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Adenosine triphosphate (ATP) has been well established as an important extracellular ligand of autocrine signaling, intercellular communication, and neurotransmission with numerous physiological and pathophysiological roles. In addition to the classical exocytosis, non-vesicular mechanisms of cellular ATP release have been demonstrated in many cell types. Although large and negatively charged ATP molecules cannot diffuse across the lipid bilayer of the plasma membrane, conductive ATP release from the cytosol into the extracellular space is possible through ATP-permeable channels. Such channels must possess two minimum qualifications for ATP permeation: anion permeability and a large ion-conducting pore. Currently, five groups of channels are acknowledged as ATP-release channels: connexin hemichannels, pannexin 1, calcium homeostasis modulator 1 (CALHM1), volume-regulated anion channels (VRACs, also known as volume-sensitive outwardly rectifying (VSOR) anion channels), and maxi-anion channels (MACs). Recently, major breakthroughs have been made in the field by molecular identification of CALHM1 as the action potential-dependent ATP-release channel in taste bud cells, LRRC8s as components of VRACs, and SLCO2A1 as a core subunit of MACs. Here, the function and physiological roles of these five groups of ATP-release channels are summarized, along with a discussion on the future implications of understanding these channels.

Fermentative organs such as the caecum, the colon, and the rumen have evolved to produce and absorb energy rich short chain fatty acids (SCFA) from otherwise indigestible substrates. Classical models postulate diffusional uptake of the undissociated acid (HSCFA). However, in net terms, a major part of SCFA absorption occurs with uptake of Na+ and resembles classical, coupled electroneutral NaCl transport. Considerable evidence suggests that the anion transporting proteins expressed by epithelia of fermentative organs are poorly selective and that their main function may be to transport acetate−, propionate−, butyrate− and HCO3− as the physiologically relevant anions. Apical uptake of SCFA thus involves non-saturable diffusion of the undissociated acid (HSCFA), SCFA−/HCO3− exchange via DRA (SLC26A3) and/or SCFA−-H+ symport (MCT1, SLC16A1). All mechanisms lead to cytosolic acidification with stimulation of Na+/H+ exchange via NHE (SLC9A2/3). Basolaterally, Na+ leaves via the Na+/K+-ATPase with recirculation of K+. Na+ efflux drives the transport of SCFA− anions through volume-regulated anion channels, such as maxi-anion channels (possibly SLCO2A1), LRRC8, anoctamins, or uncoupled exchangers. When luminal buffering is inadequate, basolateral efflux will increasingly involve SCFA−/ HCO3− exchange (AE1/2, SCL4A1/2), or efflux of SCFA− with H+ (MCT1/4, SLC16A1/3). Furthermore, protons can be basolaterally removed by NHE1 (SCL9A1) or NBCe1 (SLC4A4). The purpose of these transport proteins is to maximize the amount of SCFA transported from the tightly buffered ingesta while minimizing acid transport through the epithelium. As known from the rumen for many decades, a disturbance of these processes is likely to cause severe colonic disease.

There are many situations where one expects an ordering among K ≥ 2 experimental groups or treatments. Although there is a large body of literature dealing with the analysis under order restrictions, surprisingly, very little work has been done in the context of the design of experiments. Here, a principled approach to the design of experiments with ordered treatments is provided. In particular we propose two classes of designs which are optimal for testing different types of hypotheses. The theoretical findings are supplemented with thorough numerical experimentation and a concrete data example. It is shown that there is a substantial gain in power, or alternatively a reduction in the required sample size, when an experiment is both designed and analysed by using methods which account for order restrictions.

The upcoming vogue of climate assemblies and other forms of mini-publics are to give citizens a central role in climate policy-making and to break the political impasse. Yet climate mini-publics face challenges in political environments too, such as co-option, favoring expert opinions, and losing touch with the broader public. To remedy such pitfalls, recent papers have argued to combine synchronous deliberations of small groups of citizens with online participation procedures for the larger public. In this article, we report the results of a three-step combination model, where first a mini-public in the region of Súdwest-Fryslân (NL) was given a “carte blanche” to draft the content and the parameters of several related policy alternatives. Second, their proposals were fed into a digital participation tool to consult the wider public. Third, a citizens forum translated the outcomes of the maxi-public into policy recommendations, which were unanimously approved by the municipal council. In this paper, we report our findings of combining mini- and maxi-publics and how the actors involved evaluated the strengths and weaknesses of the combination of these two participatory approaches.

