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Potent P2Y 12 agents such as ticagrelor and prasugrel are increasingly utilized across the clinical spectrum of patients undergoing percutaneous coronary intervention (PCI). There is a paucity of data supporting their use in a patient population inclusive of both acute coronary syndrome (ACS) and chronic coronary syndrome (CCS) patients. The authors compared the efficacy and safety of ticagrelor and prasugrel in a real-world contemporary PCI cohort. Consecutive patients undergoing PCI between 2014 and 2019 discharged on either prasugrel or ticagrelor were included from the prospectively collected institutional PCI registry. Primary endpoint was the composite of death and myocardial infarction (MI), with secondary outcomes including rates of bleeding, stroke, and target vessel revascularization at 1 year. Overall, 3,858 patients were included in the study (ticagrelor: n = 2,771; prasugrel: n = 1,087), and a majority (48.4%) underwent PCI in the context of CCS. Patients prescribed ticagrelor were more likely to be female, have a history of cerebrovascular disease, and have ACS presentation, while those receiving prasugrel were more likely to be White with a higher prevalence of prior revascularization. No difference in the risk of death or MI was noted across the groups (ticagrelor vs prasugrel: 3.3% vs 3.1%; HR: 0.88; 95% CI: 0.54-1.43; P = 0.59). Rates of target vessel revascularization were significantly lower in the ticagrelor cohort (9.3% vs 14.0%; adjusted HR: 0.71; 95% CI: 0.55-0.91; P = 0.007) with no differences in stroke or bleeding. The results were consistent in patients with CCS (HR: 0.84; 95% CI: 0.46-1.54) and ACS (HR: 1.18; 95% CI: 0.46-1.54), without evidence of interaction (P = 0.37), and confirmed across multivariable adjustment and propensity score stratification analysis. In this contemporary patient population undergoing PCI, prasugrel and ticagrelor were associated with similar 1-year efficacy and safety. [Display omitted] [ABSTRACT FROM AUTHOR]

The global epidemiological transition of atherosclerotic vascular diseases is witnessing a rapid redistribution of its burden, shifting from high-income to low- and middle-income countries. With a wide clinical spectrum, spanning from intermittent claudication to more complex critical limb threatening ischemia, nonhealing ulcers, gangrene as well as acute limb ischemia, peripheral artery disease is often faced with the challenges of under-diagnosis and under-treatment despite its high prevalence. The management of peripheral arterial disease in patients with multiple comorbidities presents a formidable challenge and remains a pressing global health concern. In this review, we aim to provide an in-depth overview of the pathophysiology of peripheral artery disease and explore evidence-based management strategies encompassing pharmacological, lifestyle, interventional, and surgical approaches. By addressing these challenges, the review contributes to a better understanding of the evolving landscape of peripheral artery disease, offering insights into effective and holistic management strategies. [ABSTRACT FROM AUTHOR]

• In this manuscript we present our calculation of D.C. resistivity in a 2 d quantum critical metal and rigorously show that ρ p a r a 2 d ∝ T 4 3 near the critical point. • For the computation of resistivity we computed dynamical spin susceptibility of a 2 d quantum critical metal using Random Phase Approximation and we find that its real and imaginary parts scale as q 2 and ω q respectively. • Our RPA calculations agrees with the SCR theory calculations. It shows that re-normalized effects of soft modes just above the critical point do not affect the temperature dependence of resistivity. We calculate resistivity in the paramagnetic phase just above the curie temperature in a 2 d ferromagnetic metal. The required dynamical susceptibility in the formalism of resistivity is calculated within the Random Phase Approximation (RPA). The mechanism of resistivity is magnetic scattering, in which s -band electrons are scattered off the magnetic spin fluctuations of d-band electrons. We use the s - d Hamiltonian formalism. We find that near the quantum critical point the resistivity in 2 d scales as T 4 3 and in the high temperature limit resistivity scales as proportional to T. In contrast to it, resistivity due to phonon scattering is given by T 5 in low temperature limit as is well known. Our RPA result agrees with the Self-Consistence Renormalization (SCR) theory result. [ABSTRACT FROM AUTHOR]

