Phosphoantigens glue butyrophilin 3A1 and 2A1 to activate Vγ9Vδ2 T cells.

In both cancer and infections, diseased cells are presented to human Vγ9Vδ2 T cells through an 'inside out' signalling process whereby structurally diverse phosphoantigen (pAg) molecules are sensed by the intracellular domain of butyrophilin BTN3A11-4. Here we show how-in both humans and alpaca-multiple pAgs function as 'molecular glues' to promote heteromeric association between the intracellular domains of BTN3A1 and the structurally similar butyrophilin BTN2A1. X-ray crystallography studies visualized that engagement of BTN3A1 with pAgs forms a composite interface for direct binding to BTN2A1, with various pAg molecules each positioned at the centre of the interface and gluing the butyrophilins with distinct affinities. Our structural insights guided mutagenesis experiments that led to disruption of the intracellular BTN3A1-BTN2A1 association, abolishing pAg-mediated Vγ9Vδ2 T cell activation. Analyses using structure-based molecular-dynamics simulations, 19F-NMR investigations, chimeric receptor engineering and direct measurement of intercellular binding force revealed how pAg-mediated BTN2A1 association drives BTN3A1 intracellular fluctuations outwards in a thermodynamically favourable manner, thereby enabling BTN3A1 to push off from the BTN2A1 ectodomain to initiate T cell receptor-mediated γδ T cell activation. Practically, we harnessed the molecular-glue model for immunotherapeutics design, demonstrating chemical principles for developing both small-molecule activators and inhibitors of human γδ T cell function.

The triangular relationship between traditional Chinese medicines, intestinal flora, and colorectal cancer.

Over the past decade, colorectal cancer has reported a higher incidence in younger adults and a lower mortality rate. Recently, the influence of the intestinal flora in the initiation, progression, and treatment of colorectal cancer has been extensively studied, as well as their positive therapeutic impact on inflammation and the cancer microenvironment. Historically, traditional Chinese medicine (TCM) has been widely used in the treatment of colorectal cancer via promoted cancer cell apoptosis, inhibited cancer metastasis, and reduced drug resistance and side effects. The present research is more on the effect of either herbal medicine or intestinal flora on colorectal cancer. The interactions between TCM and intestinal flora are bidirectional and the combined impacts of TCM and gut microbiota in the treatment of colon cancer should not be neglected. Therefore, this review discusses the role of intestinal bacteria in the progression and treatment of colorectal cancer by inhibiting carcinogenesis, participating in therapy, and assisting in healing. Then the complex anticolon cancer effects of different kinds of TCM monomers, TCM drug pairs, and traditional Chinese prescriptions embodied in apoptosis, metastasis, immune suppression, and drug resistance are summarized separately. In addition, the interaction between TCM and intestinal flora and the combined effect on cancer treatment were analyzed. This review provides a mechanistic reference for the application of TCM and intestinal flora in the clinical treatment of colorectal cancer and paves the way for the combined development and application of microbiome and TCM.

A Mott-Schottky Heterojunction with Strong Chemisorption and Fast Conversion Effects for Room-Temperature Na-S Batteries.

The practical application of the room-temperature sodium-sulfur (RT Na-S) batteries is currently limited by low reversible capacity and serious capacity decay due to the sluggish reaction kinetics and shuttle effect. It is necessary to design a suitable sulfur host integrated with electrocatalysts to realize effective chemisorption and catalysis of sodium polysulfides (NaPSs). Herein, under the guidance of theoretical calculation, the Mott-Schottky heterojunction with a built-in electric field composed of iron (Fe) and iron disulfide (FeS2) components anchored on a porous carbon matrix (Fe/FeS2-PC) is designed and prepared. The enhanced chemisorption effect of Fe, the fast electrocatalytic effect of FeS2, and the fast transfer effect of the built-in electric field within the Fe/FeS2 heterojunction in the cathode of RT Na-S batteries work together to effectively improve the electrochemical performance. As a result, the Fe/FeS2-PC@S cathode exhibits high reversible capacity (815 mAh g-1 after 150 cycles at 0.2 A g-1) and excellent stability (516 mAh g-1 after 600 cycles at 5 A g-1, with only 0.07% decay per cycle). The design of the Fe/FeS2 heterojunction electrocatalyst provides a new strategy for the development of highly stable RT Na-S batteries.

