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Abstract Objective Alzheimer’s disease (AD) is a type of neurological illness that significantly impacts individuals’ daily lives. In the intelligent diagnosis of AD, 3D networks require larger computational resources and storage space for training the models, leading to increased model complexity and training time. On the other hand, 2D slices analysis may overlook the 3D structural information of MRI and can result in information loss. Approach We propose a multi-slice attention fusion and multi-view personalized fusion lightweight network for automated AD diagnosis. It incorporates a multi-branch lightweight backbone to extract features from sagittal, axial, and coronal view of MRI, respectively. In addition, we introduce a novel multi-slice attention fusion module, which utilizes a combination of global and local channel attention mechanism to ensure consistent classification across multiple slices. Additionally, a multi-view personalized fusion module is tailored to assign appropriate weights to the three views, taking into account the varying significance of each view in achieving accurate classification results. To enhance the performance of the multi-view personalized fusion module, we utilize a label consistency loss to guide the model’s learning process. This encourages the acquisition of more consistent and stable representations across all three views. Main results The suggested strategy is efficient in lowering the number of parameters and FLOPs, with only 3.75M and 4.45G respectively, and accuracy improved by 10.5% to 14% in three tasks. Moreover, in the classification tasks of AD vs. CN, AD vs. MCI and MCI vs. CN, the accuracy of the proposed method is 95.63%, 86.88% and 85.00%, respectively, which is superior to the existing methods. Conclusions The results show that the proposed approach not only excels in resource utilization, but also significantly outperforms the four comparison methods in terms of accuracy and sensitivity, particularly in detecting early-stage AD lesions. It can precisely capture and accurately identify subtle brain lesions, providing crucial technical support for early intervention and treatment.

With the development of the Internet, the number of electronic texts has increased rapidly. Automatic grammar error correction technology is an effective safeguard measure for the quality of electronic texts. To improve the quality of electronic text, this study introduces a moving window algorithm and linear interpolation smoothing algorithm to build a Cn-gram language model. On this basis, a syntactic analysis strategy is introduced to construct a syntactic error correction model integrating Cn-gram and syntactic analysis, and English grammar intelligent error correction is carried out through the model. The results show that compared with the Bi-gram and Tri-gram, the precision of the Cn-gram model is 0.85 and 0.91% higher, and the F1 value is 0.97 and 1.14% higher, respectively. Compared with the results of test set Long, the Cn-gram model has better performance on verb error correction of the Short test set, and the precision rate, recall rate, and F1 value are increased by 0.86, 3.94, and 1.87%, respectively. The comparison of the precision, recall rate, and F1 value of the proposed grammar error correction model on the complete test set shows that the precision of the study is 19.10 and 5.41% higher for subject–verb agreement errors. The recall rate is 9.55 and 10.77% higher, respectively; F1 values are higher by 12.65 and 10.59%, respectively. The above results show that the error-correcting technique of the research design has excellent error-correcting performance. It is hoped that this experiment can provide a reference for the relevant research of automatic error correction technology of electronic text.

Abstract Chordin-like 1 (CHRDL1) is a secreted protein that serves as an endogenous antagonist of bone morphogenetic proteins (BMPs). In the developing retina, Bmp4 has been demonstrated to be essential for sustaining the proliferation of progenitor cells and facilitating the differentiation of glial cells. Despite these efforts, the precise effects of Bmp4 inhibition on the developing retina are yet to be fully understood. We sought to address this question by overexpressing Chrdl1 in the developing retina. In this study, we explored the impact of Bmp4 inhibition on the developing mouse retina by conditionally overexpressing the Bmp4 inhibitor Chrdl1. Initially, we characterized the expression patterns of Bmp4 and Chrdl1 in the developing mouse retina from E10.5 to P12.5. Additionally, we utilized various molecular markers to demonstrate that Bmp4 inhibition disrupts both neuronal and Müller glial differentiation in the developing mouse retina. Moreover, through the application of RNA-seq analysis, distinctively expressed retinal genes under the modulation of Bmp4 signaling were discerned, encompassing the upregulation of Id1/2/3/4 and Hes1/5, as well as the downregulation of Neurod1/2/4 and Bhlhe22/23. Lastly, electroretinogram (ERG) and optomotor response (OMR) assays were conducted to illustrate that Bmp4 inhibition impairs the functional connectivity of various cells in the retina and consequently affects visual function. Collectively, this study demonstrates that inhibiting Bmp4 promotes the differentiation of retinal neurons over Müller glia by activating the expression of genes associated with neuron specification. These findings offer molecular insights into the role of Bmp4 signaling in mammalian retinal development.

Lactic acid bacteria play a dual role by enhancing both the flavor and nutritional benefits of fermented foods, and helping the body to prevent a variety of diseases caused by oxidation. The fulfillment of these beneficial functions is inseparable from the antioxidant activity of lactic acid bacteria. This article elaborates on the antioxidant mechanism of lactic acid bacteria including regulating antioxidant enzymes, regulating signaling pathways, scavenging free radicals, and inhibiting lipid peroxidation and metal ion chelation. The current status of the application of the antioxidant activity of lactic acid bacteria in dairy, meat, aquatic, and fruit and vegetable products is also reviewed. Finally, this article outlines the in vitro and in vivo evaluation methods for the antioxidant activity of lactic acid bacteria, aiming to provide a reference for deepening the application of lactic acid bacteria in the food processing sector.

Black garlic is produced through the fermentation of fresh garlic under conditions of high temperature and humidity, wherein various chemical reactions occur, gradually diminishing the pungent odor associated with garlic and imparting the distinctive sweet and sour flavor characteristic of black garlic. This article reviews the changes in chemical components and flavor substances during the processing of black garlic, discusses the key factors that influence the evolution of its aroma profile, and analyzes the flavor characteristics of black garlic.

Objective To focus on the efficacy at variable frequency stimulation (VFS) after deep brain stimulation (DBS) for the treatment of axial symptoms in Parkinson's disease (PD). Methods Clinical data of 12 patients with PD who underwent bilateral DBS followed by VFS more than one year from January 2018 to June 2022 at Tianjin Huanhu Hospital, Tianjin University were retrospectively analyzed. Axial symptoms were assessed using Unified Parkinson's Disease Rating Scale (UPDRS)-gait posture, Timed Up and Go Test (TUGT) time and the occurrence of freezing of gait (FOG), The Freezing of Gait - Questionnaire (FOG - Q), and Berg Balance Scale (BBS). The above indicators were recorded one week before DBS surgery and in the drug "off" period (baseline), at the end of high frequency stimulation (the end of HFS), at one month follow-up of VFS (short-term VFS), and at one year or more follow-up of VFS (long-term VFS). Results Compared with baseline, BBS scores increased at the end of HFS (t = - 2.845, P = 0.008); UPDRS-gait posture (t = 12.703, P = 0.000; t = 11.737, P = 0.000), TUGT time (t = 8.923, P = 0.000; t = 8.025, P = 0.000) and the occurrence of FOG (t = 4.448, P = 0.000; t = 4.181, P = 0.000), and FOGQ scores (t = 9.186, P = 0.000; t = 8.186, P = 0.000) decreased, while the BBS scores increased (t = - 7.686, P = 0.000; t = - 6.106, P = 0.000) in both short-term VFS and long-term VFS. Compared with the end of HFS, UPDRS-gait posture (t = 11.583, P = 0.000; t = 10.618, P = 0.000), TUGT time (t = 6.922, P = 0.000; t = 6.022, P = 0.000) and the occurrence of FOG (t = 3.612, P = 0.001; t = 3.344, P = 0.002), and FOG-Q scores (t = 7.915, P = 0.000; t = 6.915, P = 0.000) decreased, while the BBS scores increased (t = - 4.842, P = 0.000; t = - 3.262, P = 0.003) in short-term VFS and long-term VFS. Conclusions For PD patients with HFS but poor axial symptoms efficacy after DBS, the use of VFS significantly improves multifaceted axial symptoms with reliable long-term efficacy.

