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Following autosomal dominant polycystic kidney disease (ADPKD) progression by measuring organ volumes requires low measurement variability. The objective of this study is to reduce organ volume measurement variability on MRI of ADPKD patients by utilizing all pulse sequences to obtain multiple measurements which allows outlier analysis to find errors and averaging to reduce variability. In order to make measurements on multiple pulse sequences practical, a 3D multi-modality multi-class segmentation model based on nnU-net was trained/validated using T1, T2, SSFP, DWI and CT from 413 subjects. Reproducibility was assessed with test–re-test methodology on ADPKD subjects (n = 19) scanned twice within a 3-week interval correcting outliers and averaging the measurements across all sequences. Absolute percent differences in organ volumes were compared to paired students t-test. Dice similarlity coefficient > 97%, Jaccard Index > 0.94, mean surface distance < 1 mm and mean Hausdorff Distance < 2 cm for all three organs and all five sequences were found on internal (n = 25), external (n = 37) and test–re-test reproducibility assessment (38 scans in 19 subjects). When averaging volumes measured from five MRI sequences, the model automatically segmented kidneys with test–re-test reproducibility (percent absolute difference between exam 1 and exam 2) of 1.3% which was better than all five expert observers. It reliably stratified ADPKD into Mayo Imaging Classification (area under the curve = 100%) compared to radiologist. 3D deep learning measures organ volumes on five MRI sequences leveraging the power of outlier analysis and averaging to achieve 1.3% total kidney test–re-test reproducibility. [ABSTRACT FROM AUTHOR]

• We propose an FTN which is fully relied on Transformer. • We leverage sliding window tokenization to construct hierarchical features. • Spatial Pyramid Transformer to increase efficiency. • Transformer Decoder is proposed to aggregate hierarchical features. Automatic skin lesion analysis in terms of skin lesion segmentation and disease classification is of great importance. However, these two tasks are challenging as skin lesion images of multi-ethnic population are collected using various scanners in multiple international medical institutes. To address them, most recent works adopt convolutional neural networks (CNNs) for skin lesion analysis. However, due to the intrinsic locality of the convolution operator, CNNs lack the ability to capture contextual information and long-range dependency. To improve the baseline performance established by CNNs, we propose a Fully Transformer Network (FTN) to learn long-range contextual information for skin lesion analysis. FTN is a hierarchical Transformer computing features using Spatial Pyramid Transformer (SPT). SPT has linear computational complexity as it introduces a spatial pyramid pooling (SPP) module into multi-head attention (MHA)to largely reduce the computation and memory usage. We conduct extensive skin lesion analysis experiments to verify the effectiveness and efficiency of FTN using ISIC 2018 dataset. Our experimental results show that FTN consistently outperforms other state-of-the-art CNNs in terms of computational efficiency and the number of tunable parameters due to our efficient SPT and hierarchical network structure. The code and models will be public available at: https://github.com/Novestars/Fully-Transformer-Network. [ABSTRACT FROM AUTHOR]

Graphite intercalation compounds are promising anode materials for potassium-ion batteries, but still have problems of sluggish kinetics and a large volume expansion upon potassiation. Porous carbons with a large ion-accessible area used as anode materials can have a high gravimetric capacity and structural stability. However, to avoid a low volumetric performance in porous carbons, an electrode must have both a high density and fast ion-transport channels and these pose stringent requirements for the pore structure. Here we use a flowable sulfur template to produce continually- and precisely-tunable pores in three-dimensional graphene assemblies. During capillary drying of graphene hydrogel, sulfur accompanied with the shrinking graphene sheets controls the formation of pores with precise sizes by tuning the usage. The pores formed are open and interlinked due to the existence of a flowable sulfur template in the graphene network. This obtained graphene-assembly with well-controlled interconnected pores is used as potassium-ion battery anodes and gives a stable cycling performance (500 cycles) and an ultrahigh volumetric capacity. Image 1 • Flowable templating for synthesis of porous carbons with fully interconnected texture. • Sulfur as a flowable and continuous template to tune capillary shrinkage of graphene artefact. • Shape and size of pore structure including pore connections solely dependent on sulfur usage. • Graphene-built porous carbons with fast ion transport and large ion storage for batteries. • Ultrahigh volumetric potassium storage with an ultralong life over 500 cycles. [ABSTRACT FROM AUTHOR]

Nod-like receptor protein 3 (NLRP3), a therapeutic target that has a close relationship with inflammatory diseases, has drawn significant attention from researchers in the field. An increasing number of NLRP3 inhibitors have been reported since NLRP3 was identified as a biomarker and inflammatory therapeutic target. Inhibiting NLRP3 has been widely studied as therapeutics for the treatment of cryopyrin associated periodic syndrome (CAPS), inflammatory bowel disease (IBD), nonalcoholic steatohepatitis (NASH), arthrolithiasis, Alzheimer's disease (AD) and Parkinson's disease (PD). This review updates the recently reported (2019 to mid-2023) molecule inhibitors targeting the NLRP3 inflammasome pathway, summarizes their structure-activity relationships (SARs), and discusses the therapeutic effects on inflammatory diseases. I hope this review will contribute to the development of novel inhibitors targeting NLRP3 inflammasome pathway as potential drugs. [Display omitted] • NLRP3 is a key node in the regulation of NLRP3 inflammasome pathways. • Targeting NLRP3 is a promising method for inflammatory diseases. • This review updates the recent reported NLRP3 inflammasome inhibitors. • This review summarizes the SARs of NLRP3 inflammasome inhibitors. [ABSTRACT FROM AUTHOR]