Modified R-BAC plus BTK inhibitor regimen in newly diagnosed young patients with mantle cell lymphoma: a real-world retrospective study.

To explore the optimal treatment for young patients with untreated mantle cell lymphoma (MCL), we compared the efficacy and safety of R-CHOP/R-DHAP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone/rituximab, dexamethasone, cytarabine and cisplatin) and R-BAP (rituximab, bendamustine, cytarabine, and prednisone) plus BTK (Bruton's tyrosine kinase) inhibitors in newly diagnosed patients. Eighty-three young patients (≤ 65 years old) with newly diagnosed MCL admitted to the First Affiliated Hospital of Zhengzhou University from January 1, 2014, to June 1, 2023, using R-CHOP/R-DHAP or R-BAP plus BTK inhibitor were assessed in this study. The median age at presentation was 60 (42-65) years in 83 patients, including 64 males and 19 females; 59 were treated with R-CHOP/R-DHAP regimen chemotherapy, and 24 were treated with R-BAP in combination with the BTK inhibitor regimen. The median follow-up was 17 months (2-86 months) in 83 patients, and the median PFS (progression-free survival) time was not reached. The CRR (complete response rate) of the R-BAP group was higher than that of the R-CHOP/R-DHAP group (87.5% vs. 54.2%, P = 0.005). The ORR (overall response rate) was not significantly different between the two groups (ORR: 91.7% vs. 84.7%, P = 0.497). The PFS (progression-free survival) of the R-BAP group was longer than that of the R-CHOP/R-DHAP group (P = 0.013), whereas OS was not significantly different between the two groups (P = 0.499). The most common adverse effect in both groups was hematotoxicity, with a higher incidence of grade 3-4 lymphopenia and grade 3-4 thrombocytopenia in the R-BAP group than in the R-CHOP/R-DHAP group (P = 0.015 and P = 0.039). Male sex (HR = 4.257, P = 0.013), LDH (lactate dehydrogenase) ≥ 245 U/L (HR = 3.221, P = 0.012), pleomorphic-blastoid (HR = 2.802, P = 0.043) and R-CHOP/R-DHAP regimen (HR = 7.704, P = 0.047) were independent risk factors for PFS. Ki67 ≥ 30% (HR = 8.539, P = 0.005) was an independent risk factor for OS. First-line treatment with R-BAP in combination with BTK inhibitor improved CRR and prolonged PFS in young patients with mantle cell lymphoma and adverse events were tolerable.

Identification of degradation products of brivaracetam using liquid chromatography quadrupole time-of-flight tandem mass spectrometry: Degradation pathway elucidation.

RATIONALE: Pyrrolidone-based drugs find widespread use in treating conditions such as epilepsy and Alzheimer's disease, and in various other medical applications. Brivaracetam, the latest generation of pyrrolidone drugs, has exhibited significant promise owing to chemical structure modifications. Its affinity to the SV2A receptor is double that of the previous-generation drug, levetiracetam. Consequently, brivaracetam holds substantial potential for diverse applications. As a novel drug not yet included in the pharmacopeias of developed nations, comprehensive analysis and research are necessary to guarantee its safe utilization in clinical settings. METHODS: A liquid chromatography quadrupole time-of-flight tandem mass spectrometry (LC/QTOFMS) method has been developed to effectively separate, identify and characterize both the degradation products and process-related substances of brivaracetam. Stress testing of the sample was carried out following the guidelines outlined in ICH Q1A(R2). The structures of these impurities were identified through positive electrospray ionization QTOF high-resolution MS and NMR spectroscopy. Additionally, the formation mechanism of each degradation product is thoroughly discussed. RESULTS: Under the analytical conditions outlined in this paper, brivaracetam and its degradation products were effectively separated. Thirteen degradation products were detected and characterized, shedding light on their origins and degradation pathways. Among these, three degradation products align with previously reported impurities, and two unreported degradation products were synthesized and confirmed through NMR spectroscopy. The stress testing results revealed the instability of brivaracetam under acidic, alkaline, oxidative and thermal stress conditions, while it exhibited relative stability under photolytic stress conditions. CONCLUSION: The study developed an analytical method for brivaracetam that enabled the effective detection and separation of brivaracetam and its 13 degradation products. This method addresses a gap in both current domestic and foreign drug standards. The structures of all the major degradation products were characterized by high-resolution LC/QTOFMS, which is essential for quality control during the drug production process, stability evaluation and the establishment of proper storage conditions.

