Jingqianshu granules mitigates premenstrual depression by regulating orexin signaling.

Introduction: Premenstrual dysphoric disorder (PMDD), a severe form of premenstrual syndrome (PMS), is a serious health disorder that affects patient moods. It is caused by cyclic psychological symptoms and its pathogenesis is still unclear. Abnormalities in the basolateral amygdala (BLA) orexin system, which are important causes of the development of depressive mood, have not been reported in PMDD, so exploring its intrinsic mechanisms is meaningful for enriching the pathomechanisms of PMDD. Methods: High performance liquid chromatography was used for the determination of the active ingredients of Jingqianshu granules. Developing a rat model of premenstrual depression using the forced swimming test (FST). The experiment consisted of two parts. In Part 1, the rats were divided into the control group, the model group, the model + Jingqianshu group, and the model + fluoxetine group. The FST, open field test, and elevated plus maze test, were used to assess the behavior of the rats as well as to evaluate the effect of drug intervention. Immunofluorescence and RT-qPCR were used to detect the expression of orexin and its receptors OX1R and OX2R genes and proteins. The expression of Toll-like receptor 4, nuclear factor kappa-B, tumor necrosis factor-α, interleukin 6, and interleukin-1ß in the BLA brain region was detected by Western-Blot. In part 2, the rats were injected intracerebrally with orexin-A. Observe the behavioral activities of rats in the control group, model group, and model+orexin-A group. Immunofluorescence was used to detect microglia in the BLA area of rats, and the expression levels of the above inflammatory factors were detected by Western-Blot. Results: The five components of Jingqianshu granules are: paeoniflorin, erulic acid, liquiritin, hesperidin, and paeonol. During the estrous cycle, rats exhibited depressive-like behavior during the non-receptive phase of the behavioral test, which disappeared during the receptive phase. Immunofluorescence and RT-qPCR showed reduced gene and protein expression of orexin, OX1R, and OX2R in the BLA region of rats in the model group.WB showed elevated levels of inflammatory factors. All returned to control levels after drug treatment. In part 2, injection of orexin-A into the BLA brain region of model rats resulted in reduced immunoreactivity of microglia and decreased expression levels of inflammatory factors. Discussion: Jianqianshu granules can achieve the purpose of treating premenstrual depression by regulating orexin-mediated inflammatory factors, which provides a new idea for further research on the pathogenesis of PMDD. However, the current study is still preliminary and the pathogenesis of PMDD is complex. Therefore, more in-depth exploration is needed.

Engineering Plateau Phase Transition in Quantum Anomalous Hall Multilayers.

The plateau phase transition in quantum anomalous Hall (QAH) insulators corresponds to a quantum state wherein a single magnetic domain gives way to multiple domains and then reconverges back to a single magnetic domain. The layer structure of the sample provides an external knob for adjusting the Chern number C of the QAH insulators. Here, we employ molecular beam epitaxy to grow magnetic topological insulator multilayers and realize the magnetic field-driven plateau phase transition between two QAH states with odd Chern number change ΔC. We find that critical exponents extracted for the plateau phase transitions with ΔC = 1 and ΔC = 3 in QAH insulators are nearly identical. We construct a four-layer Chalker-Coddington network model to understand the consistent critical exponents for the plateau phase transitions with ΔC = 1 and ΔC = 3. This work will motivate further investigations into the critical behaviors of plateau phase transitions with different ΔC in QAH insulators.

Development of a Quorum Sensing-Mediated Bacterial Autolytic System in Escherichia coli for Automatic Release of Intracellular Products.

