Highly fluorinated nitrobenzene derivatives are suitable substrates for palladium-catalyzed C−F bond arylation using readily available palladium catalysts under both conventional heating and ...microwave conditions. Arylation occurs ortho to the nitro group offering a synthetic route to polyfluorinated 2-arylnitrobenzene systems. The regiochemistry of the arylation reactions suggests that there is a significant directing interaction between the nitro group and the incoming nucleophilic palladium catalyst which is facilitated by the presence of several fluorine atoms attached the ring. Investigations into the regioselectivity and reactivity of several tetrafluoro- and trifluoronitrobenzene derivatives provides further evidence for the highly nucleophilic character of the oxidative addition step in contrast to the concerted mechanism of more conventional Suzuki−Miyaura coupling reactions involving aryl iodides and bromides.
Context. Heating the solar corona to several million degrees requires the conversion of magnetic energy into thermal energy. In this paper, we investigate whether an unstable magnetic thread within a ...coronal loop can destabilise a neighbouring magnetic thread. Aims. By running a series of simulations, we aim to understand under what conditions the destabilisation of a single magnetic thread can also trigger a release of energy in a nearby thread. Methods. The 3D magnetohydrodynamics code, Lare3d, is used to simulate the temporal evolution of coronal magnetic fields during a kink instability and the subsequent relaxation process. We assume that a coronal magnetic loop consists of non-potential magnetic threads that are initially in an equilibrium state. Results. The non-linear kink instability in one magnetic thread forms a helical current sheet and initiates magnetic reconnection. The current sheet fragments, and magnetic energy is released throughout that thread. We find that, under certain conditions, this event can destabilise a nearby thread, which is a necessary requirement for starting an avalanche of energy release in magnetic threads. Conclusions. It is possible to initiate an energy release in a nearby, non-potential magnetic thread, because the energy released from one unstable magnetic thread can trigger energy release in nearby threads, provided that the nearby structures are close to marginal stability.
Chronic hepatitis B virus (HBV) infection affects 257 million people globally. Current therapies suppress HBV but viral rebound occurs on cessation of therapy; novel therapeutic strategies are ...urgently required. To develop a therapeutic HBV vaccine that can induce high magnitude T cells to all major HBV antigens, we have developed a novel HBV vaccine using chimpanzee adenovirus (ChAd) and modified vaccinia Ankara (MVA) viral vectors encoding multiple HBV antigens. ChAd vaccine alone generated very high magnitude HBV specific T cell responses to all HBV major antigens. The inclusion of a shark Invariant (SIi) chain genetic adjuvant significantly enhanced the magnitude of T-cells against HBV antigens. Compared to ChAd alone vaccination, ChAd-prime followed by MVA-boost vaccination further enhanced the magnitude and breadth of the vaccine induced T cell response. Intra-cellular cytokine staining study showed that HBV specific CD8+ and CD4+ T cells were polyfunctional, producing combinations of IFNγ, TNF-α, and IL-2. In summary, we have generated genetically adjuvanted ChAd and MVA vectored HBV vaccines with the potential to induce high-magnitude T cell responses through a prime-boost therapeutic vaccination approach. These pre-clinical studies pave the way for new studies of HBV therapeutic vaccination in humans with chronic hepatitis B infection.
Physical disturbances in streams have important effects on rates of gross primary production (GPP) and ecosystem respiration (ER). Underlying lithology can control sediment size, amount, and ...evolution in the stream, influencing substrate stability and in turn benthic organisms. We assessed patterns of disturbance and recovery for metabolic processes of GPP and ER associated with periods of increased flow and suspended sediment flux between December and April in two streams in the Oregon Coast Range with differing lithologies (basalt and sandstone). The results of whole‐stream metabolism modelling indicate that the two study streams have varying patterns of response and recovery rates after storm events. Both streams were heterotrophic during the entirety of the study period with changes in heterotrophy driven by changes in ER. Poststorm GPP decreased in both streams, but the basalt basin had greater proportional decreases and recovered slower than the sandstone basin. This result was unexpected and appeared to be associated with lower light availability in the basalt basin driven by increased turbidity during storm events; the coarser basalt substrate weathers into smaller size fractions than the finer sandstone substrate, remaining in suspension over longer periods and limiting light availability to benthic primary producers. The rates of ER in the sandstone basin did not change from prestorm to poststorm, whereas rates of ER in the basalt basin had varying responses. Overall, our results indicated that the underlying lithology of small mountain streams can drive variability in GPP by controlling sediment size and light availability during storms events.
