The neonatal crystallizable fragment receptor (FcRn) functions as an intracellular protection receptor for immunoglobulin G (IgG). Recently, several clinical studies have reported the lowering of ...circulating monomeric IgG levels through FcRn blockade for the potential treatment of autoimmune diseases. Many autoimmune diseases, however, are derived from the effects of IgG immune complexes (ICs). We generated, characterized, and assessed the effects of SYNT001, a FcRn-blocking monoclonal antibody, in mice, nonhuman primates (NHPs), and humans. SYNT001 decreased all IgG subtypes and IgG ICs in the circulation of humans, as we show in a first-in-human phase 1, single ascending dose study. In addition, IgG IC induction of inflammatory pathways was dependent on FcRn and inhibited by SYNT001. These studies expand the role of FcRn in humans by showing that it controls not only IgG protection from catabolism but also inflammatory pathways associated with IgG ICs involved in a variety of autoimmune diseases.
This article gives a critical review of the current data on the specific conductivity of aqueous potassium hydroxide (KOH) solutions. Empirical correlations relating concentration to density were ...developed to compare specific conductivity data given in weight percentage KOH and molarity of KOH. Available data on specific conductivity is related with respect to one another and compared to experimental data. Based on these comparisons, specific sets of reported data were used to develop an equation relating specific conductivity of aqueous KOH to temperature and concentration. This empirical correlation was developed over a molarity range of 0–12 at temperatures of
0
–
100
∘
C
. The correlation has been compared with that proposed by See and White and shows greater accuracy over the concentration range modeled.
Nickel undergoes significant deactivation as a cathode during alkaline water electrolysis in 8 mol/l KOH at 70
°C. Addition of dissolved V
2O
5 was found to result in reactivation of the nickel ...cathode and formation of a vanadium-bearing deposit. Tafel measurements at different electrode states indicated no change in the Tafel parameters for the fresh (or initial) and vanadium-modified states. Furthermore, vanadium addition did not appear to enhance the electrocatalytic activity beyond that for fresh nickel. A rotating ring-disk electrode was used for detection of solution intermediates of the hydrogen evolution reaction in KOH with and without dissolved V
2O
5. Based on cyclic voltammograms for the ring (with a hydrogen-evolving Ni disk), no solution intermediates were detected before or after vanadium addition. The action of vanadium was through a solid surface species as opposed to a homogeneous species in solution. A mercury electrode was then used to shift hydrogen evolution cathodically, revealing the potential region masked by large hydrogen currents on a nickel electrode. Cyclic voltammetry on mercury in KOH with dissolved V
2O
5 showed a cathodic peak that was absent in voltammograms for blank KOH. Therefore, formation of the deposit occurred at a potential coincident with that of hydrogen evolution on nickel.
Synaptic ribbons are presynaptic protein structures found at many synapses that convey graded, "analog" sensory signals in the visual, auditory, and vestibular pathways. Ribbons, typically anchored ...to the presynaptic membrane and surrounded by tethered synaptic vesicles, are thought to regulate or facilitate vesicle delivery to the presynaptic membrane. No direct evidence exists, however, to indicate how vesicles interact with the ribbon or, once attached, move along the ribbon's surface to reach the presynaptic release sites at its base. To address these questions, we have created, validated, and tested a passive vesicle diffusion model of retinal rod bipolar cell ribbon synapses. We used axial (bright-field) electron tomography in the scanning transmission electron microscopy to obtain 3D structures of rat rod bipolar cell terminals in 1-μm-thick sections of retinal tissue at an isotropic spatial resolution of ∼3 nm. The resulting structures were then incorporated with previously published estimates of vesicle diffusion dynamics into numerical simulations that accurately reproduced electrophysiologically measured vesicle release/replenishment rates and vesicle pool sizes. The simulations suggest that, under physiologically realistic conditions, diffusion of vesicles crowded on the ribbon surface gives rise to a flow field that enhances delivery of vesicles to the presynaptic membrane without requiring an active transport mechanism. Numerical simulations of ribbon-vesicle interactions predict that transient binding and unbinding of multiple tethers to each synaptic vesicle may achieve sufficiently tight association of vesicles to the ribbon while permitting the fast diffusion along the ribbon that is required to sustain high release rates.
