Experimental investigation of a cook-off temperature in a hot barrel

AbstractThe experimental investigations of the effect of contact time/temperature on initiating the cook-off using 7.62 mm calibre cartridge cases (CC) were conducted previously. These cartridges were filled with commercial off-the-shelf (COTS) double based (DB) propellant (Bulls Eye) and were loaded in a hot chamber. The thermal explosion temperature is of great significance to both weapon designers and safety inspectors as it provides the operational limit and safe operating temperature. For CC under test, it was found that the cook-off temperatures of this propellant were encountered with the heat transfer profile of the simulated gun barrel between 151.4 °C and 153.4 °C, with a reaction occurring in less than 300 s after the round was chambered. Usefully, each experiment was found to be consistent and repeatable

MRSA sepsis and acute respiratory distress syndrome during veno-arterial extracorporeal membrane oxygenation (ECMO).

Presentation: A 39 year old female African American presented with respiratory distress two days after ERCP for pancreatitis. The patient quickly deteriorated, required intubation, and developed severe hypotension requiring vasopressors. VA-ECMO was initiated for ARDS and SIRS due to on-going pancreatitis. Pre ECMO ABG: PH 7.01, PaCO2 70, PaO2 70 with FiO2 100% with PEEP 15 Profound hypotension, required 2 pressors Preliminary results of cultures were negative at the time of ECMO placement. Presented 24th Annual ELSO Conference. Philadelphia, PA. Sep 19-21, 2013

Associations with age and glomerular filtration rate in a referred population with chronic kidney disease: Methods and baseline data from a UK multicentre cohort study (NURTuRE-CKD)

BACKGROUND: Chronic kidney disease (CKD) is common but heterogenous and is associated with multiple adverse outcomes. The National Unified Renal Translational Research Enterprise (NURTuRE)-CKD cohort was established to investigate risk factors for clinically important outcomes in persons with CKD referred to secondary care. METHODS: Eligible participants with CKD stages G3-4 or stages G1-2 plus albuminuria > 30 mg/mmol were enrolled from 16 nephrology centres in England, Scotland and Wales from 2017 to 2019. Baseline assessment included demographic data, routine laboratory data and research samples. Clinical outcomes are being collected over 15 years by the UK Renal Registry using established data linkage. Baseline data are presented with subgroup analysis by age, sex and estimated GFR (eGFR). RESULTS: 2996 participants were enrolled. Median (interquartile range) age was 66 (54 to 74) years, 58.5% were male, eGFR 33.8 (24.0 to 46.6) ml/min/1.73m2 and UACR 209 (33 to 926) mg/g. 1883 participants (69.1%) were in high-risk CKD categories. Primary renal diagnosis was CKD of unknown cause in 32.3%, glomerular disease in 23.4% and diabetic kidney disease in 11.5%. Older participants and those with lower eGFR had higher systolic blood pressure and were less likely to be treated with renin-angiotensin system inhibitors (RASi) but were more likely to receive a statin. Female participants were less likely to receive a RASi or statin. CONCLUSIONS: NURTuRE-CKD is a prospective cohort of persons who are at relatively high risk of adverse outcomes. Long-term follow-up and a large biorepository create opportunities for research to improve risk prediction and investigate underlying mechanisms to inform new treatment development

PAM50 proliferation score as a predictor of weekly paclitaxel benefit in breast cancer

To identify a group of patients who might benefit from the addition of weekly paclitaxel to conventional anthracycline-containing chemotherapy as adjuvant therapy of node-positive operable breast cancer. The predictive value of PAM50 subtypes and the 11-gene proliferation score contained within the PAM50 assay were evaluated in 820 patients from the GEICAM/9906 randomized phase III trial comparing adjuvant FEC to FEC followed by weekly paclitaxel (FEC-P). Multivariable Cox regression analyses of the secondary endpoint of overall survival (OS) were performed to determine the significance of the interaction between treatment and the (1) PAM50 subtypes, (2) PAM50 proliferation score, and (3) clinical and pathological variables. Similar OS analyses were performed in 222 patients treated with weekly paclitaxel versus paclitaxel every 3 weeks in the CALGB/9342 and 9840 metastatic clinical trials. In GEICAM/9906, with a median follow up of 8.7 years, OS of the FEC-P arm was significantly superior compared to the FEC arm (unadjusted HR = 0.693, p = 0.013). A benefit from paclitaxel was only observed in the group of patients with a low PAM50 proliferation score (unadjusted HR = 0.23, p < 0.001; and interaction test, p = 0.006). No significant interactions between treatment and the PAM50 subtypes or the various clinical–pathological variables, including Ki-67 and histologic grade, were identified. Finally, similar OS results were obtained in the CALGB data set, although the interaction test did not reach statistical significance (p = 0.109). The PAM50 proliferation score identifies a subset of patients with a low proliferation status that may derive a larger benefit from weekly paclitaxel. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10549-013-2416-2) contains supplementary material, which is available to authorized users

