Structural equation model testing and the quality of natural killer cell activity measurements

BACKGROUND: Browne et al. [Browne, MacCallum, Kim, Andersen, Glaser: When fit indices and residuals are incompatible. Psychol Methods 2002] employed a structural equation model of measurements of target cell lysing by natural killer cells as an example purportedly demonstrating that small but statistically significant ill model fit can be dismissed as "negligible from a practical point of view". METHODS: Reanalysis of the natural killer cell data reveals that the supposedly negligible ill fit obscured important, systematic, and substantial causal misspecifications. RESULTS: A clean-fitting structural equation model indicates that measurements employing higher natural-killer-cell to target-cell ratios are more strongly influenced by a progressively intrusive factor, whether or not the natural killer cell activity is activated by recombinant interferon γ (rIFN γ). The progressive influence may reflect independent rate limiting steps in cell recognition and attachment, spatial competition for cell attachment points, or the simultaneous lysings of single target cells by multiple natural killer cells. CONCLUSIONS: If the progressively influential factor is ultimately identified as a mere procedural impediment, the substantive conclusion will be that measurements of natural killer cell activity made at lower effector to target ratios are more valid. Alternatively, if the individual variations in the progressively influential factor are modifiable, this may presage a new therapeutic route to enhancing natural killer cell activity. The methodological conclusion is that, when using structural equation models, researchers should attend to significant model ill fit even if the degree of covariance ill fit is small, because small covariance residuals do not imply that the underlying model misspecifications are correspondingly small or inconsequential

Does measuring BHR add to guideline derived clinical measures in determining treatment for patients with persistent asthma?

SummaryRationaleLittle is known about the use of biomarkers in guiding treatment decisions in routine asthma management. The objective of this study was to determine whether adding a LABA to an ICS would control bronchial hyperresponsiveness (BHR) at an overall lower dose of ICS when titration of medication was based upon the assessment of routine clinical measures with or without the measurement of BHR.MethodsAfter a 2-week run-in period, subjects (⩾12 years) were randomized to one of three treatment groups. Two groups followed a BHR treatment strategy (based on clinical parameters [lung function, asthma symptoms, and bronchodilator use] and BHR) and were treated with either fluticasone propionate/salmeterol (FSCBHR group) or fluticasone propionate (FPBHR group) (n=156 each). The third group followed a clinical treatment algorithm (based on clinical parameters alone) and were treated with fluticasone propionate (FPREF group; n=154). All treatments were administered via Diskus®. Treatment doses were adjusted as needed every 8 weeks for 40 weeks according to the subject's derived severity class, which was based on clinical measures of asthma control with or without BHR.ResultsThe mean total daily inhaled corticosteroids (ICS) dose during the double-blind treatment period was lower, although not statistically significant, in the FSCBHR group compared with the FPBHR group (a difference of −42.9mcg; p=0.07). Compared with the FPREF group, the mean total daily ICS dose was higher in the FSCBHR group (a difference of 85.2mcg) and was significantly higher in the FPBHR group (a difference of 131.2mcg, p=0.037).ConclusionThis study demonstrated that for most subjects, control of BHR was maintained when treatment was directed toward control of clinical parameters. In addition, there was a trend towards control of BHR and clinical measures at a lower dose of ICS when used concurrently with salmeterol

Perceptions of Barriers and Benefits of Manure Use in Cropping Systems

Animal agriculture is tasked with recycling the nitrogen and phosphorus in manures in an environmentally sound manner, typically as a soil fertility amendment. The increasing complexity of animal agriculture and its feed supply has resulted in significant specialization of businesses often separating production of animals from feed grains and forage production. The recycling of manure nutrients often requires voluntary transfer of manures to crop farms with little or no history of manure in a fertility program. The ability of manure to compete with commercially available fertilizers is essential for this transfer to be considered by crop farmers. A project team engaged in a needs assessment of farmers’ and their advisors’ perceptions of the benefits of manure use in cropping systems as well as the challenges that could create barriers for such transfers. We learned from those surveyed there exists a strong recognition of manure’s fertility, yield, and soil health benefits. However, soil health benefits of manure may be less well understood by farmers compared with fertility benefits. Manure’s water quality benefits through soil aggregation and less mobile nutrient forms are not perceived to exist or understood sufficiently for communicating to others. Finally, many challenges associated with manure frequently become barriers to manure use. The group identified four challenges most likely to prevent manure recycling including 1) transportation costs, 2) odor, 3) logistical barriers, and 4) agronomic concerns that will need to be addressed to encourage an expanded role of manure in more cropland

The Importance of Stopping Environmental Dumping in Ghana: The Case of Inefficient New and Used Cooling Appliances With Obsolete Refrigerants

Environmentally harmful product dumping ( environmental dumping ) of new and used low-efficiency cooling appliances with obsolete ozone-depleting and greenhouse gas refrigerants in African countries impoverishes communities, hinders economic development, threatens ecological systems, and harms public health. The use of low-efficiency cooling appliances increases energy demand, leading to higher power plant emissions and limiting affordable energy access in African countries. These low-efficiency appliances and products contain ozone-depleting refrigerants with high global-warming potential (GWP) or ozone-safe refrigerants with high GWP. Environmental dumping of these appliances and products makes it more difficult for countries to meet their international climate obligations and for the world to meet the Paris Agreement\u27s climate change mitigation targets. Ghana faces high levels of environmental dumping, despite a national ban on importing used cooling appliances and established efficiency standards for new air conditioners and refrigerators. Through the Energy Commission\u27s Office of Renewable Energy, Energy Efficiency, & Climate Change (REEECC), the government of Ghana is partnering with the Institute for Governance & Sustainable Development (IGSD) to stop environmental dumping. This article provides a list of interventions that can be implemented by Ghana, by governments in countries that export to Ghana, and by industry and other stakeholders. Notably, these actions focus on the shared responsibility of exporting countries and manufacturers by calling on exporting countries to update and enhance enforcement of their laws, and on global manufacturers to stop exporting inefficient products with obsolete refrigerants to Ghana and other African countries