Aims. Four different approximate approaches used to model the stressing of coronal magnetic fields due to an imposed photospheric motion are compared with each other and the results from a full ...time-dependent magnetohydrodynamic (MHD) code. The assumptions used for each of the approximate methods are tested by considering large photospheric footpoint displacements. Methods. We consider a simple model problem, comparing the full non-linear MHD, determined with the Lare2D numerical code, with four approximate approaches. Two of these, magneto-frictional relaxation and a quasi-1D Grad-Shafranov approach, assume sequences of equilibria, whilst the other two methods, a second-order linearisation of the MHD equations and Reduced MHD, are time dependent. Results. The relaxation method is very accurate compared to full MHD for force-free equilibria for all footpoint displacements, but has significant errors when the plasma β0 is of order unity. The 1D approach gives an extremely accurate description of the equilibria away from the photospheric boundary layers, and agrees well with Lare2D for all parameter values tested. The linearised MHD equations correctly predict the existence of photospheric boundary layers that are present in the full MHD results. As soon as the footpoint displacement becomes a significant fraction of the loop length, the RMHD method fails to model the sequences of equilibria correctly. The full numerical solution is interesting in its own right, and care must be taken for low β0 plasmas if the viscosity is too high.
Cavernous malformations (CM) of the central nervous system constitute rare vascular lesions. They are usually asymptomatic, which has allowed their management to become quite debatable. Even when ...they become symptomatic their optimal mode and timing of treatment remains controversial.
A consensus may navigate neurosurgeons through the decision-making process of selecting the optimal treatment for asymptomatic and symptomatic CMs.
A 17-item questionnaire was developed to address controversial issues in relation to aspects of the treatment, surgical planning, optimal surgical strategy for specific age groups, the role of stereotactic radiosurgery, as well as a follow-up pattern. Consequently, a three-stage Delphi process was ran through 19 invited experts with the goal of reaching a consensus. The agreement rate for reaching a consensus was set at 70%.
A consensus for surgical intervention was reached on the importance of the patient's age, symptomatology, and hemorrhagic recurrence; and the CM's location and size. The employment of advanced MRI techniques is considered of value for surgical planning. Observation for asymptomatic eloquent or deep-seated CMs represents the commonest practice among our panel. Surgical resection is considered when a deep-seated CM becomes symptomatic or after a second bleeding episode. Asymptomatic, image-proven hemorrhages constituted no indication for surgical resection for our panelists. Consensus was also reached on not resecting any developmental venous anomalies, and on resecting the associated hemosiderin rim only in epilepsy cases.
Our Delphi consensus provides an expert common practice for specific controversial issues of CM patient management.
The global burden of neurologic disorders is a leading cause of disability and death worldwide and has increased the demand for treatments and rehabilitation. Our proposed integrated ...osteopathic-neurologic examination (ONE) provides the physician with expanded diagnostic and point-of-care treatment modalities while allowing the physician to make a more tangible effect in patient care. By incorporating the osteopathic structural somatic examination with the complete neurologic evaluation, somatic dysfunction, occurring as a consequence or independent of neurologic injury, can be identified and treated using osteopathic manipulative techniques at time of visit. Using the proposed integrated examination, the physician can determine the interplay between structural and neurologic findings to identify patterns of change that coincide with more specific diagnoses and the chronicity of a condition. Tangible benefits from the ONE approach translate to more accurate clinical assessment and enhanced patient and physician satisfaction.