The genesis and prediction of high-porosity and low-permeability sandstone reservoirs are hot spots in oil and gas geology research worldwide. High-porosity and low-permeability sandstone reservoirs are developed in the Cretaceous Bashkirchik Formation of the Luntai Uplift in the northern Tarim Basin, China. In this article, we conducted a systematic study on the geological origin and logging identification of high-porosity and low-permeability tight sandstone based on core observation, thin section, logging index response, and mathematical discrimination methods. The results show that the K1bs sandstone segment in the study area generally contains calcium carbonate, which mainly comes from carbonate rock debris and calcite cement. Calcite cement mainly fills the pores between primary particles, and it is the main factor leading to the densification of the reservoir. The geological origin of the formation of low-permeability layer is mainly due to the early cementation of carbonate, and the development mode of the low-permeability layer is “high content of calcium debris → severe calcium cementation → poor petrophysical properties → formation of low-permeability layer.” The low-permeability layer has the characteristics of high gamma and high resistivity, and the multi-parameter discriminant method established based on the Fisher criterion has a good identification effect for the low-permeability layer. The low-permeability layer has a small thickness, poor stability and continuity, and strong longitudinal heterogeneity, thus it can form a low-permeability baffle inside the reservoir, which greatly reduces the oil and gas migration capacity.

Abstract Remote sensing image object detection is widely used in civil and military fields. The important task is to detect objects such as ships, planes, airports, harbours and so on, and then it can obtain object category and position information. It is of great significance to use remote sensing images to observe the densely arranged and directional targets such as cars and ships parked in parking lots and harbours. The object detection task mainly includes object localization and classification. Remote sensing images contain large number of small objects and dense scenes due to the long shooting distance and wide coverage. Small objects occupy few pixels in the image, and they are easily miss‐detected. In dense scenes, the overlapping part of each object is large, so it is easy to detect objects repeatedly. The traditional small object detection methods deliver low accuracy and take long time. Therefore, object detection is very challenging. We put forward a novel deep learning‐based single shot multibox detector (SSD) model for object detection. First, we propose an improved inception network to optimize SSD to strengthen the small object feature extraction ability (FEA) in the shallow network. Second, the feature pyramid network is modified to enhance the fusion effect. Third, the deep feature fusion module is designed to improve the FEA of the deep network. Finally, the extracted image features are matched with candidate boxes with different aspect ratios to perform object detection and location with different scales. Experiments on DOTA show that the proposed algorithm can adapt to the remote sensing object detection in different backgrounds, and effectively improve the detection effect of remote sensing objects in complex scenes.

With the improvement of irrigation and transportation infrastructures, single tobacco cultivation has been converted into tobacco–vegetable double cultivation in Yunnan Province. High residual nitrogen (N) levels in soil before tobacco transplanting induced by the excessive N input during the vegetable cultivation season resulted in a reduction of economic income and the quality of flue-cured tobacco. Therefore, the objective of this paper is to describe the optimization of N management and to provide a better understanding of the mechanism of optimal N application rate on the economic benefit and quality of tobacco. A field experiment with six N application rates (0, 45, 60, 75, 90, and 105 kg N ha−1) was carried out with a randomized block design in 2021 and 2022 in Yunnan Province. The economic value and yield, intrinsic chemical and processing quality, leaf growth rate and agronomic characters were determined.

Abstract Tetraparvovirus is an emerging parvovirus infecting a variety of mammals and humans, and associated with human diseases including severe acute respiratory infection and acute encephalitis syndrome. In the present study, a Tetraparvovirus ungulate 1 (formerly known as bovine hokovirus) strain HNU-CBY-2023 was identified and characterized from diseased Chinese Simmental from Hunan province, China. The nearly complete genome of HNU-CBY-2023 is 5346 nt in size and showed genomic identities of 85-95.5% to the known Tetraparvovirus ungulate 1 strains from GenBank, indicating a rather genetic variation. Phylogenetic and genetic divergence analyses indicated that Tetraparvovirus ungulate 1 could be divided into two genotypes (I and II), and HNU-CBY-2023 was clustered into genotype II. This study, for the first time, identified Tetraparvovirus ungulate 1 from domestic cattle from mainland China, which will be helpful to understand the prevalence and genetic diversity of Tetraparvovirus ungulate 1.

Microphthalmia, mostly an autosomal dominant disorder, is a worldwide severe congenital ocular malformation that causes visual impairment. Our investigation unveiled a total of 30 genes associated with microphthalmia. Employing the CytoHubba and PPI network, we identified Bmp4 as the most pivotal hub gene. Subsequently, the conditional overexpression of Bmp4 in the retina caused highly distinctive microphthalmia, manifested by retinal disorganization with ganglion cell misalignment. Significant reduction in the number and abnormal distribution location of retinal cells in microphthalmia model mice. Elevated Bmp4 was associated with an increase in retinal apoptosis and a decrease in proliferating cells, which exacerbates the development of microphthalmia. Here we identify Bmp4 as an extremely important gene responsible for microphthalmia and the involved mechanisms. Overexpression of Bmp4 induces retinal cell ectopic expression and developmental defects, highlighting the importance of a well-balanced Bmp4 level in shaping the embryonic retina during early development.

BackgroundSepsis is an inflammatory disease that leads to severe mortality, highlighting the urgent need to identify new therapeutic strategies for sepsis. Proteomic research serves as a primary source for drug target identification. We employed proteome-wide Mendelian randomization (MR), genetic correlation analysis, and colocalization analysis to identify potential targets for sepsis and sepsis-related death.MethodsGenetic data for plasma proteomics were obtained from 35,559 Icelandic individuals and an initial MR analysis was conducted using 13,531 sepsis cases from the FinnGen R10 cohort to identify associations between plasma proteins and sepsis. Subsequently, significant proteins underwent genetic correlation analysis, followed by replication in 54,306 participants from the UK Biobank Pharma Proteomics Project and validation in 11,643 sepsis cases from the UK Biobank. The identified proteins were then subjected to colocalization analysis, enrichment analysis, and protein-protein interaction network analysis. Additionally, we also investigated a MR analysis using plasma proteins on 1,896 sepsis cases with 28-day mortality from the UK Biobank.ResultsAfter FDR correction, MR analysis results showed a significant causal relationship between 113 plasma proteins and sepsis. Genetic correlation analysis revealed that only 8 proteins had genetic correlations with sepsis. In the UKB-PPP replication analysis, only 4 proteins were found to be closely associated with sepsis, while validation in the UK Biobank sepsis cases found overlaps for 21 proteins. In total, 30 proteins were identified in the aforementioned analyses, and colocalization analysis revealed that only 2 of these proteins were closely associated with sepsis. Additionally, in the 28-day mortality MR analysis of sepsis, we also found that only 2 proteins were significant.ConclusionsThe identified plasma proteins and their associated metabolic pathways have enhanced our understanding of the complex relationship between proteins and sepsis. This provides new avenues for the development of drug targets and paves the way for further research in this field.