The inhibitory impact of Schisandrin on inflammation and oxidative stress alleviates LPS-induced acute kidney injury.

Inflammation and oxidative stress (OS) are the major pathogenic characteristics of acute kidney injury (AKI). Studies have shown that Schisandrin (Sch) could regulate inflammatory disease. However, the function and mechanism of Sch in AKI progression are still unknown. Here, we investigated Sch's potential effects and mechanism on mice's renal damage and macrophages induced by lipopolysaccharide (LPS). Sch decreased LPS-induced inflammatory factor production while increasing the activity of related antioxidant enzymes in macrophages and mouse kidney tissues. Hematoxylin and eosin staining revealed that Sch may have the ability to profoundly inhibit inflammatory cell invasion and tissue damage caused by LPS in renal tissue. Furthermore, Western blot and immunohistochemical studies showed that Sch exerted its effects mainly through up-regulation of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 and inhibition of Toll-like receptor 4‒mitogen-activated protein kinases/nuclear factor-kappa B pathways. Collectively, this study illustrates that Sch suppresses LPS-stimulated AKI by descending inflammation and OS, illuminating prospective AKI treatment options.

An Enhanced Indoor Three-Dimensional Localization System with Sensor Fusion Based on Ultra-Wideband Ranging and Dual Barometer Altimetry.

Accurate three-dimensional (3D) localization within indoor environments is crucial for enhancing item-based application services, yet current systems often struggle with localization accuracy and height estimation. This study introduces an advanced 3D localization system that integrates updated ultra-wideband (UWB) sensors and dual barometric pressure (BMP) sensors. Utilizing three fixed UWB anchors, the system employs geometric modeling and Kalman filtering for precise tag 3D spatial localization. Building on our previous research on indoor height measurement with dual BMP sensors, the proposed system demonstrates significant improvements in data processing speed and stability. Our enhancements include a new geometric localization model and an optimized Kalman filtering algorithm, which are validated by a high-precision motion capture system. The results show that the localization error is significantly reduced, with height accuracy of approximately ±0.05 m, and the Root Mean Square Error (RMSE) of the 3D localization system reaches 0.0740 m. The system offers expanded locatable space and faster data output rates, delivering reliable performance that supports advanced applications requiring detailed 3D indoor localization.

A Planar Multi-Inertial Navigation Strategy for Autonomous Systems for Signal-Variable Environments.

The challenge of precise dynamic positioning for mobile robots is addressed through the development of a multi-inertial navigation system (M-INSs). The inherent cumulative sensor errors prevalent in traditional single inertial navigation systems (INSs) under dynamic conditions are mitigated by a novel algorithm, integrating multiple INS units in a predefined planar configuration, utilizing fixed distances between the units as invariant constraints. An extended Kalman filter (EKF) is employed to significantly enhance the positioning accuracy. Dynamic experimental validation of the proposed 3INS EKF algorithm reveals a marked improvement over individual INS units, with the positioning errors reduced and stability increased, resulting in an average accuracy enhancement rate exceeding 60%. This advancement is particularly critical for mobile robot applications that demand high precision, such as autonomous driving and disaster search and rescue. The findings from this study not only demonstrate the potential of M-INSs to improve dynamic positioning accuracy but also to provide a new research direction for future advancements in robotic navigation systems.