Mucedorus: the last ludic playbook, the first stage Arcadia

This article argues that two seemingly contradictory factors contributed to and sustained the success of the anonymous Elizabethan play Mucedorus (c. 1590; pub. 1598). First, that both the initial composition of Mucedorus and its Jacobean revival were driven in part by the popularity of its source, Philip Sidney's Arcadia. Second, the playbook's invitation to amateur playing allowed its romance narrative to be adopted and repurposed by diverse social groups. These two factors combined to create something of a paradox, suggesting that Mucedorus was both open to all yet iconographically connected to an elite author's popular text. This study will argue that Mucedorus pioneered the fashion for “continuations” or adaptations of the famously unfinished Arcadia, and one element of its success in print was its presentation as an affordable and performable version of Sidney's elite work. The Jacobean revival of Mucedorus by the King's Men is thus evidence of a strategy of engagement with the Arcadia designed to please the new Stuart monarchs. This association with the monarchy in part determined the cultural functions of the Arcadia and Mucedorus through the Interregnum to the close of the seventeenth century

The FERM and PDZ Domain-Containing Protein Tyrosine Phosphatases, PTPN4 and PTPN3, Are Both Dispensable for T Cell Receptor Signal Transduction

PTPN3 and PTPN4 are two closely-related non-receptor protein tyrosine phosphatases (PTP) that, in addition to a PTP domain, contain FERM (Band 4.1, Ezrin, Radixin, and Moesin) and PDZ (PSD-95, Dlg, ZO-1) domains. Both PTP have been implicated as negative-regulators of early signal transduction through the T cell antigen receptor (TCR), acting to dephosphorylate the TCRζ chain, a component of the TCR complex. Previously, we reported upon the production and characterization of PTPN3-deficient mice which show normal TCR signal transduction and T cell function. To address if the lack of a T cell phenotype in PTPN3-deficient mice can be explained by functional redundancy of PTPN3 with PTPN4, we generated PTPN4-deficient and PTPN4/PTPN3 double-deficient mice. As in PTPN3 mutants, T cell development and homeostasis and TCR-induced cytokine synthesis and proliferation were found to be normal in PTPN4-deficient and PTPN4/PTPN3 double-deficient mice. PTPN13 is another FERM and PDZ domain-containing non-receptor PTP that is distantly-related to PTPN3 and PTPN4 and which has been shown to function as a negative-regulator of T helper-1 (Th1) and Th2 differentiation. Therefore, to determine if PTPN13 might compensate for the loss of PTPN3 and PTPN4 in T cells, we generated mice that lack functional forms of all three PTP. T cells from triple-mutant mice developed normally and showed normal cytokine secretion and proliferative responses to TCR stimulation. Furthermore, T cell differentiation along the Th1, Th2 and Th17 lineages was largely unaffected in triple-mutants. We conclude that PTPN3 and PTPN4 are dispensable for TCR signal transduction

Functionally Inert HIV-Specific Cytotoxic T Lymphocytes Do Not Play a Major Role in Chronically Infected Adults and Children

