Discovery of a novel BTK inhibitor S-016 and identification of a new strategy for the treatment of lymphomas including BTK inhibitor-resistant lymphomas.

Bruton's tyrosine kinase (BTK) has emerged as a therapeutic target for B-cell malignancies, which is substantiated by the efficacy of various irreversible or reversible BTK inhibitors. However, on-target BTK mutations facilitating evasion from BTK inhibition lead to resistance that limits the therapeutic efficacy of BTK inhibitors. In this study we employed structure-based drug design strategies based on established BTK inhibitors and yielded a series of BTK targeting compounds. Among them, compound S-016 bearing a unique tricyclic structure exhibited potent BTK kinase inhibitory activity with an IC50 value of 0.5 nM, comparable to a commercially available BTK inhibitor ibrutinib (IC50 = 0.4 nM). S-016, as a novel irreversible BTK inhibitor, displayed superior kinase selectivity compared to ibrutinib and significant therapeutic effects against B-cell lymphoma both in vitro and in vivo. Furthermore, we generated BTK inhibitor-resistant lymphoma cells harboring BTK C481F or A428D to explore strategies for overcoming resistance. Co-culture of these DLBCL cells with M0 macrophages led to the polarization of M0 macrophages toward the M2 phenotype, a process known to support tumor progression. Intriguingly, we demonstrated that SYHA1813, a compound targeting both VEGFR and CSF1R, effectively reshaped the tumor microenvironment (TME) and significantly overcame the acquired resistance to BTK inhibitors in both BTK-mutated and wild-type BTK DLBCL models by inhibiting angiogenesis and modulating macrophage polarization. Overall, this study not only promotes the development of new BTK inhibitors but also offers innovative treatment strategies for B-cell lymphomas, including those with BTK mutations.

A Novel IRAK4 Inhibitor DW18134 Ameliorates Peritonitis and Inflammatory Bowel Disease.

IRAK4 is a critical mediator in NF-κB-regulated inflammatory signaling and has emerged as a promising therapeutic target for the treatment of autoimmune diseases; however, none of its inhibitors have received FDA approval. In this study, we identified a novel small-molecule IRAK4 kinase inhibitor, DW18134, with an IC50 value of 11.2 nM. DW18134 dose-dependently inhibited the phosphorylation of IRAK4 and IKK in primary peritoneal macrophages and RAW264.7 cells, inhibiting the secretion of TNF-α and IL-6 in both cell lines. The in vivo study demonstrated the efficacy of DW18134, significantly attenuating behavioral scores in an LPS-induced peritonitis model. Mechanistically, DW18134 reduced serum TNF-α and IL-6 levels and attenuated inflammatory tissue injury. By directly blocking IRAK4 activation, DW18134 diminished liver macrophage infiltration and the expression of related inflammatory cytokines in peritonitis mice. Additionally, in the DSS-induced colitis model, DW18134 significantly reduced the disease activity index (DAI) and normalized food and water intake and body weight. Furthermore, DW18134 restored intestinal damage and reduced inflammatory cytokine expression in mice by blocking the IRAK4 signaling pathway. Notably, DW18134 protected DSS-threatened intestinal barrier function by upregulating tight junction gene expression. In conclusion, our findings reported a novel IRAK4 inhibitor, DW18134, as a promising candidate for treating inflammatory diseases, including peritonitis and IBD.

Anti-immunoglobulin E provides an additional therapy to conventional steroids for Kimura's disease.

Kimura's disease (KD) is a chronic inflammatory disease characterized by painless subcutaneous head and neck swelling, eosinophilia, and elevated serum immunoglobulin (Ig) E levels. There are various therapies, including surgery, radiation, systemic steroids, and immune suppressants, but their efficacy remains moderate due to the high recurrence rate. Biologics, like monoclonal antibodies, have shown tremendous effectiveness for chronic inflammatory diseases. Omalizumab is a monoclonal antibody against IgE and has not been approved for KD so far. We describe two refractory KD cases that responded to a small dose of steroids plus omalizumab. Additionally, we reviewed another 13 KD cases that were treated with biologics, including omalizumab, rituximab, dupilumab, and mepolizumab. The results indicate that biologics provide an alternative treatment strategy for KD.

Effect of Hydrothermal Aging on the Tribological Performance of Nitrile Butadiene Rubber Seals.