Sensory processing in the auditory system requires that synapses, neurons, and circuits encode information with particularly high temporal and spectral precision. In the amphibian papillia, sound ...frequencies up to 1 kHz are encoded along a tonotopic array of hair cells and transmitted to afferent fibers via fast, repetitive synaptic transmission, thereby promoting phase locking between the presynaptic and postsynaptic cells. Here, we have combined serial section electron microscopy, paired electrophysiological recordings, and Monte Carlo diffusion simulations to examine novel mechanisms that facilitate fast synaptic transmission in the inner ear of frogs (Rana catesbeiana and Rana pipiens). Three-dimensional anatomical reconstructions reveal specialized spine-like contacts between individual afferent fibers and hair cells that are surrounded by large, open regions of extracellular space. Morphologically realistic diffusion simulations suggest that these local enlargements in extracellular space speed transmitter clearance and reduce spillover between neighboring synapses, thereby minimizing postsynaptic receptor desensitization and improving sensitivity during prolonged signal transmission. Additionally, evoked EPSCs in afferent fibers are unaffected by glutamate transporter blockade, suggesting that transmitter diffusion and dilution, and not uptake, play a primary role in speeding neurotransmission and ensuring fidelity at these synapses.
Patients who are immunocompromised because of malignancy have an increased risk of herpes zoster and herpes zoster-related complications. We aimed to investigate the efficacy and safety of an ...inactivated varicella zoster virus (VZV) vaccine for herpes zoster prevention in patients with solid tumour or haematological malignancies.
This phase 3, two-arm, randomised, double-blind, placebo-controlled, multicentre trial with an adaptive design was done in 329 centres across 40 countries. The trial included adult patients with solid tumour malignancies receiving chemotherapy and those with haematological malignancies, either receiving or not receiving chemotherapy. Patients were randomly assigned (1:1) to receive four doses of VZV vaccine inactivated by γ irradiation or placebo approximately 30 days apart. The patients, investigators, trial site staff, clinical adjudication committee, and sponsor's clinical and laboratory personnel were masked to the group assignment. The primary efficacy endpoint was herpes zoster incidence in patients with solid tumour malignancies receiving chemotherapy, which was assessed in the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of inactivated VZV vaccine or placebo). The primary safety endpoint was serious adverse events up to 28 days after the fourth dose in patients with solid tumour malignancies receiving chemotherapy. Safety endpoints were assessed in all patients who received at least one dose of inactivated VZV vaccine or placebo and had follow-up data. This trial is registered (NCT01254630 and EudraCT 2010-023156-89).
Between June 27, 2011, and April 11, 2017, 5286 patients were randomly assigned to receive VZV vaccine inactivated by γ irradiation (n=2637) or placebo (n=2649). The haematological malignancy arm was terminated early because of evidence of futility at a planned interim analysis; therefore, all prespecified haematological malignancy endpoints were deemed exploratory. In patients with solid tumour malignancies in the modified intention-to-treat population, confirmed herpes zoster occurred in 22 of 1328 (6·7 per 1000 person-years) VZV vaccine recipients and in 61 of 1350 (18·5 per 1000 person-years) placebo recipients. Estimated vaccine efficacy against herpes zoster in patients with solid tumour malignancies was 63·6% (97·5% CI 36·4 to 79·1), meeting the prespecified success criterion. In patients with solid tumour malignancies, serious adverse events were similar in frequency across treatment groups, occurring in 298 (22·5%) of 1322 patients who received the vaccine and in 283 (21·0%) of 1346 patients who received placebo (risk difference 1·5%, 95% CI −1·7 to 4·6). Vaccine-related serious adverse events were less than 1% in each treatment group. Vaccine-related injection-site reactions were more common in the vaccine group than in the placebo group. In the haematological malignancy group, VZV vaccine was well tolerated and estimated vaccine efficacy against herpes zoster was 16·8% (95% CI −17·8 to 41·3).
The inactivated VZV vaccine was well tolerated and efficacious for herpes zoster prevention in patients with solid tumour malignancies receiving chemotherapy, but was not efficacious for herpes zoster prevention in patients with haematological malignancies.
Merck & Co, Inc.
