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Inertial sensors are widely used in various applications, such as human motion monitoring and pedestrian positioning. However, inertial sensors cannot accurately define the process of human movement, a limitation that causes data drift in the process of human body positioning, thus seriously affecting positioning accuracy and stability. The traditional pedestrian dead-reckoning algorithm, which is based on a single inertial measurement unit, can suppress the data drift, but fails to accurately calculate the number of walking steps and heading value, thus it cannot meet the application requirements. This study proposes an indoor dynamic positioning method with an error self-correcting function based on the symmetrical characteristics of human motion to obtain the definition basis of human motion process quickly and to solve the abovementioned problems. On the basis of this proposed method, an ultra-wide band (UWB) method is introduced. An unscented Kalman filter is applied to fuse inertial sensors and UWB data, inertial positioning is applied to compensation for the defects of susceptibility to UWB signal obstacles, and UWB positioning is used to overcome the error accumulation of inertial positioning. The above method can improve both the positioning accuracy and the response of the positioning results. Finally, this study designs an indoor positioning test system to test the static and dynamic performances of the proposed indoor positioning method. Results show that the positioning system both has high accuracy and good real-time performance.

Temozolomide (TMZ) was used for the treatment of glioblastoma (GBM) for over a decade, but its treatment benefits are limited by acquired resistance, a process that remains incompletely understood. Here we report that an enhancer, located between the promoters of marker of proliferation Ki67 ( MKI67 ) and O6-methylguanine-DNA-methyltransferase ( MGMT ) genes, is activated in TMZ-resistant patient-derived xenograft (PDX) lines and recurrent tumor samples. Activation of the enhancer correlates with increased MGMT expression, a major known mechanism for TMZ resistance. We show that forced activation of the enhancer in cell lines with low MGMT expression results in elevated MGMT expression. Deletion of this enhancer in cell lines with high MGMT expression leads to a dramatic reduction of MGMT and a lesser extent of Ki67 expression, increased TMZ sensitivity, and impaired proliferation. Together, these studies uncover a mechanism that regulates MGMT expression, confers TMZ resistance, and potentially regulates tumor proliferation. Temozolomide (TMZ) resistance in glioblastomas (GBM) is associated with increased MGMT expression. Here, the authors identify an enhancer between the promoters of MKI67 and MGMT , that when activated drives MGMT expression despite MGMT promoter methylation to confer TMZ resistance in GBM.

Hashizume et al . report a new therapeutic strategy for treating pediatric gliomas with mutations in the H3F3A gene by inhibiting histone demethylation. Pediatric brainstem gliomas often harbor oncogenic K27M mutation of histone H3.3. Here we show that GSKJ4 pharmacologic inhibition of K27 demethylase JMJD3 increases cellular H3K27 methylation in K27M tumor cells and demonstrate potent antitumor activity both in vitro against K27M cells and in vivo against K27M xenografts. Our results demonstrate that increasing H3K27 methylation by inhibiting K27 demethylase is a valid therapeutic strategy for treating K27M-expressing brainstem glioma.

Background Colposcopy is indispensable for the diagnosis of cervical lesions. However, its diagnosis accuracy for high‐grade squamous intraepithelial lesion (HSIL) is at about 50%, and the accuracy is largely dependent on the skill and experience of colposcopists. The advancement in computational power made it possible for the application of artificial intelligence (AI) to clinical problems. Here, we explored the feasibility and accuracy of the application of AI on precancerous and cancerous cervical colposcopic image recognition and classification. Methods The images were collected from 6002 colposcopy examinations of normal control, low‐grade squamous intraepithelial lesion (LSIL), and HSIL. For each patient, the original, Schiller test, and acetic‐acid images were all collected. We built a new neural network classification model based on the hybrid algorithm. EfficientNet‐b0 was used as the backbone network for the image feature extraction, and GRU(Gate Recurrent Unit)was applied for feature fusion of the three modes examinations (original, acetic acid, and Schiller test). Results The connected network classifier achieved an accuracy of 90.61% in distinguishing HSIL from normal and LSIL. Furthermore, the model was applied to “Trichotomy”, which reached an accuracy of 91.18% in distinguishing the HSIL, LSIL and normal control at the same time. Conclusion Our results revealed that as shown by the high accuracy of AI in the classification of colposcopic images, AI exhibited great potential to be an effective tool for the accurate diagnosis of cervical disease and for early therapeutic intervention in cervical precancer. Our connected network classifier distinguished high‐grade squamous intraepithelial lesion (HSIL) from normal and low‐grade squamous intraepithelial lesion (LSIL). And distinguishing the HSIL, LSIL and normal control at the same time.