Duvelisib attenuates bleomycin-induced pulmonary fibrosis via inhibiting the PI3K/Akt/mTOR signalling pathway.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that seriously threatens the health of patients. The pathogenesis of IPF is still unclear, and there is a lack of effective therapeutic drugs. Myofibroblasts are the main effector cells of IPF, leading to excessive deposition of extracellular matrix (ECM) and promoting the progression of fibrosis. Inhibiting the excessive activation and relieving autophagy blockage of myofibroblasts is the key to treat IPF. PI3K/Akt/mTOR pathway plays a key regulatory role in promoting fibroblast activation and autophagy inhibition in lung fibrosis. Duvelisib is a PI3K inhibitor that can simultaneously inhibit the activities of PI3K-δ and PI3K-γ, and is mainly used for the treatment of relapsed/refractory chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma tumour (SLL). In this study, we aimed to examine the effects of Duvelisib on pulmonary fibrosis. We used a mouse model of bleomycin-induced pulmonary fibrosis to evaluate the effects of Duvelisib on pulmonary fibrosis in vivo and further explored the potential pharmacological mechanisms of Duvelisib in lung fibroblasts in vitro. The in vivo experiments showed that Duvelisib significantly alleviated bleomycin-induced collagen deposition and improved pulmonary function. In vitro and in vivo pharmacological experiments showed that Duvelisib dose-dependently suppressed lung fibroblast activation and improved autophagy inhibition by inhibiting the phosphorylation of PI3K, Akt and mTOR. Our results indicate that Duvelisib can alleviate the severity of pulmonary fibrosis and provide potential drugs for the treatment of pulmonary fibrosis.

Origin, evolution and diversification of plant ARGONAUTE proteins.

Argonaute (AGO) proteins are central players in RNA interference in eukaryotes. They associate with small RNAs (sRNA) and lead to transcriptional or posttranscriptional silencing of targets, thereby regulating diverse biological processes. The molecular and biological functions of AGO proteins have been extensively characterized, particularly in a few angiosperm species, leading to the recognition that the AGO family has expanded to accommodate diverse sRNAs thereby performing diverse biological functions. However, understanding of the expansion of AGO proteins in plants is still limited, due to a dearth of knowledge of AGO proteins in green algal groups. Here, we identified more than 2900 AGO proteins from 244 plant species, including green algae, and performed a large-scale phylogenetic analysis. The phylogeny shows that the plant AGO family gave rise to four clades after the emergence of hydrobiontic algae and prior to the emergence of land plants. Subsequent parallel expansion in ferns and angiosperms resulted in eight main clades in angiosperms: AGO2, AGO7, AGO6, AGO4, AGO1, AGO10a, AGO10b and AGO5. On the basis of this phylogeny, we identified two novel AGO4 orthologs that Arabidopsis does not have, and redefined AGO10, which is composed of AGO10a and AGO10b. Finally, we propose a hypothetical evolutionary model of AGO proteins in plants. Our studies provide a deeper understanding of the phylogenetic relationships of AGO family members in the green lineage, which would help to further reveal their roles as RNAi effectors.

Berberine ameliorates depression-like behaviors in mice via inhibiting NLRP3 inflammasome-mediated neuroinflammation and preventing neuroplasticity disruption.

OBJECTIVES: Neuroinflammation has been suggested that affects the processing of depression. There is renewed interest in berberine owing to its anti-inflammatory effects. Herein, we investigated whether berberine attenuate depressive-like behaviors via inhibiting NLRP3 inflammasome activation in mice model of depression. METHODS: Adult male C57BL/6N mice were administrated corticosterone (CORT, 20 mg/kg/day) for 35 days. Two doses (100 mg/kg/day and 200 mg/kg/day) of berberine were orally administrated from day 7 until day 35. Behavioral tests were performed to measure the depression-like behaviors alterations. Differentially expressed gene analysis was performed for RNA-sequencing data in the prefrontal cortex. NLRP3 inflammasome was measured by quantitative reverse transcription polymerase chain reaction, western blotting, and immunofluorescence labeling. The neuroplasticity and synaptic function were measured by immunofluorescence labeling, Golgi-Cox staining, transmission electron microscope, and whole-cell patch-clamp recordings. RESULTS: The results of behavioral tests demonstrated that berberine attenuated the depression-like behaviors induced by CORT. RNA-sequencing identified that NLRP3 was markedly upregulated after long-term CORT exposure. Berberine reversed the concentrations of peripheral and brain cytokines, NLRP3 inflammasome elicited by CORT in the prefrontal cortex and hippocampus were decreased by berberine. In addition, the lower frequency of neuronal excitation as well as the dendritic spine reduction were reversed by berberine treatment. Together, berberine increases hippocampal adult neurogenesis and synaptic plasticity induced by CORT. CONCLUSION: The anti-depressants effects of berberine were accompanied by reduced the neuroinflammatory response via inhibiting the activation of NLRP3 inflammasome and rescued the neuronal deterioration via suppression of impairments in synaptic plasticity and neurogenesis.