The highly sensitive quantitation of virus-specific CD8+ T cells using major histocompatibility complex–peptide tetramer assays has revealed higher levels of cytotoxic T lymphocytes (CTLs) in acute and chronic virus infections than were recognized previously. However, studies in lymphocytic choriomeningitis virus infection have shown that tetramer assays may include measurement of a substantial number of tetramer-binding cells that are functionally inert. Such phenotypically silent CTLs, which lack cytolytic function and do not produce interferon (IFN)-γ, have been hypothesized to explain the persistence of virus in the face of a quantitatively large immune response, particularly when CD4 help is impaired. In this study, we examined the role of functionally inert CTLs in chronic HIV infection. Subjects studied included children and adults (n = 42) whose viral loads ranged from <50 to >100,000 RNA copies/ml plasma. Tetramer assays were compared with three functional assays: enzyme-linked immunospot (Elispot), intracellular cytokine staining, and precursor frequency (limiting dilution assay [LDA]) cytotoxicity assays. Strong positive associations were observed between cell numbers derived by the Elispot and the tetramer assay (r = 0.90). An even stronger association between tetramer-derived numbers and intracellular cytokine staining for IFN-γ was present (r = 0.97). The majority (median 76%) of tetramer-binding cells were consistently detectable via intracellular IFN-γ cytokine staining. Furthermore, modifications to the LDA, using a low input cell number into each well, enabled LDAs to reach equivalence with the other methods of CTL enumeration. These data together show that functionally inert CTLs do not play a significant role in chronic pediatric or adult HIV infection

Immunodominant HIV-1 Cd4+ T Cell Epitopes in Chronic Untreated Clade C HIV-1 Infection

Background: A dominance of Gag-specific CD8+ T cell responses is significantly associated with a lower viral load in individuals with chronic, untreated clade C human immunodeficiency virus type 1 (HIV-1) infection. This association has not been investigated in terms of Gag-specific CD4+ T cell responses, nor have clade C HIV-1–specific CD4+ T cell epitopes, likely a vital component of an effective global HIV-1 vaccine, been identified. Methodology/Principal Findings: Intracellular cytokine staining was conducted on 373 subjects with chronic, untreated clade C infection to assess interferon-gamma (IFN-γ) responses by CD4+ T cells to pooled Gag peptides and to determine their association with viral load and CD4 count. Gag-specific IFN-γ–producing CD4+ T cell responses were detected in 261/373 (70%) subjects, with the Gag responders having a significantly lower viral load and higher CD4 count than those with no detectable Gag response (p<0.0001 for both parameters). To identify individual peptides targeted by HIV-1–specific CD4+ T cells, separate ELISPOT screening was conducted on CD8-depleted PBMCs from 32 chronically infected untreated subjects, using pools of overlapping peptides that spanned the entire HIV-1 clade C consensus sequence, and reconfirmed by flow cytometry to be CD4+ mediated. The ELISPOT screening identified 33 CD4+ peptides targeted by 18/32 patients (56%), with 27 of the 33 peptides located in the Gag region. Although the breadth of the CD4+ responses correlated inversely with viral load (p = 0.015), the magnitude of the response was not significantly associated with viral load. Conclusions/Significance: These data indicate that in chronic untreated clade C HIV-1 infection, IFN-γ–secreting Gag-specific CD4+ T cell responses are immunodominant, directed at multiple distinct epitopes, and associated with viral control

A structural explanation for the binding of endocytic dileucine motifs by the AP2 complex.

Most transmembrane proteins are selected as transport-vesicle cargo through the recognition of short, linear amino-acid motifs in their cytoplasmic portions by vesicle coat proteins. For clathrin-coated vesicles, the motifs are recognized by clathrin adaptors. The AP2 adaptor complex (subunits α, β2, μ2 and σ2) recognizes both major endocytic motifs: YxxΦ motifs1 (where Φ can be F, I, L, M or V) and [ED]xxxL[LI] acidic dileucine motifs. Here we describe the binding of AP2 to the endocytic dileucine motif from CD4 (ref. 2). The major recognition events are the two leucine residues binding in hydrophobic pockets on σ2. The hydrophilic residue four residues upstream from the first leucine sits on a positively charged patch made from residues on the σ2 and α subunits. Mutations in key residues inhibit the binding of AP2 to ‘acidic dileucine’ motifs displayed in liposomes containing phosphatidylinositol-4,5-bisphosphate, but do not affect binding to YxxΦ motifs through μ2. In the ‘inactive’ AP2 core structure3 both motif-binding sites are blocked by different parts of the β2 subunit. To allow a dileucine motif to bind, the β2 amino terminus is displaced and becomes disordered; however, in this structure the YxxΦ-binding site on μ2 remains blocked.D.J.O., B.T.K. and S.E.M. are funded by a Wellcome Trust Senior Research Fellowship to D.J.O. S.H. and K.S. are supported by grants from the Deutsche Forschungsgemeinschaft (SFB635 and SFB670)