When a 35 kV distribution network has the problem of insufficient reactive power, the input of a shunt reactor is a common compensation method. Vacuum circuit breakers are widely used in 35 kV distribution networks because of their superior arc extinguishing performance and convenient maintenance. However, in recent years, accidents involving vacuum circuit breakers breaking shunt reactors have occurred more frequently in China, such as high-frequency phase-to-phase short circuits, inter-turn burning losses, bus outlet short circuits, etc., which can cause serious damage and pose a greater threat to the safety of the power system. This paper focuses on the switching overvoltage generated by the vacuum circuit breaker cutting off the shunt reactor. Firstly, the mechanism of overvoltage generation is analyzed theoretically. It is concluded that the equivalent chopping current of the other two phases caused by the continuous reignition of the first open phase is the root cause of the high-amplitude interphase overvoltage. Based on the MODELS custom programming module in EMTP/ATP, according to the process of breaking and reigniting the circuit breaker, this paper uses Fortran language to compile the program and establishes a model of a vacuum circuit breaker, including power frequency current interception, high-frequency current, zero-crossing, breaking, and arc reignition modules. The vacuum circuit breaker is simulated for hundreds of continuous reignitions in milliseconds. Finally, a simulation study on the overvoltage suppression measures of a 35 kV shunt reactor is carried out. The comprehensive comparison of various suppression measures provides a reference for the reasonable selection of actual engineering conditions.

Nucleotide-binding leucine-rich repeat receptors (NLRs) function as core components of innate immunity in both plants and animals. In animals, NLR activation initiates caspase-mediated immune signaling. In contrast, plants lack caspases but instead contain metacaspases (MCAs/MCs), yet their role in antiviral immunity and whether they interface with NLR signaling remain largely unexplored. Here, we demonstrate that cleavage of the conserved immune regulator Bcl-2-associated athanogene 3 (BAG3) by metacaspase 4 (MCAIIa/MC4) induces cell death and activates antiviral immunity in plants. Upon Begomovirus infection, MC4 cleaves BAG3 to release its N-terminal functional domain (BAG3-N) from autoinhibition. BAG3-N assembles into oligomers and induces cell death, effectively inhibiting viral replication. This signaling also interfaces with NLR networks in certain plant species. Viral replication-associated proteins (Reps) counteract this defense response by binding to BAG3-N, highlighting an evolutionary arms race between plants and viruses. Evolutionary analyses reveal that a lysine substitution at position 50 of BAG3 confers its ability to induce cell death in angiosperms. These findings identify BAG3 as a conserved immune regulator linking metacaspase activation to antiviral defense, providing a mechanistic basis for engineering crops with enhanced resistance to insect-borne viruses. This study identifies BAG3 as a conserved immune regulator in plants and demonstrates that its cleavage by metacaspase 4 triggers cell death and antiviral defense, offering a potential strategy for engineering virus-resistant crops.

Background Weight control has consistently been regarded as a significant preventive measure against diabetic nephropathy. however, the potential impact of substantial fluctuations in body fat during this process on the risk of diabetic nephropathy remains uncertain. This study aimed to investigate the association between body fat variation rate and diabetic nephropathy incident in American patients with type 2 diabetes. Methods The study used data from the Action to Control Cardiovascular Risk in diabetes (ACCORD) trial to calculate body fat variation rates over two years and divided participants into Low and High groups. The hazard ratio and 95% confidence interval were estimated using a Cox proportional hazards model, and confounding variables were addressed using propensity score matching. Results Four thousand six hundred nine participants with type 2 diabetes were studied, with 1,511 cases of diabetic nephropathy observed over 5 years. High body fat variation rate was linked to a higher risk of diabetic nephropathy compared to low body fat variation rate (HR 1.13, 95% CI 1.01–1.26). Statistically significant interaction was observed between body fat variation rate and BMI (P interaction = 0.008), and high level of body fat variation rate was only associated with increased risk of diabetic nephropathy in participants with BMI > 30 (HR 1.34 and 95% CI 1.08–1.66). Conclusions Among participants with Type 2 Diabetes Mellitus, body fat variation rate was associated with increased risk of diabetic nephropathy. Furthermore, the association was modified by BMI, and positive association was demonstrated in obese but not non-obese individuals. Consequently, for obese patients with diabetes, a more gradual weight loss strategy is recommended to prevent drastic fluctuations in body fat. Trial registration Clinical Trials. gov, no. NCT000000620 (Registration Date 199909). Graphical Abstract