The compact (R
0
~1.2-1.3m) Fusion Nuclear Science Facility (FNSF) is aimed at providing a fully integrated, continuously driven fusion nuclear environment of copious fusion neutrons. This facility ...would be used to test, discover, and understand the complex challenges of fusion plasma material interactions, nuclear material interactions, tritium fuel management, and power extraction. Such a facility properly designed would provide, initially at the JET-level plasma pressure (~30%T
2
) and conditions (e.g., Hot-Ion H-Mode, Q<1)), an outboard fusion neutron flux of 0.25 MW/m
2
while requiring a fusion power of ~19 MW. If and when this research is successful, its performance can be extended to 1 MW/m
2
and ~76 MW by reaching for twice the JET plasma pressure and Q. High-safety factor q and moderate-plasmas are used to minimize or eliminate plasma-induced disruptions, to deliver reliably a neutron fluence of 1 MW-yr/m
2
and a duty factor of 10% presently anticipated for the FNS research. Success of this research will depend on achieving time-efficient installation and replacement of all internal components using remote handling (RH). This in turn requires modular designs for the internal components, including the single-turn toroidal field coil center-post. These device goals would further dictate placement of support structures and vacuum weld seals behind the internal and shielding components. If these goals could be achieved, the FNSF would further provide a ready upgrade path to the Component Test Facility (CTF), which would aim to test, for ≤6 MW-yr/m
2
and 30% duty cycle, the demanding fusion nuclear engineering and technologies for DEMO. This FNSF-CTF would thereby complement the ITER Program, and support and help mitigate the risks of an aggressive world fusion DEMO R&D Program. The key physics and technology research needed in the next decade to manage the potential risks of this FNSF are identified.
Critical coupling in integrated photonic devices enables the efficient transfer of energy from a waveguide to a resonator, a key operation for many applications. This condition is achieved when the ...resonator loss rate is equal to the coupling rate to the bus waveguide. Carefully matching these quantities is challenging in practice, due to variations in the resonator properties resulting from fabrication and external conditions. Here, we demonstrate that efficient energy transfer to a non-critically coupled resonator can be achieved by tailoring the excitation signal in time. We rely on excitations oscillating at complex frequencies to load an otherwise overcoupled resonator, demonstrating that a virtual critical coupling condition is achieved if the imaginary part of the complex frequency equals the mismatch between loss and coupling rate. We probe a microring resonator with tailored pulses and observe a minimum intensity transmission
in contrast to a continuous-wave transmission
, corresponding to 8 times enhancement of intracavity intensity. Our technique opens opportunities for enhancing and controlling on-demand light-matter interactions for linear and nonlinear photonic platforms.
The Lewis acidic redox-active and photoactive ruthenium(II) bipyridyl moiety in combination with amide (CO−NH) groups has been incorporated into acyclic, macrocyclic, and lower rim calix4arene ...structural frameworks to produce a new class of anion receptor with the dual capability of sensing anionic guest species via electrochemical and optical methodologies. Single-crystal X-ray structures of (1)Cl and (11)H2PO4 reveal the importance of hydrogen bonding to the overall anion complexation process. In the former complex, six hydrogen bonds (two amide and four C−H groups) stabilize the Cl- anion and three hydrogen bonds (two amide and one calix4arene hydroxyl) effect H2PO4 - complexation with 11. Proton NMR titration investigations in deuterated DMSO solutions reveal these receptors form strong and, in the case of the macrocyclic 5 and calix4arene-containing receptor 11, highly selective complexes with H2PO4 -. Cyclic and square-wave voltammetric studies have demonstrated these receptors to electrochemically recognize Cl-, Br-, H2PO4 -, and HSO4 - anions. The calix4arene anion receptor 11 selectively electrochemically senses H2PO4 - in the presence of 10-fold excess amounts of HSO4 - and Cl-. Fluorescence emission spectral recognition of H2PO4 - in DMSO solutions is displayed by 3, 5, and 11.
It is increasingly recognized that a significant component of apparent self-discharge in supercapacitors is, in fact, due to charge redistribution. This charge redistribution is due to the limited ...mobility and hence high resistance of ions moving in the smallest pores of the carbon electrodes. A simple two-branch equivalent circuit has been used to model this charge redistribution and has been applied to an ultramicroporous aqueous electrochemical capacitor. The results indicate that a substantial fraction of the total capacitance is found in the smallest pores and that the resistance to ionic movement is four orders of magnitude higher than in the bulk electrolyte. A survey of the literature indicates that many commercial capacitors with organic electrolyte have similar electrical properties. These properties mean that a significant fraction of the overall pore surface and hence capacitance of the electrode is not accessible during time frames of practical interest and is therefore wasted. A mechanism for the low mobility of ions in micropores is proposed.
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