Design, synthesis and bioactivity evaluation of isobavachin derivatives as hURAT1 inhibitors for hyperuricemia agents.

Previously, we reported a novel natural scaffold compound, isobavachin (4',7-dihydroxy-8-prenylflavanone), as a highly potent hURAT1 inhibitor with anti-hyperuricemia effect. However, the structure-activity relationship remains unknown and the poor pharmacokinetic (PK) parameters may limit further clinical use. Herein, a series of isobavachin derivatives were rationally designed and synthesized to explore the structure-activity relationship of isobavachin target hURAT1, and to improve their PK properties. Among them, compounds 15d, 15f, 15g, 27b and 27d showed promising hURAT1 inhibitory activities, which could comparable to that of isobavachin (IC50 = 0.24 µM). In addition, 27b also inhibited another urate reabsorption transporter GLUT9 with an IC50 of 4.47 µM. Compound 27b displayed greater urate-lowering activity in a hyperuricemia mouse model at a dose of 10 mg/kg compared to isobavachin and lesinurad. Overall, our results suggest that compound 27b represents a novel, safe hURAT1 and GLUT9 dual-target inhibitor with excellent drug availability and is worthy of further investigation as an anti-hyperuricemia agent.

IL1RAP-specific T cell engager depletes acute myeloid leukemia stem cells.

BACKGROUND: The interleukin-1 receptor accessory protein (IL1RAP) is highly expressed on acute myeloid leukemia (AML) bulk blasts and leukemic stem cells (LSCs), but not on normal hematopoietic stem cells (HSCs), providing an opportunity to target and eliminate the disease, while sparing normal hematopoiesis. Herein, we report the activity of BIF002, a novel anti-IL1RAP/CD3 T cell engager (TCE) in AML. METHODS: Antibodies to IL1RAP were isolated from CD138+ B cells collected from the immunized mice by optoelectric positioning and single cell sequencing. Individual mouse monoclonal antibodies (mAbs) were produced and characterized, from which we generated BIF002, an anti-human IL1RAP/CD3 TCE using Fab arm exchange. Mutations in human IgG1 Fc were introduced to reduce FcγR binding. The antileukemic activity of BIF002 was characterized in vitro and in vivo using multiple cell lines and patient derived AML samples. RESULTS: IL1RAP was found to be highly expressed on most human AML cell lines and primary blasts, including CD34+ LSC-enriched subpopulation from patients with both de novo and relapsed/refractory (R/R) leukemia, but not on normal HSCs. In co-culture of T cells from healthy donors and IL1RAPhigh AML cell lines and primary blasts, BIF002 induced dose- and effector-to-target (E:T) ratio-dependent T cell activation and leukemic cell lysis at subnanomolar concentrations. BIF002 administered intravenously along with human T cells led to depletion of leukemic cells, and significantly prolonged survival of IL1RAPhigh MOLM13 or AML patient-derived xenografts with no off-target side effects, compared to controls. Of note, BiF002 effectively redirects T cells to eliminate LSCs, as evidenced by the absence of disease initiation in secondary recipients of bone marrow (BM) from BIF002+T cells-treated donors (median survival not reached; all survived > 200 days) compared with recipients of BM from vehicle- (median survival: 26 days; p = 0.0004) or isotype control antibody+T cells-treated donors (26 days; p = 0.0002). CONCLUSIONS: The novel anti-IL1RAP/CD3 TCE, BIF002, eradicates LSCs and significantly prolongs survival of AML xenografts, representing a promising, novel treatment for AML.

Serotonylation in tumor-associated fibroblasts contributes to the tumor-promoting roles of serotonin in colorectal cancer.

Accumulated studies have highlighted the diverse roles of 5-hydroxytryptamine (5-HT), or serotonin, in cancer biology, particularly in colorectal cancer (CRC). While 5-HT primarily exerts its effects through binding to various 5-HT receptors, receptor-independent mechanisms such as serotonylation remain unclear. This study revealed that depleting 5-HT, either through genetic silencing of Tph1 or using a selective TPH1 inhibitor, effectively reduced the growth of CRC tumors. Interestingly, although intrinsic 5-HT synthesis exists in CRC, it is circulating 5-HT that mediates the cancer-promoting function of 5-HT. Blocking the function of 5-HT receptors showed that the oncogenic roles of 5-HT in CRC operate through a mechanism that is separate from its receptor. Instead, serotonylation of histone H3Q5 (H3Q5ser) was found in CRC cells and cancer-associated fibroblasts (CAFs). H3Q5ser triggers a phenotypic switch of CAFs towards an inflammatory-like CAF (iCAF) subtype, which further enhances CRC cell proliferation, invasive characteristics, and macrophage polarization. Knockdown of the 5-HT transporter SLC22A3 or inhibition of TGM2 reduces H3Q5ser levels and reverses the tumor-promoting phenotypes of CAFs in CRC. Collectively, this study sheds light on the serotonylation-dependent mechanisms of 5-HT in CRC progression, offering insights into potential therapeutic strategies targeting the serotonin pathway for CRC treatment.

