome from native in vivo biology. Differences accumulating during an overnight rest (18 hours) could confound relevant biologic variance related to many underlying disease states.

RIG-I- like receptors (RLRs) play an important role in immune defense against West Nile virus (WNV). Here, using a systems biology approach, the authors show that macrophage polarization to a proinflammatory M1 phenotype via RIG-I and MDA5 signaling is critical for innate immune control in WNV-infected mouse tissues.

Reward Deficiency Syndrome (RDS) encompasses many mental health disorders, including a wide range of addictions and compulsive and impulsive behaviors. Described as an octopus of behavioral dysfunction, RDS refers to abnormal behavior caused by a breakdown of the cascade of reward in neurotransmission due to genetic and epigenetic influences. The resultant reward neurotransmission deficiencies interfere with the pleasure derived from satisfying powerful human physiological drives. Epigenetic repair may be possible with precision gene-guided therapy using formulations of KB220, a nutraceutical that has demonstrated pro-dopamine regulatory function in animal and human neuroimaging and clinical trials. Recently, large GWAS studies have revealed a significant dopaminergic gene risk polymorphic allele overlap between depressed and schizophrenic cohorts. A large volume of literature has also identified ADHD, PTSD, and spectrum disorders as having the known neurogenetic and psychological underpinnings of RDS. The hypothesis is that the true phenotype is RDS, and behavioral disorders are endophenotypes. Is it logical to wonder if RDS exists everywhere? Although complex, “the answer is blowin’ in the wind,” and rather than intangible, RDS may be foundational in species evolution and survival, with an array of many neurotransmitters and polymorphic loci influencing behavioral functionality.

Cholestatic liver diseases are a significant cause of morbidity and mortality and the leading indication for pediatric liver transplant. These include diseases such as biliary atresia, Alagille syndrome, progressive intrahepatic cholestasis entities, ductal plate abnormalities including Caroli syndrome and congenital hepatic fibrosis, primary sclerosing cholangitis, bile acid synthesis defects, and certain metabolic disease. Medical management of these patients typically includes supportive care for complications of chronic cholestasis including malnutrition, pruritus, and portal hypertension. However, there are limited effective interventions to prevent progressive liver damage in these diseases, leaving clinicians to ultimately rely on liver transplantation in many cases. Agents such as ursodeoxycholic acid, bile acid sequestrants, and rifampicin have been mainstays of treatment for years with the understanding that they may decrease or alter the composition of the bile acid pool, though clinical response to these medications is frequently insufficient and their effects on disease progression remain limited. Recently, animal and human studies have identified potential new therapeutic targets which may disrupt the enterohepatic circulation of bile acids, alter the expression of bile acid transporters or decrease the production of bile acids. In this article, we will review bile formation, bile acid signaling, and the relevance for current and newer therapies for pediatric cholestasis. We will also highlight further areas of potential targets for medical intervention for pediatric cholestatic liver diseases.

The recombinant Canarypox ALVAC-HIV/gp120/alum vaccine regimen was the first to significantly decrease the risk of HIV acquisition in humans, with equal effectiveness in both males and females. Similarly, an equivalent SIV-based ALVAC vaccine regimen decreased the risk of virus acquisition in Indian rhesus macaques of both sexes following intrarectal exposure to low doses of SIVmac251. Here, we demonstrate that the ALVAC-SIV/gp120/alum vaccine is also efficacious in female Chinese rhesus macaques following intravaginal exposure to low doses of SIVmac251 and we confirm that CD14+ classical monocytes are a strong correlate of decreased risk of virus acquisition. Furthermore, we demonstrate that the frequency of CD14+ cells and/or their gene expression correlates with blood Type 1 CD4+ T helper cells, α4β7+ plasmablasts, and vaginal cytocidal NKG2A+ cells. To better understand the correlate of protection, we contrasted the ALVAC-SIV vaccine with a NYVAC-based SIV/gp120 regimen that used the identical immunogen. We found that NYVAC-SIV induced higher immune activation via CD4+Ki67+CD38+ and CD4+Ki67+α4β7+ T cells, higher SIV envelope-specific IFN-γ producing cells, equivalent ADCC, and did not decrease the risk of SIVmac251 acquisition. Using the systems biology approach, we demonstrate that specific expression profiles of plasmablasts, NKG2A+ cells, and monocytes elicited by the ALVAC-based regimen correlated with decreased risk of virus acquisition.

