First direct kinetic measurement of i -C4H5 (CH2CHCCH2) + O-2 reaction : Toward quantitative understanding of aromatic ring formation chemistry

The kinetics of the i -C 4 H 5 (buta-1,3-dien-2-yl) radical reaction with molecular oxygen has been measured over a wide temperature range (275-852 K) at low pressures (0.8-3 Torr) in direct, time-resolved experiments. The measurements were performed using a laminar flow reactor coupled to photoionization mass spectrometer (PIMS), and laser photolysis of either chloroprene (2-chlorobuta-1,3-diene) or isoprene was used to produce the resonantly stabilized i -C 4 H 5 radical. Under the experimental conditions, the measured bimolecular rate coefficient of i -C 4 H 5 + O 2 reaction is independent of bath gas density and exhibits weak, negative temperature dependency, and can be described by the expression k 3 = (1.45 +/- 0.05) & times; 10 & minus;12 & times; ( T /298 K) & minus;(0.13 +/- 0.05) cm 3 s & minus;1 . The measured bimolecular rate coefficient is surprisingly fast for a resonantly stabilized radical. Under combustion conditions, the reactions of i -C 4 H 5 radical with ethylene and acetylene are believed to play an important role in forming the first aromatic ring. However, the current measurements show that i C 4 H 5 + O 2 reaction is significantly faster under combustion conditions than previous estimations suggest and, consequently, inhibits the soot forming propensity of i -C 4 H 5 radicals. The bimolecular rate coefficient estimates used for the i -C 4 H 5 + O 2 reaction in recent combustion simulations show significant variation and are up to two orders of magnitude slower than the current, measured value. All estimates, in contrast to our measurements, predict a positive temperature dependency. The observed products for the i -C 4 H 5 + O 2 reaction were formaldehyde and ketene. This is in agreement with the one theoretical study available for i C 4 H 5 + O 2 reaction, which predicts the main bimolecular product channels to be H 2 CO + C 2 H 3 + CO and H 2 CCO + CH 2 CHO. (c) 2020 The Combustion Institute. Published by Elsevier Inc. All rights reserved.Peer reviewe

Cosmological perturbations in Palatini modified gravity

Two approaches to the study of cosmological density perturbations in modified theories of Palatini gravity have recently been discussed. These utilise, respectively, a generalisation of Birkhoff's theorem and a direct linearization of the gravitational field equations. In this paper these approaches are compared and contrasted. The general form of the gravitational lagrangian for which the two frameworks yield identical results in the long-wavelength limit is derived. This class of models includes the case where the lagrangian is a power-law of the Ricci curvature scalar. The evolution of density perturbations in theories of the type $f(R)=R-c /R^ b$ is investigated numerically. It is found that the results obtained by the two methods are in good agreement on sufficiently large scales when the values of the parameters (b,c) are consistent with current observational constraints. However, this agreement becomes progressively poorer for models that differ significantly from the standard concordance model and as smaller scales are considered

Endoplasmic reticulum stress inhibition protects against excitotoxic neuronal injury in the rat brain.

Elevated brain glutamate with activation of neuronal glutamate receptors accompanies neurological disorders, such as epilepsy and brain trauma. However, the mechanisms by which excitotoxicity triggers neuronal injury are not fully understood. We have studied the glutamate receptor agonist kainic acid (KA) inducing seizures and excitotoxic cell death. KA caused the disintegration of the endoplasmic reticulum (ER) membrane in hippocampal neurons and ER stress with the activation of the ER proteins Bip, Chop, and caspase-12. Salubrinal, inhibiting eIF2alpha (eukaryotic translation initiation factor 2 subunit alpha) dephosphorylation, significantly reduced KA-induced ER stress and neuronal death in vivo and in vitro. KA-induced rise in intracellular calcium was not affected by Salubrinal. The results show that ER responses are essential parts of excitotoxicity mediated by glutamate receptor activation and that Salubrinal decreases neuronal death in vivo. Inhibition of ER stress by small molecular compounds may be beneficial for treatment of various neuronal injuries and brain disorders

Equilibrium hydrostatic equation and Newtonian limit of the singular f(R) gravity

We derive the equilibrium hydrostatic equation of a spherical star for any gravitational Lagrangian density of the form $L=\sqrt{-g}f(R)$. The Palatini variational principle for the Helmholtz Lagrangian in the Einstein gauge is used to obtain the field equations in this gauge. The equilibrium hydrostatic equation is obtained and is used to study the Newtonian limit for $f(R)=R-\frac{a^{2}}{3R}$. The same procedure is carried out for the more generally case $f(R)=R-\frac{1}{n+2}\frac{a^{n+1}}{R^{n}}$ giving a good Newtonian limit.Comment: Revised version, to appear in Classical and Quantum Gravity