ICDXML: enhancing ICD coding with probabilistic label trees and dynamic semantic representations.

Accurately assigning standardized diagnosis and procedure codes from clinical text is crucial for healthcare applications. However, this remains challenging due to the complexity of medical language. This paper proposes a novel model that incorporates extreme multi-label classification tasks to enhance International Classification of Diseases (ICD) coding. The model utilizes deformable convolutional neural networks to fuse representations from hidden layer outputs of pre-trained language models and external medical knowledge embeddings fused using a multimodal approach to provide rich semantic encodings for each code. A probabilistic label tree is constructed based on the hierarchical structure existing in ICD labels to incorporate ontological relationships between ICD codes and enable structured output prediction. Experiments on medical code prediction on the MIMIC-III database demonstrate competitive performance, highlighting the benefits of this technique for robust clinical code assignment.

Highly Pathogenic Avian Influenza A Virus in Wild Migratory Birds, Qinghai Lake, China, 2022.

In July 2022, an outbreak of highly pathogenic avian influenza A(H5N1) virus clade 2.3.4.4b occurred among migratory birds at Qinghai Lake in China. The virus circulated in June, and reassortants emerged after its introduction into the area. Surveillance in 2023 showed that the virus did not establish a stable presence in wild waterfowl.

Transcriptomic and metabolomic analyses reveal mechanisms underpinning resistance of Chinese wild grape to Colletotrichum viniferum.

Grape ripe rot is one of the most important diseases caused by Colletotrichum spp. Chinese wild grape (Vitis davidii) is highly resistant to Colletotrichum viniferum infection. But mechanisms underlying the resistance remain largely unclear. In this study, transcriptomic and metabolomic responses of V. davidii to C. viniferum were studied before and after 1, 2, 4, and 6 days of inoculation. C. viniferum infection induced the expression of a large number of defense-related genes. KEGG analysis indicated that the differentially expressed genes (DEGs) were largely those involved in alpha-linolenic acid metabolism, flavonoid biosynthesis, phenylpropanoid biosynthesis, stilbenoid biosynthesis, and other defense-related metabolic pathways. Based on transcriptome data and experimental analysis, we found that jasmonic acid (JA) biosynthesis was closely related to V. davidii resistance to C. viniferum. In addition, many genes related to the synthesis of lignin and phytoalexin resveratrol are upregulated by pathogen infection, and metabolomic analysis showed that there was an increasing accumulation of resveratrol on day 6 of C. viniferum inoculation. Further analysis indicated that transcription factors, such as VdWRKY75 regulated the biosynthesis of lignin and stilbenes. A working model for V. davidii against C. viniferum infection was proposed. The infection of C. viniferum induced JA production, JA along with transcription factors regulated the biosynthesis of secondary metabolites, such as lignin and resveratrol that enhanced plant resistance to C. viniferum. This study elucidated molecular mechanisms underlying the resistance of Chinese wild V. davidii to C. viniferum which can provide a theoretical basis for grape disease resistance breeding.

Five-year longitudinal surveillance reveals the continual circulation of both alpha- and beta-coronaviruses in Plateau and Gansu pikas (Ochotona spp.) at Qinghai Lake, China1.

The discovery of alphacoronaviruses and betacoronaviruses in plateau pikas (Ochotona curzoniae) expanded the host range of mammalian coronavirus (CoV) to a new order - Lagomorpha. However, the diversity and evolutionary relationships of CoVs in these plateau-region-specific animal population remains uncertain. We conducted a five-year longitudinal surveillance of CoVs harboured by pikas around Qinghai Lake, China. CoVs were identified in 33 of 236 plateau pikas and 2 of 6 Gansu pikas (Ochotona cansus), with a total positivity rate of 14.5%, and exhibiting a wide spatiotemporal distribution across seven sampling sites and six time points. Through meta-transcriptomic sequencing and RT-PCR, we recovered 16 near-complete viral genome sequences. Phylogenetic analyses classified the viruses as variants of either pika alphacoronaviruses or betacoronaviruses endemic to plateau pikas from the Qinghai-Tibet Plateau region. Of particular note, the pika-associated betacoronaviruses may represent a novel subgenus within the genus Betacoronavirus. Tissue tropism, evaluated using quantitative real-time PCR, revealed the presence of CoV in the rectal and/or lung tissues, with the highest viral loads at 103.55 or 102.80 RNA copies/µL. Surface plasmon resonance (SPR) assays indicated that the newly identified betacoronavirus did not bind to human or pika Angiotensin-converting enzyme 2 (ACE2) or Dipeptidyl peptidase 4 (DPP4). The findings highlight the ongoing circulation and broadening host spectrum of CoVs among pikas, emphasizing the necessity for further investigation to evaluate their potential public health risks.

