Citations

Resistant hypertension (RH) is a high-risk phenotype characterized by blood pressure readings ≥130/80 mmHg despite maximally tolerated therapy with three antihypertensive agents, including a diuretic, or controlled blood pressure requiring four or more medications. The diagnosis of RH requires a structured evaluation that confirms accurate blood pressure measurement, excludes pseudoresistance—particularly nonadherence and white coat hypertension—and identifies secondary causes such as obstructive sleep apnea, primary aldosteronism, renovascular disease, pheochromocytoma, and Cushing syndrome. RH arises from overlapping mechanisms, including activation of the renin–angiotensin–aldosterone system (RAAS), sympathetic overactivity, arterial stiffness, volume expansion, and immune-mediated pathways. Management begins with lifestyle modification and optimized triple therapy, followed by mineralocorticoid receptor antagonists as the preferred fourth-line treatment. Emerging pharmacological options, such as sodium–glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, endothelin receptor antagonists, aldosterone synthase inhibitors, and angiotensin receptor and neprilysin inhibitors (ARNIs), offer additional therapeutic potential; meanwhile, device-based interventions, including renal denervation and baroreflex activation therapy, have shown sustained blood pressure reductions in selected patients. Future directions highlight precision medicine, digital health technologies, and artificial intelligence as methods to improve diagnosis, guide individualized therapy, and enhance long-term blood pressure control.

KIF20A is a critical kinesin for cell division and a promising anti-cancer drug target. The mechanisms underlying its cellular roles remain elusive. Interestingly, unusual coupling between the nucleotide- and microtubule-binding sites of this kinesin-6 has been reported, but little is known about how its divergent sequence leads to atypical motility properties. We present here the first high-resolution structure of its motor domain that delineates the highly unusual structural features of this motor, including a long L6 insertion that integrates into the core of the motor domain and that drastically affects allostery and ATPase activity. Together with the high-resolution cryo-electron microscopy microtubule-bound KIF20A structure that reveals the microtubule-binding interface, we dissect the peculiarities of the KIF20A sequence that influence its mechanochemistry, leading to low motility compared to other kinesins. Structural and functional insights from the KIF20A pre-power stroke conformation highlight the role of extended insertions in shaping the motor's mechanochemical cycle. Essential for force production and processivity is the length of the neck linker in kinesins. We highlight here the role of the sequence preceding the neck linker in controlling its backward docking and show that a neck linker four times longer than that in kinesin-1 is required for the activity of this motor.