ObjectiveTo explore the relationship between the exposure level of particulate matter 2.5 (PM2.5) and particulate matter 10 (PM10) in the air of pregnant women during preconception and first trimester of pregnancy and the risk of gestational diabetes mellitus (GDM).MethodsThe data of pregnant women delivered in 22 monitoring hospitals in Hebei Province from 2019 to 2021 were collected, and the daily air quality data of their cities were used to calculate the exposure levels of PM2.5 and PM10 in different pregnancy stages, and logistic regression model was used to analyze the impact of exposure levels of PM2.5 and PM10 on GDM during preconception and first trimester of pregnancy.Results108,429 singleton live deliveries were included in the study, of which 12,967 (12.0%) women had a GDM diagnosis. The prevalence of GDM increased over the course of the study from 10.2% (2019) to 14.9% (2021). From 2019 to 2021, the average exposure of PM2.5 and PM10 was relatively 56.67 and 103.08μg/m3 during the period of preconception and first trimester of pregnancy in Hebei Province. Handan, Shijiazhuang, and Xingtai regions had the most severe exposure to PM2.5 and PM10, while Zhangjiakou, Chengde, and Qinhuangdao had significantly lower exposure levels than other regions. The GDM group had statistically higher exposure concentrations of PM2.5 and PM10 during the period of preconception, first trimester, preconception and first trimester (P

Objective: Screening of polyvinyl alcohol-fish gelatin-solanum nigrum anthocyanin （PVA/FG-SNA） composite packaging film with optimal structure and properties. Methods: Optimizing the fabrication process of films through orthogonal tests, and using thickness, moisture content, water vapor permeability （WVP）, tensile strength （TS）, elongation at break （EB）, Fourier infrared spectroscopy （FTIR）, X-diffraction （XRD）, scanning electron microscopy （SEM）, and thermogravimetric （TG） analysis to explore the effects of SNAs with different mass fractions on the properties and microstructures of PVA-FG film; In addition, the pH color response and NH3 sensitivity of the PVA/FG-SNA composite film were monitored. Results: When the mass ratio of PVA-to-FG, heating temperature and time were 60∶40, 95 ℃, and 1.5 h, respectively. The water solubility and WVP of the PVA-FG film were （36.03±2.63）%, and 2.91×10-4 g·mm/（m2·h·Pa）, separately. With the increment of SNA dosage, the thickness, moisture content, WVP, and EB of the PVA-FG film also increased. When the mass fraction of SNA was 0.2%, the thickness, moisture content, WVP, TS, and EB of the composite film were （0.07±0.01） mm, （11.09±0.25）%, 5.45×10-4 g·mm/（m2·h·Pa）, （21.12±1.07） MPa, and （373.77±8.59）%, respectively. At the same time the composite film had good compatibility among its components. In addition, the PVA/FG-0.2% SNA film showed good color response under NH3 atmosphere conditions, which could be used as a pH-indicating film. Conclusion: This article optimized the water resistance of the PVA-FG composite base film. The hydrophobic and mechanical properties of the PVA-FG composite base film are negatively correlated with the amount of SNA dosage, and SNA can significantly enhance the pH and NH3 sensitivity of the film.

As one of the most widely used plasticizers, BPA is often used in various types of food packaging. However, the leaching of BPA from food and water and the emission of BPA in the manufacturing process can harm human health. In recent years, carbon-based composites have shown excellent performance in the detection of BPA due to their unique physical and chemical properties. The rapid detection of BPA by electrochemical sensors based on carbon-based composites has become a research hotspot. This article provides an overview of BPA and the application of carbon-based materials modified electrochemical sensors in the detection of BPA, as well as prospects for the development direction of electrochemical detection of BPA.

Acinetobacter baumannii is a non-fermentative Gram-negative bacterium that can cause nosocomial infections in critically ill patients. Carbapenem-resistant A. baumannii (CRAB) has spread rapidly in clinical settings and has become a key concern. The main objective of this study was to identify the distribution of integrons and biofilm-formation-related virulence genes in CRAB isolates. A total of 269 A. baumannii isolates (219 isolates of CRAB and 50 isolates of carbapenem-sensitive A. baumannii (CSAB)) were collected. Carbapenemase genes (blaKPC, blaVIM, blaIMP, blaNDM, and blaOXA-23-like) and biofilm-formation-related virulence genes (abal, bfms, bap, and cusE) were screened with PCR. Class 1 integron was screened with PCR, and common promoters and gene cassette arrays were determined with restriction pattern analysis combined with primer walking sequencing. Whole-genome sequencing was conducted, and data were analyzed for a blaOXA-23-like-negative isolate. All 219 CRAB isolates were negative for blaKPC, blaVIM, blaIMP, and blaNDM, while blaOXA-23-like was detected in 218 isolates. The detection rates for abal, bfms, bap, and cusE in 219 CRAB were 93.15%, 63.93%, 88.13%, and 77.63%, respectively. Class 1 integron was detected in 75 CRAB (34.25%) and in 3 CSAB. The single gene cassette array aacA4-catB8-aadA1 with relatively strong PcH2 promoter was detected in class 1 integrons. The blaOXA-23-like-negative CRAB isolate was revealed to be a new sequence type (Oxford 3272, Pasteur 2520) carrying blaOXA-72, blaOXA-259, and blaADC-26. In conclusion, blaOXA-23-like was the main reason for CRAB’s resistance to carbapenems. A new (Oxford 3272, Pasteur 2520) CRAB sequence type carrying the blaOXA-72, blaOXA-259, and blaADC-26 was reported.

Abstract Here we presented an electrophysiological dataset collected from layer V of the primary motor cortex (M1) and the corresponding behavior dataset from normal and hemi-parkinson rats over 5 consecutive weeks. The electrophysiological dataset was constituted by the raw wideband signal, neuronal spikes, and local field potential (LFP) signal. The open-field test was done and recorded to evaluate the behavior variation of rats among the entire experimental cycle. We conducted technical validation of this dataset through sorting the spike data to form action potential waveforms and analyzing the spectral power of LFP data, then based on these findings a closed-loop DBS protocol was developed by the oscillation activity response of M1 LFP signal. Additionally, this protocol was applied to the hemi-parkinson rat for five consecutive days while simultaneously recording the electrophysiological data. This dataset is currently the only publicly available dataset that includes longitudinal closed-loop DBS recordings, which can be utilized to investigate variations of neuronal activity within the M1 following long-term closed-loop DBS, and explore additional reliable biomarkers.

To systematically investigate the factors affecting the performance of permeable concrete on road surfaces, blocks with different porosity, particle sizes, water-to-cement ratios, and cement-to-aggregate ratios were prepared. Additionally, varying amounts of admixtures were added to some blocks to explore the influence of the admixture types and content on the performance of permeable concrete. The results indicate that the larger the particle size of the aggregate used in the block preparation, the higher the permeability coefficient of the blocks and the lower the compressive strength. The water-to-cement ratio affects the strength of the cement matrix, resulting in variations in the block strength. A higher cement-to-aggregate ratio leads to a lower porosity in the permeable concrete, a higher cement matrix content, a reduced permeability coefficient, and an increased compressive strength of the blocks.

Abstract The endothelial glycocalyx, located at the luminal surface of the endothelium, plays an important role in the regulation of leukocyte adhesion, vascular permeability, and vascular homeostasis. Endomucin (EMCN), a component of the endothelial glycocalyx, is a mucin-like transmembrane glycoprotein selectively expressed by venous and capillary endothelium. We have previously shown that knockdown of EMCN impairs retinal vascular development in vivo and vascular endothelial growth factor 165 isoform (VEGF165)-induced cell migration, proliferation, and tube formation by human retinal endothelial cells in vitro and that EMCN is essential for VEGF165-stimulated clathrin-mediated endocytosis and signaling of VEGF receptor 2 (VEGFR2). Clathrin-mediated endocytosis is an essential step in receptor signaling and is of paramount importance for a number of receptors for growth factors involved in angiogenesis. In this study, we further investigated the molecular mechanism underlying EMCN’s involvement in the regulation of VEGF-induced endocytosis. In addition, we examined the specificity of EMCN's role in angiogenesis-related cell surface receptor tyrosine kinase endocytosis and signaling. We identified that EMCN interacts with AP2 complex, which is essential for clathrin-mediated endocytosis. Lack of EMCN did not affect clathrin recruitment to the AP2 complex following VEGF stimulation, but it is necessary for the interaction between VEGFR2 and the AP2 complex during endocytosis. EMCN does not inhibit VEGFR1 and FGFR1 internalization or their downstream activities since EMCN interacts with VEGFR2 but not VEGFR1 or FGFR1. Additionally, EMCN also regulates VEGF121-induced VEGFR2 phosphorylation and internalization. Graphical Abstract

