Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers

Myo-inositol hexakisphosphate (IP6) is a natural product known to inhibit vascular calcification (VC), but with limited potency and low plasma exposure following bolus administration. Here we report the design of a series of inositol phosphate analogs as crystallization inhibitors, among which 4,6-di-O-(methoxy-diethyleneglycol)-myo-inositol-1,2,3,5-tetrakis(phosphate), (OEG <sub>2</sub> ) <sub>2</sub> -IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety profiles than IP6 after subcutaneous injection. (OEG <sub>2</sub> ) <sub>2</sub> -IP4 potently stabilizes calciprotein particle (CPP) growth, consistently demonstrates low micromolar activity in different in vitro models of VC (i.e., human serum, primary cell cultures, and tissue explants), and largely abolishes the development of VC in rodent models, while not causing toxicity related to serum calcium chelation. The data suggest a mechanism of action independent of the etiology of VC, whereby (OEG <sub>2</sub> ) <sub>2</sub> -IP4 disrupts the nucleation and growth of pathological calcification

Inhibitors of Calcium Oxalate Crystallization for the Treatment of Oxalate Nephropathies

Calcium oxalate (CaOx) crystal‐induced nephropathies comprise a range of kidney disorders, for which there are no efficient pharmacological treatments. Although CaOx crystallization inhibitors have been suggested as a therapeutic modality already decades ago, limited progress has been made in the discovery of potent molecules with efficacy in animal disease models. Herein, an image‐based machine learning approach to systematically screen chemically modified myo‐inositol hexakisphosphate (IP6) analogues is utilized, which enables the identification of a highly active divalent inositol phosphate molecule. To date, this is the first molecule shown to completely inhibit the crystallization process in the nanomolar range, reduce crystal–cell interactions, thereby preventing CaOx‐induced transcriptomic changes, and decrease renal CaOx deposition and kidney injury in a mouse model of hyperoxaluria. In conclusion, IP6 analogues based on such a scaffold may represent a new treatment option for CaOx nephropathies.ISSN:2198-384

Small-Molecule Allosteric Triggers of Clostridium difficile Toxin B Auto-proteolysis as a Therapeutic Strategy

ISSN:2451-945

Experiences of insecurity among non-standard workers across different welfare states : A qualitative cross-country study

In recent decades, economic crises and political reforms focused on employment flexibilization have increased the use of non-standard employment (NSE). National political and economic contexts determine how employers interact with labour and how the state interacts with labour markets and manages social welfare policies. These factors influence the prevalence of NSE and the level of employment insecurity it creates, but the extent to which a country’s policy context mitigates the health influences of NSE is unclear. This study describes how workers experience insecurities created by NSE, and how this influences their health and well-being, in countries with different welfare states: Belgium, Canada, Chile, Spain, Sweden, and the United States. Interviews with 250 workers in NSE were analysed using a multiple-case study approach. Workers in all countries experienced multiple insecurities (e.g., income and employment insecurity) and relational tension with employers/clients, with negative health and well-being influences, in ways that were shaped by social inequalities (e.g., related to family support or immigration status). Welfare state differences were reflected in the level of workers’ exclusion from social protections, the time scale of their insecurity (threatening daily survival or longer-term life planning), and their ability to derive a sense of control from NSE. Workers in Belgium, Sweden, and Spain, countries with more generous welfare states, navigated these insecurities with greater success and with less influence on health and well-being. Findings contribute to our understanding of the health and well-being influences of NSE across different welfare regimes and suggest the need in all six countries for stronger state responses to NSE. Increased investment in universal and more equal rights and benefits in NSE could reduce the widening gap between standard and NSE.

Measurements of the Total and Differential Higgs Boson Production Cross Sections Combining the H??????? and H???ZZ*???4??? Decay Channels at s\sqrt{s}=8??????TeV with the ATLAS Detector

Measurements of the total and differential cross sections of Higgs boson production are performed using 20.3~fb$^{-1}$ of $pp$ collisions produced by the Large Hadron Collider at a center-of-mass energy of $\sqrt{s} = 8$ TeV and recorded by the ATLAS detector. Cross sections are obtained from measured $H \rightarrow \gamma \gamma$ and $H \rightarrow ZZ ^{*}\rightarrow 4\ell$ event yields, which are combined accounting for detector efficiencies, fiducial acceptances and branching fractions. Differential cross sections are reported as a function of Higgs boson transverse momentum, Higgs boson rapidity, number of jets in the event, and transverse momentum of the leading jet. The total production cross section is determined to be $\sigma_{pp \to H} = 33.0 \pm 5.3 \, ({\rm stat}) \pm 1.6 \, ({\rm sys}) \mathrm{pb}$. The measurements are compared to state-of-the-art predictions.Measurements of the total and differential cross sections of Higgs boson production are performed using 20.3  fb-1 of pp collisions produced by the Large Hadron Collider at a center-of-mass energy of s=8  TeV and recorded by the ATLAS detector. Cross sections are obtained from measured H→γγ and H→ZZ*→4ℓ event yields, which are combined accounting for detector efficiencies, fiducial acceptances, and branching fractions. Differential cross sections are reported as a function of Higgs boson transverse momentum, Higgs boson rapidity, number of jets in the event, and transverse momentum of the leading jet. The total production cross section is determined to be σpp→H=33.0±5.3 (stat)±1.6 (syst)  pb. The measurements are compared to state-of-the-art predictions.Measurements of the total and differential cross sections of Higgs boson production are performed using 20.3 fb$^{-1}$ of $pp$ collisions produced by the Large Hadron Collider at a center-of-mass energy of $\sqrt{s} = 8$ TeV and recorded by the ATLAS detector. Cross sections are obtained from measured $H \rightarrow \gamma \gamma$ and $H \rightarrow ZZ ^{*}\rightarrow 4\ell$ event yields, which are combined accounting for detector efficiencies, fiducial acceptances and branching fractions. Differential cross sections are reported as a function of Higgs boson transverse momentum, Higgs boson rapidity, number of jets in the event, and transverse momentum of the leading jet. The total production cross section is determined to be $\sigma_{pp \to H} = 33.0 \pm 5.3 \, ({\rm stat}) \pm 1.6 \, ({\rm sys}) \mathrm{pb}$. The measurements are compared to state-of-the-art predictions

Search for Scalar Diphoton Resonances in the Mass Range 65−60065-600 GeV with the ATLAS Detector in pppp Collision Data at s\sqrt{s} = 8 TeVTeV

A search for scalar particles decaying via narrow resonances into two photons in the mass range 65–600 GeV is performed using $20.3\text{}\text{}{\mathrm{fb}}^{-1}$ of $\sqrt{s}=8\text{}\text{}\mathrm{TeV}$ $pp$ collision data collected with the ATLAS detector at the Large Hadron Collider. The recently discovered Higgs boson is treated as a background. No significant evidence for an additional signal is observed. The results are presented as limits at the 95% confidence level on the production cross section of a scalar boson times branching ratio into two photons, in a fiducial volume where the reconstruction efficiency is approximately independent of the event topology. The upper limits set extend over a considerably wider mass range than previous searches