Abstract Background The release of tumor necrosis factor-α (TNF-α) appears depend on the P2X7 receptor, a purinergic receptor. In the present study, we addressed the question of whether P2X7 receptor-mediated TNF-α regulation is involved in pathogenesis and outcome of status epilepticus (SE). Methods SE was induced by pilocarpine in rats that were intracerebroventricularly infused with saline-, 2',3'-O-(4-benzoylbenzoyl)-adenosine 5'-triphosphate (BzATP), adenosine 5'-triphosphate-2',3'-dialdehyde (OxATP), A-438079, or A-740003 prior to SE induction. Thereafter, we performed Fluoro-Jade B staining and immunohistochemical studies for TNF-α and NF-κB subunit phosphorylations. Results Following SE, P2X7 receptor agonist (BzATP) infusion increased TNF-α immunoreactivity in dentate granule cells as compared with that in saline-infused animals. In addition, TNF-α immunoreactivity was readily apparent in the mossy fibers, while TNF-α immunoreactivity in CA1-3 pyramidal cells was unaltered. However, P2X7 receptor antagonist (OxATP-, A-438079, and A-740003) infusion reduced SE-induced TNF-α expression in dentate granule cells. In the CA3 region, BzATP infusion attenuated SE-induced neuronal damage, accompanied by enhancement of p65-Ser276 and p65-Ser311 NF-κB subunit phosphorylations. In contrast, OxATP-, A-438079, and A-740003 infusions increased SE-induced neuronal death. Soluble TNF p55 receptor (sTNFp55R), and cotreatment with BzATP and sTNFp55R infusion also increased SE-induced neuronal damage in CA3 region. However, OxATP-, sTNFp55R or BzATP+sTNFp55R infusions could not exacerbate SE-induced neuronal damages in the dentate gyrus and the CA1 region, as compared to BzATP infusion. Conclusions These findings suggest that TNF-α induction by P2X7 receptor activation may ameliorate SE-induced CA3 neuronal damage via enhancing NF-κB p65-Ser276 and p65-Ser311 phosphorylations.

Ion-specific effects in aqueous solution, known as the Hofmeister effect, are prevalent in diverse systems ranging from pure ionic to complex protein solutions. The objective of this paper is to explicitly demonstrate how complex ion-ion and ion-water interactions manifest themselves in the Hofmeister effect based on a series of recent experimental observations. These effects are not considered in the classical descriptions of ion effects, such as the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory, and therefore they fail to describe the origin of the phenomenological Hofmeister effect. However, given that models considering the basic forces of electrostatic and van der Waals interactions can offer rationalization for the core experimental observations, a universal interaction model stands a chance of being developed. In this perspective, we separately derive the contribution from ion-ion electrostatic interactions and ion-water interactions from second harmonic generation (SHG) data at the air-ion solution interface, which yields an estimate of the ion-water interactions in solution. The Hofmeister ion effect observed for biological solutes in solution should be similarly influenced by contributions from ion-ion and ion-water interactions, where the same ion-water interaction parameters derived from SHG data at the air-ion solution interface could be applicable. A key experimental data set available from solution systems to probe ion-water interactions is the modulation of water diffusion dynamics near ions in a bulk ion solution, as well as near biological liposome surfaces. This is obtained from Overhauser dynamic nuclear polarization (ODNP), a nuclear magnetic resonance (NMR) relaxometry technique. The surface water diffusivity is influenced by the contribution from ion-water interactions, both from localized surface charges and adsorbed ions, although the relative contribution of the former is larger on liposome surfaces. In this perspective, ion-water interaction energy values derived from experimental data for various ions are compared with theoretical values in the literature. Ultimately, quantifying ion-induced changes in the surface energy for the purpose of developing valid theoretical models for ion-water interactions will be critical to rationalizing the Hofmeister effect.

Abstract Background Status epilepticus (SE) induces severe vasogenic edema in the piriform cortex (PC) accompanied by neuronal and astroglial damages. To elucidate the mechanism of SE-induced vasogenic edema, we investigated the roles of tumor necrosis factor (TNF)-α in blood-brain barrier (BBB) disruption during vasogenic edema and its related events in rat epilepsy models provoked by pilocarpine-induced SE. Methods SE was induced by pilocarpine in rats that were intracerebroventricularly infused with saline-, and soluble TNF p55 receptor (sTNFp55R) prior to SE induction. Thereafter, we performed Fluoro-Jade B staining and immunohistochemical studies for TNF-α and NF-κB subunits. Results Following SE, most activated microglia showed strong TNF-α immunoreactivity. In addition, TNF p75 receptor expression was detected in endothelial cells as well as astrocytes. In addition, only p65-Thr435 phosphorylation was increased in endothelial cells accompanied by SMI-71 expression (an endothelial barrier antigen). Neutralization of TNF-α by soluble TNF p55 receptor (sTNFp55R) infusion attenuated SE-induced vasogenic edema and neuronal damages via inhibition of p65-Thr435 phosphorylation in endothelial cells. Furthermore, sTNFp55R infusion reduced SE-induced neutrophil infiltration in the PC. Conclusion These findings suggest that impairments of endothelial cell functions via TNF-α-mediated p65-Thr 485 NF-κB phosphorylation may be involved in SE-induced vasogenic edema. Subsequently, vasogenic edema results in extensive neutrophil infiltration and neuronal-astroglial loss.

