Role of per- and polyfluoroalkyl substances in the cardiorenal system: Unraveling crosstalk from the network of pollutants and phenotypes.

Although per- and polyfluoroalkyl substances (PFAS) have been frequently linked to cardiovascular and renal disease separately, evidence remains scarce regarding their systematic effect. Therefore, we recruited 546 newly diagnosed acute coronary syndrome (ACS) patients and detected seven myocardial enzymes and six kidney function biomarkers. Twelve PFAS were also assessed with ultra-high-performance liquid chromatography-tandem mass spectrometry. Generalized linear model and restricted cubic spline model were applied to single pollutant analysis. Quantile g-computation was used for mixture analysis. Network model was utilized to identify central and bridge nodes of pollutants and phenotypes. In the present study, perfluorohexane sulfonic acid was positively associated with uric acid (UA) (ß= 0.04, 95% confidence interval (CI): 0.01, 0.07), and perfluorobutanoic acid was negatively associated with estimated glomerular filtration rate (ß= -0.04, 95% CI: -0.07, -0.01) but positively associated with UA (ß= 0.03, 95% CI: 0.01, 0.06). In mixture analysis, each quantile increase in the PFAS mixture was significantly associated with UA (ß= 0.08, 95% CI: 0.04, 0.11). Network analysis revealed that perfluorooctanoate, UA, and myoglobin were denoted as bridge nodes, and the first principal component of lactate dehydrogenase and creatine kinase- myocardial band was identified as the node with the highest strength and expected influence. This study investigates the systematic impact of PFAS exposure through cardiorenal interaction network, which highlights that PFAS may serve as an upstream approach in UA-modulated cardiorenal network to affect cardiorenal system comprehensively.

Association between dietary copper intake and bone mineral density in children and adolescents aged 8-19 years: A cross-sectional study.

PURPOSE: Some studies showed the possible role of copper intake on bone mineral density (BMD) in adults or the elderly, but the association remained uncertain in children and adolescents. Our research explored the association between copper intake and BMD in individuals aged 8-19 years from the National Health and Nutrition Examination Survey (NHANES) 2011-2016. METHODS: In the present study, 6,965 individuals aged 8-19 (mean age 13.18 ± 3.38 years) were enrolled from the NHANES 2011-2016. Copper intake was evaluated by averaging two 24-hour copper dietary intake recalls. Multivariate linear regression analyses were used to explore the association between copper intake and total BMD, subtotal BMD, and total spine BMD in children and adolescents. Stratified analyses and interaction tests were performed by age, gender, and race. RESULTS: Participants of the higher quartile of copper intake were more likely to be older, men, Non-Hispanic White, and Other Hispanic. They have higher values of poverty income ratio (PIR), serum phosphorus, blood urea nitrogen, serum vitamin D, and BMD and lower values of body mass index (BMI), cholesterol, total protein, and serum cotinine. In the fully adjusted model, we found positive associations between copper intake and total BMD (ß = 0.013, 95CI: 0.006, 0.019)), subtotal BMD (ß = 0.020, 95CI: 0.015, 0.024), and total spine BMD (ß = 0.014, 95CI: 0.009, 0.019). Stratified analyses showed that the association was stronger in men, individuals aged 14-19, Non-Hispanic White, and Other Hispanic. CONCLUSIONS: Our study suggests that copper intake is positively associated with BMD in U.S. children and adolescents. The study emphasizes the role of copper intake on bone health in the early stages of life. However, more investigations are needed to verify our findings and their underlying mechanisms.

Metric learning guided sinogram denoising for cone beam CT enhancement.

