Adsorption Kinetics of Polymer/Surfactant Mixtures at an Expanding Air/Water Interface

The dynamic adsorption mechanisms of a range of polymer/surfactant mixtures have been studied at the expanding air/water interface created by an overflowing cylinder. The composition of the adsorption layer from mixed systems is obtained using a new approach, co-modelling ellipsometry data and NR data recorded on only one isotopic contrast, without deuterated polymer. The precision and accuracy of the interfacial compositions using this novel approach match those obtained by NR measurements using multiple isotopic contrasts and deuterated polymer, and exceeds those in the absence of deuterated polymer. For weakly interacting PEO/surfactant mixtures adsorption is competitive, the interfacial composition can be rationalised in terms of competitive adsorption. At high surfactant concentrations polymer adsorption is inhibited by the increasing surfactant coverage, although in PEO/SDS mixtures positive interactions between the two components allow PEO to adsorb until an SDS monolayer is present. For oppositely charged mixtures of PSS and CnTAB surfactants, synergistic adsorption occurs at low surfactant concentrations, and the formation of polymer/surfactant complexes has a marked effect on interfacial adsorption, although polymer adsorption is controlled by free polymer molecules. Aggregation occurs around charge neutrality, the material in these aggregates cannot reach the interface due to their size, and at higher surfactant concentrations polymer can no longer adsorb. Mixtures of PEI/SDS at high pH behave similarly to the PSS/CnTAB systems, with progressive aggregation depleting the system of surface active material and limiting adsorption. However at low pH the aggregates can reach the interface by convection where they spread material across the surface in the form of a thin layer of nanometer thickness by Marangoni flows. This work proves that examination of the dynamic adsorption behaviour of polymer/surfactant systems is invaluable to understanding their adsorption mechanisms. Furthermore there is a clear and incontrovertible link between the dynamic interfacial adsorption and bulk phase behaviour

Critical ethnography for school and community renewal around social class differences affecting learning

Understanding and exploring complex and protracted social questions requires sophisticated investigative approaches. In this article we intend looking at a research approach capable of providing a better understanding of what is going on in schools, students and communities in "exceptionally challenging contexts" (Harris et al., 2006)-code for schools and communities that have as a result of wider social forces, been historically placed in situations of disadvantage.C

Improved quantification of HIV-1 infected CD4 + T cells using an optimised method of intracellular HIV-1 gag p24 antigen detection

The capacity of CD8+ T cells to inhibit HIV-1 replication in vitro strongly correlates with virus control in vivo. Post-hoc evaluations of HIV-1 vaccine candidates suggest that this immunological parameter is a promising benchmark of vaccine efficacy. Large-scale analysis of CD8+ T cell antiviral activity requires a rapid, robust and economical assay for accurate quantification of HIV-1 infection in primary CD4+ T cells. Detection of intracellular HIV-1 p24 antigen (p24 Ag) by flow cytometry is one such method but it is thought to be less sensitive and quantitative than p24 Ag ELISA. We report that fixation and permeabilisation of HIV-infected cells using paraformaldehyde/50% methanol/Nonidet P-40 instead of a conventional paraformaldehyde/saponin-based protocol improved their detection across multiplicities of infection (MOI) ranging from 10-2 to 8×10-5, and by nearly two-fold (p<0.001) at the optimal MOI tested (10-2). The frequency of infected cells was strongly correlated with p24 Ag release during culture, thus validating its use as a measure of productive infection. We were also able to quantify infection with a panel of HIV-1 isolates representing the major clades. The protocol described here is rapid and cost-effective compared with ELISA and thus could be a useful component of immune monitoring of HIV-1 vaccines and interventions to reduce viral reservoirs. © 2013 Elsevier B.V