Escherichia coli, one of the most efficient expression hosts for recombinant proteins, is widely used in chemical, medical, food, and other industries. De novo engineering of gene regulation circuits and cell density-controlled E. coli cell lysis are promising directions for the release of intracellular bioproducts. Here, we developed an E. coli autolytic system, named the quorum sensing-mediated bacterial autolytic (QS-BA) system, by incorporating an acyl-homoserine lactone (AHL)-based YasI/YasR-type quorum sensing circuit from Pseudoalteromonas into E. coli cells. The results showed that the E. coli QS-BA system can release the intracellular bioproducts into the cell culture medium in terms of E. coli cell density, which offers an environmentally-friendly, economical, efficient, and flexible E. coli lysis platform for production of recombinant proteins. The QS-BA system has the potential to serve as an integrated system for the large-scale production of target products in E. coli for medical and industrial applications.

Exposure to zinc and dialkyldimethyl ammonium compound alters bacterial community structure and resistance gene levels in partial sulfur autotrophic denitrification coupled with the Anammox process.

Dialkyldimethyl ammonium compound (DADMAC) is widely used in daily life as a typical disinfectant and often co-exists with the heavy metal zinc in sewage environments. This study investigated the effects of co-exposure to zinc (1 mg/L) and DADMAC (0.2-5 mg/L) on the performance, bacterial community, and resistance genes (RGs) in a partial sulfur autotrophic denitrification coupled with anaerobic ammonium oxidation (PSAD-Anammox) system in a sequencing batch moving bed biofilm reactor for 150 days. Co-exposure to zinc and low concentration (0.2 mg/L) DADMAC did not affect the nitrogen removal ability of the PASD-Anammox system, but increased the abundance and transmission risk of free RGs in water. Co-exposure to zinc and medium-to-high (2-5 mg/L) DADMAC led to fluctuations in and inhibition of nitrogen removal, which might be related to the enrichment of heterotrophic denitrifying bacteria dominated by Denitratisoma. Co-exposure to zinc and high concentration DADMAC (5 mg/L) stimulated the secretion of extracellular polymeric substances and increased the proliferation risk of intracellular RGs in sludge. This study provided insights into the application of PSAD-Anammox system and the ecological risks of wastewater containing zinc and DADMAC.

Vasculopathy Augments Cardiovascular Risk in Community-Dwelling Elderly with Left Ventricular Hypertrophy.

This study aimed to investigate the impact of various vasculopathies alongside left ventricular hypertrophy (LVH) on cardiovascular risk in the elderly. This prospective cohort study included 3339 older adults from the Northern Shanghai Study, classified into four mutually exclusive left ventricular (LV) geometry groups based on echocardiographic data: normal geometry, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. Vasculopathy was categorized into three primary types: arteriosclerosis, atherosclerosis, and renal senescence. Major adverse cardiovascular events (MACEs) were defined as non-fatal acute myocardial infarction, non-fatal stroke, and cardiovascular deaths according to ICD-10 codes. Over a median follow-up period of 5.7 years, 221 incident cases of MACEs were identified. Concentric hypertrophy exhibited the highest prevalence of hypertension, the most significant increase in vascular stiffness, and the highest rate of MACEs. The adjusted Cox regression analysis showed that eccentric hypertrophy is associated with an increased risk of MACEs (HR: 1.638 [95% CI: 1.151-2.331], p = 0.006), while concentric hypertrophy shows an even higher risk (HR: 1.751 [95% CI: 1.127-2.721], p = 0.013). Conversely, concentric remodeling was not significantly associated with an increased risk of MACEs. Renal senescence presents a moderate but significant risk for MACEs, with an HR of 1.361 (95% CI: 1.019-1.819; p = 0.037) when adjusted for LVH. The Kaplan-Meier analysis showed that patients with LVH and multiple vasculopathies experience the most significant decrease in survival probability (log-rank p < 0.001). The subgroup analysis revealed that LVH significantly raises the risk of MACEs, especially in older males with hypertension, diabetes, or vasculopathy. This study reinforces the importance of LVH as a predictor of adverse cardiovascular outcomes and underscores the compounded risk associated with the presence of multiple vasculopathies. Additionally, it highlights renal senescence as a distinct and independent risk factor for MACEs, separate from LVH.