Real drilling near the upper Ordovician pinch-out line in the Tahe Oilfield shows that the drilling encountered karst reservoir. However, due to the transitional position between the denudation area and the overlying area and the special karst geological background, the existing drilling and completion data show that the reservoir space types in this area are complex and diverse. In this article, the classification of reservoir space near the Upper Ordovician pinch-out line and the extraction of logging response characteristics have been carried out based on drilling, logging, core, and crude oil quality data. Through this study, the classification scheme of karst reservoir space in the study area is proposed. The reservoir space types of karst reservoirs include fracture–cave, fracture–pore (light and low resistivity), fracture–pore (heavy and high resistivity), dissolved pore–pore (light and low resistivity), dissolved pore–pore (heavy and high resistivity), isolated pore (relatively isolated distribution of pores and fractures, weakly connected), and cave-type reservoir (sand and gravel filled or semi-unfilled). Furthermore, conventional logging parameters and five parameters sensitive to reservoir properties are extracted. The intersection maps based on the combination forms, fluid properties, and reservoir space effectiveness of different types of reservoir spaces are effective in distinguishing seven types of reservoir spaces and two types of stratified karst reservoirs. In this study, the reservoir space types and logging response characteristics of reservoirs near the Upper Ordovician pinch-out line are defined, which can provide a reliable geological basis for the quantitative identification and distribution evaluation of karst reservoirs.

Abstract Growth factor receptor-bound protein 2 (GRB2) is a cytoplasmic adapter for tyrosine kinase signaling and a nuclear adapter for homology-directed-DNA repair. Here we find nuclear GRB2 protects DNA at stalled replication forks from MRE11-mediated degradation in the BRCA2 replication fork protection axis. Mechanistically, GRB2 binds and inhibits RAD51 ATPase activity to stabilize RAD51 on stalled replication forks. In GRB2-depleted cells, PARP inhibitor (PARPi) treatment releases DNA fragments from stalled forks into the cytoplasm that activate the cGAS–STING pathway to trigger pro-inflammatory cytokine production. Moreover in a syngeneic mouse metastatic ovarian cancer model, GRB2 depletion in the context of PARPi treatment reduced tumor burden and enabled high survival consistent with immune suppression of cancer growth. Collective findings unveil GRB2 function and mechanism for fork protection in the BRCA2-RAD51-MRE11 axis and suggest GRB2 as a potential therapeutic target and an enabling predictive biomarker for patient selection for PARPi and immunotherapy combination.

Abstract Introduction First‐line osimertinib plus chemotherapy significantly prolonged progression‐free survival of patients with EGFR‐mutated advanced non‐small cell lung cancer (NSCLC) compared to osimertinib, according to the FLAURA2 trial. Methods We established a Markov model to compare the cost‐effectiveness of osimertinib plus chemotherapy with that of osimertinib alone. Clinical data were obtained from the FLAURA and FLAURA2 trials, and additional data were extracted from online resources and publications. Sensitivity analyses were conducted to evaluate the robustness of the findings. We used A willingness‐to‐pay threshold of $150,000 per quality‐adjusted life‐years (QALYs) gained. The main outcomes were QALYs, overall costs, incremental cost‐effectiveness ratio (ICER), incremental net monetary benefit, and incremental net health benefit. Subgroup analyses were conducted according to patients' mutation type and central nervous system (CNS) metastatic status. Results In a 20‐year time horizon, the ICER of osimertinib plus chemotherapy versus osimertinib alone was $223,727.1 per QALY gained. The sensitivity analyses identified the cost of osimertinib and the hazard ratio for overall survival as the top 2 influential factors and a 1.9% probability of osimertinib plus chemotherapy to be cost‐effective. The subgroup analyses revealed ICERs of $132,614.1, $224,449.8, $201,464.1, and $130,159.7 per QALY gained for L858R mutations, exon 19 deletions, CNS metastases, and no CNS metastases subgroups, respectively. Conclusions From the perspective of the United States health care system, osimertinib plus chemotherapy is not cost‐effective compared to osimertinib alone for treatment‐naïve patients with EGFR‐mutated advanced NSCLC, but more favorable cost‐effectiveness occurs in patients with L858R mutations and patients without baseline CNS metastases.

Pyrrolizidine alkaloids (PAs) are a group of naturally occurring alkaloids widely present in plants. PAs are highly hepatotoxic and have been documented to cause many incidents of human and animal poisoning. Retrorsine (RTS) is a pyrrolizidine alkaloid (PA) derived from the Compositae Senecio, which has been shown to cause hepatotoxicity. Human liver poisoning occurs through the consumption of RTS-contaminated food, and animals can also be poisoned by ingesting RTS-containing toxic plants. The mechanism of RTS-induced liver toxicity is not fully understood. In this study, we demonstrated that RTS-induced oxidative stress plays a pivotal role in RTS-induced liver toxicity involving apoptosis and autophagy. The results showed that RTS treatment in the cultured Primary rat hepatocytes caused cytotoxicity and release of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in a time- and dose-dependent manner. Our study showed that treatment of RTS induced ROS and MDA (malondialdehyde, a lipid peroxidation marker) in the hepatocytes, and reduced antioxidant capacity (GSH content, SOD activity), suggesting RTS treatment caused oxidative stress response in the hepatocytes. Furthermore, we found that RTS induced apoptosis and autophagy in the hepatocytes, and RTS-induced apoptosis and autophagy could be alleviated by ROS scavenger N-acetylcysteine (NAC) and the MAPK pathway inhibitors suggesting ROS/MAPK signaling pathway plays a role in RTS induced apoptosis and autophagy. Collectively, this study reveals the regulatory mechanism of oxidative stress in RTS-induced apoptosis and autophagy in the hepatocytes, providing important insights of molecular mechanisms of hepatotoxicity induced by RTS and related pyrrolizidine alkaloids in liver. This mechanism provides a basis for the prevention and treatment of PA poisoning in humans and animals.

The ciliary body, located at the junction of the choroid and iris, is crucial in the development of the embryonic eye. Notch2 signalling, Wnt signalling, transforming growth factor β (TGF-β) signalling, and Pax6 signalling are critical for coordinating the ciliary body formation. These signalling pathways are coordinated with each other and participate in the ciliary body development, ensuring the precise formation and optimal functioning of the eye structure. Although rare, ciliary body hypoplasia, ciliary tumours, and genetic-related iritis indicate the intricate nature of ciliary body development. Given the ciliary body's important biological significance and potential medical relevance, we aim to provide a comprehensive overview of the developmental molecular mechanisms governing ciliary body formation and function. Here, we focus on the intricate signalling pathways governing ciliary body development and corresponding genetic ciliary diseases.

In the Chinese electricity market, the deviation between monthly actual electricity demand and generation plans has become particularly prominent amidst deepening power system reform. This study focuses on the uncertainties of wind power and photovoltaic power generation in the medium to long term electricity market. It also examines the impact of maintenance scheduling for conventional generation units on the implementation of medium to long-term generation scheduling plans. The article proposes a model for optimizing the joint generation and maintenance scheduling on a monthly basis. The model is based on deviation handling and employs upward and downward price incentive mechanisms. The aim is to minimize the cost of adjusting the deviation of monthly transaction contract quantities. To deal with the challenges posed by source-load uncertainties, the model utilizes fuzzy chance-constrained programming. The research findings confirm that the proposed model can significantly reduce system operating costs, curtailment of wind power and photovoltaic power, and enhance the market integration of renewable energy. Additionally, it can achieve uniformity in the completion rate of monthly contract quantities for conventional thermal power units, ensuring a balanced power system in terms of economy and security. The study presents an optimization method for executing contract quantities in the electricity market, contributing to improved efficiency in power resource allocation and reduced energy losses. The research enriches the theoretical foundation of power system scheduling and provides practical operational guidelines for power dispatch, making it significant for promoting sustainable development in the power industry and ensuring energy security.