The aim of the study was to evaluate the facilitatory effects of inhaled corticosteroid on in vitro parameters of lymphocyte beta 2-adrenoceptor function in asthmatic patients. Serum cortisol level ...was also evaluated as a measure of systemic bioactivity. Ten (four female) asthmatic subjects were evaluated, mean (SEM) age was 28.6(2.0) years, and FEV1 was 79.9%(8.7) predicted. Single doses of inhaled placebo (PL), fluticasone propionate, 1,000 micrograms (F1000), fluticasone propionate, 2,000 micrograms(F2000), or oral prednisolone, 50 mg(PRED), were given at 10 PM the previous night and measurements were made 10 h later. Values for beta 2-receptor density (logBmax: fmol/10(6)cells) were significantly (p < 0.05) greater than PL with PRED but not with inhaled fluticasone (as means and 95% confidence interval CI for difference vs PL): PL, 0.27; F1000, 0.30; F2000, 0.32; and PRED, 0.48 (95% CI vs PL, 0.075 to 0.341). Maximal cyclic adenosine monophosphate (cAMP) responses to isoproterenol hydrochloride (isoprenaline (Emax; pmol/10(6)cells) mirrored those for Bmax: PL, 4.00; F1000, 4.68; F2000, 4.26; and PRED, 7.46 (95% CI vs PL, -0.01 to 6.91). Receptor affinity (Kd) was not significantly altered by any treatment. There was significant (p < 0.05) suppression of serum cortisol (nmol/L) with F2000 and PRED compared with PL: PL, 307.9; F1000, 323.2; F2000, 130.1 (95% CI vs PL, 69.76 to 285.8) and PRED, 51.8 (95% CI vs PL, 144.11 to 368.01). Thus, high-dose inhaled fluticasone propionate did not have any facilitatory effects on lymphocyte beta 2-adrenoceptor parameters as compared with oral prednisolone which upregulated beta 2-receptor density and increased cAMP response. In contrast, high-dose inhaled fluticasone (2,000 micrograms) significantly suppressed serum cortisol. In conclusion, there would appear to be a dissociation in systemic sensitivity between effects of inhaled corticosteroid on adrenal suppression and lymphocyte beta 2-adrenoceptor regulation.
Aims.To perform numerical experiments of particle acceleration in the complex magnetic and electric field environment of the stressed solar corona.Methods.The magnetic and electric fields are ...obtained from a 3-D MHD experiment that resembles a coronal loop with photospheric regions at both footpoints. Photospheric footpoint motion leads to the formation of a hierarchy of stochastic current sheets. Particles (protons and electrons) are traced within these current sheets starting from a thermal distribution using a relativistic test particle code.Results.In the corona the particles are subject to acceleration as well as deceleration, and a considerable portion of them leave the domain having received a net energy gain. Particles are accelerated to high energies in a very short time (both species can reach energies up to 100 GeV within $5 \times 10^{-2} $ s for electrons and $5 \times 10^{-1}$ s for protons). The final energy distribution shows that while one quarter of the particles retain their thermal distribution, the rest have been accelerated, forming a two-part power law. Accelerated particles are either trapped within electric field regions of opposite polarities, or escape the domain mainly through the footpoints. The particle dynamics are followed in detail and it is shown how this dynamic affects the time evolution of the system and the energy distribution. The scaling of these results with time and length scale is examined and the Bremstrahlung signature of X-ray photons resulting from escaping particles hitting the chromosphere is calculated and found to have a main power law part with an index $\gamma = - 1.8$, steeper than observed. Possible resolutions of this discrepency are discussed.
A better understanding of mechanisms that regulate CD8
T cell responses to therapeutic vaccines is needed to develop approaches to enhance vaccine efficacy for chronic viral infections and cancers. ...We show here that NK cell depletion enhanced antigen-specific T cell responses to chimp adenoviral vector (ChAdOx) vaccination in a mouse model of chronic HBV infection (CHB). Probing the mechanism underlying this negative regulation, we observed that CHB drove parallel up-regulation of programmed cell death ligand 1 (PD-L1) on liver-resident NK cells and programmed cell death 1 (PD-1) on intrahepatic T cells. PD-L1-expressing liver-resident NK cells suppressed PD-1
CD8
T cells enriched within the HBV-specific response to therapeutic vaccination. Cytokine activation of NK cells also induced PD-L1, and combining cytokine activation with PD-L1 blockade resulted in conversion of NK cells into efficient helpers that boosted HBV-specific CD8
T cell responses to therapeutic vaccination in mice and to chronic infection in humans. Our findings delineate an immunotherapeutic combination that can boost the response to therapeutic vaccination in CHB and highlight the broader importance of PD-L1-dependent regulation of T cells by cytokine-activated NK cells.
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