Efficient Regulation of Polysulfides by MoS2 /MoO3 Heterostructures for High-Performance Li-S Batteries.

The notorious shuttle effect and sluggish conversion of polysulfides seriously hinder the practical application of Lithium-sulfur (Li-S) batteries. In this study, a novel architecture of MoS2 /MoO3 heterostructure uniformly distributed on carbon nanotubes (MoS2 /MoO3 @CNT) is designed and introduced into Li-S batteries via decorating commercial separator to regulate the redox reactions of polysulfides. Systematic experiments and theoretical calculations showed that the heterostructure not only provides sufficient surface affinity to capture polysulfides and acts as an active catalyst to promote the conversion of polysulfides, but also the highly conductive CNT enables rapid electron/ion migration. As a result, Li-S batteries with the MoS2 /MoO3 @CNT-PP separator deliver an impressive reversible capacity (1015 mAh g-1 at 0.2 A g-1 after 100 cycles), excellent rate capacity (873 mAh g-1 at 5 A g-1 ), and low self-discharge capacity loss (94.6% capacity retention after 7 days of standing). Moreover, even at an elevated temperature of 70 °C, it still exhibits high-capacity retention (800 mAh g-1 at 1 A g-1 after 100 cycles). Encouragingly, when the sulfur load is increased to 8.7 mg cm-2 , the high reversible areal capacity of 6.61 mAh cm-2 can be stably maintained after 100 cycles, indicating a high potential for practical application.

Emerging advances in engineered macrophages for tumor immunotherapy.

Macrophages are versatile antigen-presenting cells. Recent studies suggest that engineered modifications of macrophages may confer better tumor therapy. Genetic engineering of macrophages with specific chimeric antigen receptors offers new possibilities for treatment of solid tumors and has received significant attention. In vitro gene editing of macrophages and infusion into the body can inhibit the immunosuppressive effect of the tumor microenvironment in solid tumors. This strategy is flexible and can be applied to all stages of cancer treatment. In contrast, nongenetic engineering tools are used to block relevant signaling pathways in immunosuppressive responses. In addition, macrophages can be loaded with drugs and engineered into cellular drug delivery systems. Here, we analyze the effect of the chimeric antigen receptor platform on macrophages and other existing engineering modifications of macrophages, highlighting their status, challenges and future perspectives. Indeed, our analyses show that new approaches in the treatment of solid tumors will likely exploit macrophages, an innate immune cell.

Prediction of coronary heart disease based on combined reinforcement multitask progressive time-series networks.

Coronary heart disease is the first killer of human health. At present, the most widely used approach of coronary heart disease diagnosis is coronary angiography, a surgery that could potentially cause some physical damage to the patients, together with some complications and adverse reactions. Furthermore, coronary angiography is expensive thus cannot be widely used in under development country. On the other hand, the heart color Doppler echocardiography report, blood biochemical indicators and personal information, such as gender, age and diabetes, can reflect the degree of heart damage in patients to some extent. This paper proposes a combined reinforcement multitask progressive time-series networks (CRMPTN) model to predict the grade of coronary heart disease through heart color Doppler echocardiography report, blood biochemical indicators and ten basic body information items about the patients. In this model, the first step is to perform deep reinforcement learning (DRL) pre-training through asynchronous advantage actor-critic (A3C). Training data is adopted to optimize the recurrent neural network (RNN) that parameterizes the stochastic policy. In the second step, soft parameter sharing module, hard parameter sharing module and progressive time-series networks are used to predict the status of coronary heart disease. The experimental results show that after DRL pre-training, the multiple tasks in the model interact with each other and learn together to achieve satisfactory results and outperform other state-of-the-art methods.

Identification of novel lncRNA prognostic biomarkers and their associated ceRNAs in bladder urothelial carcinoma.