Coexistence of Superconductivity and Antiferromagnetism in Topological Magnet MnBi2Te4 Films.

The interface of two materials can harbor unexpected emergent phenomena. One example is interface-induced superconductivity. In this work, we employ molecular beam epitaxy to grow a series of heterostructures formed by stacking together two nonsuperconducting antiferromagnetic materials, an intrinsic antiferromagnetic topological insulator MnBi2Te4 and an antiferromagnetic iron chalcogenide FeTe. Our electrical transport measurements reveal interface-induced superconductivity in these heterostructures. By performing scanning tunneling microscopy and spectroscopy measurements, we observe a proximity-induced superconducting gap on the top surface of the MnBi2Te4 layer, confirming the coexistence of superconductivity and antiferromagnetism in the MnBi2Te4 layer. Our findings will advance the fundamental inquiries into the topological superconducting phase in hybrid devices and provide a promising platform for the exploration of chiral Majorana physics in MnBi2Te4-based heterostructures.

Mussel-inspired immunomodulatory and osteoinductive dual-functional hydroxyapatite nanoplatform for promoting bone regeneration.

Simultaneously modulating the inflammatory microenvironment and promoting local bone regeneration is one of the main challenges in treating bone defects. In recent years, osteoimmunology has revealed that the immune system plays an essential regulatory role in bone regeneration and that macrophages are critical components. In this work, a mussel-inspired immunomodulatory and osteoinductive dual-functional hydroxyapatite nano platform (Gold/hydroxyapatite nanocomposites functionalized with polydopamine - PDA@Au-HA) is developed to accelerate bone tissues regeneration by regulating the immune microenvironment. PDA coating endows nanomaterials with the ability to scavenge reactive oxygen species (ROS) and anti-inflammatory properties, and it also exhibits an immunomodulatory ability to inhibit M1 macrophage polarization and activate M2 macrophage secretion of osteogenesis-related cytokines. Most importantly, this nano platform promotes the polarization of M2 macrophages and regulates the crosstalk between macrophages and pre-osteoblast cells to achieve bone regeneration. Au-HA can synergistically promote vascularized bone regeneration through sustained release of Ca and P particles and gold nanoparticles (NPs). This nano platform has a synergistic effect of good compatibility, scavenging of ROS, and anti-inflammatory and immunomodulatory capability to accelerate the bone repair process. Thus, our research offers a possible therapeutic approach by exploring PDA@Au-HA nanocomposites as a bifunctional platform for tissue regeneration.

The Effect of Antibacterial-Osteogenic Surface Modification on the Osseointegration of Titanium Implants: A Static and Dynamic Strategy.

Titanium (Ti) and its alloys are widely used biomaterials in bone repair. Although these biomaterials possess stable properties and good biocompatibility, the high elastic modulus and low surface activity of Ti implants have often been associated with infection, inflammation, and poor osteogenesis. Therefore, there is an urgent need to modify the surface of Ti implants, where changes in surface morphology or coatings loading can confer specific functions to help them adapt to the osseointegration formation phase and resist bacterial infection. This can further ensure a healthy microenvironment for bone regeneration as well as the promotion of immunomodulation, angiogenesis, and osteogenesis. Therefore, in this review, we evaluated various functional Ti implants after surface modification, both in terms of static modifications and dynamic response strategies, mainly focusing on the synergistic effects of antimicrobial activities and functionalized osteogenic. Finally, the current challenges and future perspectives are summarized to provide innovative and effective solutions for osseointegration and bone defect repair.

Phenacetin promoted the rapid start-up and stable maintenance of partial nitrification: Responses of nitrifiers and antibiotic resistance genes.