BACKGROUND: Cone beam computed tomography (CBCT) is a widely available modality, but its clinical utility has been limited by low detail conspicuity and quantitative accuracy. Convenient post-reconstruction denoising is subject to back projected patterned residual, but joint denoise-reconstruction is typically computationally expensive and complex. PURPOSE: In this study, we develop and evaluate a novel Metric-learning guided wavelet transform reconstruction (MEGATRON) approach to enhance image domain quality with projection-domain processing. METHODS: Projection domain based processing has the benefit of being simple, efficient, and compatible with various reconstruction toolkit and vendor platforms. However, they also typically show inferior performance in the final reconstructed image, because the denoising goals in projection and image domains do not necessarily align. Motivated by these observations, this work aims to translate the demand for quality enhancement from the quantitative image domain to the more easily operable projection domain. Specifically, the proposed paradigm consists of a metric learning module and a denoising network module. Via metric learning, enhancement objectives on the wavelet encoded sinogram domain data are defined to reflect post-reconstruction image discrepancy. The denoising network maps measured cone-beam projection to its enhanced version, driven by the learnt objective. In doing so, the denoiser operates in the convenient sinogram to sinogram fashion but reflects improvement in reconstructed image as the final goal. Implementation-wise, metric learning was formalized as optimizing the weighted fitting of wavelet subbands, and a res-Unet, which is a Unet structure with residual blocks, was used for denoising. To access quantitative reference, cone-beam projections were simulated using the X-ray based Cancer Imaging Simulation Toolkit (XCIST). In both learning modules, a data set of 123 human thoraxes, which was from Open-Source Imaging Consortium (OSIC) Pulmonary Fibrosis Progression challenge, was used. Reconstructed CBCT thoracic images were compared against ground truth FB and performance was assessed in root mean square error (RMSE), peak signal-to-noise ratio (PSNR), and structural similarity index (SSIM). RESULTS: MEGATRON achieved RMSE in HU value, PSNR, and SSIM were 30.97 ± 4.25, 37.45 ± 1.78, and 93.23 ± 1.62, respectively. These values are on par with reported results from sophisticated physics-driven CBCT enhancement, demonstrating promise and utility of the proposed MEGATRON method. CONCLUSION: We have demonstrated that incorporating the proposed metric learning into sinogram denoising introduces awareness of reconstruction goal and improves final quantitative performance. The proposed approach is compatible with a wide range of denoiser network structures and reconstruction modules, to suit customized need or further improve performance.

A novel 3D-printed educational model for the training of laparoscopic bile duct Exploration:a pilot study for beginning trainees.

Background: Laparoscopic common bile duct exploration (LCBDE) is a minimally invasive procedure for the removal of bile duct stones that is often performed by experienced hepatobiliary surgeons; beginners do not easily master this approach. Aim: To investigate the effectiveness and practicality of a three-dimensional printed (3DP) anatomical model based on radiographic images in the training of LCBDE techniques and formulate standardized educational workflows. Methods: Colored LCBDE training models were produced using 3DP technology. Twenty standardized training trainees were randomly divided into two groups: a 3DP model training group and a traditional laparoscopic simulation training group. Both groups received the same number of teaching hours. After a 4-weeks training course, the trainees' subjective and objective progress in basic knowledge and manipulations were evaluated and compared. Results: Compared with traditional laparoscopic simulation, 3DP model simulation training is of great significance in improving trainers' understanding of surgical procedures and cooperation during the operation. Trainees with 3DP models training demonstrated a significant improvement in their understanding of the key points of surgery (χ2 = 6.139, p = 0.013) and skills scores, especially in core procedural steps operation. More importantly, the trainees showed higher levels of satisfaction and self-confidence while assisting in the surgery. Conclusion: With the development of 3DP models, improvements in the learning effect for theoretical understanding and practical skills were significant. The present study is the initial educational experience with 3DP models to facilitate the operational capabilities of the trainees for LCBDE.

Effectiveness of Second-Line Cabozantinib in Metastatic Clear Cell Renal Cell Carcinoma Patients After First-Line Treatment with Immune Checkpoint Inhibitor-based Combinations.

