The Lipid Kinase PIP5K1C Regulates Pain Signaling and Sensitization

SummaryNumerous pain-producing (pronociceptive) receptors signal via phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. However, it is currently unknown which lipid kinases generate PIP2 in nociceptive dorsal root ganglia (DRG) neurons and if these kinases regulate pronociceptive receptor signaling. Here, we found that phosphatidylinositol 4-phosphate 5 kinase type 1C (PIP5K1C) is expressed at higher levels than any other PIP5K and, based on experiments with Pip5k1c+/− mice, generates at least half of all PIP2 in DRG neurons. Additionally, Pip5k1c haploinsufficiency reduces pronociceptive receptor signaling and TRPV1 sensitization in DRG neurons as well as thermal and mechanical hypersensitivity in mouse models of chronic pain. We identified a small molecule inhibitor of PIP5K1C (UNC3230) in a high-throughput screen. UNC3230 lowered PIP2 levels in DRG neurons and attenuated hypersensitivity when administered intrathecally or into the hindpaw. Our studies reveal that PIP5K1C regulates PIP2-dependent nociceptive signaling and suggest that PIP5K1C is a therapeutic target for chronic pain

AMP Is an Adenosine A 1 Receptor Agonist

Numerous receptors for ATP, ADP, and adenosine exist; however, it is currently unknown whether a receptor for the related nucleotide adenosine 5′-monophosphate (AMP) exists. Using a novel cell-based assay to visualize adenosine receptor activation in real time, we found that AMP and a non-hydrolyzable AMP analog (deoxyadenosine 5′-monophosphonate, ACP) directly activated the adenosine A1 receptor (A1R). In contrast, AMP only activated the adenosine A2B receptor (A2BR) after hydrolysis to adenosine by ecto-5′-nucleotidase (NT5E, CD73) or prostatic acid phosphatase (PAP, ACPP). Adenosine and AMP were equipotent human A1R agonists in our real-time assay and in a cAMP accumulation assay. ACP also depressed cAMP levels in mouse cortical neurons through activation of endogenous A1R. Non-selective purinergic receptor antagonists (pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid and suramin) did not block adenosine- or AMP-evoked activation. Moreover, mutation of His-251 in the human A1R ligand binding pocket reduced AMP potency without affecting adenosine potency. In contrast, mutation of a different binding pocket residue (His-278) eliminated responses to AMP and to adenosine. Taken together, our study indicates that the physiologically relevant nucleotide AMP is a full agonist of A1R. In addition, our study suggests that some of the physiological effects of AMP may be direct, and not indirect through ectonucleotidases that hydrolyze this nucleotide to adenosine

Does Arbitration Blossom When State Courts are Bad?

It is often conjectured that non-state dispute resolution blossoms when state courts are not independent or are perceived as low-quality courts. This conjecture implies a substitutive relationship between state and non-state dispute resolution. An alternative hypothesis argues that both the quality and the frequency of use of these two alternative mechanisms are complementary: societies with high-quality state courts would also be able to provide high-quality non-state dispute resolution. This is the first study that puts these hypotheses to an empirical test. It turns out that the lower the perceived quality of state courts, the less frequently conflicting firms resort to them. Second, firms in common-law countries turn away from state courts significantly more often than firms in civil-law countries. This result sheds doubt on the robustness of results generated within the legal traditions literature. Finally, in states that have created the preconditions for arbitration, businesspeople resort significantly more often to state courts. We interpret this as evidence in favor of the complementarity hypothesis

RELICS: Strong Lens Models for Five Galaxy Clusters From the Reionization Lensing Cluster Survey