Curvature singularities, tidal forces and the viability of Palatini f(R) gravity

In a previous paper we showed that static spherically symmetric objects which, in the vicinity of their surface, are well-described by a polytropic equation of state with 3/2<Gamma<2 exhibit a curvature singularity in Palatini f(R) gravity. We argued that this casts serious doubt on the validity of Palatini f(R) gravity as a viable alternative to General Relativity. In the present paper we further investigate this characteristic of Palatini f(R) gravity in order to clarify its physical interpretation and consequences.Comment: 15 pages. CQG in press. Part of the material moved to an appendix, discussion on the meV scale predictions of Palatini f(R) gravity adde

the CUTHIVAC-001 randomized trial

Targeting of different tissues via transcutaneous (TC), intradermal (ID) and intramuscular (IM) injection has the potential to tailor the immune response to DNA vaccination. In this Phase I randomised controlled clinical trial in HIV-1 negative volunteers we investigate whether the site and mode of DNA vaccination influences the quality of the cellular immune responses. We adopted a strategy of concurrent immunization combining IM injection with either ID or TC administration. As a third arm we assessed the response to IM injection administered with electroporation (EP). The DNA plasmid encoded a MultiHIV B clade fusion protein designed to induce cellular immunity. The vaccine and regimens were well tolerated. We observed differential shaping of vaccine induced virus-specific CD4 + and CD8 + cell-mediated immune responses. DNA given by IM + EP promoted strong IFN-γ responses and potent viral inhibition. ID + IM without EP resulted in a similar pattern of response but of lower magnitude. By contrast TC + IM (without EP) shifted responses towards a more Th-17 dominated phenotype, associated with mucosal and epidermal protection. Whilst preliminary, these results offer new perspectives for differential shaping of desired cellular immunity required to fight the wide range of complex and diverse infectious diseases and cancers

Recurrence of Type 1 Diabetes After Simultaneous Pancreas-Kidney Transplantation, Despite Immunosuppression, Is Associated With Autoantibodies and Pathogenic Autoreactive CD4 T-Cells

ObjectiveTo investigate if recurrent autoimmunity explained hyperglycemia and C-peptide loss in three immunosuppressed simultaneous pancreas-kidney (SPK) transplant recipients.Research design and methodsWe monitored autoantibodies and autoreactive T-cells (using tetramers) and performed biopsy. The function of autoreactive T-cells was studied with in vitro and in vivo assays.ResultsAutoantibodies were present pretransplant and persisted on follow-up in one patient. They appeared years after transplantation but before the development of hyperglycemia in the remaining patients. Pancreas transplant biopsies were taken within approximately 1 year from hyperglycemia recurrence and revealed beta-cell loss and insulitis. We studied autoreactive T-cells from the time of biopsy and repeatedly demonstrated their presence on further follow-up, together with autoantibodies. Treatment with T-cell-directed therapies (thymoglobulin and daclizumab, all patients), alone or with the addition of B-cell-directed therapy (rituximab, two patients), nonspecifically depleted T-cells and was associated with C-peptide secretion for &gt;1 year. Autoreactive T-cells with the same autoantigen specificity and conserved T-cell receptor later reappeared with further C-peptide loss over the next 2 years. Purified autoreactive CD4 T-cells from two patients were cotransplanted with HLA-mismatched human islets into immunodeficient mice. Grafts showed beta-cell loss in mice receiving autoreactive T-cells but not control T-cells.ConclusionsWe demonstrate the cardinal features of recurrent autoimmunity in three such patients, including the reappearance of CD4 T-cells capable of mediating beta-cell destruction. Markers of autoimmunity can help diagnose this underappreciated cause of graft loss. Immune monitoring during therapy showed that autoimmunity was not resolved by the immunosuppressive agents used

Autocrine Endocannabinoid Signaling through CB 1 Receptors Potentiates OX 1 Orexin Receptor Signaling s

ABSTRACT It has been proposed that OX 1 orexin receptors and CB 1 cannabinoid receptors can form heteromeric complexes, which affect the trafficking of OX 1 receptors and potentiate OX 1 receptor signaling to extracellular signal-regulated kinase (ERK). We have recently shown that OX 1 receptor activity releases high levels of the endocannabinoid 2-arachidonoyl glycerol (2-AG), suggesting an alternative route for OX 1 -CB 1 receptor interaction in signaling, for instance, in retrograde synaptic transmission. In the current study, we set out to investigate this possibility utilizing recombinant Chinese hamster ovary K1 cells. 2-AG released from OX 1 receptor-expressing cells acted as a potent paracrine messenger stimulating ERK activity in neighboring CB 1 receptor-expressing cells. When OX 1 and CB 1 receptors were expressed in the same cells, OX 1 stimulation-induced ERK phosphorylation and activity were strongly potentiated. The potentiation but not the OX 1 response as such was fully abolished by specific inhibition of CB 1 receptors or the enzyme responsible for 2-AG generation, diacylglycerol lipase (DAGL). Although the results do not exclude the previously proposed OX 1 -CB 1 heteromerization, they nevertheless unequivocally identify DAGL-dependent 2-AG generation as the pivotal determinant of the OX 1 -CB 1 synergism and thus suggest a functional rather than a molecular interaction of OX 1 and CB 1 receptors

Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin

Immune responses to autoantigens are in part controlled by deletion of autoreactive cells through genetically regulated selection mechanisms. We have directly analyzed peripheral CD4+ proinsulin (PI) 76–90 (SLQPLALEGSLQKRG)-specific T cells using soluble fluorescent major histocompatibility complex class II tetramers. Subjects with type I diabetes and healthy controls with high levels of peripheral proinsulin-specific T cells were characterized by the presence of a disease-susceptible polymorphism in the insulin variable number of tandem repeats (INS-VNTR) gene. Conversely, subjects with a ‘protective' polymorphism in the INS-VNTR gene had nearly undetectable levels of proinsulin tetramer-positive T cells. These results strongly imply a direct relationship between genetic control of autoantigen expression and peripheral autoreactivity, in which proinsulin genotype restricts the quantity and quality of the potential T-cell response. Using a modified tetramer to isolate low-avidity proinsulin-specific T cells from subjects with the susceptible genotype, transcript arrays identified several induced pro-apoptotic genes in the control, but not diabetic subjects, likely representing a second peripheral mechanism for maintenance of tolerance to self antigens