Methyl jasmonate (MeJA) is a known elicitor of plant specialized metabolism, including triterpenoid saponins. Saponaria vaccaria is an annual herb used in traditional Chinese medicine, containing large quantities of oleanane-type triterpenoid saponins with anticancer properties and structural similarities to the vaccine adjuvant QS-21. Leveraging the MeJA-elicited saponin biosynthesis, we identify multiple enzymes catalyzing the oxidation and glycosylation of triterpenoids in S. vaccaria . This exploration is aided by Pacbio full-length transcriptome sequencing and gene expression analysis. A cellulose synthase-like enzyme can not only glucuronidate triterpenoid aglycones but also alter the product profile of a cytochrome P450 monooxygenase via preference for the aldehyde intermediate. Furthermore, the discovery of a UDP-glucose 4,6-dehydratase and a UDP-4-keto-6-deoxy-glucose reductase reveals the biosynthetic pathway for the rare nucleotide sugar UDP- d -fucose, a likely sugar donor for fucosylation of plant natural products. Our work enables the production and optimization of high-value saponins in microorganisms and plants through synthetic biology approaches. Methyl jasmonate triggers saponin production in Saponaria vaccaria . Using transcriptome data and heterologous expression, the authors identify P450s and glycosyltransferases that modify triterpenoids. They also discover the pathway for UDP-D-fucose biosynthesis.

Nuclear factor-κB (NF-κB) is an important transcription factor that induces the expression of antiviral genes and viral genes. NF-κB activation needs the activation of NF-κB upstream molecules, which include receptors, adaptor proteins, NF-κB (IκB) kinases (IKKs), IκBα, and NF-κB dimer p50/p65. To survive, viruses have evolved the capacity to utilize various strategies that inhibit NF-κB activity, including targeting receptors, adaptor proteins, IKKs, IκBα, and p50/p65. To inhibit NF-κB activation, viruses encode several specific NF-κB inhibitors, including NS3/4, 3C and 3C-like proteases, viral deubiquitinating enzymes (DUBs), phosphodegron-like (PDL) motifs, viral protein phosphatase (PPase)-binding proteins, and small hydrophobic (SH) proteins. Finally, we briefly describe the immune evasion mechanism of human immunodeficiency virus 1 (HIV-1) by inhibiting NF-κB activity in productive and latent infections. This paper reviews a viral mechanism of immune evasion that involves the suppression of NF-κB activation to provide new insights into and references for the control and prevention of viral diseases.

Background The prevalence of vascular calcification (VC) in chronic kidney disease (CKD) patients remains substantial, but currently, there are no effective pharmaceutical therapies available. BRCA1/BRCA2-containing complex subunit 36 (BRCC36) has been implicated in osteoblast osteogenic conversion; however, its specific role in VC remains to be fully elucidated. The aim of this study was to investigate the role and underlying mechanisms of BRCC36 in VC. Methods The association between BRCC36 expression and VC was examined in radial arteries from patients with CKD, high-adenine-induced CKD mice, and vascular smooth muscle cells (VSMCs). Western blotting, real-time polymerase chain reaction, immunofluorescence, and immunohistochemistry were used to analyse gene expression. Gain- and loss-of-function experiments were performed to comprehensively investigate the effects of BRCC36 on VC. Coimmunoprecipitation and TOPFlash luciferase assays were utilized to further investigate the regulatory effects of BRCC36 on the Wnt/β-catenin pathway. Results BRCC36 expression was downregulated in human calcified radial arteries, calcified aortas from CKD mice, and calcified VSMCs. VSMC-specific BRCC36 overexpression alleviated calcium deposition in the vasculature, whereas BRCC36 depletion aggravated VC progression. Furthermore, BRCC36 inhibited the osteogenic differentiation of VSMCs in vitro. Rescue experiments revealed that BRCC36 exerts the protective effects on VC partly by regulating the Wnt/β-catenin signalling pathway. Mechanistically, BRCC36 inhibited the Wnt/β-catenin pathway by decreasing the K63-linked ubiquitination of β-catenin. Additionally, pioglitazone attenuated VC partly through upregulating BRCC36 expression. Conclusions Our research results emphasize the critical role of the BRCC36-β-catenin axis in VC, suggesting that BRCC36 or β-catenin may be promising therapeutic targets to prevent the progression of VC in CKD patients. Graphical Abstract