Strong gravitational lensing by galaxy clusters magnifies background galaxies, enhancing our ability to discover statistically significant samples of galaxies at z>6, in order to constrain the high-redshift galaxy luminosity functions. Here, we present the first five lens models out of the Reionization Lensing Cluster Survey (RELICS) Hubble Treasury Program, based on new HST WFC3/IR and ACS imaging of the clusters RXC J0142.9+4438, Abell 2537, Abell 2163, RXC J2211.7-0349, and ACT-CLJ0102-49151. The derived lensing magnification is essential for estimating the intrinsic properties of high-redshift galaxy candidates, and properly accounting for the survey volume. We report on new spectroscopic redshifts of multiply imaged lensed galaxies behind these clusters, which are used as constraints, and detail our strategy to reduce systematic uncertainties due to lack of spectroscopic information. In addition, we quantify the uncertainty on the lensing magnification due to statistical and systematic errors related to the lens modeling process, and find that in all but one cluster, the magnification is constrained to better than 20% in at least 80% of the field of view, including statistical and systematic uncertainties. The five clusters presented in this paper span the range of masses and redshifts of the clusters in the RELICS program. We find that they exhibit similar strong lensing efficiencies to the clusters targeted by the Hubble Frontier Fields within the WFC3/IR field of view. Outputs of the lens models are made available to the community through the Mikulski Archive for Space TelescopesComment: Accepted to Ap

RELICS: High-Resolution Constraints on the Inner Mass Distribution of the z=0.83 Merging Cluster RXJ0152.7-1357 from strong lensing

Strong gravitational lensing (SL) is a powerful means to map the distribution of dark matter. In this work, we perform a SL analysis of the prominent X-ray cluster RXJ0152.7-1357 (z=0.83, also known as CL 0152.7-1357) in \textit{Hubble Space Telescope} images, taken in the framework of the Reionization Lensing Cluster Survey (RELICS). On top of a previously known $z=3.93$ galaxy multiply imaged by RXJ0152.7-1357, for which we identify an additional multiple image, guided by a light-traces-mass approach we identify seven new sets of multiply imaged background sources lensed by this cluster, spanning the redshift range [1.79-3.93]. A total of 25 multiple images are seen over a small area of ~0.4 $arcmin^2$, allowing us to put relatively high-resolution constraints on the inner matter distribution. Although modestly massive, the high degree of substructure together with its very elongated shape make RXJ0152.7-1357 a very efficient lens for its size. This cluster also comprises the third-largest sample of z~6-7 candidates in the RELICS survey. Finally, we present a comparison of our resulting mass distribution and magnification estimates with those from a Lenstool model. These models are made publicly available through the MAST archive.Comment: 15 Pages, 7 Figures, 4 Tables Accepted for publication in Ap

Orally Active Adenosine A 1 Receptor Agonists with Antinociceptive Effects in Mice

Adenosine A1 receptor (A1AR) agonists have antinociceptive effects in multiple preclinical models of acute and chronic pain. Although numerous A1AR agonists have been developed, clinical applications of these agents have been hampered by their cardiovascular side effects. Herein we report a series of novel A1AR agonists, some of which are structurally related to adenosine 5′-monophosphate (5′-AMP), a naturally occurring nucleotide that itself activates A1AR. These novel compounds potently activate A1AR in several orthogonal in vitro assays and are subtype selective for A1AR over A2AAR, A2BAR, and A3AR. Among them, UNC32A (3a) is orally active and has dose-dependent antinociceptive effects in wild-type mice. The antinociceptive effects of 3a were completely abolished in A1AR knockout mice, revealing a strict dependence on A1AR for activity. The apparent lack of cardiovascular side effects when administered orally and high affinity (Ki of 36 nM for the human A1AR) make this compound potentially suitable as a therapeutic

EC85-219 1985 Nebraska Swine Report

This 1985 Nebraska Swine Report was prepared by the staff in Animal Science and cooperating departments for use in the Extension and Teaching programs at the University of Nebraska-Lincoln. Authors from the following areas contributed to this publication: Swine Nutrition, swine diseases, pathology, economics, engineering, swine breeding, meats, agronomy, and diagnostic laboratory. It covers the following areas: breeding, disease control, feeding, nutrition, economics, housing and meats

Discovery of FERM domain protein-protein interaction inhibitors for MSN and CD44 as a potential therapeutic approach for Alzheimer\u27s disease.