The emergence of multidrug-resistant bacteria along with a declining pipeline of clinically useful antibiotics has led to the urgent need for the development of more effective antibacterial agents to treat drug-resistant bacteria. We previously discovered compound OB-158 with potent antibacterial activity but exhibited poor oral bioavailability. Herein, a systematic structural optimization of OB-158 to improve pharmacokinetic profiles yielded 26 novel biaryloxazolidinone analogues, and their activities against Gram-positive S. aureus , multidrug resistant S. aureus and Enterococcus faecalis were evaluated. Remarkably, compound 8b was identified with potent antibacterial activity against S. aureus (MIC = 0.06 μg/mL), MSSA (MIC = 0.125 μg/mL), MRSA (MIC = 0.06 μg/mL), LRSA (MIC = 0.125 μg/mL) and LREFa (MIC = 0.5 μg/mL). Compound 8b was demonstrated as a promising candidate through druglikeness evaluation including metabolism in microsomes and plasma, Caco-2 cell permeability, plasma protein binding, cytotoxicity, and inhibition of CYP450 and human monoamine oxidase. Notably, compound 8b displayed excellent PK profile with appropriate T 1/2 of 1.49 h, high peak plasma concentration (C max = 2320 ng/mL), high plasma exposure (AUC 0− t = 8310 h ng/mL), and superior oral bioavailability (F = 68.1 %) in Sprague-Dawley rats. Ultimately, in vivo efficacy of compound 8b in a mouse model of LRSA systemic infection was also demonstrated. Taken together, compound 8b represents a promising drug candidate for the treatment of linezolid-resistant Gram-positive bacterial strains infection. [Display omitted] • 26 biaryloxazolidinone analogues were designed and synthesized. • Compound 8b showed potent antibacterial activity against MDR Gram-positive bacteria. • Compound 8b showed excellent PK and safety profiles. • Compound 8b showed potent in vivo efficacy in a mouse model of LRSA systemic infection. [ABSTRACT FROM AUTHOR]

[Display omitted] In this study, we have designed, synthesized and tested three series of novel dihydropteridone derivatives possessing isoindolin-1-one or isoindoline moieties as potent inhibitors of PLK1/BRD4. Remarkably, most of the compounds showed preferable inhibitory activity against PLK1 and BRD4. Compound SC10 exhibited excellent inhibitory activity with IC 50 values of 0.3 nM and 60.8 nM against PLK1 and BRD4, respectively. Meanwhile, it demonstrated significant anti-proliferative activities against three tumor-derived cell lines (MDA-MB-231 IC 50 = 17.3 nM, MDA-MB-361 IC 50 = 8.4 nM, and MV4-11 IC 50 = 5.4 nM). Moreover, SC10 exhibited moderate rat liver microsomal stability (CLint = 21.3 µL·min−1·mg−1), acceptable pharmacokinetic profile (AUC 0-t = 657 ng·h·mL−1, oral bioavailability of 21.4 %) in Sprague-Dawley rats, reduced hERG toxicity, acceptable PPB and CYP450 inhibition. Further research indicated that SC10 could induce MV4-11 cell arrest at the S phase and apoptosis in a dose-dependent manner. This investigation provided us with an initial point for developing novel anticancer agents as dual inhibitors of PLK1 and BRD4. [ABSTRACT FROM AUTHOR]

Polo like kinase 1 (PLK1) is a serine/threonine kinase that is widely distributed in eukaryotic cells and plays an important role in multiple phases of the cell cycle. Its importance in tumorigenesis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of novel dihydropteridone derivatives (13a-13v and 21g-21l) possessing oxadiazoles moiety as potent inhibitors of PLK1. Compound 21g exhibited improved PLK1 inhibitory capability with an IC 50 value of 0.45 nM and significant anti-proliferative activities against four tumor-derived cell lines (MCF-7 IC 50 = 8.64 nM, HCT-116 IC 50 = 26.0 nM, MDA-MB-231 IC 50 = 14.8 nM and MV4-11 IC 50 = 47.4 nM) with better pharmacokinetic characteristics than BI2536 in mice (AUC 0-t = 11 227 ng h mL−1 vs 556 ng h mL−1). Moreover, 21g exhibited moderate liver microsomal stability and excellent pharmacokinetic profile (AUC 0-t = 11227 ng h mL−1, oral bioavailability of 77.4%) in Balb/c mice, acceptable PPB, improved PLK1 inhibitory selectivity, and no apparent toxicity was observed in the acute toxicity assay (20 mg/kg). Further investigation showed that 21 g could arrest HCT-116 cells in G2 phase and induce apoptosis in a dose-dependent manner. These results indicate that 21g is a promising PLK1 inhibitor. [Display omitted] • Novel dihydropteridone derivatives were designed and synthesized for PLK1 inhibitors. • 21 g exhibited an IC 50 value of 0.45 nM against PLK1, notably antiproliferative activity. • 21 g exhibited excellent PK profile, acceptable PPB, and improved PLK1 selectivity. • 21 g was well tolerated at a dose of 20 mg/kg with no acute toxicity. [ABSTRACT FROM AUTHOR]