In potato (Solanum tuberosum) production, the number of tubers harvested and their sizes are related to the plant population. Field maps of the spatial variation in plant density can therefore provide a decision support tool for spatially variable harvest timing to optimize tuber sizes by allowing densely populated management zones more tuber-bulking time. Computer vision has been proposed to enumerate plant numbers using images from unmanned aerial vehicles (UAV) but inaccurate predictions in images of merged canopies remains a challenge. Some research has been done on individual potato plant bounding box prediction but there is currently no information on the spatial structure of plant density that these models may reveal and its relationship with potato yield quality attributes. In this study, the Faster Region-based Convolutional Neural Network (FRCNN) framework was used to produce a plant detection model and estimate plant densities across a UAV orthomosaic. Using aerial images of 2 mm ground sampling distance (GSD) collected from potatoes at 40 days after planting, the FRCNN model was trained to an average precision (aP) of 0.78 on unseen testing data. The model was then used to generate predictions on quadrants imposed on orthorectified rasters captured at 14 and 18 days after emergence. After spatially interpolating the plant densities, the resultant surfaces were highly correlated to manually-determined plant density (R2 = 0.80). Further correlations were observed with tuber number (r = 0.54 at Butter Hill; r = 0.53 at Horse Foxhole), marketable tuber weight per plant (r = −0.57 at Buttery Hill; r = −0.56 at Horse Foxhole) and the normalized difference vegetation index (r = 0.61). These results show that accurate two-dimensional maps of plant density can be constructed from UAV imagery with high correlation to important yield components, despite the loss of accuracy of FRCNN models in partially merged canopies.

This article describes a unique therapeutic precision intervention, a formulation of enkephalinase inhibitors, enkephalin, and dopamine-releasing neuronutrients, to induce dopamine homeostasis for detoxification and treatment of individuals genetically predisposed to developing reward deficiency syndrome (RDS). The formulations are based on the results of the addiction risk severity (GARS) test. Based on both neurogenetic and epigenetic evidence, the test evaluates the presence of reward genes and risk alleles. Existing evidence demonstrates that the novel genetic risk testing system can successfully stratify the potential for developing opioid use disorder (OUD) related risks or before initiating opioid analgesic therapy and RDS risk for people in recovery. In the case of opioid use disorders, long-term maintenance agonist treatments like methadone and buprenorphine may create RDS, or RDS may have been in existence, but not recognized. The test will also assess the potential for benefit from medication-assisted treatment with dopamine augmentation. RDS methodology holds a strong promise for reducing the burden of addictive disorders for individuals, their families, and society as a whole by guiding the restoration of dopamine homeostasisthrough anti-reward allostatic neuroadaptations. WC 175.

The oligoadenylate-synthetase (Oas) gene locus provides innate immune resistance to virus infection. In mouse models, variation in the Oas1b gene influences host susceptibility to flavivirus infection. However, the impact of Oas variation on overall innate immune programming and global gene expression among tissues and in different genetic backgrounds has not been defined. We examined how Oas1b acts in spleen and brain tissue to limit West Nile virus (WNV) susceptibility and disease across a range of genetic backgrounds. The laboratory founder strains of the mouse Collaborative Cross (CC) (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, and NZO/HlLtJ) all encode a truncated, defective Oas1b, whereas the three wild-derived inbred founder strains (CAST/EiJ, PWK/PhJ, and WSB/EiJ) encode a full-length OAS1B protein. We assessed disease profiles and transcriptional signatures of F1 hybrids derived from these founder strains. F1 hybrids included wild-type Oas1b (F/F), homozygous null Oas1b (N/N), and heterozygous offspring of both parental combinations (F/N and N/F). These mice were challenged with WNV, and brain and spleen samples were harvested for global gene expression analysis. We found that the Oas1b haplotype played a role in WNV susceptibility and disease metrics, but the presence of a functional Oas1b allele in heterozygous offspring did not absolutely predict protection against disease. Our results indicate that Oas1b status as wild-type or truncated, and overall Oas1b gene dosage, link with novel innate immune gene signatures that impact specific biological pathways for the control of flavivirus infection and immunity through both Oas1b-dependent and independent processes.