Designing and optimizing the flow-field structure for the liquid phase Br2/HBr electrolyte solution of H2/Br2 redox flow batteries (RFBs) is important for improving cell performance. In this study, two electrolyte flow modes, i.e. the flow-by and flow-through modes, are simulated by using a three-dimensional H2/Br2 RFB model. The model is first applied to real-scale H2/Br2 cell geometries and then validated against the experimental polarization curves acquired using the two different flow modes. The model predictions compare well with the experimental data and further highlight the advantages of using the flow-through mode relative to the flow-by mode. Detailed multi-dimensional contours of the electrolyte flow velocity and key species distributions reveal that more uniform diffusion and stronger convective transport are achieved by using the flow-through mode, which alleviates the ohmic loss associated with charge transport in the Br2 electrode.

Angiogenesis is a morphogenic process resulting in the formation of new blood vessels from pre-existing ones, usually in hypoxic micro-environments. The initial steps of angiogenesis depend on robust differentiation of oligopotent endothelial cells into the Tip and Stalk phenotypic cell fates, controlled by NOTCH-dependent cell-cell communication. The dynamics of spatial patterning of this cell fate specification are only partially understood. Here, by combining a controlled experimental angiogenesis model with mathematical and computational analyses, we find that the regular spatial Tip-Stalk cell patterning can undergo an order-disorder transition at a relatively high input level of a pro-angiogenic factor VEGF. The resulting differentiation is robust but temporally unstable for most cells, with only a subset of presumptive Tip cells leading sprout extensions. We further find that sprouts form in a manner maximizing their mutual distance, consistent with a Turing-like model that may depend on local enrichment and depletion of fibronectin. Together, our data suggest that NOTCH signaling mediates a robust way of cell differentiation enabling but not instructing subsequent steps in angiogenic morphogenesis, which may require additional cues and self-organization mechanisms. This analysis can assist in further understanding of cell plasticity underlying angiogenesis and other complex morphogenic processes.

Reconfigurable tactile displays are being used to provide refreshable Braille information; however, the delivered information is currently limited to an alternative of Braille because of difficulties in controlling the deformation height. Herein, we present a photothermally activated polymer-bilayer-based morphable tactile display that can programmably generate tangible three-dimensional topologies with varying textures on a thin film surface. The morphable tactile display was composed of a heterogeneous polymer structure that integrated a stiffness-tunable polymer into a light-absorbing elastomer, near-infra-red light-emitting diode (NIR-LED) array, and small pneumatic chamber. Topological expression was enabled by producing localized out-of-plane deformation that was reversible, height-adjustable, and latchable in response to light-triggered stiffness modulation at each target area under switching of stationary pneumatic pressure. Notably, the tactile display could express a spatial softness map of the latched topology upon re-exposing the target areas to modulated light from the NIR-LED array. We expect the developed tactile display to open a pathway for generating high-dimensional tactile information on electronic devices and enable realistic interaction in augmented and virtual environments.

Purpose

To assess usefulness of adding contrast-enhanced ultrasonography (CEUS) to fusion imaging (FI) for percutaneous radiofrequency ablation (RFA) of hepatocellular carcinomas (HCCs) inconspicuous on FI alone. Therapeutic outcomes of RFA under CEUS-added FI guidance for HCCs inconspicuous on FI alone were also evaluated.

Methods

This prospective study was approved by the institutional review board and informed consent was obtained from all patients. Planning US was performed with FI for 126 patients with a single HCC (1-2 cm) to evaluate the feasibility of RFA by grading lesion conspicuity score using a four-point scale. RFA was performed under CEUS-added FI guidance for HCCs inconspicuous on FI alone. We evaluated how many HCCs initially inconspicuous on FI became conspicuous after adding CEUS. After CEUS-added FI-guided RFA, therapeutic outcomes including rates of technical success, primary technique efficacy, major complications, and local tumor progression were assessed.

Results

After adding CEUS, 90.5% (19/21) of all tumors initially inconspicuous on FI became conspicuous, thus enabling direct targeting for RFA. Technical success and primary technique efficacy rates were 94.7% (18/19) and 100% (19/19), respectively. No major complications were observed after RFA. Cumulative local tumor progression rates after RFA were estimated to be 5.3%, 10.8%, and 10.8% at 1, 2, and 3 years, respectively.

Conclusion

Adding CEUS to FI is useful for improving the conspicuity of HCCs inconspicuous on FI alone, thus enabling successful percutaneous RFA with excellent therapeutic outcomes.

The pharmacokinetic properties of antibodies are largely dictated by the pH-dependent binding of the IgG fragment crystallizable (Fc) domain to the human neonatal Fc receptor (hFcRn). Engineered Fc domains that confer a longer circulation half-life by virtue of more favorable pH-dependent binding to hFcRn are of great therapeutic interest. Here we developed a pH Toggle switch Fc variant containing the L309D/Q311H/N434S (DHS) substitutions, which exhibits markedly improved pharmacokinetics relative to both native IgG1 and widely used half-life extension variants, both in conventional hFcRn transgenic mice and in new knock-in mouse strains. engineered specifically to recapitulate all the key processes relevant to human antibody persistence in circulation, namely: (i) physiological expression of hFcRn, (ii) the impact of hFcγRs on antibody clearance and (iii) the role of competing endogenous IgG. DHS-IgG retains intact effector functions, which are important for the clearance of target pathogenic cells and also has favorable developability.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.