High temperature and humidity affect the tribological performance of nitrile butadiene rubber (NBR) seals, which affects the precise positioning of cylinder systems. Therefore, it is crucial to study the effect of hydrothermal aging on the tribological performance of the NBR seals. In this study, the changes in the tribological performance of the NBR seals under hydrothermal aging conditions were investigated. The results show that the volatilization of additives and the increase in crosslink density of the NBR seals occurs in the hydrothermal aging environment, leading to the deterioration of their surface quality, elastic deformability, and tribological performance. The formation of surface micropores due to additive volatilization is the main factor in the degradation of tribological performance.

Development and Validation of a Nomogram for Prediction of the Risk of MAFLD in an Overweight and Obese Population.

Background and Aims: Metabolic associated fatty liver disease (MAFLD) is a serious condition, and a simple method is needed for practitioners to identify patients with the disease and have a high risk of disease progression. Methods: We developed and validated a nomogram for fatty liver disease and reclassified the risk factors for MAFLD. The development cohort had 335 patients who received bioelectrical impedance analysis and liver ultrasound attenuation measurements at Shenzhen People's Hospital between September 2020 and June 2021. The validation cohort had 200 patients from other hospitals who received the same evaluation. A random forest procedure and binary logistic analysis were used to screen for risk factors, establish a fatty liver disease predictive model, and forecast the risk of MAFLD. The performance of the nomogram was evaluated by measurement of discrimination, calibration, and clinical usefulness. Results: The nomogram provided good predictions in a model that included body mass index (BMI) and waist circumference. The areas under the curve of the nomogram were 0.793 in the development cohort and 0.774 in the validation cohort. The nomogram performed well for calibration, category-free net reclassification improvement, and integrated discrimination improvement. Decision curve analysis indicated the nomogram performed better than BMI for predicting net outcome. Conclusions: The nomogram was an effective screening tool for fatty liver disease, and for those overweight individuals, may help physicians make appropriate decisions regarding treatment of MAFLD.

3D Printing of Tricalcium Phosphate/Poly Lactic-co-glycolic Acid Scaffolds Loaded with Carfilzomib for Treating Critical-sized Rabbit Radial Bone Defects.

The rapid development of scaffold-based bone tissue engineering strongly relies on the fabrication of advanced scaffolds and the use of newly discovered functional drugs. As the creation of new drugs and their clinical approval often cost a long time and billions of U.S. dollars, producing scaffolds loaded with repositioned conventional drugs whose biosafety has been verified clinically to treat critical-sized bone defect has gained increasing attention. Carfilzomib (CFZ), an approved clinical proteasome inhibitor with a much fewer side effects, is used to replace bortezomib to treat multiple myeloma. It is also reported that CFZ could enhance the activity of alkaline phosphatase and increase the expression of osteogenic transcription factors. With the above consideration, in this study, a porous CFZ/ß-tricalcium phosphate/poly lactic-co-glycolic acid scaffold (designated as "cytidine triphosphate [CTP]") was produced through cryogenic three-dimensional (3D) printing. The hierarchically porous CTP scaffolds were mechanically similar to human cancellous bone and can provide a sustained CFZ release. The implantation of CTP scaffolds into critical-sized rabbit radius bone defects improved the growth of new blood vessels and significantly promoted new bone formation. To the best of our knowledge, this is the first work that shows that CFZ-loaded scaffolds could treat nonunion of bone defect by promoting osteogenesis and angiogenesis while inhibiting osteoclastogenesis, through the activation of the Wnt/ß-catenin signaling. Our results suggest that the loading of repositioned drugs with effective osteogenesis capability in advanced bone tissue engineering scaffold is a promising way to treat critical-sized defects of a long bone.

An Optimization Method of Ambiguity Function Based on Multi-Antenna Constrained and Application in Vehicle Attitude Determination.

The global navigation satellite system (GNSS)-based multi-antenna attitude determination method has the advantages of a simple algorithm and no error accumulation with time in long endurance operation. However, it is sometimes difficult to simultaneous obtain the fixed solutions of all antennas in vehicle attitude determination. If float or incorrect fixed solutions are used, precision and reliability of attitude cannot be guaranteed. Given this fact, a baseline-constrained ambiguity function method (BCAFM) based on a self-built four GNSS antennas hardware platform is proposed. The coordinates obtained by BCAFM can replace the unreliable real-time kinematic (RTK) float or incorrect fixed solutions, so as to assist the direct method for attitude determination. In the proposed BCAFM, the baseline constraint is applied to improve search efficiency (searching time), and the ambiguity function value (AFV) formula is optimized to enhance the discrimination of true peak. The correctness of the proposed method is verified by vehicle attitude determination results and baseline length difference. Experimental results demonstrate that the function values of error peaks are reduced, and the only true peak can be identified accurately. The valid epoch proportion increases by 14.95% after true peak coordinates are used to replace the GNSS-RTK float or incorrect fixed solutions. The precision of the three attitude angles is 0.54°, 1.46°, and 1.15°, respectively. Meanwhile, the RMS of baseline length difference is 3.8 mm.

