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Genetic and molecular underpinnings of atrial fibrillation
Atrial fibrillation (AF) increases stroke and heart failure risks. This review examines genetic and molecular mechanisms underlying AF. We review genes linked to AF and mechanisms by which they alter AF risk. We highlight gene expression differences between atrial and ventricular cardiomyocytes, regulatory mechanisms responsible for these differences, and their contribution to AF. Understanding AF mechanisms through the lens of atrial gene regulation is crucial for developing targeted AF therapies.
C(sp3)–heteroatom bond formation by iron-catalyzed soft couplings
Carbon–heteroatom bonds are of great importance due to their prevalence in pharmaceuticals, agrochemicals, materials, and natural products. Despite the effective use of metal-catalyzed cross-coupling reactions between sp2-hybridized organohalides and soft heteroatomic nucleophiles for carbon–heteroatom bond formation, the use of sp3-hybridized organohalides remain limited and the coupling with thiols remains elusive. Here, we report the coupling of sp3-hybridized benzyl or tertiary halides with soft thiol nucleophiles catalyzed by iron and extend the utility to alcohol and amine nucleophiles. The reaction is broad in substrate scope for both coupling partners and applicable in the construction of congested tri- and tetrasubstituted carbon centers as well as β-quaternary heteroatomic products. The synthetic utility is further emphasized by gram-scale synthesis and rapid herbicide library synthesis. Overall, we provide an efficient method to prepare pharmaceutically and materially relevant carbon–heteroatom bonds by expanding iron-catalyzed cross-coupling reactions to the coupling of sp3-hybridized organohalides with soft nucleophiles.
Solution-processable polymer membranes with hydrophilic subnanometre pores for sustainable lithium extraction
Membrane-based separation processes hold great promise for sustainable extraction of lithium from brines for the rapidly expanding electric vehicle industry and renewable energy storage. However, it remains challenging to develop high-selectivity membranes that can be upscaled for industrial processes. Here we report solution-processable polymer membranes with subnanometre pores with excellent ion separation selectivity in electrodialysis processes for lithium extraction. Polymers of intrinsic microporosity incorporated with hydrophilic functional groups enable fast transport of monovalent alkali cations (Li+, Na+ and K+) while rejecting relatively larger divalent ions such as Mg2+. The polymer of intrinsic microporosity membranes surpasses the performance of most existing membrane materials. Furthermore, the membranes were scaled up and integrated into an electrodialysis stack, demonstrating excellent selectivity in simulated salt-lake brines. This work will inspire the development of selective membranes for a wide range of sustainable separation processes critical for resource recovery and a global circular economy.
Synthesis and characterization of soquelitinib a selective ITK inhibitor that modulates tumor immunity
ITK is a kinase involved in T cell activation, proliferation and differentiation. In mice, selective knock-out of the ITK gene produces Th1 skewing of T helper cell differentiation. Soquelitinib, a covalent ITK inhibitor, blocks ITK activity with greater than 100-fold selectivity compared to inhibition of a related kinase, RLK. We describe the chemistry and biologic effects of soquelitinib. In vitro studies with normal or malignant T cells demonstrated that soquelitinib suppresses Th2 cytokine production preferentially with relative sparing of Th1 cytokines. Soquelitinib inhibits the in vivo growth of several syngeneic murine tumors including those that do not express ITK. Treatment with soquelitinib leads to increased tumor infiltration of normal CD8+ cells that possess enhanced T effector function. Soquelitinib reduced expression of T cell exhaustion markers and was able to restore T effector function to exhausted cells. Pharmacologic selective ITK inhibition may represent a novel approach to cancer immunotherapy.
Convergent evolution of complex adaptive traits modulates angiogenesis in high-altitude Andean and Himalayan human populations
Convergent adaptations represent paradigmatic examples of the capacity of natural selection to influence organisms’ biology. However, the possibility to investigate the genetic determinants underpinning convergent complex adaptive traits has been offered only recently by methods for inferring polygenic adaptations from genomic data. Relying on this approach, we demonstrate how high-altitude Andean human groups experienced pervasive selective events at angiogenic pathways, which resemble those previously attested for Himalayan populations despite partial convergence at the single-gene level was observed. This provides additional evidence for the drivers of convergent evolution of enhanced blood perfusion in populations exposed to hypobaric hypoxia for thousands of years.
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