MAXI J1535-571 outburst was dramatic and the accretion flow exhibits spectra-temporal characteristics related to one another. In this study, MAXI J1535-571 data observed by SWIFT/BAT (Swift/Burst Alert Telescope) and MAXI/GSC (Monitor of All-sky X-ray Image/Gas slit camera) was analyzed. The physical and phenomenological models that explain the components of the accretion flow were adopted in fitting/modelling the data in XSPEC v12.10.1f. The accretion flow characteristics and photon index–quasi-periodic oscillation frequency (Γ–vQPO) relation and their correlations were determined. The resonance condition in the range of (0.507–1.248) ± 0.080 indicates that the components of the accretion flow timescales are comparable. The QPO frequency of 0.840–4.961 Hz was obtained. This affirms the TCAF model prediction of the presence of QPO in the accretion flow during the hard spectral states. The components of accretion flow rates are anti-correlated. This suggests that components of the accretion flow interact at varying distances and cause the distribution of energy spectral indices in the post-shock region/Compton cloud. The photon index–QPO frequency is tightly correlated with a coefficient of 0.973. Hence, the variations/fluctuation of accretion flow/rates seems to be the underlying physical processes/mechanisms responsible for the origin of Γ–vQPO relation in the hard-intermediate spectral state.

The Maxi-Cl phenotype accounts for the majority (app. 60%) of reports on the large-conductance maxi-anion channels (MACs) and has been detected in almost every type of cell, including placenta, endothelium, lymphocyte, cardiac myocyte, neuron, and glial cells, and in cells originating from humans to frogs. A unitary conductance of 300–400 pS, linear current-to-voltage relationship, relatively high anion-to-cation selectivity, bell-shaped voltage dependency, and sensitivity to extracellular gadolinium are biophysical and pharmacological hallmarks of the Maxi-Cl channel. Its identification as a complex with SLCO2A1 as a core pore-forming component and two auxiliary regulatory proteins, annexin A2 and S100A10 (p11), explains the activation mechanism as Tyr23 dephosphorylation at ANXA2 in parallel with calcium binding at S100A10. In the resting state, SLCO2A1 functions as a prostaglandin transporter whereas upon activation it turns to an anion channel. As an efficient pathway for chloride, Maxi-Cl is implicated in a number of physiologically and pathophysiologically important processes, such as cell volume regulation, fluid secretion, apoptosis, and charge transfer. Maxi-Cl is permeable for ATP and other small signaling molecules serving as an electrogenic pathway in cell-to-cell signal transduction. Mutations at the SLCO2A1 gene cause inherited bone and gut pathologies and malignancies, signifying the Maxi-Cl channel as a perspective pharmacological target.

Purpose Open-wedge high tibial osteotomy (HTO) is an established treatment for young and middle-aged patients with medial compartment knee osteoarthritis and varus malalignment. Although not intended, a lateral cortex fracture might occur during this procedure. Different fixation devices are available to repair such fractures. This study was performed to evaluate osteotomy healing after fixation with two different locking plates. Methods Sixty-nine medial open-wedge HTO without bone grafting were followed until osteotomy healing. Results In patients with an intact lateral hinge, no problems were noted with either locking plate. A fracture of the lateral cortex occurred in 21 patients (30.4 %). In ten patients, the fracture was not recognized during surgery but was visible on the radiographs at the 6-week follow-up. Lateral cortex fracture resulted in non-union with the need for surgical treatment in three out of eight (37.5 %) patients using the newly introduced locking plate (Position HTO Maxi Plate), while this did not occur with a well-established locking plate (TomoFix) (0 out of 13, p  = 0.023). Conclusion With regard to other adverse events, no differences between both implants were observed. In cases of lateral cortex fracture, fixation with a smaller locking plate resulted in a relevant number of non-unions. Therefore, it is recommended that bone grafting, another fixation system, or an additional lateral fixation should be used in cases with lateral cortex fracture. Level of evidence III.