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that applies a stable, low-intensity (1–2 mA) direct current to modulate neuronal activity in the cerebral cortex. This technique is effective, simple to operate, affordable, and widely employed across various fields. tDCS has been extensively used in clinical and translational research, with growing applications in military and competitive sports domains. In recent years, the use of tDCS in sports science has garnered significant attention from researchers. Numerous studies have demonstrated that tDCS can enhance muscle strength, explosive power, and aerobic metabolism, reduce fatigue, and improve cognition, thereby serving as a valuable tool for enhancing athletic performance. Additionally, recent research has shed light on the physiological mechanisms underlying tDCS, including its modulation of neuronal resting membrane potential to alter cortical excitability, enhancement of synaptic plasticity to regulate long-term potentiation, modulation of neurovascular coupling to improve regional cerebral blood flow, and improvement of cerebral network functional connectivity, which activates and reinforces specific brain regions. tDCS also enhances the release of excitatory neurotransmitters, further regulating brain function. This article, after outlining the role of tDCS in improving physical performance, delves into its mechanisms of action to provide a deeper understanding of how tDCS enhances athletic performance and offers novel approaches and perspectives for physical performance enhancement.

This review examines recent advancements in electrochemical immunosensors for the detection of organophosphate pesticides, focusing on strategies to enhance sensitivity and selectivity. The widespread use of these pesticides has necessitated the development of rapid, accurate, and field-deployable detection methods. We discuss the fundamental principles of electrochemical immunosensors and explore innovative approaches to improve their performance. These include the utilization of nanomaterials such as metal nanoparticles, carbon nanotubes, and graphene for signal amplification; enzyme-based amplification strategies; and the design of three-dimensional electrode architectures. The integration of these sensors into microfluidic and lab-on-a-chip devices has enabled miniaturization and automation, while screen-printed and disposable electrodes have facilitated on-site testing. We analyze the challenges faced in real sample analysis, including matrix effects and the stability of biological recognition elements. Emerging trends such as the application of artificial intelligence for data interpretation and the development of aptamer-based sensors are highlighted. The review also considers the potential for commercialization and the hurdles that must be overcome for widespread adoption. Future research directions are identified, including the development of multi-analyte detection platforms and the integration of sensors with emerging technologies like the Internet of Things. This comprehensive overview provides insights into the current state of the field and outlines promising avenues for future development in organophosphate pesticide detection.

Introduction: The combination of immune checkpoint inhibitors (ICIs) and chemotherapy is a promising first-line therapy for patients with advanced non-squamous non-small cell lung cancer (NSCLC). The cost-effectiveness of combinations with different ICIs is yet to be compared. Methods: We utilized Bayesian network meta-analyses for the comparisons of overall survival, progression-free survival, and incidence of adverse events of the included treatments in the total population and subgroups with different programmed death-ligand 1 tumor proportional scores (TPS). The cost-effectiveness of the treatments from the perspectives of the US and Chinese healthcare systems was assessed using Markov models. Results: Three combinations, including pembrolizumab + chemotherapy (PembroC), nivolumab + ipilimumab + chemotherapy (NivoIpiC), and atezolizumab + chemotherapy (AteC), were included in our study. In terms of efficacy, PembroC was most likely to be ranked first for extending progression-free survival (PFS) (93.16%) and overall survival (OS) (90.73%). Nevertheless, from the US perspective, NivoIpiC and PembroC showed incremental cost-effectiveness ratios (ICERs) of $68,963.1/quality-adjusted life-years (QALY) and $179,355.6/QALY, respectively, compared with AteC. The one-way sensitivity analysis revealed that the results were primarily sensitive to the hazard ratios for OS or the cost of immunotherapy agents. At a willingness-to-pay (WTP) threshold of $150,000/QALY, NivoIpiC had the highest probability of being cost-effective (63%). As for the Chinese perspective, NivoIpiC and PembroC had ICERs of $145,983.4/QALY and $195,863.3/QALY versus AteC, respectively. The results were primarily sensitive to the HRs for OS. At a WTP threshold of $38,017/QALY, AteC had the highest probability of cost-effectiveness (94%). Conclusion: Although PembroC has the optimal efficacy, NivoIpiC and AteC were the most favorable treatments in terms of cost-effectiveness for patients with advanced non-squamous NSCLC from the US and Chinese perspectives, respectively.

Background Approximately two-thirds of patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) do not respond to or relapse after anti-CD19 chimeric antigen receptor T (CAR T)-cell therapy, leading to poor outcomes. Previous studies have suggested that intensified lymphodepletion and hematological stem cell infusion can promote adoptively transferred T-cell expansion, enhancing antitumor effects. Therefore, we conducted a phase I/II clinical trial in which CNCT19 (an anti-CD19 CAR T-cell) was administered after myeloablative high-dose chemotherapy and autologous stem cell transplantation (HDT/ASCT) in patients with R/R LBCL.Methods Transplant-eligible patients with LBCL who were refractory to first-line immunochemotherapy or experiencing R/R status after salvage chemotherapy were enrolled. The study aimed to evaluate the safety and efficacy of this combinational therapy. Additionally, frozen peripheral blood mononuclear cell samples from this trial and CNCT19 monotherapy studies for R/R LBCL were used to evaluate the impact of the combination therapy on the in vivo behavior of CNCT19 cells.Results A total of 25 patients with R/R LBCL were enrolled in this study. The overall response and complete response rates were 92.0% and 72.0%, respectively. The 2-year progression-free survival rate was 62.3%, and the overall survival was 68.5% after a median follow-up of 27.0 months. No unexpected toxicities were observed. All cases of cytokine release syndrome were of low grade. Two cases (8%) experienced grade 3 or higher CAR T-cell-related encephalopathy syndrome. The comparison of CNCT19 in vivo behavior showed that patients in the combinational therapy group exhibited enhanced in vivo expansion of CNCT19 cells and reduced long-term exhaustion formation, as opposed to those receiving CNCT19 monotherapy.Conclusions The combinational therapy of HDT/ASCT and CNCT19 demonstrates impressive efficacy, improved CNCT19 behavior, and a favorable safety profile.Trial registration numbers ChiCTR1900025419 and NCT04690192.

Summary: Although the small GTPase RAB37 acts as an organizer of autophagosome biogenesis, the upstream regulatory mechanism of autophagy via guanosine diphosphate (GDP)-guanosine triphosphate (GTP) exchange in maintaining retinal function has not been determined. We found that retinitis pigmentosa GTPase regulator (RPGR) is a guanine nucleotide exchange factor that activates RAB37 by accelerating GDP-to-GTP exchange. RPGR directly interacts with RAB37 via the RPGR-RCC1-like domain to promote autophagy through stimulating exchange. Rpgr knockout (KO) in mice leads to photoreceptor degeneration owing to autophagy impairment in the retina. Notably, the retinopathy phenotypes of Rpgr KO retinas are rescued by the adeno-associated virus-mediated transfer of pre-trans-splicing molecules, which produce normal Rpgr mRNAs via trans-splicing in the Rpgr KO retinas. This rescue upregulates autophagy through the re-expression of RPGR in KO retinas to accelerate GDP-to-GTP exchange; thus, retinal homeostasis reverts to normal. Taken together, these findings provide an important missing link for coordinating RAB37 GDP-GTP exchange via the RPGR and retinal homeostasis by autophagy regulation.

