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This reflective contribution tells the story of a veteran public sector crisis management (CM) researcher’s 35-year journey with educating students and CM practitioners, It offers preliminary insights about how the pandemic experience might – and should – induce a significant rethink of how educators conceptualize the nature of crises and the challenges governments and public agencies face in coping with them.

Companion diagnostic immunohistochemistry (IHC) tests are developed and performed without incorporating the tools and principles of laboratory metrology. Basic analytic assay parameters such as lower limit of detection (LOD) and dynamic range are unknown to both assay developers and end users. We solved this problem by developing completely new tools for IHC-calibrators with units of measure traceable to National Institute of Standards & Technology (NIST) Standard Reference Material (SRM) 1934. In this study, we demonstrate the clinical impact and opportunity for incorporating these changes into PD-L1 testing. Forty-one laboratories in North America and Europe were surveyed with newly-developed PD-L1 calibrators. The survey sampled a broad representation of commercial and laboratory-developed tests (LDTs). Using the PD-L1 calibrators, we quantified analytic test parameters that were previously only inferred indirectly after large clinical studies. The data show that the four FDA-cleared PD-L1 assays represent three different levels of analytic sensitivity. The new analytic sensitivity data explain why some patients' tissue samples were positive by one assay and negative by another. The outcome depends on the assay's lower LOD. Also, why previous attempts to harmonize certain PD-L1 assays were unsuccessful; the assays' dynamic ranges were too disparate and did not overlap. PD-L1 assay calibration also clarifies the exact performance characteristics of LDTs relative to FDA-cleared commercial assays. Some LDTs' analytic response curves are indistinguishable from their predicate FDA-cleared assay. IHC assay calibration represents an important transition for companion diagnostic testing. The new tools will improve patient treatment stratification, test harmonization, and foster accuracy as tests transition from clinical trials to broad clinical use.

This paper aims to conceptualise attitudes towards brand genuinuity by developing and validating a psychometric scale through four studies. Study 1 generates a pool of potential scale items through a review of the literature, thesaurus search, focus groups, and expert surveys. Study 2 confirms the unidimensionality of the scale items using confirmatory factor analysis. Study 3 establishes convergent, discriminant, predictive, and nomological validity. Finally, Study 4 confirms the generalisability of the scale by applying it in a different context. The process resulted in a 5-item unidimensional scale measuring attitudes towards the brand’s genuinuity. The results demonstrated that brand genuinuity is a unique construct, and distinct from related concepts, brand sincerity, and brand heritage. The development and validation of the current scale fill an important gap in the advertising literature. It provides a better understanding of and mechanism to measure attitudes towards brand genuinuity, which could not be measured with previous scales. Likewise, the scale provides important insights for brand managers and will be an important tool for managers to test and confirm the degree to which new advertising material exhibits brand genuinuity.

There is no cure for HIV infection, and lifelong antiretroviral therapy (ART) is required. N-803 is an IL-15 superagonist comprised of an N72D mutant IL-15 molecule attached to its alpha receptor and a human IgG1 fragment designed to increase IL-15 activity. Preclinical studies with both HIV and SIV suggest that the drug has potential to reduce virus reservoirs by activating virus from latency and enhancing effector function. We conducted a phase 1 study of N-803 ( NCT02191098 ) in people living with HIV, the primary objective of which was to assess the safety and tolerability of the drug, with an exploratory objective of assessing the impact on peripheral virus reservoirs. ART-suppressed individuals were enrolled into a dose-escalation study of N-803 in four different cohorts (0.3, 1.0, 3.0 and 6.0 mcg kg

This paper presents a comparative study of six common pseudospectral (PS) methods for solving optimal spacecraft attitude control problems. The problems of minimum time, minimum control effort, and...

Associations between human genetic variation and clinical phenotypes have become a foundation of biomedical research. Most repositories of these data seek to be disease-agnostic and therefore lack disease-focused views. The Type 2 Diabetes Knowledge Portal (T2DKP) is a public resource of genetic datasets and genomic annotations dedicated to type 2 diabetes (T2D) and related traits. Here, we seek to make the T2DKP more accessible to prospective users and more useful to existing users. First, we evaluate the T2DKP's comprehensiveness by comparing its datasets with those of other repositories. Second, we describe how researchers unfamiliar with human genetic data can begin using and correctly interpreting them via the T2DKP. Third, we describe how existing users can extend their current workflows to use the full suite of tools offered by the T2DKP. We finally discuss the lessons offered by the T2DKP toward the goal of democratizing access to complex disease genetic results.