Background: Cabozantinib, a tyrosine kinase inhibitor (TKI), is a prevalent second-line (2 L) therapy and was approved for use after progression on TKIs. However, the 1 L treatment setting has changed since the approval of cabozantinib monotherapy in salvage therapy settings. Objective: To assess the differential effectiveness of cabozantinib after prior progression on 1 L ipilimumab with nivolumab (IPI + NIVO) compared to programmed death receptor-1 (PD-1) or PD-1 ligand (PD-L1) inhibitors (PD1/L1i) with TKIs. Methods: Utilizing a nationwide electronic health record (EHR)-derived de-identified database, we included patients with metastatic clear cell renal cell carcinoma (mccRCC) who received 1 L treatment with an immune checkpoint inhibitor (ICI)-based combination and 2 L treatment with cabozantinib monotherapy. These patients were categorized based on the type of 1 L ICI-based combination received: IPI + NIVO vs. PD1/L1i with TKI. Real-world time to next therapy (rwTTNT) and real-world overall survival (rwOS) were summarized using Kaplan-Meier curves and compared using Cox-proportional hazard models adjusted for International mRCC Database Consortium (IMDC) risk groups. Results: Among 12,285 patients with metastatic renal cell carcinoma, 237 were eligible and included. Median rwTTNT was 8 months for the IPI + NIVO subgroup and 7.5 months for the PD1/L1i + TKI subgroup (HR 1.05, 95% CI: 0.74-1.49, p = 0.8). Median rwOS was 17 months for IPI + NIVO and 16 months for PD1/L1i + TKI subgroup (HR 0.79, 95% CI: 0.52-1.20, p = 0.3). Conclusions: Cabozantinib remains effective as a 2 L therapy for mccRCC independent of the type of prior 1 L ICI-based combination. Further research is needed to validate these findings and explore the ideal sequencing of therapies.

Knowledge-based in silico fragmentation and annotation of mass spectra for natural products with MassKG.

Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) is a potent analytical technique utilized for identifying natural products from complex sources. However, due to the structural diversity, annotating LC-MS/MS data of natural products efficiently remains challenging, hindering the discovery process of novel active structures. Here, we introduce MassKG, an algorithm that combines a knowledge-based fragmentation strategy and a deep learning-based molecule generation model to aid in rapid dereplication and the discovery of novel NP structures. Specifically, MassKG has compiled 407,720 known NP structures and, based on this, generated 266,353 new structures using chemical language models for the discovery of potential novel compounds. Furthermore, MassKG demonstrates exceptional performance in spectra annotation compared to state-of-the-art algorithms. To enhance usability, MassKG has been implemented as a web server for annotating tandem mass spectral data (MS/MS, MS2) with a user-friendly interface, automatic reporting, and fragment tree visualization. Lastly, the interpretive capability of MassKG is comprehensively validated through composition analysis and MS annotation of Panax notoginseng, Ginkgo biloba, Codonopsis pilosula, and Astragalus membranaceus. MassKG is now accessible at https://xomics.com.cn/masskg.

The effect of exogenous mitochondria in enhancing the survival and volume retention of transplanted fat tissue in a nude mice model.

BACKGROUND: Despite the pivotal role of fat grafting in plastic, reconstructive, and aesthetic surgery, inconsistent survival rates of transplanted adipose tissue, primarily due to early ischemic and hypoxic insults, remain a significant challenge. The infusion of healthy mitochondria has emerged as a promising intervention to support tissue recovery from ischemic, hypoxic, and other types of damages across various organ systems. OBJECTIVES: This study aims to evaluate the impact of supplementing human adipose tissue grafts with healthy exogenous mitochondria on their volume and mass retention rates when transplanted into the subcutaneous layers of nude mice. This approach seeks to improve and optimize fat grafting techniques. METHODS: Human adipose tissues were preconditioned with exogenous mitochondria (10 µg/mL), a combination of exogenous mitochondria and the inhibitor Dyngo-4a, Dyngo-4a alone, or PBS, and then transplanted into the subcutaneous tissue of 24 nude mice. Samples were harvested at 1 and 3 months post-transplantation for analysis of mass and volume retention. The structural morphology and integrity of the adipose tissues were assessed using Hematoxylin and Eosin (H&E) staining. RESULTS: Mitochondrial preconditioning significantly enhanced the retention of mass and volume in fat grafts, demonstrating superior structural morphology and integrity compared to the control group. CONCLUSIONS: This study highlights the potential of exogenous mitochondrial augmentation in fat transplantation to significantly improve fat graft survival, thereby optimizing the success of fat grafting procedures.

