An Autotaxin-Induced Ocular Hypertension Mouse Model Reflecting Physiological Aqueous Biomarker.

Purpose: Animal models of ocular hypertension (OH) have been developed to understand the pathogenesis of glaucoma and facilitate drug discovery. However, many of these models are fraught with issues, including severe intraocular inflammation and technical challenges. Lysophosphatidic acid (LPA) is implicated in trabecular meshwork fibrosis and increased resistance of aqueous outflow, factors that contribute to high intraocular pressure (IOP) in human open-angle glaucoma. We aimed to elevate IOP by increasing expression of the LPA-producing enzyme autotaxin (ATX) in mouse eyes. Methods: Tamoxifen-inducible ATX transgenic mice were developed. Tamoxifen was administered to six- to eight-week-old mice via eye drops to achieve ATX overexpression in the eye. IOP and retinal thickness were measured over time, and retinal flat-mount were evaluated to count retinal ganglion cells (RGCs) loss after three months. Results: Persistent elevation of ATX expression in mouse eyes was confirmed through immunohistochemistry and LysoPLD activity measurement. ATX Tg mice exhibited significantly increased IOP for nearly two months following tamoxifen treatment, with no anterior segment changes or inflammation. Immunohistochemical analysis revealed enhanced expression of extracellular matrix near the angle after two weeks and three months of ATX induction. This correlated with reduced outflow facility, indicating that sustained ATX overexpression induces angle fibrosis, elevating IOP. Although inner retinal layer thickness remained stable, peripheral retina showed a notable reduction in RGC cell count. Conclusions: These findings confirm the successful creation of an open-angle OH mouse model, in which ATX expression in the eye prompts fibrosis near the angle and maintains elevated IOP over extended periods.

Hierarchical medical image report adversarial generation with hybrid discriminator.

BACKGROUND AND OBJECTIVES: Generating coherent reports from medical images is an important task for reducing doctors' workload. Unlike traditional image captioning tasks, the task of medical image report generation faces more challenges. Current models for generating reports from medical images often fail to characterize some abnormal findings, and some models generate reports with low quality. In this study, we propose a model to generate high-quality reports from medical images. METHODS: In this paper, we propose a model called Hybrid Discriminator Generative Adversarial Network (HDGAN), which combines Generative Adversarial Network (GAN) with Reinforcement Learning (RL). The HDGAN model consists of a generator, a one-sentence discriminator, and a one-word discriminator. Specifically, the RL reward signals are judged on the one-sentence discriminator and one-word discriminator separately. The one-sentence discriminator can better learn sentence-level structural information, while the one-word discriminator can learn word diversity information effectively. RESULTS: Our approach performs better on the IU-X-ray and COV-CTR datasets than the baseline models. For the ROUGE metric, our method outperforms the state-of-the-art model by 0.36 on the IU-X-ray, 0.06 on the MIMIC-CXR and 0.156 on the COV-CTR. CONCLUSIONS: The compositional framework we proposed can generate more accurate medical image reports at different levels.

Asymmetric synthesis of P-stereogenic phosphindane oxides via kinetic resolution and their biological activity.

The importance of P-stereogenic heterocycles has been widely recognized with their extensive use as privileged chiral ligands and bioactive compounds. The catalytic asymmetric synthesis of P-stereogenic phosphindane derivatives, however, remains a challenging task. Herein, we report a catalytic kinetic resolution of phosphindole oxides via rhodium-catalyzed diastereo- and enantioselective conjugate addition to access enantiopure P-stereogenic phosphindane and phosphindole derivatives. This kinetic resolution method features high efficiency (s factor up to >1057), excellent stereoselectivities (all >20:1 dr, up to >99% ee), and a broad substrate scope. The obtained chiral phosphindane oxides exhibit promising therapeutic efficacy in autosomal dominant polycystic kidney disease (ADPKD), and compound 3az is found to significantly inhibit renal cyst growth both in vitro and in vivo, thus ushering in a promising scaffold for ADPKD drug discovery. This study will not only advance efforts towards the asymmetric synthesis of challenging P-stereogenic heterocycles, but also surely inspire further development of P-stereogenic entities for bioactive small-molecule discovery.