Diffuse midline glioma (DMG) is an aggressive brain tumour with high mortality and limited clinical therapeutic options. Although in vitro research has shown the effectiveness of medication, successful translation to the clinic remains elusive. A literature search highlighted the high variability and lack of standardisation in protocols applied for establishing the commonly used HSJD-DIPG-007 patient-derived xenograft (PDX) model, based on animal host, injection location, number of cells inoculated, volume, and suspension matrices. This study evaluated the HSJD-DIPG-007 PDX model with respect to its ability to mimic human disease progression for therapeutic testing in vivo. The mice received intracranial injections of HSJD-DIPG-007 cells suspended in either PBS or Matrigel. Survival, tumour growth, and metastases were assessed to evaluate differences in the suspension matrix used. After cell implantation, no severe side effects were observed. Additionally, no differences were detected in terms of survival or tumour growth between the two suspension groups. We observed delayed metastases in the Matrigel group, with a significant difference compared to mice with PBS-suspended cells. In conclusion, using Matrigel as a suspension matrix is a reliable method for establishing a DMG PDX mouse model, with delayed metastases formation and is a step forward to obtaining a standardised in vivo PDX model.

Many fuels are currently considered for reducing the emissions in shipping; Methanol, LNG, Ammonia, Nuclear, Biodiesel, etc. However, Bio-ethanol is not considered at all.This research looked into all aspects of ethanol in a comparison with its most closely related alternative methanol. Using a similar approach as found in earlier comparisons. Though updating the data as well as the application ot vessels relevant for the Dutch ship owners. This research identified that 2nd generation bio-ethanol would in price be close to 2nd generation bio-methanol, but with several technical advantages. Furthermore the bio-ethanol production capacity is far larger than that of any of the other alternative fuels for shipping and with the ongoing electrification of cars, this capacity will most likely be looking for a new market in the future, putting pressure on the price. Hence the report calls for further investigations and reconsiderations of bio-ethanol as a marine fuel.

The replacement of chloroquine with artemisinin-based combination therapies (ACTs) for over a decade has had varying impacts on the ability of malaria parasite to sustain its chloroquine resistance prowess in different malaria-endemic regions. We evaluated the frequency of Plasmodium falciparum chloroquine resistance transporter (PfCRT) mutations in an endemic area of southwest Nigeria 17 years after replacement of chloroquine with ACTs for malaria treatment. Genomic DNA was isolated from dried blood spot samples obtained from 129 patients (aged 1-35 years) with microscopically confirmed P. falciparum infection. PfCRT fragments covering codons 72-76, CVMNK (wildtype) and A220 were amplified and sequenced. Two mutant PfCRT haplotypes on residues 72-76 (CVIET and CVINT) were identified with a prevalence of 18.6% and 2.3%, respectively. Interestingly, the CVINT haplotype was identified for the first time in this region. A220S changes were found in 16.3% of samples occurring concurrently with the CVIET haplotype, while a Q271E mutation occurred in a wildtype isolate. The reduced prevalence of the PfCRT mutant alleles in this study may suggest a gradual disappearance of chloroquine-resistant malaria parasites following reduced drug pressure. It may also be an indicator of the ability of malaria parasites to develop resistance gradually against the current first-line regimen.

Correction to: Nature Published online 9 December 2021 In the version of this article initially published, Noha A. Yousri (Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar and Department of Computer and Systems Engineering, Alexandria University, Egypt) and Steven C. Hunt (Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA and Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar) were not included in the author list. In addition, Hieab H. H. Adams (Department of Radiology and Nuclear Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands and Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands) was shown with an incorrect second affiliation in the HTML and PDF versions of the article. Finally, in the HTML version, Cristen J. Willer was mistakenly listed with an extra affiliation (Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia). The authors and affiliations have been corrected in the HTML and PDF versions of the article.

La Trobe University Faculty of Science, Technology and Engineering Murray Darling Freshwater Research CentreMDFRC item.Bacterial production is important in aquatic carbon cycles because it represents a key component whereby dissolved and particulate carbon can be recycled back into food webs. Despite its acknowledged importance, few studies have examined bacterial production in lowland rivers. Since studies have suggested bacterial production is closely related to some carbon pools, we anticipated this to be the case in the Murray River, but that the timing and type of carbon inputs in the Murray River may lead to bacterial dynamics that differ from studies from other sites. Bacterial abundance and production were measured at three contrasting sites of the lowland Murray River, southeastern Australia, over an 18- month period. Bacterial abundance varied across the three sites on the Murray River and was correlated with chlorophyll a concentrations but not with temperature, nutrients, particulate organic carbon and dissolved organic carbon concentrations. Bacterial production also varied across the sites. Lowest production was at the site most immediately downstream of a large reservoir, with production generally ranging from 0.88 to 8.00 mu g CL-1 h(-1). Bacterial production in a reach within a large forest ranged from 4.00 to 17.38 mu CL-1 h(-1). Production at the reach furthest downstream ranged from 1.04 to 23.50 mu g C L-1 h(-1). Bacterial production in the Murray River was generally greater than in the European River Spree, reaches of the Meuse and Rhine without immediate impacts from major urban centres and the Amazon River, but was similar to the concentration measured in the Mississippi and Hudson Rivers. Bacterial production was closely correlated with chlorophyll a concentration and total phosphorus, but not with temperature, dissolved organic carbon, particulate organic carbon or inorganic nitrogen. Despite the differences in production and respiration measured at different sites across the Murray River, bacterial growth efficiency was very similar at the three sites. Bacterial populations in the Murray River appear to be influenced by reach-specific conditions rather than broad-scale drivers such as temperature, carbon and nutrient concentrations.