NUCLEAR FACTOR-Y-POLYCOMB REPRESSIVE COMPLEX2 dynamically orchestrates starch and seed storage protein biosynthesis in wheat.

The endosperm in cereal grains is instrumental in determining grain yield and seed quality, as it controls starch and seed storage protein (SSP) production. In this study, we identified a specific nuclear factor-Y (NF-Y) trimeric complex in wheat (Triticum aestivum L.), consisting of TaNF-YA3-D, TaNF-YB7-B, and TaNF-YC6-B, and exhibiting robust expression within the endosperm during grain filling. Knockdown of either TaNF-YA3 or TaNF-YC6 led to reduced starch but increased gluten protein levels. TaNF-Y indirectly boosted starch biosynthesis genes by repressing TaNAC019, a repressor of cytosolic small ADP-glucose pyrophosphorylase 1a (TacAGPS1a), sucrose synthase 2 (TaSuS2), and other genes involved in starch biosynthesis. Conversely, TaNF-Y directly inhibited the expression of Gliadin-γ-700 (TaGli-γ-700) and low molecular weight-400 (TaLMW-400). Furthermore, TaNF-Y components interacted with SWINGER (TaSWN), the histone methyltransferase subunit of Polycomb repressive complex 2 (PRC2), to repress TaNAC019, TaGli-γ-700, and TaLMW-400 expression through trimethylation of histone H3 at lysine 27 (H3K27me3) modification. Notably, weak mutation of FERTILIZATION INDEPENDENT ENDOSPERM (TaFIE), a core PRC2 subunit, reduced starch but elevated gliadin and LMW-GS contents. Intriguingly, sequence variation within the TaNF-YB7-B coding region was linked to differences in starch and SSP content. Distinct TaNF-YB7-B haplotypes affect its interaction with TaSWN-B, influencing the repression of targets like TaNAC019 and TaGli-γ-700. Our findings illuminate the intricate molecular mechanisms governing TaNF-Y-PRC2-mediated epigenetic regulation for wheat endosperm development. Manipulating the TaNF-Y complex holds potential for optimizing grain yield and enhancing grain quality.

Real-World Primary Resistance to First-Line Immune-Based Combinations in Patients with Advanced Renal Cell Carcinoma (ARON-1).

BACKGROUND: Therapeutic advancements based on immuno-oncology combinations have revolutionized the management of patients with renal cell carcinoma. However, patients who have progressive disease as the best response, "primary refractory" (Pref), face dismal outcomes. OBJECTIVE: Our multicenter retrospective real-world study aims to assess the prevalence and clinicopathological characteristics of Pref patients. METHODS: This study collected data from 72 centers across 22 countries (1709 patients), involving patients aged ≥18 years with metastatic clear cell renal cell carcinoma. All patients were treated with first-line immune-oncology combinations. Data included patient demographics, histology, metastatic sites, and treatment responses. Radiological assessments followed Response Evaluation Criteria in Solid Tumors version 1.1. Statistical analyses employed Kaplan-Meier method, Cox proportional hazard models, logistic regression, and the receiver operating characteristic curve. RESULTS: In our study, the Pref rate was 19%. Nivolumab/ipilimumab showed the highest Pref rate (27%), while pembrolizumab/lenvatinib exhibited the lowest (10%). Primary refactory patients demonstrated significantly lower median overall survival (7.6 months) compared with non-Pref patients (55.7 months), p < 0.001. At the multivariate analysis, nephrectomy, sarcomatoid de-differentiation, intermediate/poor International Metastatic RCC Database Consortium risk, and bone and brain metastases emerged as significant predictors of overall survival for Pref patients with renal cell carcinoma. Logistic regression showed a significant relationship between liver metastases, intermediate/poor International Metastatic RCC Database Consortium risk, and no surgery and an increased risk of Pref. This study presents limitations, mainly because of its retrospective design. CONCLUSIONS: The ARON-1 study provides valuable insights into Pref patients, emphasizing the challenges of this precociously resistant subgroup. Identified predictors could guide risk stratification, aiding clinicians in tailored therapeutic approaches.