Targeting the STAT3 pathway with STAT3 degraders.

Signal transducer and activator of transcription 3 (STAT3) has been widely considered as a therapeutic target for various diseases, especially tumors. Thus far, several STAT3 inhibitors have been advanced to clinical trials; however, the development of STAT3 inhibitors is hindered by numerous dilemmas. Fortunately, STAT3 degraders represent an alternative and promising strategy to block STAT3, attracting extensive research interest. Here, we analyze the recent advancements of STAT3 degraders, including proteolysis targeting chimeras (PROTACs) and small-molecule natural products, focusing on their structures, mechanisms, and biological activities. We discuss the potential opportunities and challenges for developing STAT3 degraders. It is hoped that this Review will provide insights into the discovery of potent STAT3-targeting drugs.

Tandem Catalysis for Simultaneous Removal of NOx and C3H8 with Inhibition of N2O.

Tandem catalysis is widely adopted for multipollutant control in mobile sources but has rarely been reported in stationary source emission elimination. This work proposed a tandem arrangement way with up-streamed V2O5/TiO2 + down-streamed Cr2O3/TiO2 catalysts, which could achieve the efficient synergistic control of NOx and C3H8 in industrial flue gas. Moreover, this arrangement successfully alleviated the unwanted N2O formation during the NH3 -SCR process. Compared to the conventional impregnation method of the Cr2O3-V2O5/TiO2 catalyst, the tandem catalysts of V2O5/TiO2 + Cr2O3/TiO2 could enhance the NOx and C3H8 conversion by 4.2% and 39.5%, respectively, at 350 °C. It might be attributed to the fact that Cr species was the active site for C3H8 oxidation, and the tandem arrangement of catalysts was beneficial to even dispersion of active components on supports. Furthermore, due to the preferential NOx removal over the up-streamed V2O5/TiO2 catalyst, the tandem catalysts obviously alleviated the N2O formation caused by Cr species during the NH3-SCR process. Herein, it significantly decreased N2O formation by 240.5% at 350 °C compared to the Cr2O3-V2O5/TiO2 catalyst, achieving multipollutant emission control from industrial flue gas with the performance of "one stone three birds".

Facilely Fabricated Single-Site Ptδ+-O(OH)x- Species Associated with Alkali on Zirconia Exhibiting Superior Catalytic Oxidation Reactivity.

Fabrication of robust isolated atom catalysts has been a research hotspot in the environment catalysis field for the removal of various contaminants, but there are still challenges in improving the reactivity and stability. Herein, through facile doping alkali metals in Pt catalyst on zirconia (Pt-Na/ZrO2), the atomically dispersed Ptδ+-O(OH)x- associated with alkali metal via oxygen bridge was successfully fabricated. This novel catalyst presented remarkably higher CO and hydrocarbon (HCs: C3H8, C7H8, C3H6, and CH4) oxidation activity than its counterpart (Pt/ZrO2). Systematically direct and solid evidence from experiments and density functional theory calculations demonstrated that the fabricated electron-rich Ptδ+-O(OH)x- related to Na species rather than the original Ptδ+-O(OH)x-, serving as the catalytically active species, can readily react with CO adsorbed on Ptδ+ to produce CO2 with significantly decreasing energy barrier in the rate-determining step from 1.97 to 0.93 eV. Additionally, owing to the strongly adsorbed and activated water by Na species, those fabricated single-site Ptδ+-O(OH)x- linked by Na species could be easily regenerated during the oxidation reaction, thus considerably boosting its oxidation reactivity and durability. Such facile construction of the alkali ion-linked active hydroxyl group was also realized by Li and K modification which could guide to the design of efficient catalysts for the removal of CO and HCs from industrial exhaust.

Discovery of Novel HDAC3 Inhibitors with PD-L1 Downregulating/Degrading and Antitumor Immune Effects.