West Nile Virus (WNV) is a mosquito-transmitted virus from the Flaviviridae family that causes fever in 1 in 5 infected people. WNV can also become neuro-invasive and cross the blood-brain barrier leading to severe neurological symptoms in a subset of WNV infected individuals [1]. WNV neuro-invasion is believed to be influenced by a number of factors including host genetics. In order to explore these effects and recapitulate the complex immune genetic differences among individuals, we studied gene expression following WNV infection in the Collaborative Cross (CC) model. The CC is a mouse genetics resource composed of >70 independently bred, octo-parental recombinant inbred mouse lines [2]. To identify the individual host gene expression signatures influencing protection or susceptibility to WNV disease and WNV neuroinvasion, we used the nanostring nsolver platform to quantify gene expression in brain tissue isolated from WNV-infected CC mice at days 4, 7 and 12 post-infection [3]. This nanostring technology provided a high throughput, non-amplification based mRNA quantitation method to detect immune genes involved in neuro-invasion. Data was deposited into the Gene Expression Omnibus (GEO) under accession GSE85999.

Flaviviruses are hematophagous arthropod-viruses that pose global challenges to human health. Like Zika virus, West Nile Virus (WNV) is a flavivirus for which no approved vaccine exists [1]. The role host genetics play in early detection and response to WNV still remains largely unexplained. In order to capture the impact of genetic variation on innate immune responses, we studied gene expression following WNV infection using the collaborative cross (CC). The CC is a mouse genetics resource composed of hundreds of independently bred, octo-parental recombinant inbred mouse lines [2]. To accurately capture the host immune gene expression signatures of West Nile infection, we used the nanostring platform to evaluate expression in spleen tissue isolated from CC mice infected with WNV over a time course of 4, 7, and 12 days' post-infection [3]. Nanostring is a non-amplification based digital method to quantitate gene expression that uses color-coded molecular barcodes to detect hundreds of transcripts in a sample. Using this approach, we identified unique gene signatures in spleen tissue at days 4, 7, and 12 following WNV infection, which delineated distinct differences between asymptomatic and symptomatic CC lines. We also identified novel immune genes. Data was deposited into the Gene Expression Omnibus under accession GSE86000.

Dynamic Line Rating (DLR) is a process which electrical network operators can implement to improve efficiency by dynamically adjusting the load capacity as conditions allow. To implement DLR an accurate model of the conductors and their clearances is needed. Airborne LiDAR, while expensive, is the most common method of collecting line data as it is fast and is of high quality. State of the art methods for automatically reconstructing conductors first classify conductor points before fitting conductor models. This approach works well for high tension lines with significant separation between conductors but tends to perform poorly in urban environments where conductors are packed tightly together and surrounded by clutter. The method presented in this article attempts to overcome these challenges by performing an informed search for the conductors, anchored to the utility poles. Before the conductors are classified, their layout and sag are estimated, converting conductor segmentation into a linear problem; and a 3D to 2D projection is used to improve density and simplify clustering. The work also attempts to reduce the cost of conductor reconstruction by utilising lower-cost vehicle-mounted LiDAR. By avoiding point classification, higher precision can be achieved in scenarios where previous methods have suffered from significantly degraded performance.