The article presents an analysis of the maximum efficiency and maximum load power, which are available to obtain in periodic wireless power transfer (WPT) systems. The numerical computations of the proposed WPT structures are performed using the finite element method and branch current method. Two theoretical models are discussed, i.e., a numerical model with simplified structure and boundary conditions as well as an equivalent circuit model is proposed to solve WPT systems with many magnetically coupled planar coils. A multivariate analysis is performed, which takes into account the variability of the number of turns, distance between a transmitting and receiving coil, and the frequency of an energy source. The outputs, such as overall efficiency, power of the source and power transferred to a load are discussed. The formulas for the load impedance required to maximize the efficiency or load power, which are taking into account the electrical parameters of the system resulting from its geometry, are presented. The results obtained from proposed models are consistent, which confirm the correctness of the adopted circuit model, which is less complex and faster to compute than numerical one. It is also possible to perform a quick assessment of electrical parameters of the analyzed WPT structure, using presented analytical formulas and numerical model or experimental data. The results allow for a detailed discussion of the dependence of the efficiency and power of the WPT system with respect to geometry of spiral coils.

We study the multi-wavelength spectral properties of the black hole X-ray binary MAXI J1348–630 using quasi-simultaneous ALMA, NICER, and Swift observations during the decay phase of the January 2019 outburst. In millimeter wavelengths, radio continuum emissions in the frequency range of 89.56–351.44 GHz are measured. We found that the flux densities at millimeter wavelength varied between 12.18 mJy and 18.47 mJy with spectral index (α) of 0.28±0.02. The broadband spectrum suggests that the source was accompanied by weak synchrotron emission from the compact jets. Broadband spectral study indicates that MAXI J1348–630 falls in the regime of “radio-quiet” during the decay phase of the outburst. The NICER spectrum is fitted by a combined model of disk blackbody component (diskbb) along with a comptonization component (simpl) which explains the power-law continuum caused by the thermal Comptonisation of soft disk photons in a hot gas of electrons. The NICER spectrum is dominated by the comptonised components during the decay phase of the outburst close to the hard state of the source. We have investigated the correlation between X-ray and radio luminosity using quasi-simultaneous ALMA and NICER data to understand the source nature by locating the source in the LX-LR diagram. The correlation study of radio/X-ray luminosity suggests that MAXI J1348–630 did not follow the well-known track for black holes and it is a new member of a restricted group of sources.

Background Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation and damage in which fibroblast-like synoviocytes (FLS) play a central role. Invasiveness and proliferation of FLS in RA is dependent on activity of the K Ca 1.1 potassium channel. Peptide blockers of K Ca 1.1, such as iberiotoxin (IbTX), can be delivered subcutaneously to treat animal models of RA. We tested whether an engineered probiotic oral delivery platform could effectively deliver IbTX systemically in a rat model of RA. Results A plasmid for inducible secretion of IbTX was constructed and transformed into probiotic Limosilactobacillus reuteri ATCC PTA-6475 to generate LrIbTX. No differences in growth rate between LrIbTX and the control strain were detected in vitro, and live LrIbTX was recovered from the feces of rats following oral gavage. IbTX was detected in the sera of healthy rats orally gavaged with LrIbTX by a K Ca 1.1 competitive binding assay using a biotinylated IbTX analog and streptavidin-conjugated fluorophore. Collagen-induced arthritis (CIA), an animal model of RA, was used to measure the effect of LrIbTX versus injected IbTX or control L. reuteri expressing an irrelevant protein on clinical score, histologic inflammation, and bone density. Oral LrIbTX and injected IbTX had similar efficacy in treating CIA in rats as measured by clinical joint swelling and histologic inflammation, which were significantly improved versus control bacteria or vehicle injection. No treatments induced measurable levels of anti-IbTX IgG, and there were no differences in macroscopic bone damage or anti-collagen II IgM and IgG levels between CIA groups. Injected IbTX and oral LrIbTX were also equivalent in inhibiting an active delayed-type hypersensitivity (DTH) reaction in rats. Conclusions This work describes the effective oral delivery of a candidate therapeutic peptide, IbTX, via engineered L. reuteri to treat an animal model of autoimmune disease and demonstrates systemic distribution of an intestinally produced peptide. We anticipate that oral delivery of engineered microbes may be a generalizable strategy for enhancing the oral bioavailability of peptide therapeutics.