We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.

In dieser Rezension wird "How to Do Public Policy" von Anke Hassel und Kai Wegrich als ein originelles und hervorragend geeignetes Lehrbuch für Studierende und (angehende) Führungskräfte der öffentlichen Verwaltung, des Public Managements und der Policy-Analyse vorgestellt. Das Buch unterscheidet sich von vergleichbaren Texten dadurch, dass es Politikgestaltung zuvorderst als strategische, politische Tätigkeit betrachtet sowie handlungsorientierte Einsichten betont anstelle der üblichen "Modelle des Politikprozesses" aus der Vogelperspektive. Das Buch beruht auf einem soliden Verständnis des aktuellen Forschungsstands der Policy-Analyse, meidet jedoch Klischees. Es vermittelt seinen Leserinnen und Lesern in gelungener Weise das nötige Rüstzeug, um die praktischen Herausforderungen der Politikgestaltung im 21. Jahrhundert in ihren institutionellen und politischen Dynamiken zu erkennen und zu gestalten.

Contains fulltext : 291572.pdf (Publisher’s version ) (Open Access) Crosstalk between glomerular endothelial cells and glomerular epithelial cells (podocytes) is increasingly becoming apparent as a crucial mechanism to maintain the integrity of the glomerular filtration barrier. However, in vitro studies directly investigating the effect of this crosstalk on the glomerular filtration barrier are scarce because of the lack of suitable experimental models. Therefore, we developed a custom-made glomerulus-on-a-chip model recapitulating the glomerular filtration barrier, in which we investigated the effects of co-culture of glomerular endothelial cells and podocytes on filtration barrier function and the phenotype of these respective cell types. The custom-made glomerulus-on-a-chip model was designed using soft lithography. The chip consisted of two parallel microfluidic channels separated by a semi-permeable polycarbonate membrane. The glycocalyx was visualized by wheat germ agglutinin staining and the barrier integrity of the glomerulus-on-a-chip model was determined by measuring the transport rate of fluorescently labelled dextran from the top to the bottom channel. The effect of crosstalk on the transcriptome of glomerular endothelial cells and podocytes was investigated via RNA-sequencing. Glomerular endothelial cells and podocytes were successfully cultured on opposite sides of the membrane in our glomerulus-on-a-chip model using a polydopamine and collagen A double coating. Barrier integrity of the chip model was significantly improved when glomerular endothelial cells were co-cultured with podocytes compared to monocultures of either glomerular endothelial cells or podocytes. Co-culture enlarged the surface area of podocyte foot processes and increased the thickness of the glycocalyx. RNA-sequencing analysis revealed the regulation of cellular pathways involved in cellular differentiation and cellular adhesion as a result of the interaction between glomerular endothelial cells and podocytes. We present a novel custom-made glomerulus-on-a-chip co-culture model and demonstrated for the first time using a glomerulus-on-a-chip model that co-culture affects the morphology and transcriptional phenotype of glomerular endothelial cells and podocytes. Moreover, we showed that co-culture improves barrier function as a relevant functional readout for clinical translation. This model can be used in future studies to investigate specific glomerular paracrine pathways and unravel the role of glomerular crosstalk in glomerular (patho) physiology.

RNA-binding proteins are essential regulators of RNA processing and function. Translational repression assays can be used to study how they interact with specific RNA sequences by insertion of such a consensus sequence into the 5’ untranslated region of a reporter mRNA and measuring reporter protein translation. The straightforward set-up of these translational repression assays avoids the need for the isolation of the protein or the RNA providing speed, robustness and a low-cost method. Here, we report the optimization of the assay to function with linear RNA sequences instead of the previously reported hairpin type sequences to allow the study of a wider variety of RNA-binding proteins. Multiplication of a consensus sequence strongly improves the signal allowing analysis by both fluorescence intensity measurements and flow cytometry.

Vine copulas have become the standard tool for modelling complex probabilistic dependence. It has been shown that the number of regular vines grows extremely quickly with the number of nodes. Chimera is the first attempt to map the vast space of regular vines. Software for operating with regular vines is available for R, matlab and Python. However, no dataset containing all regular vines is available. Our atlas of regular vines, Chimera, comprises all 24 4 × 4 matrices representing regular vines on 4 nodes, 480 5 × 5 matrices representing regular vines on 5 nodes, 23,040 6 × 6 matrices representing regular vines on 6 nodes, 2,580,480 7 × 7 matrices representing regular vines on 7 nodes and 660,602,880 8 × 8 matrices representing regular vines on 8 nodes. Regular vines in Chimera are classified according to their tree-equivalence class. We fit all regular vines to synthetic data to demonstrate the potential of Chimera. Chimera provides thus a tool for researchers to navigate this vast space in an orderly fashion.