ABSTRACT Induction of interferon beta (IFN-β), IFN-stimulated genes (ISGs), and inflammatory responses is critical for control of viral infection. We recently identified an essential linkage of stimulation of the inflammatory cytokine interleukin-1β (IL-1β) and induction of ISGs that function as host restriction pathways against the emerging flavivirus West Nile virus (WNV) in vivo. Here we utilized ex vivo global transcriptome analysis of primary dendritic cells, known targets of WNV replication, to define gene signatures required for this IL-1β-driven antiviral response. Dendritic cells that were deficient in IL-1 receptor signaling showed dysregulation of cell-intrinsic defense genes and loss of viral control during WNV infection. Surprisingly, we found that in wild-type cells, IL-1β treatment, in the absence of infection, drove the transcription of IFN-β and ISGs at late times following treatment. Expression of these antiviral innate immune genes was dependent on the transcription factor IFN regulatory factor 3 (IRF3) and appears to reflect a general shift in IL-1β signaling from an early inflammatory response to a late IFN-mediated response. These data demonstrate that inflammatory and antiviral signals integrate to control viral infection in myeloid cells through a process of IL-1β-to-IRF3 signaling crosstalk. Strategies to exploit these cytokines in the activation of host defense programs should be investigated as novel therapeutic approaches against individual pathogens. IMPORTANCE West Nile virus is an emerging mosquito-borne flavivirus that can result in serious illness, neuropathology, and death in infected individuals. Currently, there are no vaccines or therapies for human use against West Nile virus. Immune control of West Nile virus infection requires inflammatory and antiviral responses, though the effect that each arm of this response has on the other is unclear. The significance of our research is in defining how virus-induced inflammatory responses regulate critical antiviral immune programs for effective control of West Nile virus infection. These data identify essential mechanisms of immune control that can inform therapeutic efforts against West Nile virus, with potential efficacy against other neuroinvasive viruses.

Although the spleen is a major site for West Nile virus (WNV) replication and spread, relatively little is known about which innate cells in the spleen replicate WNV, control viral dissemination, and/or prime innate and adaptive immune responses. Here we tested if splenic macrophages (MΦs) were necessary for control of WNV infection. We selectively depleted splenic MΦs, but not draining lymph node MΦs, by injecting mice intravenously with clodronate liposomes several days prior to infecting them with WNV. Mice missing splenic MΦs succumbed to WNV infection after an increased and accelerated spread of virus to the spleen and the brain. WNV-specific Ab and CTL responses were normal in splenic MΦ-depleted mice; however, numbers of NK cells and CD4 and CD8 T cells were significantly increased in the brains of infected mice. Splenic MΦ deficiency led to increased WNV in other splenic innate immune cells including CD11b- DCs, newly formed MΦs and monocytes. Unlike other splenic myeloid subsets, splenic MΦs express high levels of mRNAs encoding the complement protein C1q, the apoptotic cell clearance protein Mertk, the IL-18 cytokine and the FcγR1 receptor. Splenic MΦ-deficient mice may be highly susceptible to WNV infection in part to a deficiency in C1q, Mertk, IL-18 or Caspase 12 expression.

Infection with West Nile virus (WNV) leads to a range of disease outcomes, including chronic infection, though lack of a robust mouse model of chronic WNV infection has precluded identification of the immune events contributing to persistent infection. Using the Collaborative Cross, a population of recombinant inbred mouse strains with high levels of standing genetic variation, we have identified a mouse model of persistent WNV disease, with persistence of viral loads within the brain. Compared to lines exhibiting no disease or marked disease, the F1 cross CC(032x013)F1 displays a strong immunoregulatory signature upon infection that correlates with restraint of the WNV-directed cytolytic response. We hypothesize that this regulatory T cell response sufficiently restrains the immune response such that a chronic infection can be maintained in the CNS. Use of this new mouse model of chronic neuroinvasive virus will be critical in developing improved strategies to prevent prolonged disease in humans.

Point normal calculation and cloud registration are two of the most common operations in point cloud processing. However, both are vulnerable to issues of numerical precision and loss of significance. This paper documents how loss of significance in the open-source Point Cloud Library can create erroneous point normals and cause cloud registration to fail. Several test clouds are used to demonstrate how the loss of significance is caused by tight point spacing and clouds being shifted far from the origin of their coordinate system. The results show that extreme loss of significance can cause point normals to be calculated with a random orientation, and cause meters of error during cloud registration. Depending on the structure of the point cloud, loss of significance can occur when the cloud is at hundreds or even tens of meters from the origin of its coordinate system. Shifting to larger data types (e.g., from 32-bit “floats” to 64-bit “doubles”) can alleviate the problem but will not solve it completely. Several “best practice” recommendations for avoiding this issue are proposed. But the only solution guaranteed to eliminate loss of significance is de-meaning the entire cloud, or clusters of points before processing.