A facile method for late stage diversification of lead molecules for the M1 PAM program using biosynthesis is described. Liver microsomes from several species are screened to identify a high turnover system. Subsequent incubations using less than 1 mg of substrate generate nanomole quantities of drug metabolites that are purified, characterized by microcryoprobe NMR spectroscopy, and quantified to known concentrations to enable rapid biology testing. The late-stage diversification of lead compounds provides rapid SAR feedback to the medicinal chemistry design cycle. [ABSTRACT FROM AUTHOR]

Euler-Euler (two-fluid) model was applied to simulate the hydrodynamics of the fuel reactor of the 1 MW th chemical-looping system with Geldart B particles. The drag models of Wen-Yu and Gidaspow were used along with the restitution coefficient of 0.6 and the specularity coefficient of 0 and 1. The results of the numerical simulation were compared with the experimental data from the 1 MW th chemical-looping combustion pilot plant at Technische Universitӓt Darmstadt. The volume fraction of methane agrees well with the measurements for all cases, while the predicted volume fractions of CO 2 , CO and H 2 were different from the experimental values due to improper reaction of CO and H 2 with ilmenite. Predicted pressure drop values along the height of the fuel reactor were similar to the experimental values for all cases. Nevertheless all cases overestimate the pressure at the bottom of the reactor by about 10 mbar. Keeping the drag model constant, the outgoing mass flow of the ilmenite was higher for the specularity coefficient (ϕ = 1) as compared to the specularity coefficient of (ϕ = 0). This is due to higher rate of reaction for (ϕ = 1), which is increasing the temperature of the outgoing gases and therefore increasing the gas velocity, resulting in a higher entrainment of ilmenite particles.. [ABSTRACT FROM AUTHOR]

Abstract: A series of peracetylated O-aryl α,β-d-ribofuranosides have been synthesized and an efficient biocatalytic methodology has been developed for the separation of their anomers which was otherwise almost impossible by column chromatographic or other techniques. The incubation of 2,3,5-tri-O-acetyl-1-O-aryl-α,β-d-ribofuranoside with Lipozyme® TL IM immobilized on silica led to the selective deacetylation of only one acetoxy group, viz the C-5′-O-acetoxy group of the α-anomer over the other acetoxy groups derived from the two secondary hydroxyl groups present in the molecule and also over three acetoxy groups (derived from one primary and two secondary hydroxyls of the β-anomer). This methodology led to the easy synthesis of both, α- and β-anomers of O-aryl d-ribofuranosides. All the arylribofuranosides were screened for inhibition of Src kinase. 1-O-(3-Methoxyphenyl)-β-d-ribofuranoside exhibited the highest activity for inhibition of Src kinase (IC50 =95.0μM). [Copyright &y& Elsevier]

Abstract: Previous studies on the in vitro metabolism of 4-alkylsulfonyl-2-pyridone-based glucokinase activators revealed a facile, non-enzymatic displacement of the 4-alkylsulfonyl group by glutathione. In the present studies, a role for glutathione-S-transferases (GST) as catalysts in the desulfonylation reaction was demonstrated using a combination of human liver microsomes, human liver cytosol and human GSTs. The identification of a glutathione conjugate in circulation following intravenous administration of a candidate 4-methylsulfonyl-2-pyridone to rats confirmed the relevance of the in vitro findings. [ABSTRACT FROM AUTHOR]