Proteomic studies have identified moesin (MSN), a protein containing a four-point-one, ezrin, radixin, moesin (FERM) domain, and the receptor CD44 as hub proteins found within a coexpression module strongly linked to Alzheimer\u27s disease (AD) traits and microglia. These proteins are more abundant in Alzheimer\u27s patient brains, and their levels are positively correlated with cognitive decline, amyloid plaque deposition, and neurofibrillary tangle burden. The MSN FERM domain interacts with the phospholipid phosphatidylinositol 4,5-bisphosphate (PI

A Semi-Physiologically Based Pharmacokinetic Model Describing the Altered Metabolism of Midazolam Due to Inflammation in Mice

This is the author's accepted manuscript.Purpose To investigate influence of inflammation on metabolism and pharmacokinetics (PK) of midazolam (MDZ) and construct a semi-physiologically based pharmacokinetic (PBPK) model to predict PK in mice with inflammatory disease. Methods Glucose-6-phosphate isomerase (GPI)-mediated inflammation was used as a preclinical model of arthritis in DBA/1 mice. CYP3A substrate MDZ was selected to study changes in metabolism and PK during the inflammation. The semi-PBPK model was constructed using mouse physiological parameters, liver microsome metabolism, and healthy animal PK data. In addition, serum cytokine, and liver-CYP (cytochrome P450 enzymes) mRNA levels were examined. Results The in vitro metabolite formation rate was suppressed in liver microsomes prepared from the GPI-treated mice as compared to the healthy mice. Further, clearance of MDZ was reduced during inflammation as compared to the healthy group. Finally, the semi-PBPK model was used to predict PK of MDZ after GPI-mediated inflammation. IL-6 and TNF-α levels were elevated and liver-cyp3a11 mRNA was reduced after GPI treatment. Conclusion The semi-PBPK model successfully predicted PK parameters of MDZ in the disease state. The model may be applied to predict PK of other drugs under disease conditions using healthy animal PK and liver microsomal data as inputs

JWST's PEARLS: dust attenuation and gravitational lensing in the backlit-galaxy system VV 191

We derive the spatial and wavelength behavior of dust attenuation in the multiple-armed spiral galaxy VV191b using backlighting by the superimposed elliptical system VV191a in a pair with an exceptionally favorable geometry for this measurement. Imaging using JWST and HST spans the wavelength range 0.3-4.5 microns with high angular resolution, tracing the dust in detail from 0.6 to 1.5 microns. Distinct dust lanes continue well beyond the bright spiral arms, and trace a complex web, with a very sharp radial cutoff near 1.7 Petrosian radii. We present attenuation profiles and coverage statistics in each band at radii 14-21 kpc. We derive the attenuation law with wavelength; the data both within and between the dust lanes clearly favor a stronger reddening behavior (R ~ 2.0 between 0.6 and 0.9 microns, approaching unity by 1.5 microns) than found for starbursts and star-forming regions of galaxies. Power-law extinction behavior lambda^(-beta) gives beta=2.1 from 0.6-0.9 microns. R decreases at increasing wavelengths (R~1.1 between 0.9 and 1.5 microns), while beta steepens to 2.5. Mixing regions of different column density flattens the wavelength behavior, so these results suggest a different grain population than in our vicinity. The NIRCam images reveal a lens arc and counterimage from a background galaxy at z~1, spanning 90 degrees azimuthally at 2.8" from the foreground elliptical galaxy nucleus, and an additional weakly-lensed galaxy. The lens model and imaging data give a mass/light ratio 7.6 in solar units within the Einstein radius 2.0 kpc.Comment: Accepted by Astron. J. Analysis redone since submission, using updated JWST calibrations. Dust reddening behavior is steeper with wavelength and lensed galaxy redshift lower than we first derive