Bladder urothelial carcinoma (BUCA) is a common malignant tumor with a high rate of metastasis and recurrence. The lack of specific and sensitive biomarkers for the prognostic assessment makes it important to seek alternatives. Recent studies have demonstrated that long noncoding RNAs (lncRNAs) function as competitive endogenous RNAs (ceRNAs) and play an important role in BUCA prognosis. Therefore, this study aimed to establish a prognosis-related lncRNAs-microRNAs (miRNAs)-messenger RNA (mRNA) (pceRNA) network and identify novel prognostic biomarkers. Integrated weighted coexpression analysis, functional clustering, and ceRNA network were used for the prognostic assessment of BUCA. The transcriptome sequencing datasets of lncRNA, miRNA, and mRNA from The Cancer Genome Atlas database were used for the identification of key lncRNAs and construction of the lncRNAs expression signature for prognostic prediction of BUCA patients. Then, 14 differentially expressed lncRNAs (DE-lncRNAs) were identified as candidate prognostic RNAs based on the ceRNAs network and functional clustering. In the Cox regression analysis, two (AC008676.1 and ADAMTS9-AS1) of all DE-lncRNAs were significantly associated with overall survival (OS) of BUCA patients. This two DE-lncRNA signature was significantly correlated with OS and was an independent prognostic factor, which was confirmed in an independent dataset of GSE216037. Moreover, we constructed the pceRNA network that includes 2 DE-lncRNAs, 9 DE-miRNAs, and 10 DE-mRNAs. Pathway enrichment analysis showed that AC008676.1 and ADAMTS9-AS1 are involved in several cancer-related pathways such as proteoglycans in cancer and TGF-beta signaling pathway. The novel-identified DE-lncRNA prognostic signature and the pceRNA network in this study will be valuable risk predictors and diagnostic markers for BUCA.

Evaluation and control of Alternaria alternata causing leaf spot in soybean in Northeast China.

AIM: The aims of this study were to characterize the causal agent of soybean leaf spot and determine the pathogenicity of the pathogen to the main crops in Northeast China and detect the sensitivity of pathogens to the main chemical fungicides and the potted control effect. METHODS AND RESULTS: In 2020 and 2021, an uncommon leaf spot was observed in Harbin, Heilongjiang Province (125°42'-130°10'E, 44°04'-46°40'N), China. The pathogen can infect soybean leaves and cause leaf spot. We collected diseased soybean leaves and isolated four pathogen organisms, all of which were identified as Alternaria alternata through morphological and molecular identification. Koch's postulates were used to confirm pathogenicity. To the best of our knowledge, this is the first report on soybean leaf spot disease caused by A. alternata in northeast China. Moreover, A. alternata had a broad host range and caused leaf spot in most legumes. However, it did not infect medicated lentil (Dolicho Lablab L.) or tobacco (Nicotiana tabacum L.). Assessment of A. alternaria susceptibility to fungicides by spore germination method, isolates of A. alternata were most sensitive to flusilazole, with EC50 values of 0.0040-0.0053 µg ml-1. Through two pot experiments, the average control efficacy of 0.1 mg ml-1 flusilazole on soybean leaf spot caused by A. alternata was 80.7%. CONCLUSIONS: The work reported that A. alternata is the pathogen organism that causes soybean leaf spot in northern China. The pathogen organism can infect a variety of leguminous plants. Considering the control cost and effect, flusilazole is more suitable for controlling leaf spot disease in the field, and benzoxystrobin can be used as an alternative fungicide.

Differentiation Between Internal Carotid Artery Hypoplasia and Acquired Narrowing by Neurovascular Ultrasound: Case Series and Literature Review.

Uniformly narrowed internal carotid artery (ICA) without proximal steno-occlusion or parietal anomalies is often subject to misdiagnosis due to lack of awareness. We combined our experiences of 4 cases with 29 previously published cases to form a retrospective series including 18 cases of ICA hypoplasia and 15 cases of ICA acquired narrowing. The ultrasonic manifestations of ICA acquired narrowing and ICA hypoplasia are extremely similar, but narrowed ICA without intracranial occlusion or bottle-neck-sign highly indicates ICA hypoplasia, whereas moyamoya vessels favor ICA acquired narrowing, thus promoting the understanding of and discriminability between the two on neurovascular ultrasound.