RNA technology and nanocarriers empowering in vivo chimeric antigen receptor therapy.

The remarkable success of mRNA-based coronavirus 2019 (COVID-19) vaccines has propelled the advancement of nanomedicine, specifically in the realm of RNA technology and nanomaterial delivery systems. Notably, significant strides have been made in the development of RNA-based in vivo chimeric antigen receptor (CAR) therapy. In comparison to the conventional ex vivo CAR therapy, in vivo CAR therapy offers several benefits including simplified preparation, reduced costs, broad applicability and decreased potential for carcinogenic effects. This review summarises the RNA-based CAR constructs in in vivo CAR therapy, discusses the current applications of in vivo delivery vectors and outlines the immune cells edited with CAR molecules. We aim for the conveyed messages to contribute towards the advancement of in vivo CAR application.

Effectiveness of ChatGPT 4.0 in Telemedicine-Based Management of Metastatic Prostate Carcinoma.

The recent rise in telemedicine, notably during the COVID-19 pandemic, highlights the potential of integrating artificial intelligence tools in healthcare. This study assessed the effectiveness of ChatGPT versus medical oncologists in the telemedicine-based management of metastatic prostate cancer. In this retrospective study, 102 patients who met inclusion criteria were analyzed to compare the competencies of ChatGPT and oncologists in telemedicine consultations. ChatGPT's role in pre-charting and determining the need for in-person consultations was evaluated. The primary outcome was the concordance between ChatGPT and oncologists in treatment decisions. Results showed a moderate concordance (Cohen's Kappa = 0.43, p < 0.001). The number of diagnoses made by both parties was not significantly different (median number of diagnoses: 5 vs. 5, p = 0.12). In conclusion, ChatGPT exhibited moderate agreement with oncologists in management via telemedicine, indicating the need for further research to explore its healthcare applications.

Effects of Yellow Sea Warm Current on zooplankton community composition and functional groups in winter.

The Yellow Sea Warm Current (YSWC) constitutes a significant hydrological feature in the Yellow Sea, particularly prominent during winter, facilitating the transport of warm, saline waters and warm-water species from the open sea to the Bohai and Yellow Seas. The YSWC induces alterations in the community structure and function of zooplankton. However, the effects of the YSWC on the functional trait compositions and functional groups of zooplankton remain unclear. This study aimed to elucidate the influence of the YSWC on the community structure, functional trait composition, and functional groups of zooplankton during winter of 2016. The YSWC significantly impacted the zooplankton assemblage in the central Yellow Sea (CYSA), resulting in notable distinctions from the Shandong coastal assemblage (SCA) and Jiangsu coastal assemblage (JCA). Compared to the SCA and JCA (comprising 45 and 34 taxa, with abundances of 119.4 ± 114.6 ind·m-3 and 82.8 ± 62.1 ind·m-3, respectively), the CYSA exhibited higher species richness and abundance (with 51 taxa and 144.4 ± 103.4 ind·m-3, respectively). This study documented a total of 11 warm-water species, showing a decreasing trend in both species richness and abundance from south to north. The CYSA was characterized by the predominance of medium‒sized, current‒feeding, omnivorous‒herbivorous broadcast spawners, whereas the SCA and the JCA were predominantly dominated by giant‒sized, ambush‒feeding carnivores. The Qingdao-Shidao anticyclonic eddy in the southern of Shandong Province led to a significant increase in the abundance of zooplankton, potentially impacting Yellow Sea fishery resource. This research contributed to a deeper understanding of how YSWC influence the zooplankton community and offered fresh insights into the effects of YSWC on zooplankton function traits and functional groups.