Targeting the programmed cell death-1/ligand 1 (PD-1/PD-L1) pathway is one of the most promising cancer treatment strategies. Studies have shown that HDAC inhibitors can enhance the antitumor immune response by modulating the expression of PD-L1. Herein, we designed and synthesized a series of novel hydrazide-based small molecule HDAC inhibitors; among them, compound HQ-30 showed selective HDAC3 inhibition (IC50 = 89 nM) and remarkable PD-L1-degrading activity (DC50 = 5.7 µM, Dmax = 80% at 10 µM). Further studies revealed that HQ-30 induced the degradation of PD-L1 by regulating cathepsin B (CTSB) in the lysosomes. Further, HQ-30 could enhance the infiltration of CD3+ CD4+ helper T and CD3+ CD8+ cytotoxic T cells in tumors, thus activating the tumor immune microenvironment. Moreover, HQ-30 possessed a benign toxicity profile (LD50 > 1000 mg/kg) and favorable pharmacokinetic properties (F = 57%). Taken together, HQ-30 is worthy of further investigation as a small molecule-based epigenetic modulator of tumor immunotherapy.

Metformin synergizes with gilteritinib in treating FLT3-mutated leukemia via targeting PLK1 signaling.

Fms-like tyrosine kinase 3 (FLT3) mutations, present in over 30% of acute myeloid leukemia (AML) cases and dominated by FLT3-internal tandem duplication (FLT3-ITD), are associated with poor outcomes in patients with AML. While tyrosine kinase inhibitors (TKIs; e.g., gilteritinib) are effective, they face challenges such as drug resistance, relapse, and high costs. Here, we report that metformin, a cheap, safe, and widely used anti-diabetic agent, exhibits a striking synergistic effect with gilteritinib in treating FLT3-ITD AML. Metformin significantly sensitizes FLT3-ITD AML cells (including TKI-resistant ones) to gilteritinib. Metformin plus gilteritinib (low dose) dramatically suppresses leukemia progression and prolongs survival in FLT3-ITD AML mouse models. Mechanistically, the combinational treatment cooperatively suppresses polo-like kinase 1 (PLK1) expression and phosphorylation of FLT3/STAT5/ERK/mTOR. Clinical analysis also shows improved survival rates in patients with FLT3-ITD AML taking metformin. Thus, the metformin/gilteritinib combination represents a promising and cost-effective treatment for patients with FLT3-mutated AML, particularly for those with low income/affordability.

Multi-Scale Feature and Multi-Channel Selection toward Parkinson's Disease Diagnosis with EEG.

OBJECTIVE: Motivated by Health Care 4.0, this study aims to reducing the dimensionality of traditional EEG features based on manual extracted features, including statistical features in the time and frequency domains. METHODS: A total of 22 multi-scale features were extracted from the UNM and Iowa datasets using a 4th order Butterworth filter and wavelet packet transform. Based on single-channel validation, 29 channels with the highest R2 scores were selected from a pool of 59 common channels. The proposed channel selection scheme was validated on the UNM dataset and tested on the Iowa dataset to compare its generalizability against models trained without channel selection. RESULTS: The experimental results demonstrate that the proposed model achieves an optimal classification accuracy of 100%. Additionally, the generalization capability of the channel selection method is validated through out-of-sample testing based on the Iowa dataset Conclusions: Using single-channel validation, we proposed a channel selection scheme based on traditional statistical features, resulting in a selection of 29 channels. This scheme significantly reduced the dimensionality of EEG feature vectors related to Parkinson's disease by 50%. Remarkably, this approach demonstrated considerable classification performance on both the UNM and Iowa datasets. For the closed-eye state, the highest classification accuracy achieved was 100%, while for the open-eye state, the highest accuracy reached 93.75%.

Enhancing Emission and Stability in Na-Doped Cs3Cu2I5 Nanocrystals.

Lead-free Cs3Cu2I5 metal halides have garnered significant attention recently due to their non-toxic properties and deep-blue emission. However, their relatively low photoluminescence quantum efficiency and poor stability have limited their applications. In this work, sodium iodide (NaI) is used to facilitate the synthesis of Cs3Cu2I5 nanocrystals (NCs), demonstrating improved photoluminescence intensity, photoluminescence quantum yield, and stability. Systematic optoelectronic characterizations confirm that Na+ is successfully incorporated into the Cs3Cu2I5 lattice without altering its crystal structure. The improved Photoluminescence Quantum Yield (PLQY) and stability are attributed to the strengthened chemical bonding, which effectively suppresses vacancy defects in the lattice. Additionally, light-emitting diodes (LEDs) based on 10% NaI-doped Cs3Cu2I5 NCs were assembled, emitting vibrant blue light with a maximum radiant intensity of 82 lux and Commission Internationale de l'Eclairage (CIE) chromaticity coordinates of (0.15, 0.1). This work opens new possibilities for commercial lighting display applications.