Phenacetin (PNCT) belongs to one of the earliest synthetic antipyretics. However, impact of PNCT on nitrifying microorganisms in wastewater treatment plants and its potential microbial mechanism was still unclear. In this study, PN could be initiated within six days by PNCT anaerobic soaking treatment (8 mg/L). In order to improve the stable performance of PN, 21 times of PNCT aerobic soaking treatment every three days was conducted and PN was stabilized for 191 days. After PN was damaged, ten times of PNCT aerobic soaking treatment every three days was conducted and PN was recovered after once soaking, maintained over 88 days. Ammonia oxidizing bacteria might change the dominant oligotype to gradually adjust to PNCT, and the increase of abundance and activity of Nitrosomonas promoted the initiation of PN. For nitrite-oxidizing bacteria (NOB), the increase of Candidatus Nitrotoga and Nitrospira destroyed PN, but PN could be recovered after once aerobic soaking illustrating NOB was not resistant to PNCT. KEGG and COG analysis suggested PNCT might disrupt rTCA cycle of Nitrospira, resulting in the decrease of relative abundance of Nitrospira. Moreover, PNCT did not lead to the sharp increase of absolute abundances of antibiotic resistance genes (ARGs), and the risk of ARGs transmission was negligible.

Immune checkpoint inhibitors combined with paclitaxel-based chemotherapy versus chemotherapy alone as first-line treatment in HER2-negative advanced gastric cancer: result of a multicenter retrospective study.

Background: Platinum-based chemotherapy combined with immune checkpoint inhibitors (ICIs) is now becoming the standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer (AGC). In China, paclitaxel has shown good efficacy and tolerability in AGC as an alternative for first-line therapy. Combining ICIs with paclitaxel-based chemotherapy may lead to improved tumor immune microenvironment, but evidence in paclitaxel combing with ICIs as first-line regimen is lacking. This multicenter, retrospective research aims to compare effectiveness and tolerability of paclitaxel-based chemotherapy combined with ICIs versus chemotherapy alone as a first-line treatment of HER2-negative AGC in a real-world setting. Methods: Eighty-six patients with HER2-negative AGC were included from 2017 to 2022. Among them, 57 patients received paclitaxel-based chemotherapy plus ICIs, and 29 patients received paclitaxel-based chemotherapy alone. We compared the efficacy and incidence of adverse events between the two therapy options. Results: Significant improvements in median progression-free survival (PFS) (8.77 versus 7.47 months; P=0.04) and median overall survival (OS) (15.70 versus 14.33 months; P=0.04) were observed in the ICIs combined with paclitaxel-based chemotherapy group. The use of ICIs also significantly prolonged the duration of response (DOR) (7.47 versus 4.59 months; P=0.02). Meanwhile, the ICIs plus chemotherapy group demonstrated significantly improved objective response rate (ORR) (50.9% vs. 27.6%; P=0.03) and disease control rate (DCR) (98.3% vs. 82.8%; P=0.01), and the side effects were tolerable. Conclusions: In summary, for HER2-negative AGC, ICIs plus paclitaxel-based chemotherapy is effective with mild toxicities, which should be considered as an alternative first-line therapy regimen.

Sensitivity Decouple Learning for Image Compression Artifacts Reduction.

With the benefit of deep learning techniques, recent researches have made significant progress in image compression artifacts reduction. Despite their improved performances, prevailing methods only focus on learning a mapping from the compressed image to the original one but ignore the intrinsic attributes of the given compressed images, which greatly harms the performance of downstream parsing tasks. Different from these methods, we propose to decouple the intrinsic attributes into two complementary features for artifacts reduction, i.e., the compression-insensitive features to regularize the high-level semantic representations during training and the compression-sensitive features to be aware of the compression degree. To achieve this, we first employ adversarial training to regularize the compressed and original encoded features for retaining high-level semantics, and we then develop the compression quality-aware feature encoder for compression-sensitive features. Based on these dual complementary features, we propose a Dual Awareness Guidance Network (DAGN) to utilize these awareness features as transformation guidance during the decoding phase. In our proposed DAGN, we develop a cross-feature fusion module to maintain the consistency of compression-insensitive features by fusing compression-insensitive features into the artifacts reduction baseline. Our method achieves an average 2.06 dB PSNR gains on BSD500, outperforming state-of-the-art methods, and only requires 29.7 ms to process one image on BSD500. Besides, the experimental results on LIVE1 and LIU4K also demonstrate the efficiency, effectiveness, and superiority of the proposed method in terms of quantitative metrics, visual quality, and downstream machine vision tasks.