To address the inaccuracy of the observed rotor position caused by the large estimated back-electromotive force harmonics of the high-speed permanent magnet synchronous motor (HSPMSM) under the conventional sliding mode observer, this paper presents an adaptive full-order sliding mode observer for back-electromotive force (EMF) based on the accurate mathematical model of the HSPMSM in the discrete-time domain. The accuracy of the sliding mode observer is improved under high-speed operating conditions by using the proposed method. To further reduce the harmonic component of the observed back EMF, a synchronous fundamental frequency extraction filter (SFEF) is used to obtain the back EMF, and then, the extracted observed EMF is fed in;to the normalized phase-locked loop to obtain the rotor position. The simulation results in Matlab are presented to demonstrate the feasibility and effectiveness of the proposed method.

This review explores the emerging role of screen-printed electrodes (SPEs) in the detection of breast cancer biomarkers. We discuss the fundamental principles and fabrication techniques of SPEs, highlighting their adaptability and cost-effectiveness. The review examines various modification strategies, including nanomaterial incorporation, polymer coatings, and biomolecule immobilization, which enhance sensor performance. We analyze the application of SPEs in detecting protein, genetic, and metabolite biomarkers associated with breast cancer, presenting recent advancements and innovative approaches. The integration of SPEs with microfluidic systems and their potential in wearable devices for continuous monitoring are explored. While emphasizing the promising aspects of SPE-based biosensors, we also address current challenges in sensitivity, specificity, and real-world applicability. The review concludes by discussing future perspectives, including the potential for early screening and therapy monitoring, and the steps required for clinical implementation. This comprehensive overview aims to stimulate further research and development in SPE-based biosensors for improved breast cancer management.

Abstract Objectives Explore the therapeutic role of human umbilical mesenchymal stem cells (hUMSCs) transplantation for regeneration of ECM components and restoration of follicular development in mice. Background The extracellular matrix (ECM) is crucial to maintain ovary function and regulate follicular development, as it participates in important cell signaling and provides physical support to the cells. However, it is unknown how hUMSCs affect the expression of ECM-related genes in ovaries treated with cyclophosphamide (CTX) and busulfan (BUS). Methods In the present study, we used 64 six- to eight-week-old ICR female mice to established mouse model. The mice were randomly divided into four groups (n = 16/group): control, POI, POI + hUMSCs, and POI + PBS group. The premature ovarian insufficiency (POI) mouse model was established by intraperitoneal injection of CTX and BUS for 7days, then, hUMSCs or PBS were respectively injected via the tail vein in POI + hUMSCs or POI + PBS group. Another 7days after injection, the mice were sacrificed to harvest the ovary tissue. The ovaries were immediately frozen with liquid nitrogen or fixed with 4% PFA for subsequent experiments. To screen differentially expressed genes (DEGs), we performed transcriptome sequencing of ovaries. Thereafter, a Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to predict the related biological functions. Retrieval of interacting genes for ECM-related DEGs was performed using the function of STRINGdb (version 2.6.5) to evaluate potential protein-protein interaction (PPI) networks. Furthermore, qRT-PCR and IHC were performed to assess the differential expression of selected DEGs in control, damaged, hUMSCs-transplanted and non-transplanted ovaries. Results Chemotherapy caused mouse ovarian follicular reserve depletion, and hUMSCs transplantation partially restored follicular development. Our results revealed that ECM-receptor interaction and ECM organization were both downregulated in the damaged ovaries. Further investigation showed that ECM-related genes were downregulated in the CTX and BUS treatment group and partially rescued in hUMSCs injection group but not in the PBS group. qRT-PCR and IHC verified the results: collagen IV and laminin gamma 3 were both expressed around follicle regions in normal ovaries, chemotherapy treatment disrupted their expression, and hUMSCs transplantation rescued their localization and expression to some extent. Conclusion Our data demonstrated that ECM-related genes participate in the regulation of ovarian reserve, hUMSCs treatment rescued abnormal expression and localization of collagen IV and laminin gamma 3 in the damaged ovaries. The results suggest that hUMSCs transplantation can maintain ECM-stable microenvironments, which is beneficial to follicular development.

Abstract The tremendous impact of the coronavirus pandemic on the global aviation industry has led to many cases of airline financial distress and bankruptcy. The Asia–Pacific region (APAC) contains more than half of the world’s population, and its airlines had the highest profit margin of any region. In this study, we investigate whether corporate sustainability practice can reduce the financial distress risk of air carriers, and, if so, what would the effect be in APAC? We first examine the relationship between environmental, social, and governance disclosure and the likelihood of financial distress of airlines as measured by the Altman Z″-score. Second, we analyze the moderating role of being an APAC airline in this relationship. The findings support the claim that implementing environmental actions may increase financial distress risk, and by improving social and governance activities, airlines can mitigate the risk of financial distress. The negative influence of the environmental pillar and the positive influence of the social pillar can be smaller for APAC airlines. Our study provides empirical evidence of the influence of environmental, social, and governance (ESG) on the likelihood of financial distress in the airline industry. Moreover, we analyze the moderating role of being an APAC airline in the relationship between sustainability and financial distress. This study has significant implications for executives, managers, and policymakers in the aviation industry on ESG strategy decisions and the general issue of sustainability.

Background: Tumor treating fields (TTF) was first approved for treatment of glioblastoma. Recently, the LUNAR study demonstrated that TTF + standard therapy (ST) extended survival in patients with advanced non-small cell lung cancer (NSCLC). This primary objective of this study is to analyze the cost-effectiveness of this treatment from the United States healthcare payers’ perspective.Methods: A 3-health-state Markov model was established to compare the cost-effectiveness of TTF + ST and that of ST alone. Clinical data were extracted from the LUNAR study, supplemented by additional cost and utility data obtained from publications or online sources. One-way sensitivity analysis, probabilistic sensitivity analysis, and scenario analysis were conducted. The willingness-to-pay (WTP) threshold per quality-adjusted life-years (QALYs) gained was set to $150,000. The main results include total costs, QALYs, incremental cost-effectiveness ratio (ICER) and incremental net monetary benefit (INMB). Subgroup analyses were conducted for two types of ST, including immune checkpoint inhibitor, and docetaxel.Results: During a 10-year time horizon, the costs of TTF + ST and ST alone were $431,207.0 and $128,125.9, and the QALYs were 1.809 and 1.124, respectively. The ICER of TTF + ST compared to ST was $442,732.7 per QALY, and the INMB was -$200,395.7 at the WTP threshold. The cost of TTF per month was the most influential factor in cost-effectiveness, and TTF + ST had a 0% probability of being cost-effective at the WTP threshold compared with ST alone.Conclusion: TTF + ST is not a cost-effective treatment for advanced NSCLC patients who progressed after platinum-based therapy from the perspective of the United States healthcare payers.

The awareness of protecting traditional culture and humanistic landscapes is increasing year by year, and the protection of ancient gardens is becoming more and more a consensus among people. This paper takes the architectural profile of Guyi Garden as the research basis, introduces the specific application of 3D laser scanning technology, plans the scope of architectural data acquisition in Guyi Garden, and designs the corresponding architectural data acquisition program. With respect to the acquired point cloud data of GuYiYuan, the bilateral filtering algorithm is used to reduce the noise of the data, the curvature thinning algorithm is combined to reduce the point cloud data of the buildings in GuYiYuan, the point cloud data are spliced based on the connection point, and the ICP algorithm with the introduction of the optimization of the rotational angle constraints is introduced to realize the alignment of the point cloud data. In addition, the shadows generated from the point cloud data are removed by combining the relighting method, and the linear transformation method is also used to globally correct the texture image generated from the point cloud data. The point cloud density was reduced from 0.95m² to 0.01m² when the thinning rate was increased from 8% to 96%, and the alignment error of the improved ICP algorithm under 25dB Gaussian white noise was only 0.083*10-4mm. The maximum error accuracy of the two-dimensional model of Yiyi Nodang generated based on the point cloud data was only 0.007m, and the error of the three-dimensional model was controlled to be within the range of ±9mm. Accurate architectural data can be obtained through the use of 3D laser scanning technology, leading to a new method for digitally preserving historical buildings.