Photodynamic inactivation of edible photosensitizers for fresh food preservation: Comprehensive mechanism of action and enhancement strategies.

Foodborne harmful bacteria not only cause waste of fresh food, but also pose a major threat to human health. Among many new sterilization and preservation technologies, photodynamic inactivation (PDI) has the advantages of low-cost, broad-spectrum, energy-saving, nontoxic, and high efficiency. In particular, PDI based on edible photosensitizers (PSs) has a broader application prospect due to edible, accessible, and renewable features, it also can maximize the retention of the nutritional characteristics and sensory quality of the food. Therefore, it is meaningful and necessary to review edible PSs and edible PSs-mediated PDI, which can help to arouse interest and concern and promote the further development of edible PSs-mediated PDI in the future field of nonthermally sterilized food preservation. Herein, the classification and modification of edible PSs, PS-mediated in vivo and PS-mediated in vitro mechanism of PDI, strengthening strategy to improve PDI efficiency by the structure change synergistic and multitechnical means, as well as the application in fresh food preservation were reviewed systematically. Finally, the deficiency and possible future perspectives of edible PSs-mediated PDI were articulated. This review aimed to provide new perspective for the future food preservation and microbial control.

Niche and interspecific associations of dominant plant species in antimony mining ecological damaged site in Nandan, Guangxi, China.

In order to provide a guide for plant selection of ecological restoration at antimony (Sb) mining ecological damaged sites, species composition, importance value, niche, and interspecific associations of tree, shrub, and herb layers were examined at Sb mining site in Nandan City, Guangxi, China. The results showed that 23 vascular plant species were recorded at the Sb mining ecological damaged site, belonging to 22 genera and 13 families, primarily Gramineae, Cyperaceae, Fabaceae, and Asteraceae. The highest importance values for trees, shrubs, and herbs were observed in Rhus chinensis (56.7%), Coriaria nepalensis (56.3%), and Eremochloa ciliaris (44.0%), which were characterized by fairly large niche widths of 1.58, 1.32 and 1.57, respectively. The highest niche overlap values were found between R. chinensis and Triadica sebifera in the tree layer, and between Thysanolaena latifolia and Bidens pilosa in the herb layer, with the value of 0.68 and 0.99, respectively. Shrub layer exhibited a lower range of niche overlap (0.30-0.42), suggesting significant niche differentiation among different species. In the tree and shrub layers, most species showed insignificantly negative associations, the proportion was 83.3% and 66.7%, respectively, indicating that the plant community was not stable. Herb layer generally exhibited significantly positive correlations, with 52.4% of species pairs showing positive correlation, indicating weak resource competition among species. Overall, plant community at Sb mining ecological damaged site was unstable. In the process of ecological restoration, trees and shrubs that can adapt to the conditions and have positive associations should be prioritized in species selection, such as R. chinensis, C. lanceolata, C. nepalensis, and B. nivea. This will promote vegetation positive succession, rehabilitate the ecosystem and ensure sustainable development at Sb mining ecological damaged sites.

The Mitochondrial Transplantation: A New Frontier in Plastic Surgery.

Challenges such as difficult wound healing, ischemic necrosis of skin flaps, and skin aging are prevalent in plastic surgery. Previous research has indeed suggested that these challenges in plastic surgery are often linked to cellular energy barriers. As the powerhouses of the cell, mitochondria play a critical role in sustaining cellular vitality and health. Fundamentally, issues like ischemic and hypoxic damage to organs and tissues, as well as aging, stem from mitochondrial dysfunction, which leads to a depletion of cellular energy. Hence, having an adequate number of high-quality, healthy mitochondria is vital for maintaining tissue stability and cell survival. In recent years, there has been preliminary exploration into the protective effects of mitochondrial transplantation against cellular damage in systems such as the nervous, cardiovascular, and respiratory systems. For plastic surgery, mitochondrial transplantation is an extremely advanced research topic. This review focuses on the novel applications and future prospects of mitochondrial transplantation in plastic surgery, providing insights for clinicians and researchers, and offering guidance to patients seeking innovative and effective treatment options.