Achievement of a Parameter Window for the Selective Laser Melting Formation of a GH3625 Alloy.

In the selective laser melting (SLM) process, adjusting process parameters contributes to achieving the desired molten pool morphology, thereby enhancing the mechanical properties and dimensional accuracy of manufactured components. The parameter window characterizing the relationship between molten pool morphology and process parameters serves as an effective tool to improve SLM's forming quality. This work established a mesoscale model of the SLM process for a GH3625 alloy based on the discrete element method (DEM) and computational fluid dynamics (CFD) to simulate the forming process of a single molten track. Subsequently, the formation mechanism and evolution process of the molten pool were revealed. The effects of laser power and scanning speed on the molten pool size and molten track morphology were analyzed. Finally, a parameter window was established from the simulation results. The results indicated that reducing the scanning speed and increasing the laser power would lead to an increase in molten pool depth and width, resulting in the formation of an uneven width in the molten track. Moreover, accelerating the scanning speed and decreasing the laser power cause a reduction in molten pool depth and width, causing narrow and discontinuous molten tracks. The accuracy of the simulation was validated by comparing experimental and simulated molten pool sizes.

An injectable dental pulp-derived decellularized matrix hydrogel promotes dentin repair through modulation of macrophage response.

Maintaining the viability of damaged pulp is critical in clinical dentistry. Pulp capping, by placing dental material over the exposed pulp, is a main approach to promote pulp-dentin healing and mineralized tissue formation. The dental materials are desired to impact on intricate physiological mechanisms in the healing process, including early regulation of inflammation, immunity, and cellular events. In this study, we developed an injectable dental pulp-derived decellularized matrix (DPM) hydrogel to modulate macrophage responses and promote dentin repair. The DPM derived from porcine dental pulp has high collagen retention and low DNA content. The DPM was solubilized by pepsin digestion (named p-DPM) and subsequently injected through a 25G needle to form hydrogel facilely at 37 °C. In vitro results demonstrated that the p-DPM induced the M2-polarization of macrophages and the migration, proliferation, and dentin differentiation of human dental pulp stem cells from deciduous teeth (SHEDs). In a mouse subcutaneous injection test, the p-DPM hydrogel was found to facilitate cell recruitment and M2 polarization during the early phase of implantation. Additionally, the acute pulp restoration in rat models proved that injectable p-DPM hydrogel as a pulp-capping agent had excellent efficacy in dentin regeneration. This study demonstrates that the DPM promotes dentin repair by modulating macrophage responses, and has a potential for pulp-capping applications in dental practice.

A Janus, robust, biodegradable bacterial cellulose/Ti3C2Tx MXene bilayer membranes for guided bone regeneration.

Guided bone regeneration (GBR) stands as an essential modality for craniomaxillofacial bone defect repair, yet challenges like mechanical weakness, inappropriate degradability, limited bioactivity, and intricate manufacturing of GBR membranes hindered the clinical efficacy. Herein, we developed a Janus bacterial cellulose(BC)/MXene membrane through a facile vacuum filtration and etching strategy. This Janus membrane displayed an asymmetric bilayer structure with interfacial compatibility, where the dense layer impeded cell invasion and the porous layer maintained stable space for osteogenesis. Incorporating BC with Ti3C2Tx MXene significantly enhanced the mechanical robustness and flexibility of the material, enabling clinical operability and lasting GBR membrane supports. It also contributed to a suitable biodegradation rate, which aligned with the long-term bone repair period. After demonstrating the desirable biocompatibility, barrier role, and osteogenic capability in vitro, the membrane's regenerative potential was also confirmed in a rat cranial defect model. The excellent bone repair performance could be attributed to the osteogenic capability of MXene nanosheets, the morphological cues of the porous layer, as well as the long-lasting, stable regeneration space provided by the GBR membrane. Thus, our work presented a facile, robust, long-lasting, and biodegradable BC/MXene GBR membrane, offering a practical solution to craniomaxillofacial bone defect repair.