Objective To compare the efficacy and safety of the modified versus standard Valsalva maneuver in the treatment of paroxysmal supraventricular tachycardia (PSVT). Methods The PubMed, Embase, Web of Science, CNKI, WanFang Data, and VIP electronic databases were searched to identify studies comparing the modified and standard Valsalva maneuvers in the treatment of PSVT from database inception to 1 May 2023. Two reviewers independently screened the literature, extracted the data, and assessed the risk of bias of all included studies. Results Nineteen randomized controlled trials involving 2527 patients with PSVT were included. The overall rate of cardioversion was higher in the modified than standard Valsalva group (risk ratio [RR] = 1.80, 95% confidence interval [CI] = 1.61–2.01), as was the success rate of cardioversion after a single Valsalva maneuver (RR = 2.05, 95% CI = 1.74–2.41). There was no statistically significant difference in adverse reactions between the two groups (RR = 1.07, 95% CI = 0.82–1.38). Conclusion Current evidence suggests that the modified Valsalva maneuver can significantly improve the success rate of cardioversion in patients with PSVT without increasing adverse reactions. The modified Valsalva maneuver is therefore worth promoting and should be considered as a routine first treatment. INPLASY registration number: 2023100092

As rubber is a hyperelastic material, its nonlinear deformation behavior during aging is significantly influenced by various factors, including the material characteristics, demonstrating a significant uncertainty. Most of the existing uncertain prediction methods of rubber nonlinear property degradation are based on the probability density function, which requires a large number of samples to obtain the probability distribution and requires a lot of work. Therefore, the interval model is used in this study to characterize the uncertainty. However, the traditional interval constitutive models ignore the correlation between interval variables, and the prediction results have large errors. In order to minimize prediction errors and improve prediction accuracy, an interval Mooney–Rivlin (M–R) correlation model that considers the correlation between parameters was established. To address the influence of uncertainties, an interval Arrhenius model was constructed. The M–R model requires multiple fittings of stress–strain curves to obtain the model parameters, and the prediction process is relatively complex. Therefore, combing the two proposed models, the relationship equations of rubber tensile stress with aging temperature and aging time were first established by interval Arrhenius, and then the interval M–R model was used to obtain the variation ranges of parameters C10{C}_{10} and C01{C}_{01}. By contrasting this with the measured rubber aging information, the effectiveness of the proposed model was confirmed. Compared with the prediction model based on the average value, the maximum error of prediction of this model is reduced by about 60%. Compared with the traditional interval model, the prediction region is significantly reduced, which further improves the prediction accuracy. The above results indicate that this interval aging lifetime prediction model is suitable for characterizing the nonlinear stress–strain behavior of rubber-like elastomers.

Summary: Appropriate histone modifications emerge as essential cell fate regulators of neuronal identities across neocortical areas and layers. Here we showed that NSD1, the methyltransferase for di-methylated lysine 36 of histone H3 (H3K36me2), controls both area and layer identities of the neocortex. Nsd1-ablated neocortex showed an area shift of all four primary functional regions and aberrant wiring of cortico-thalamic-cortical projections. Nsd1 conditional knockout mice displayed defects in spatial memory, motor learning, and coordination, resembling patients with the Sotos syndrome carrying NSD1 mutations. On Nsd1 loss, superficial-layer pyramidal neurons (PNs) progressively mis-expressed markers for deep-layer PNs, and PNs remained immature both morphologically and electrophysiologically. Loss of Nsd1 in postmitotic PNs causes genome-wide loss of H3K36me2 and re-distribution of DNA methylation, which accounts for diminished expression of neocortical layer specifiers but ectopic expression of non-neural genes. Together, H3K36me2 mediated by NSD1 is required for the establishment and maintenance of region- and layer-specific neocortical identities.

AbstractBackground Anti-CD19 chimeric antigen receptors (CARs) T-cell therapy has been shown to have excellent efficacy in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (ALL). But many patients are refractory to anti-CD19-CAR T-cell therapy or relapse again.Methods Five patients with R/R B-ALL did not respond to anti-CD19-CAR T-cell therapy or had a disease progression again after CAR-T cell therapy. They received a salvage therapy of Blinatumomab. The clinical response, CD19 expression on ALL cells, the proportion of CD3+ T cells, level of cytokine levels of interleukin-6 (IL-6), hematological toxicity, grade of cytokine release syndrome (CRS), and immune effector cell-associated neurotoxic syndrome (ICANS) were observed in salvage therapy of Blinatumomab.Results Four patients obtained CR/CRi, even in patients without high expression of CD19 in B-ALL cells, while the other patient received NR after Blinatumomab therapy. The CD19 expression on ALL cells, the proportion of CD3+ T cells, and CD3+CD8+ T cells were deficient in Pt 5, who obtained PR in Blinatumomab therapy. One patient (Pt 3) was diagnosed with grade 0 hematological toxicity. The other four patients were diagnosed with grades 2–3 of hematological toxicity. The CRS was grade 0/one patient, grade 1/three, and grade 2/one. The ICANS was grade 0/four patients, grade 1/one. Rhizopus microsporus pneumonia and cryptococcal encephalopathy in two patients were controlled during Blinatumomab therapy.Conclusions Blinatumomab could be an effective and safe salvage therapy in patients with R/R B-ALL who failed/progressed after anti-CD19-CAR T therapy, even in R/R B-ALL patients without high expression of CD19 in B-ALL cells, patients with CNS leukemia or co-infection.Key messagesSome R/R B-ALL patients did not respond to anti-CD19 CAR T-cell therapy or had a disease progression again. Effective and safe salvage therapy for such patients remains to be explored.Blinatumomab could be an effective and safe salvage therapy in patients with R/R B-ALL who failed/progressed after anti-CD19-CAR T therapy, even in patients without high expression of CD19 in B-ALL cells.Blinatumomab could be an effective and safe salvage therapy in patients with R/R B-ALL who failed/progressed after anti-CD19-CAR T therapy, even in patients with CNS leukemia or co-infection.

Construction joints accelerate concrete carbonation, which is one critical durability concern of concrete infrastructures. However, due to the lack of experimental data, it is still challenging to quantify its negative impact on concrete carbonation resistance. In this study, the carbonation depth of construction joints in the girder of Jinshan Bridge, which was exposed to an urban atmospheric condition in a metropolitan city for 30 years, were examined. Moreover, accelerated carbonation tests were conducted to investigate the effect of the water-cement ratio, compressive stress level, carbonation time, and the surface treatment of the joint on the concrete carbonation. The results showed that the joint influence factor, defined as the ratio between the depth at the joint section and the depth of monolithic concrete, ranged from 1.34 to 3.99 with a mean value of 2.26, and a lognormal distribution represented the random nature of the factor well. Furthermore, a function for predicting the distribution curve of carbonation depth for concrete with a construction joint was proposed, and methods to improve the carbonation resistance at the construction joint were suggested: reducing concrete’s water-cement ratio and applying silane impregnation on both sides of the joint within the range of 2.0 times of cover thickness.

