Related Articles

An axis-specific mitral annuloplasty ring eliminates mitral regurgitation allowing mitral annular motion in an ovine model

Current mitral annuloplasty rings fail to restrict the anteroposterior distance while allowing dynamic mitral annular changes. We designed and manufactured a mitral annuloplasty ring that demonstrated axis-specific, selective flexibility to meet this clinical need. The objectives were to evaluate ex vivo biomechanics of this ring and to validate the annular dynamics and safety after ring implantation in vivo.

A three-step strategy for the conversion of pyridines into benzonitriles

Bioisosteric replacement is a key strategy in drug discovery. Although modifying peripheral functionalities is relatively straightforward, substituting core ring structures often demands a complete synthetic redesign. Substituting benzenes with pyridines is often pursued because the nitrogen atom in pyridine can enhance biological potency and metabolic stability. Conversely, replacing pyridines with benzenes, particularly benzonitriles, can also be of value. Benzonitriles are similarly polarized to pyridines and can effectively mimic their hydrogen-bond acceptor properties. Here we introduce a strategy for converting pyridines into benzonitriles. The method uses a three-step protocol, beginning with pyridine N-oxidation, followed by photochemical deconstruction in the presence of an amine. This sequence produces a nitrile-containing butadiene, which then undergoes a formal Diels–Alder cycloaddition with alkynes and alkenes to construct the benzonitrile ring. This methodology provides a retrosynthetic tactic for the preparation of benzonitriles from pyridine-based starting materials and enables direct, modular late-stage diversification of drug molecules.

Cryo-EM structure of PML RBCC dimer reveals CC-mediated octopus-like nuclear body assembly mechanism

Promyelocytic leukemia protein (PML) nuclear bodies (NBs) are essential in regulating tumor suppression, antiviral response, inflammation, metabolism, aging, and other important life processes. The re-assembly of PML NBs might lead to an ~100% cure of acute promyelocytic leukemia. However, until now, the molecular mechanism underpinning PML NB biogenesis remains elusive due to the lack of structural information. In this study, we present the cryo-electron microscopy (cryo-EM) structure of the PML dimer at an overall resolution of 5.3 Å, encompassing the RING, B-box1/2 and part of the coiled-coil (RBCC) domains. The integrated approach, combining crosslinking and mass spectrometry (XL-MS) and functional analyses, enabled us to observe a unique folding event within the RBCC domains. The RING and B-box1/2 domains fold around the α3 helix, and the α6 helix serves as a pivotal interface for PML dimerization. More importantly, further characterizations of the cryo-EM structure in conjugation with AlphaFold2 prediction, XL-MS, and NB formation assays, help unveil an unprecedented octopus-like mechanism in NB assembly, wherein each CC helix of a PML dimer (PML dimer A) interacts with a CC helix from a neighboring PML dimer (PML dimer B) in an anti-parallel configuration, ultimately leading to the formation of a 2 µm membrane-less subcellular organelle.

On-chip solar power source for self-powered smart microsensors in bulk CMOS process

Enhancing the photoelectric conversion efficiency of on-chip solar cells is crucial for advancing solar energy harvesting in self-powered smart microsensors for Internet of Things applications. Here we show that adopting a center electrode (CE) layout instead of a ring electrode (RE) effectively reduces the shadowing effect of surface electrodes. Using a standard 0.18 μm CMOS process, we fabricated a 0.01 mm² segmented triple-well on-chip solar cell with CEs and highly doped interconnections. Measurements demonstrate a photoelectric conversion efficiency of 25.79% under solar simulator illumination, a 17.49% improvement over conventional designs. This on-chip solar cell is used for on-chip energy harvesting, achieving a maximum end-to-end conversion efficiency of 10.20%, referring to the overall efficiency from incident light power to load power output. The proposed energy harvesting system reliably provides a stable 1 V output to the load, even under varying illumination and load conditions.

Oral submucous fibrosis: pathogenesis and therapeutic approaches

Oral submucous fibrosis (OSF), characterized by excessive deposition of extracellular matrix (ECM) that causes oral mucosal tissue sclerosis, and even cancer transformation, is a chronic, progressive fibrosis disease. However, despite some advancements in recent years, no targeted antifibrotic strategies for OSF have been approved; likely because the complicated mechanisms that initiate and drive fibrosis remain to be determined. In this review, we briefly introduce the epidemiology and etiology of OSF. Then, we highlight how cell-intrinsic changes in significant structural cells can drive fibrotic response by regulating biological behaviors, secretion function, and activation of ECM-producing myofibroblasts. In addition, we also discuss the role of innate and adaptive immune cells and how they contribute to the pathogenesis of OSF. Finally, we summarize strategies to interrupt key mechanisms that cause OSF, including modulation of the ECM, inhibition of inflammation, improvement of vascular disturbance. This review will provide potential routes for developing novel anti-OSF therapeutics.

Responses

Your email address will not be published. Required fields are marked *