Cryo-EM structure of C9ORF72-SMCR8-WDR41 reveals the role as a GAP for Rab8a and Rab11a.

A massive intronic hexanucleotide repeat (GGGGCC) expansion in C9ORF72 is a genetic origin of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recently, C9ORF72, together with SMCR8 and WDR41, has been shown to regulate autophagy and function as Rab GEF. However, the precise function of C9ORF72 remains unclear. Here, we report the cryogenic electron microscopy (cryo-EM) structure of the human C9ORF72-SMCR8-WDR41 complex at a resolution of 3.2 Å. The structure reveals the dimeric assembly of a heterotrimer of C9ORF72-SMCR8-WDR41. Notably, the C-terminal tail of C9ORF72 and the DENN domain of SMCR8 play critical roles in the dimerization of the two protomers of the C9ORF72-SMCR8-WDR41 complex. In the protomer, C9ORF72 and WDR41 are joined by SMCR8 without direct interaction. WDR41 binds to the DENN domain of SMCR8 by the C-terminal helix. Interestingly, the prominent structural feature of C9ORF72-SMCR8 resembles that of the FLNC-FNIP2 complex, the GTPase activating protein (GAP) of RagC/D. Structural comparison and sequence alignment revealed that Arg147 of SMCR8 is conserved and corresponds to the arginine finger of FLCN, and biochemical analysis indicated that the Arg147 of SMCR8 is critical to the stimulatory effect of the C9ORF72-SMCR8 complex on Rab8a and Rab11a. Our study not only illustrates the basis of C9ORF72-SMCR8-WDR41 complex assembly but also reveals the GAP activity of the C9ORF72-SMCR8 complex.

Identification of Pathogens and Evaluation of Resistance and Genetic Diversity of Maize Inbred Lines to Stalk Rot in Heilongjiang Province, China.

Maize stalk rot, caused by multiple pathogens, is a serious soilborne disease worldwide. Composition of pathogens causing maize stalk rot and resistance of maize inbred lines in Heilongjiang Province, China, are not well understood. In this study, 138 fungal isolates were collected from different maize-producing areas in Heilongjiang Province, which were identified as Fusarium graminearum (23.2%), F. subglutinans (18.9%), F. cerealis (18.9%), Bipolaris zeicola (13.0%), F. brachygibbosum (13.0%), F. temperatum (7.2%), and F. proliferatum (5.8%). Among them, F. graminearum (>20%) was the predominant species among the isolates causing maize stalk rot. B. zeicola had not previously been reported causing maize stalk rot in China. Resistance of 67 maize inbred lines to maize stalk rot was assessed, and 24 lines (35.8% of them) were highly resistant or resistant, indicating that approximately 65% of these lines were susceptible to maize stalk rot. Maize inbred lines were analyzed using simple sequence repeat markers and divided into five genetic groups with 12 pairs of primers. Additionally, analysis of molecular variance indicated that 44.2% of the genetic variation in disease resistance was distributed among populations. This study provides insight into the genetic diversity of inbred maize and may contribute useful information for breeding stalk rot disease-resistant hybrids, and facilitates development of effective strategies for managing this destructive disease complex.

Tool Wear State Identification Based on SVM Optimized by the Improved Northern Goshawk Optimization.

Tool wear condition significantly influences equipment downtime and machining precision, necessitating the exploration of a more accurate tool wear state identification technique. In this paper, the wavelet packet thresholding denoising method is used to process the acquired multi-source signals and extract several signal features. The set of features most relevant to the tool wear state is screened out by the support vector machine recursive feature elimination (SVM-RFE). Utilizing these selected features, we propose a tool wear state identification model, which utilizes an improved northern goshawk optimization (INGO) algorithm to optimize the support vector machine (SVM), hereby referred to as INGO-SVM. The simulation tests reveal that INGO demonstrates superior convergence efficacy and stability. Furthermore, a milling wear experiment confirms that this approach outperforms five other methods in terms of recognition accuracy, achieving a remarkable accuracy rate of 97.9%.