Abstract Background Blood–spinal cord barrier (BSCB) disruption is a key event after spinal cord injury (SCI), which permits unfavorable blood-derived substances to enter the neural tissue and exacerbates secondary injury. However, limited mechanical impact is usually followed by a large-scale BSCB disruption in SCI. How the BSCB disruption is propagated along the spinal cord in the acute period of SCI remains unclear. Thus, strategies for appropriate clinical treatment are lacking. Methods A SCI contusion mouse model was established in wild-type and LysM-YFP transgenic mice. In vivo two-photon imaging and complementary studies, including immunostaining, capillary western blotting, and whole-tissue clearing, were performed to monitor BSCB disruption and verify relevant injury mechanisms. Clinically applied target temperature management (TTM) to reduce the core body temperature was tested for the efficacy of attenuating BSCB disruption. Results Barrier leakage was detected in the contusion epicenter within several minutes and then gradually spread to more distant regions. Membrane expression of the main tight junction proteins remained unaltered at four hours post-injury. Many junctional gaps emerged in paracellular tight junctions at the small vessels from multiple spinal cord segments at 15 min post-injury. A previously unnoticed pathological hemodynamic change was observed in the venous system, which likely facilitated gap formation and barrier leakage by exerting abnormal physical force on the BSCB. Leukocytes were quickly initiated to transverse through the BSCB within 30 min post-SCI, actively facilitating gap formation and barrier leakage. Inducing leukocyte transmigration generated gap formation and barrier leakage. Furthermore, pharmacological alleviation of pathological hemodynamic changes or leukocyte transmigration reduced gap formation and barrier leakage. TTM had very little protective effects on the BSCB in the early period of SCI other than partially alleviating leukocyte infiltration. Conclusions Our data show that BSCB disruption in the early period of SCI is a secondary change, which is indicated by widespread gap formation in tight junctions. Pathological hemodynamic changes and leukocyte transmigration contribute to gap formation, which could advance our understanding of BSCB disruption and provide new clues for potential treatment strategies. Ultimately, TTM is inadequate to protect the BSCB in early SCI.

Cervical cancer continues to be a concern, and the prognosis of locally advanced cervical cancer remains poor. IMPA2 was previously identified as a potential oncogene and regulator of tumor apoptosis. In this study, we aim to further elucidate the underlying mechanisms of IMPA2 gene in the regulation of cervical cancer apoptosis. First, we identify AIFM2 as an upregulated gene in IMPA2-silenced cervical cancer cells, and inhibition of AIFM2 reverses IMPA2 knockdown-induced apoptosis. Further study reveals that AIFM2 regulates cell apoptosis in a mitochondrial-dependent manner with a redistribution of mitochondrial membrane potential and intracellular Ca 2+ levels. However, the analysis of the STRING database and our experimental results show that AIFM2 has little effect on cervical cancer progression and survival. Further mechanistic study demonstrates that IMPA2 and AIFM2 silencing inhibits apoptosis by activating p53. Meanwhile, the knockdown of IMPA2 enhances the chemosensitivity of cervical cancer cells by strengthening paclitaxel-induced apoptosis. Based on the above results, the IMPA2/AIFM2/p53 pathway may be a new molecular mechanism for paclitaxel treatment of cervical cancer and an effective strategy to enhance the sensitivity of cervical cancer cells to paclitaxel. Our findings display a novel function of IMPA2 in regulating cell apoptosis and paclitaxel resistance mediated by a disturbance of AIFM2 and p53 expression, potentially making it a novel therapeutic target for cervical cancer treatment.

A series of novel quinazoline derivatives bearing sulfonamide moiety was designed and synthesized, and their structure were characterized by 1H NMR, 13C NMR, and HRMS techniques. Among them, the structure of compound E1 was further confirmed through X-ray single-crystal diffraction analyses. Their anti-Tobacco mosaic virus (TMV) activities were evaluated through half-leaf method. The bioassay results showed that E8 and E19 possess excellent inhibitory activity towards TMV. The EC50 of curative activities, protective activities, and inactivating activities of E8 and E19 are 132.1, 152.8, 57.4 mg/L and 278.0, 165.3, 94.5 mg/L, respectively, which are far superior than Ribavirin (318.2, 201.5, 128.6 mg/L, respectively).

Abstract Objective To investigate the feasibility of ultra-short echo time (UTE) magnetic resonance imaging (MRI) in the assessment of cartilage endplate (CEP) damage and further evaluate the relationship between total endplate score (TEPS) and lumbar intervertebral disc (IVD) degeneration for chronic low back pain patients. Materials and methods IVD were measured in 35 patients using UTE imaging at 3T MR. Subtracted UTE images between short and long TEs were obtained to depict anatomy of CEP. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated to assess the image quality quantitatively. A new grading criterion for endplate damage evaluation was developed based on Rajasekaran.S grading system in this study. Two radiologists were employed to evaluate CEP and bony vertebral endplates (VEP) using this new grading criterion and assess TEPS, independently. Cohen’s kappa analysis was applied to evaluate the inter-observer agreement of endplate damage assessment between two radiologists, and the Kendall’s TAU-B analysis was employed to determine the relationship between TEPS and IVD degeneration evaluated with Pfirrmann grading. Results Well structural CEP was depicted on subtracted UTE images and confirmed by high SNR (33.06±2.92) and CNR values (9.4±2.08). Qualified subtracted UTE images were used by two radiologists to evaluate the degree of CEP and VEP damage. Excellent inter-observer agreement was confirmed by high value in Cohen’s kappa test (0.839, P

Background: As observed in recent genetic studies, PITX2 is one of the most popular genes with atrial fibrillation; single nucleotide polymorphism (rs2200733) at chromosome 4q25 (near PITX2) is found to be strongly associated with atrial fibrillation, but it has a difference among Chinese Han population. The basic aim of conducting this study is to find the correlation between PITX2 gene polymorphism and the risk of atrial fibrillation and to identify the possibility for early diagnosis of silent atrial fibrillation and high-risk atrial fibrillation. Methods: The study included 98 cases of atrial fibrillation patients and 88 non-atrial fibrillation patients in Affiliated Hospital of Yangzhou University were enrolled in a case-control study. The single nucleotide polymorphism of rs2200733 at 4q25 near PITX2 was genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. Results: A total of 98 patients with atrial fibrillation were genotyped, and the following frequencies were included in genotype percentages (44.9%, 50%, and 5.1%) while distribution of significant single nucleotide polymorphism rs2200733 consisted (29.55%, 53.41%, and 17.05%) which showed (χ2 = 9.159, P =.01). There was no significant difference in TC genotype frequency (P =.642), frequency of T allele (χ2 = 7.447, P =.006), and T allele was 1.806 times that of the control group (odds ratio = 1.806, 95% CI = 1.179-2.766, P =.006). According to logistic regression analysis, following results were concluded for TC genotype (odds ratio = 3.128, 95% CI = 1.053-9.287, P =.04), or TT genotype (odds ratio = 5.077, 95% CI = 1.653-15.595, P =.005) increased the risk of atrial fibrillation. Conclusions: The genotype and allele frequency distribution of rs2200733 (T/C) near PITX2 is different in the atrial fibrillation group and the control group. The T allele is a risk factor for atrial fibrillation. Compared with the CC genotype, the TT genotype increased the risk of atrial fibrillation.

Periodic arrays can support highly nontrivial modal dispersion, stemming from the interplay between localized resonances of the array elements and distributed resonances supported by the lattice. Recently, intentional defects in the periodicity, i.e., broken in situ symmetries, have been attracting significant attention as a powerful degree of freedom for dispersion control. Here we explore highly nontrivial dispersion features in the resonant response of linear arrays of plasmonic particles, including the emergence of braiding and band knots caused by band folding. We show that these phenomena can be achieved within simple dipolar arrays for which we can derive closed-form expressions for the dispersion relation. These phenomena showcase powerful opportunities stemming from broken symmetries for extreme dispersion engineering, with a wide range of applications, from plasma physics to topological wave phenomena. Our theoretical model can also be generalized to higher dimensions to explore higher-order symmetries, e.g., glide symmetry and quasi-periodicity.