This paper presents a framework for simulating visually realistic motion of underwater Remotely Operated Vehicles (ROVs) in highly complex models of aquatic environments. The models include a wide range of objects such as rocks, fish and marine plankton in addition to an ROV tether. A modified cable simulation for the underwater physical conditions has been developed for a tethered ROV. The simulation framework also incorporates models for low visibility conditions and intrinsic camera effects unique to the underwater environment. The visual models were implemented using the Unreal Engine 4 realistic game engine to be part of the presented framework. We developed a generalized method for implementing an ROV dynamics model and this method serves as a highly configurable component inside our framework. In this paper, we explore the unique characteristics of underwater simulation and the specialized models we developed for that environment. We use computer vision algorithms for feature extraction and feature tracking as a probe for comparing experiments done in our simulated environment against real underwater experiments. The experimental results presented in this paper successfully demonstrate the contribution of this realistic simulation framework to the understanding, analysis and development of computer vision and control algorithms to be used in today’s ROVs.

New systems genetics approaches are needed to rapidly identify host genes and genetic networks that regulate complex disease outcomes. Using genetically diverse animals from incipient lines of the Collaborative Cross mouse panel, we demonstrate a greatly expanded range of phenotypes relative to classical mouse models of SARS-CoV infection including lung pathology, weight loss and viral titer. Genetic mapping revealed several loci contributing to differential disease responses, including an 8.5Mb locus associated with vascular cuffing on chromosome 3 that contained 23 genes and 13 noncoding RNAs. Integrating phenotypic and genetic data narrowed this region to a single gene, Trim55, an E3 ubiquitin ligase with a role in muscle fiber maintenance. Lung pathology and transcriptomic data from mice genetically deficient in Trim55 were used to validate its role in SARS-CoV-induced vascular cuffing and inflammation. These data establish the Collaborative Cross platform as a powerful genetic resource for uncovering genetic contributions of complex traits in microbial disease severity, inflammation and virus replication in models of outbred populations.

The California wine industry has been in the midst of a prolonged boom for more than 30 years. In 1975, California was home to approximately 330 wineries; by 2006 there were nearly 2,500. There has been a dramatic shift in demand toward higher priced and higher quality table wines, as reflected in the total revenues and crush shares of the state's four major growing regions. We examine the major trends in the California wine-grape industry over the last 30 years, specifically differences that are arising between the coastal and inland growing regions and migration of the various wine-grape varieties grown throughout the state.

The California wine industry is growing and changing amidst a global revolution in grape growing, wine production, wine marketing and consumer tastes. California accounted for roughly 90% of the value of U.S. wine production in 2006. U.S. per capita wine consumption and the quality of wine consumed continue to rise. The largest California wineries have long accounted for most California wine shipments and continue to expand with respect to volume and number of labels. While small wineries sell most of their wine directly to end-users, many midsized wineries face challenges in an increasingly crowded marketplace.

ABSTRACT The broad range and diversity of interferon-stimulated genes (ISGs) function to induce an antiviral state within the host, impeding viral pathogenesis. While successful respiratory viruses overcome individual ISG effectors, analysis of the global ISG response and subsequent viral antagonism has yet to be examined. Employing models of the human airway, transcriptomics and proteomics datasets were used to compare ISG response patterns following highly pathogenic H5N1 avian influenza (HPAI) A virus, 2009 pandemic H1N1, severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome CoV (MERS-CoV) infection. The results illustrated distinct approaches utilized by each virus to antagonize the global ISG response. In addition, the data revealed that highly virulent HPAI virus and MERS-CoV induce repressive histone modifications, which downregulate expression of ISG subsets. Notably, influenza A virus NS1 appears to play a central role in this histone-mediated downregulation in highly pathogenic influenza strains. Together, the work demonstrates the existence of unique and common viral strategies for controlling the global ISG response and provides a novel avenue for viral antagonism via altered histone modifications. IMPORTANCE This work combines systems biology and experimental validation to identify and confirm strategies used by viruses to control the immune response. Using a novel screening approach, specific comparison between highly pathogenic influenza viruses and coronaviruses revealed similarities and differences in strategies to control the interferon and innate immune response. These findings were subsequently confirmed and explored, revealing both a common pathway of antagonism via type I interferon (IFN) delay as well as a novel avenue for control by altered histone modification. Together, the data highlight how comparative systems biology analysis can be combined with experimental validation to derive novel insights into viral pathogenesis.