Ecosystem-based management approaches for watershed conservation and geosustainability.

When contributors' goals and legislative and political structures vary, as they often do in the case of worldwide fish populations, it becomes more challenging to implement ethical fishing tactics. Canada, the United States, and Mexico all fish from Pacific regions anchovies in the California Modern. Climate-driven numbers and geographic dynamics may pollute the waters of collaborative aquaculture and lead to overloading. This research expands upon prior works using a game theoretic model of Tran's boundary sardine fisheries in different climatic conditions to account for ecological links. More significant economic advantages accrue from cooperation fishing tactics that consider the mackerel's role as feed for other species in the natural system, as opposed to plans that merely take note of the worth of mackerel harvests to a particular fishing nation. The maximum environmental benefit is obtained at a fishery rate for sardines barely less than the sardine Fishery Management Safe Yield. Ecological-based control of fisheries can increase sustainability and profits, but only if investors and policy makers consider the ecology in business-applicable models. Understanding and adapting to the fast alterations in habitat distributions due to climate change and designing ways to achieve viable and lucrative fishery amidst altering environments will necessitate an increased emphasis on ecosystem-based governance.

Separative and Comprehensive Effects of Grain Coarsening and Grain Refinement of Ni-38Cr-3.8Al Alloy during Thermal Deformation Process.

During thermal deformation, grain coarsening due to grain growth and grain refinement resulting from dynamic recrystallization (DRX) collectively influence the deformed grain size. To investigate the separative and comprehensive effects of the two mechanisms in the Ni-38Cr-3.8Al alloy, grain growth experiments and isothermal compression tests were conducted. Kinetics models for grain growth and DRX behaviors were established based on the experimental data, which were integrated with finite element (FE) techniques to simulate the evolution of grain size throughout the entire thermal compression process. The effects of grain coarsening and grain refinement during this process were separated and quantified based on the simulation data. The results revealed that grain coarsening predominated during the heating and holding stages, with a longer holding time and higher holding temperatures intensifying this effect. However, during the compression stage, grain coarsening and grain refinement co-existed, and their competition was influenced by deformation parameters. Specifically, grain refinement dominated at strain rates exceeding 0.1 s-1, while grain coarsening dominated at lower strain rates (<0.1 s-1) and higher deformation temperatures (>1373 K). The simulated grain sizes closely matched the experimental observations.

High-resolution detection of copy number alterations in single cells with HiScanner.

Improvements in single-cell whole-genome sequencing (scWGS) assays have enabled detailed characterization of somatic copy number alterations (CNAs) at the single-cell level. Yet, current computational methods are mostly designed for detecting chromosome-scale changes in cancer samples with low sequencing coverage. Here, we introduce HiScanner (High-resolution Single-Cell Allelic copy Number callER), which combines read depth, B-allele frequency, and haplotype phasing to identify CNAs with high resolution. In simulated data, HiScanner consistently outperforms state-of-the-art methods across various CNA types and sizes. When applied to high-coverage scWGS data from human brain cells, HiScanner shows a superior ability to detect smaller CNAs, uncovering distinct CNA patterns between neurons and oligodendrocytes. For 179 cells we sequenced from longitudinal meningioma samples, integration of CNAs with point mutations revealed evolutionary trajectories of tumor cells. These findings show that HiScanner enables accurate characterization of frequency, clonality, and distribution of CNAs at the single-cell level in both non-neoplastic and neoplastic cells.