Fabrication of N-doped carbons from waste bamboo shoot shell with high removal efficiency of organic dyes from water.

N-doped carbons were obtained from bamboo shoot shell via hydrothermal pretreatment under salt assistance followed by carbonization, using melamine as nitrogen source. The carbons with tubular morphology and surface areas in 406-489 m2/g range were used as adsorbents for the removal of methyl orange (MO) and rhodamine B (RhB). Adsorption isotherms and kinetic fitting showed much better accordance with Freundlich model and pseudo-second-order, showing balanced capacity (qe) of 50 mg/g for MO and 42 mg/g for RhB on the pristine carbons (BHC-800) at 25 °C. After N-doping treatment, carbons (BSC-M20) had qe of MO and RhB up to 140 and 100 mg/g, respectively, confirming a positive effect of N-doping on the enhancement of dyes removal. The findings indicated that hydrothermal treatment followed by carbonization was efficient to obtain N-doped carbons from biomass materials, and the present BSS-derived carbons were promising adsorbents for organic dyes removal from water.

Combined analysis and miRNA expression profiles of the flowering related genes in common wild rice (oryza rufipogon Griff.).

Common wild rice (Oryza rufipogon Griff.) is the most closely related ancestral species to Asian cultivated rice (Oryza sativa L.). It contains various valuable traits with regard to tolerance to cold, drought and salinity, flowering diversity and many quantitative trait loci with agronomic important traits. Flowering is one of the most important agronomic traits. However, flowering-related transcriptome and how to be regulated by miRNAs have not been estimated in O.rufipogon. To identify how the genes and miRNAs regulating flowering in O.rufipogon. Three O.rufipogon RNA libraries, two vegetative stages (CWRT-V1 and CWRT-V2) and one flowering stage (CWRT-F2) were constructed using leaves tissue and sequenced using Illumina deep sequencing. 27,405, 27,333, 28,979 unique genes were obtained after mapping to the reference genome from CWRT-V1, CWRT-V2 and CWRT-F2, respectively. Then differentially expressed genes (DEGs) were screened and got 1419 unique genes are likely to involve in flower development. Detailed information showed that MADS box and floral meristem identity genes, such as MADS 1, MADS14, Hd1 are involved in common wild rice. Then, combined analysis of miRNA and mRNA expression profiles was performed. Twenty three known miRNA-mRNA pairs and five new candidates were presented an anti-correlationship. Interestingly, 12 miRNAs were negatively correlated with 20 mRNAs encoding flowering-related proteins, indicating that miRNAs regulated target genes to promote flowering in CWRT-F2 group. The results provided here genomic resources for flowering related genes and how these flowering genes were regulated by miRNAs in common wild rice.

Isolation and Characterization of a Green-Tissue Promoter from Common Wild Rice (Oryza rufipogon Griff.).

Promoters play a very important role in the initiation and regulation of gene transcription. Green-tissue promoter is of great significance to the development of genetically modified crops. Based on RNA-seq data and RT-PCR expression analysis, this study screened a gene, OrGSE (GREEN SPECIAL EXPRESS), which is expressed specifically in green tissues. The study also isolated the promoter of the OrGSE gene (OrGSEp), and predicted many cis-acting elements, such as the CAAT-Box and TATA-Box, and light-responding elements, including circadian, G-BOX and GT1 CONSENSUS. Histochemical analysis and quantification of GUS activity in transgenic Arabidopsis thaliana plants expressing GUS under the control of OrGSEp revealed that this promoter is not only green tissue-specific, but also light-inducible. The ability of a series of 5'-deletion fragments of OrGSEp to drive GUS expression in Arabidopsis was also evaluated. We found that the promoter region from −54 to −114 is critical for the promoter function, and the region from −374 to −114 may contain core cis-elements involved in light response. In transgenic rice expressing GUS under the control of OrGSEp, visualization and quantification of GUS activity showed that GUS was preferentially expressed in green tissues and not in endosperm. OrGSEp is a useful regulatory element for breeding pest-resistant crops.