Abstract: A series of 3-(N-alkyl-N-phenylamino)propan-2-ol derivatives were synthesized from epichlorohydrine in a multi-step strategy and were evaluated as Src kinase inhibitors. First, epoxy ring opening of epichlorohydrine was carried out in the presence of N-alkylanilines to yield 3-(N-alkyl-N-phenylamino)-1-chloro-propan-2-ol derivatives using Ca(OTf)2 as catalyst based on our previous studies . Second, ring closure was performed under basic conditions to afford N-epoxymethyl N-alkylaniline derivatives. Finally, the epoxide ring opening with four different secondary amines and three nucleobases afforded the final products, i.e., a series of β-amino alcohols. All compounds were screened for their inhibitory activity against Src kinase and anticancer activity on human breast carcinoma cells, BT-20 cell line. Among all compounds, 3-N-methyl-N-phenylamino-1-(pyrrolidin-1-yl)propan-2-ol (13b) exhibited the highest inhibitory potency (IC50 = 66.1 μM) against Src kinase. Structure-activity relationship studies suggested that the incorporation of bulky groups at position 1 and N-substitution with groups larger than methyl moiety, reduced the inhibitory potency of the compound significantly. Compounds 3-(N-ethyl-N-phenylamino-)-1-(4-methylpiperazin-1-yl)propan-2-ol (14c) and 3-(N-ethyl-N-phenylamino)-1-(thymine-1-yl)propan-2-ol (17) were found to inhibit the growth of breast carcinoma cells by approximately 45–49% at concentration of 50 μM. [ABSTRACT FROM AUTHOR]

Abstract: Previous studies have demonstrated the CYP3A4 mediated oxidation of the 5-aminooxindole motif, present in the trifluoromethylpyrimidine class of PYK-2 inhibitors, to a reactive bis-imine species, which can be trapped with glutathione (GSH) in human liver microsomal incubations. The corresponding 5-aminobenzsultam derivatives, which should possess a similar oxidative liability, do not form GSH conjugates in microsomal incubations. In the current study, we conducted a retrospective analysis on representative 5-aminooxindole and 5-aminobenzsultam PYK-2 inhibitors utilizing CYP3A4 molecular docking and quantum chemical calculations to rationalize the bioactivation differences. Our analysis revealed key differences in (a) active site binding and (b) two-electron oxidation rates, which correlate with GSH adduct formation with the two moieties. The value of linear ion/orbitrap mass spectrometry to detect GSH conjugates with greater sensitivity, compared with conventional triple quadrupole mass spectrometry approaches, was also demonstrated in the course of these studies. [Copyright &y& Elsevier]

Plumbene, a recently discovered 2D material, has been examined for hydrogen storage. First principles calculations have been performed to investigate the hydrogen adsorption on pristine plumbene monolayer. The hydrogen molecule prefers to adsorb on three adsorption sites, i.e. H (hollow-site), T (top-site) and B (bond-site), of plumbene surface with desired adsorption energy. The adsorption energy is highest (−149 meV) at hollow site and lowest (−104 meV) at bond site. One side hydrogen decorated plumbene exhibit 3.37 wt% Hydrogen Gravimetric Density (HGD). Whereas 6.74 wt% (HGD), with the average adsorption energy of −117 meV/H 2, has been achieved in both side hydrogen decorated plumbene monolayer. Applied electric field can effectively controls the adsorption and desorption processes. Positive electric field makes the adsorption strong while the negative electric field results in weakening of hydrogen adsorption. It means electric field act as a switch to store and release hydrogen with good control and usage selectivity. Present study reveals that the plumbene is a strong candidate for hydrogen storage to meet the desired target of HGD suggested by U.S. Department of Energy by the year 2021. [Display omitted] • DFT based study is performed to examine hydrogen adsorption on plumbene. • H 2 molecules successfully get adsorbed on the plumbene with desired adsorption energy. • Both side hydrogen decorated plumbene exhibits 6.74 wt%. HGD. • Positive electric field leads to adsorption and negative field leads to desorption. • Present study reveals that plumbene is a good 2D material for hydrogen storage. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is the most common cause of death in patients with end-stage renal disease (ESRD). The initiation of dialysis for treatment of ESRD exacerbates chronic electrolyte and hemodynamic perturbations. Rapid large shifts in effective intravascular volume and electrolyte concentrations ultimately lead to subendocardial ischemia, increased left ventricular wall mass, and diastolic dysfunction, and can precipitate serious arrhythmias through a complex pathophysiological process. These factors, unique to advanced kidney disease and its treatment, increase the overall incidence of acute coronary syndrome and sudden cardiac death. To date, risk prediction models largely fail to incorporate the observed cardiovascular mortality in the CKD population; however, multimodality imaging may provide an additional prognostication and risk stratification. This comprehensive review discusses the cardiovascular risks associated with hemodialysis, and explores the pathophysiology and the novel utilization of multimodality imaging in CKD to promote a personalized approach for these patients with implications for future research. [ABSTRACT FROM AUTHOR]