Reduced Expression of IFIH1 Is Protective for Type 1 Diabetes

IFIH1 (interferon induced with helicase C domain 1), also known as MDA5 (melanoma differentiation-associated protein 5), is one of a family of intracellular proteins known to recognise viral RNA and mediate the innate immune response. IFIH1 is causal in type 1 diabetes based on the protective associations of four rare variants, where the derived alleles are predicted to reduce gene expression or function. Originally, however, T1D protection was mapped to the common IFIH1 nsSNP, rs1990760 or Thr946Ala. This common amino acid substitution does not cause a loss of function and evidence suggests the protective allele, Ala946, may mark a haplotype with reduced expression of IFIH1 in line with the protection conferred by the four rare loss of function alleles. We have performed allele specific expression analysis that supports this hypothesis: the T1D protective haplotype correlates with reduced IFIH1 transcription in interferon-β stimulated peripheral blood mononuclear cells (overall p = 0.012). In addition, we have used multiflow cytometry analysis and quantitative PCR assays to prove reduced expression of IFIH1 in individuals heterozygous for three of the T1D-associated rare alleles: a premature stop codon, rs35744605 (Glu627X) and predicted splice variants, rs35337543 (IVS8+1) and rs35732034 (IVS14+1). We also show that the nsSNP, Ile923V, does not alter pre-mRNA levels of IFIH1. These results confirm and extend the new autoimmune disease pathway of reduced IFIH1 expression and protein function protecting from T1D

Myocardial depressant effects of interleukin 6 in meningococcal sepsis are regulated by p38 mitogen-activated protein kinase

Our findings demonstrate an integral role of the p38 mitogen-activated protein kinase pathway in interleukin 6-mediated cardiac contractile dysfunction and inotrope insensitivity. Dysregulation of the p38 mitogen-activated protein kinase pathway in meningococcal septicemia suggests that this pathway may be an important target for novel therapies to reverse myocardial dysfunction in patients with meningococcal septic shock who are not responsive to inotropic support

Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene

The chromosome 16p13 region has been associated with several autoimmune diseases, including type 1 diabetes (T1D) and multiple sclerosis (MS). CLEC16A has been reported as the most likely candidate gene in the region, since it contains the most disease-associated single-nucleotide polymorphisms (SNPs), as well as an imunoreceptor tyrosine-based activation motif. However, here we report that intron 19 of CLEC16A, containing the most autoimmune disease-associated SNPs, appears to behave as a regulatory sequence, affecting the expression of a neighbouring gene, DEXI. The CLEC16A alleles that are protective from T1D and MS are associated with increased expression of DEXI, and no other genes in the region, in two independent monocyte gene expression data sets. Critically, using chromosome conformation capture (3C), we identified physical proximity between the DEXI promoter region and intron 19 of CLEC16A, separated by a loop of >150 kb. In reciprocal experiments, a 20 kb fragment of intron 19 of CLEC16A, containing SNPs associated with T1D and MS, as well as with DEXI expression, interacted with the promotor region of DEXI but not with candidate DNA fragments containing other potential causal genes in the region, including CLEC16A. Intron 19 of CLEC16A is highly enriched for transcription-factor-binding events and markers associated with enhancer activity. Taken together, these data indicate that although the causal variants in the 16p13 region lie within CLEC16A, DEXI is an unappreciated autoimmune disease candidate gene, and illustrate the power of the 3C approach in progressing from genome-wide association studies results to candidate causal genes

Hydrous upwelling across the mantle transition zone beneath the Afar Triple Junction

The mechanisms that drive the upwelling of chemical heterogeneity from the lower to upper mantle (e.g., thermal versus compositional buoyancy) are key to our understanding of whole mantle con- vective processes. We address these issues through a receiver function study on new seismic data from recent deployments located on the Afar Triple Junction, a location associated with deep mantle upwelling. The detailed images of upper mantle and mantle transition zone structure illuminate features that give insights into the nature of upwelling from the deep Earth. A seismic low-velocity layer directly above the mantle transition zone, interpreted as a stable melt layer, along with a prominent 520 km discontinuity sug- gest the presence of a hydrous upwelling. A relatively uniform transition zone thickness across the region suggests a weak thermal anomaly (<100 K) may be present and that upwelling must be at least partly driven by compositional buoyancy. The results suggest that the lower mantle is a source of volatile rich, chemically distinct upwellings that influence the structure of the upper mantle, and potentially the chemis- try of surface lavas

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707