The combination of ciprofloxacin and dialkyldimethyl ammonium compound synergistically proliferated intracellular resistance genes in nitrifying system.

Antibiotics and quaternary ammonium compounds (QACs) usually co-exist in wastewater treatment plants. Hence, three sequencing batch reactors were established and named as R1, R2 and R3, to investigate the effects of individual and combined exposure of different concentrations of ciprofloxacin (CIP) (0.2, 1.0 and 2.0 mg/L) and dialkyldimethyl ammonium compound (DADMAC) (0.4, 2.0 and 4.0 mg/L) on the performance, microbial community structures and resistance genes (RGs) in nitrifying system during 150 days. Results showed that CIP had a slight effect on ammonia oxidation activity, while 2.0 and 4.0 mg/L DADAMAC could obviously inhibit it, and the combination of CIP and DADMAC had a synergistic inhibitory effect. Besides, both CIP and DADMAC caused partial nitrification, and the order of nitrite accumulation rate was ranked as R3 > R2 > R1. The combination of CIP and DADMAC had an antagonistic effect on the increase of sludge particle size and α-Helix/(ß-Sheet + Random coil) was lowest in R3 (0.40). The combination of CIP and DADMAC synergistically stimulated most intracellular RGs in sludge, and the relative abundances of target RGs (e.g., qacEdelta1-01, qacH-01 and qnrS) at the end of operation in R3 were increased by 4.61-18.19 folds compared with those in CK, which were 1.34-5.57 folds higher than the R1 and R2. Moreover, the combination of CIP and DADMAC also promoted the transfer of RGs from sludge to water and enriched more potential hosts of RGs, further promoting the spread of RGs in nitrifying system. Thus, the combined pollution of CIP and DADMAC in wastewaters should attract more attentions.

Discovery of a Novel Orally Bioavailable FLT3-PROTAC Degrader for Efficient Treatment of Acute Myeloid Leukemia and Overcoming Resistance of FLT3 Inhibitors.

Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis-targeting chimeras (PROTACs) represent a promising approach to eliminate the resistance of FLT3 inhibitors. However, due to the poor druggability of PROTACs, the development of orally bioavailable FLT3-PROTACs faces great challenges. Herein, a novel orally bioavailable FLT3-ITD degrader A20 with excellent pharmacokinetic properties was discovered through reasonable design. A20 selectively inhibited the proliferation of FLT3-ITD mutant acute myeloid leukemia (AML) cells and potently induced FLT3-ITD degradation through the ubiquitin-proteasome system. Notably, oral administration of A20 resulted in complete tumor regression on subcutaneous AML xenograft models. Furthermore, on systemic AML xenograft models, A20 could completely eliminate the CD45+CD33+ human leukemic cells in murine and significantly prolonged the survival time of mice. Most importantly, A20 exerted significantly improved antiproliferative activity against drug-resistant AML cells compared to existing FLT3 inhibitors. These findings suggested that A20 could serve as a promising drug candidate for relapsed or refractory AML.

Spectral intelligent detection for aflatoxin B1 via contrastive learning based on Siamese network.

Aflatoxins, harmful substances found in peanuts, corn, and their derivatives, pose significant health risks. Addressing this, the presented research introduces an innovative MSGhostDNN model, merging contrastive learning with multi-scale convolutional networks for precise aflatoxin detection. The method significantly enhances feature discrimination, achieving an impressive 97.87% detection accuracy with a pre-trained model. By applying Grad-CAM, it further refines the model to identify key wavelengths, particularly 416 nm, and focuses on 40 key wavelengths for optimal performance with 97.46% accuracy. The study also incorporates a task dimensionality reduction approach for continuous learning, allowing effective ongoing aflatoxin spectrum monitoring in peanuts and corn. This approach not only boosts aflatoxin detection efficiency but also sets a precedent for rapid online detection of similar toxins, offering a promising solution to mitigate the health risks associated with aflatoxin exposure.