Numerical integration of ordinary differential equations with some invariants is considered. For such a purpose, certain projection methods have proved its high accuracy and efficiency. ...Unfortunately, however, sometimes they can exhibit instability. In this paper, a new, highly efficient projection method is proposed based on explicit Runge–Kutta methods. The key there is to employ the idea of the perturbed collocation method, which gives a unified way to incorporate scheme parameters for projection. Numerical experiments confirm the stability of the proposed method.
Small viruses that belong, for example, to the Picornaviridae, such as poliovirus and foot-and-mouth disease virus, consist simply of capsid proteins and a single-stranded RNA (ssRNA) genome. The ...capsids are quite stable in solution to protect the genome from the environment. Here, based on long-time and large-scale 6.5 × 10(6) all-atom molecular dynamics calculations for the Mahoney strain of poliovirus, we show microscopic properties of the viral capsids at a molecular level. First, we found equilibrium rapid exchange of water molecules across the capsid. The exchange rate is so high that all water molecules inside the capsid (about 200,000) can leave the capsid and be replaced by water molecules from the outside in about 25 μs. This explains the capsid's tolerance to high pressures and deactivation by exsiccation. In contrast, the capsid did not exchange ions, at least within the present simulation time of 200 ns. This implies that the capsid can function, in principle, as a semipermeable membrane. We also found that, similar to the xylem of trees, the pressure of the solution inside the capsid without the genome was negative. This is caused by coulombic interaction of the solution inside the capsid with the capsid excess charges. The negative pressure may be compensated by positive osmotic pressure by the solution-soluble ssRNA and the counter ions introduced into it.
Skin sensitisation is the regulatory endpoint that has been at the centre of concerted efforts to replace animal testing in recent years, as demonstrated by the Organisation for Economic Co-operation ...and Development (OECD) adoption of five non-animal methods addressing mechanisms under the first three key events of the skin sensitisation adverse outcome pathway. Nevertheless, the currently adopted methods, when used in isolation, are not sufficient to fulfil regulatory requirements on the skin sensitisation potential and potency of chemicals comparable to that provided by the regulatory animal tests. For this reason, a number of defined approaches integrating data from these methods with other relevant information have been proposed and documented by the OECD. With the aim to further enhance regulatory consideration and adoption of defined approaches, the European Union Reference Laboratory for Alternatives to Animal testing in collaboration with the International Cooperation on Alternative Test Methods hosted, on 4–5 October 2016, a workshop on the international regulatory applicability and acceptance of alternative non-animal approaches, i.e., defined approaches, to skin sensitisation assessment of chemicals used in a variety of sectors. The workshop convened representatives from more than 20 regulatory authorities from the European Union, United States, Canada, Japan, South Korea, Brazil and China. There was a general consensus among the workshop participants that to maximise global regulatory acceptance of data generated with defined approaches, international harmonisation and standardisation are needed. Potential assessment criteria were defined for a systematic evaluation of existing defined approaches that would facilitate their translation into international standards, e.g., into a performance-based Test Guideline. Informed by the discussions at the workshop, the ICATM members propose practical ways to further promote the regulatory use and facilitate adoption of defined approaches for skin sensitisation assessments.
This study focused on the effect of heparin on regulatory T cells (Tregs) on the allogeneic immune responses in vitro and in vivo. Heparin‐induced de novo Treg generation and maintained the survival ...and activation of Tregs, independent of its anti‐coagulant properties.