The current therapeutic cancer vaccines landscape in non-small cell lung cancer.

Currently, conventional immunotherapies for the treatment of non-small cell lung cancer (NSCLC) have low response rates and benefit only a minority of patients, particularly those with advanced disease, so novel therapeutic strategies are urgent deeded. Therapeutic cancer vaccines, a form of active immunotherapy, harness potential to activate the adaptive immune system against tumor cells via antigen cross-presentation. Cancer vaccines can establish enduring immune memory and guard against recurrences. Vaccine-induced tumor cell death prompts antigen epitope spreading, activating functional T cells and thereby sustaining a cancer-immunity cycle. The success of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rendered cancer vaccines a promising avenue, especially when combined with immunotherapy or chemoradiotherapy for NSCLC. This review delves into the intricate antitumor immune mechanisms underlying therapeutic cancer vaccines, enumerates the tumor antigen spectrum of NSCLC, discusses different cancer vaccines progress and summarizes relevant clinical trials. Additionally, we analyze the combination strategies, current limitations, and future prospects of cancer vaccines in NSCLC treatment, aiming to offer fresh insights for their clinical application in managing NSCLC. Overall, cancer vaccines offer promising potential for NSCLC treatment, particularly combining with chemoradiotherapy or immunotherapy could further improve survival in advanced patients. Exploring inhaled vaccines or prophylactic vaccines represents a crucial research avenue.

Discovery of KT-474─a Potent, Selective, and Orally Bioavailable IRAK4 Degrader for the Treatment of Autoimmune Diseases.

Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential mediator of the IL-1R and TLR signaling pathways, both of which have been implicated in multiple autoimmune conditions. Hence, blocking the activity of IRAK4 represents an attractive approach for the treatment of autoimmune diseases. The activity of this serine/threonine kinase is dependent on its kinase and scaffolding activities; thus, degradation represents a potentially superior approach to inhibition. Herein, we detail the exploration of structure-activity relationships that ultimately led to the identification of KT-474, a potent, selective, and orally bioavailable heterobifunctional IRAK4 degrader. This represents the first heterobifunctional degrader evaluated in a nononcology indication and dosed to healthy human volunteers. This molecule successfully completed phase I studies in healthy adult volunteers and patients with atopic dermatitis or hidradenitis suppurativa. Phase II clinical trials in both of these indications have been initiated.

PSAR-SR: Patches separation and artifacts removal for improving super-resolution networks.

The success of the ClassSR has led to a strategy of decomposing images being used for large image SR. The decomposed image patches have different recovery difficulties. Therefore, in ClassSR, image patches are reconstructed by different networks to greatly reduce the computational cost. However, in ClassSR, the training of multiple sub-networks inevitably increases the training difficulty. Furthermore, decomposing images with overlapping not only increases the computational cost but also inevitably produces artifacts. To address these challenges, we propose an end-to-end general framework, named patches separation and artifacts removal SR (PSAR-SR). In PSAR-SR, we propose an image information complexity module (IICM) to efficiently determine the difficulty of recovering image patches. Then, we propose a patches classification and separation module (PCSM), which can dynamically select an appropriate SR path for image patches of different recovery difficulties. Moreover, we propose a multi-attention artifacts removal module (MARM) in the network backend, which can not only greatly reduce the computational cost but also solve the artifacts problem well under the overlapping-free decomposition. Further, we propose two loss functions - threshold penalty loss (TP-Loss) and artifacts removal loss (AR-Loss). TP-Loss can better select appropriate SR paths for image patches. AR-Loss can effectively guarantee the reconstruction quality between image patches. Experiments show that compared to the leading methods, PSAR-SR well eliminates artifacts under the overlapping-free decomposition and achieves superior performance on existing methods (e.g., FSRCNN, CARN, SRResNet, RCAN and CAMixerSR). Moreover, PSAR-SR saves 53%-65% FLOPs in computational cost far beyond the leading methods. The code will be made available: https://github.com/dywang95/PSAR-SR.