• Participatory research ensured better technology packaging, validation and adoption. • Gypsum and pressmud–mediated land reclamation better alleviates sodicity stress. • Denser planting and additional N improved crop resilience and yield in sodic areas. • Improved genetic tolerance and agronomic management bridged yield gaps and enhanced farmers' income. Regaining the agricultural potential of salt–affected lands offers an opportunity of production enhancement and sustaining food security in less favourable environments. This study aims at deciphering the synergy of adaptive and mitigation strategies– using salt tolerant rice varieties with affordable land reclamation and crop management options. The study was conducted following farmers' participatory approach for 3 years (2017–19) in sodicity–affected Ghaghar Basin of Haryana, India. Compared with the locally adapted variety PB1121, using the salt tolerant Basmati CSR30 resulted in less yield reduction and better returns, providing better opportunities for stabilizing crop production, and enhancing resilience and adaptation in sodic soils irrigated with alkali water. Gypsum and pressmud–mediated land reclamation reduced soil sodicity, improved salt tolerance and increased yield by ∼35 % compared to the control (2.19 t ha–1). Transplanting two seedlings per hill at 20 × 15 cm spacing resulted in better crop establishment and plant stand, with consequent increase in yield and economic gains over the farmers' practice of randomly transplanting one seedling hill–1. The significant increase in yields with addition of ∼25 % more N confirmed the farmers' perception of using more N in sodic soils, suggesting the need for revising existing recommendations. Curve Expert model revealed genotypic variation in N requirements, with 90 kg N ha–1 for CSR30 and 140 kg N ha–1 for PB1121 as economically optimum in sodic soils. Transformative improvements involving the use of adapted stress–tolerant varieties with location–specific agronomic practices increased yield by 6% over the existing recommendations and by 24 % over farmer's practices; showing potential for bridging the rice yield gaps, halting salt–induced land degradation and improving rural livelihood in salt–affected areas. [ABSTRACT FROM AUTHOR]

A series of aryl carboxamide and benzylamino dispiro 1,2,4,5-tetraoxane analogues have been designed and synthesized in a short synthetic sequence from readily available starting materials. From this series of endoperoxides, molecules with in vitro IC50s versus Plasmodium falciparum (3D7) as low as 0.84 nM were identified. Based on an assessment of blood stability and in vitro microsomal stability, N205 ( 10a ) was selected for rodent pharmacokinetic and in vivo antimalarial efficacy studies in the mouse Plasmodium berghei and Plasmodium falciparum Pf 3D70087/N9 severe combined immunodeficiency (SCID) mouse models. The results indicate that the 4-benzylamino derivatives have excellent profiles with a representative of this series, N205, an excellent starting point for further lead optimization studies. [ABSTRACT FROM AUTHOR]

Prostaglandin E receptor subtype 3 (EP3) antagonism may treat a variety of symptoms from inflammation to cardiovascular and metabolic diseases. Previously, most EP3 antagonists were large acidic ligands that mimic the substrate, prostaglandin E2 (PGE2). This manuscript describes the optimization of a neutral small molecule amide series with improved lipophilic efficiency (LipE) also known as lipophilic ligand efficiency (LLE) ((a) Nat. Rev. Drug Disc. 2007 , 6 , 881; (b) Annu. Rep. Med. Chem. 2010 , 45 , 380). [ABSTRACT FROM AUTHOR]