Summary
Heparin is a widely used anti‐coagulant that enhances anti‐thrombin (AT) activity. However, heparin also suppresses immune and inflammatory responses in various rodent models and clinical trials, respectively. The mechanism by which heparin suppresses immune responses is unclear. The effect of heparin on regulatory T cells (Tregs) in allogeneic immune responses was analysed using an acute graft‐versus‐host disease (aGVHD) mouse model and mixed lymphocyte reactions (MLRs). In‐vitro culture systems were utilized to study the effects of heparin on Tregs. Heparin administration reduced mortality rates and increased the proportion of Tregs in the early post‐transplantation period of aGVHD mice. In both murine and human MLRs, heparin increased Tregs and inhibited responder T cell proliferation. Heparin promoted functional CD4+CD25+forkhead box protein 3 (FoxP3)+ Treg generation from naive CD4+ T cells, increased interleukin (IL)‐2 production and enhanced the activation of pre‐existing Tregs with IL‐2. Heparin‐induced Treg increases were not associated with anti‐coagulant activity through AT, but required negatively charged sulphation of heparin. Importantly, N‐acetyl heparin, a chemically modified heparin without anti‐coagulant activity, induced Tregs and decreased mortality in aGVHD mice. Our results indicate that heparin contributes to Treg‐mediated immunosuppression through IL‐2 production and suggest that heparin derivatives may be useful for immunopathological control by efficient Treg induction.
Background: Patients with natural killer (NK) cell neoplasms, aggressive NK cell leukemia (ANKL) and extranodal NK cell lymphoma, nasal type (ENKL), have poor outcome. Both diseases show a spectrum ...and the boundary of them remains unclear. The purpose of this study is to draw a prognostic model of total NK cell neoplasms.
Patients and methods: We retrospectively analyzed 172 patients (22 with ANKL and 150 with ENKL). The ENKLs consisted of 123 nasal and 27 extranasal (16 cutaneous, 9 hepatosplenic, 1 intestinal and 1 nodal) lymphomas.
Results: Complete remission rate for ENKL was 73% in stage I, but 15% in stage IV, which was consistent with that for ANKL (18%). The prognosis of ENKL was better than that of ANKL (median survival 10 versus 1.9 months, P<0.0001) but was comparable when restricted to stage IV cases (4.0 months, P=0.16). Multivariate analysis showed that four factors (non-nasal type, stage, performance status and numbers of extranodal involvement) were significant prognostic factors. Using these four variables, an NK prognostic index was successfully constructed. Four-year overall survival of patients with zero, one, two and three or four adverse factors were 55%, 33%, 15% and 6%, respectively.
Conclusion: The current prognostic model successfully stratified patients with NK cell neoplasms with different outcomes.
Measurements of electromagnetic waves in space plasmas are an important tool for our understanding of physical processes in this environment. Inter‐calibration of data from different spacecraft ...missions is necessary for combining their measurements in empirical models or case studies. We show results collected during a close conjunction of the Van Allen Probes and Arase spacecraft. The inter‐calibration is based on a fortuitous case of common observations of strong whistlers at frequencies between a few hundred hertz and 10 kHz, which are generated by the same lightning strokes and which propagate along very similar paths to the two spacecraft. Measured amplitudes of the magnetic field fluctuations are the same within ∼14% precision of our analysis, corresponding to 1.2 dB. Currently, archived electric field measurements show twice larger amplitudes on Arase compared to Van Allen Probes but they start to match within ∼33% precision (2.5 dB) once the newest results on the interface of the antennas to the surrounding plasma are included in the calibration procedures. Ray tracing simulations help us to build a consistent scenario of wave propagation to both spacecraft reflected by a successful inter‐calibration of the polarization and propagation parameters obtained from multicomponent measurements. We succeed in linking the spacecraft observations to localizations of lightning return strokes by two different ground‐based networks which independently verify the correctness of the Universal Time tags of waveform measurements by both spacecraft missions, with an uncertainty better than 10 ms.
Key Points
Measurements of electromagnetic waves on Van Allen Probes and Arase are inter‐calibrated with intense whistlers during a close conjunction
Magnetic search coil measurements are the same within 14%, polarization and propagation parameters are consistent, timing is within 10 ms
Electric field amplitudes match within 33% when we include the newest results on antenna‐plasma interface with measured plasma densities
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