Regulation of insulin signaling through reversible oxidation of the protein-tyrosine phosphatases TC45 and PTP1B

Many studies have illustrated that the production of reactive oxygen species (ROS) is important for optimal tyrosine phosphorylation and signaling in response to diverse stimuli. Protein-tyrosine phosphatases (PTPs), which are important regulators of signal transduction, are exquisitely sensitive to inhibition after generation of ROS, and reversible oxidation is becoming recognized as a general physiological mechanism for regulation of PTP function. Thus, production of ROS facilitates a tyrosine phosphorylation-dependent cellular signaling response by transiently inactivating those PTPs that normally suppress the signal. In this study, we have explored the importance of reversible PTP oxidation in the signaling response to insulin. Using a modified ingel PTP assay, we show that stimulation of cells with insulin resulted in the rapid and transient oxidation and inhibition of two distinct PTPs, which we have identified as PTP1B and TC45, the 45-kDa spliced variant of the T cell protein-tyrosine phosphatase. We investigated further the role of TC45 as a regulator of insulin signaling by combining RNA interference and the use of substrate-trapping mutants. We have shown that TC45 is an inhibitor of insulin signaling, recognizing the beta-subunit of the insulin receptor as a substrate. The data also suggest that this strategy, using ligand-induced oxidation to tag specific PTPs and using interference RNA and substrate-trapping mutants to illustrate their role as regulators of particular signal transduction pathways, may be applied broadly across the PTP family to explore function

Motor Preparatory Activity in Posterior Parietal Cortex is Modulated by Subjective Absolute Value

For optimal response selection, the consequences associated with behavioral success or failure must be appraised. To determine how monetary consequences influence the neural representations of motor preparation, human brain activity was scanned with fMRI while subjects performed a complex spatial visuomotor task. At the beginning of each trial, reward context cues indicated the potential gain and loss imposed for correct or incorrect trial completion. FMRI-activity in canonical reward structures reflected the expected value related to the context. In contrast, motor preparatory activity in posterior parietal and premotor cortex peaked in high “absolute value” (high gain or loss) conditions: being highest for large gains in subjects who believed they performed well while being highest for large losses in those who believed they performed poorly. These results suggest that the neural activity preceding goal-directed actions incorporates the absolute value of that action, predicated upon subjective, rather than objective, estimates of one's performance

On the elimination of the sweeping interactions from theories of hydrodynamic turbulence

In this paper, we revisit the claim that the Eulerian and quasi-Lagrangian same time correlation tensors are equal. This statement allows us to transform the results of an MSR quasi-Lagrangian statistical theory of hydrodynamic turbulence back to the Eulerian representation. We define a hierarchy of homogeneity symmetries between incremental homogeneity and global homogeneity. It is shown that both the elimination of the sweeping interactions and the derivation of the 4/5-law require a homogeneity assumption stronger than incremental homogeneity but weaker than global homogeneity. The quasi-Lagrangian transformation, on the other hand, requires an even stronger homogeneity assumption which is many-time rather than one-time but still weaker than many-time global homogeneity. We argue that it is possible to relax this stronger assumption and still preserve the conclusions derived from theoretical work based on the quasi-Lagrangian transformation.Comment: v1: submitted to Physica D. v2: major revisions; resubmitted to Physica D. v3: minor revisions requested by referee

High expression of STAT3 within the tumour-associated stroma predicts poor outcome in breast cancer patients

Introduction: Triple-negative breast cancer (TNBC) patients have the poorest clinical outcomes compared to other molecular subtypes of breast cancer. IL6/JAK/STAT3 signalling is upregulated in breast cancer; however, there is limited evidence for its role in TNBC. This study aimed to assess the expression of IL6/JAK/STAT3 in TNBC as a prognostic biomarker. Methods: Tissue microarrays consisting of breast cancer specimens from a retrospective cohort (n = 850) were stained for IL6R, JAK1, JAK2 and STAT3 via immunohistochemistry. Staining intensity was assessed by weighted histoscore and analysed for association with survival/clinical characteristics. In a subset of patients (n = 14) bulk transcriptional profiling was performed using TempO-Seq. Nanostring GeoMx® digital spatial profiling was utilised to establish the differential spatial gene expression in high STAT3 tumours. Results: In TNBC patients, high expression of stromal STAT3 was associated with reduced cancer-specific survival (HR = 2.202, 95% CI: 1.148–4.224, log rank p = 0.018). TNBC patients with high stromal STAT3 had reduced CD4+ T-cell infiltrates within the tumour (p = 0.001) and higher tumour budding (p = 0.003). Gene set enrichment analysis (GSEA) of bulk RNA sequencing showed high stromal STAT3 tumours were characterised by enrichment of IFNγ, upregulation of KRAS signalling and inflammatory signalling Hallmark pathways. GeoMx™ spatial profiling showed high stromal STAT3 samples. Pan cytokeratin (panCK)-negative regions were enriched for CD27 (p < 0.001), CD3 (p < 0.05) and CD8 (p < 0.001). In panCK-positive regions, high stromal STAT3 regions had higher expression of VEGFA (p < 0.05). Conclusion: High expression of IL6/JAK/STAT3 proteins was associated with poor prognosis and characterised by distinct underlying biology in TNBC