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Abstract Background Comprehensively mapping the hierarchical structure of breast cancer protein communities and identifying potential biomarkers from them is a promising way for breast cancer research. Existing approaches are subjective and fail to take information from protein sequences into consideration. Deep learning can automatically learn features from protein sequences and protein–protein interactions for hierarchical clustering. Results Using a large amount of publicly available proteomics data, we created a hierarchical tree for breast cancer protein communities using a novel hierarchical graph neural network, with the supervision of gene ontology terms and assistance of a pre-trained deep contextual language model. Then, a group-lasso algorithm was applied to identify protein communities that are under both mutation burden and survival burden, undergo significant alterations when targeted by specific drug molecules, and show cancer-dependent perturbations. The resulting hierarchical map of protein communities shows how gene-level mutations and survival information converge on protein communities at different scales. Internal validity of the model was established through the convergence on BRCA2 as a breast cancer hotspot. Further overlaps with breast cancer cell dependencies revealed SUPT6H and RAD21, along with their respective protein systems, HOST:37 and HOST:861, as potential biomarkers. Using gene-level perturbation data of the HOST:37 and HOST:861 gene sets, three FDA-approved drugs with high therapeutic value were selected as potential treatments to be further evaluated. These drugs include mercaptopurine, pioglitazone, and colchicine. Conclusion The proposed graph neural network approach to analyzing breast cancer protein communities in a hierarchical structure provides a novel perspective on breast cancer prognosis and treatment. By targeting entire gene sets, we were able to evaluate the prognostic and therapeutic value of genes (or gene sets) at different levels, from gene-level to system-level biology. Cancer-specific gene dependencies provide additional context for pinpointing cancer-related systems and drug-induced alterations can highlight potential therapeutic targets. These identified protein communities, in conjunction with other protein communities under strong mutation and survival burdens, can potentially be used as clinical biomarkers for breast cancer.

Abstract The case of Lumbar spinal stenosis (LSS) combined with tophi due to gout is rarely reported. In the course of our clinic work, we encountered a young male patient who was diagnosed with a history of gout for 5 years and was targeted as LSS combined with gouty tophi, and we would like to share this case. In addition, in order to further investigate the deep mechanism of LSS associated with gout, we obtained the intersecting genes of the two diseases based on a machine learning approach by obtaining the dataset GSE113212 related to LSS from the Gene Expression Omnibus (GEO) database, and the genes related to gout from the human gene database. We found that TGFB1, PPARG, and SAMRCC1 may be important biomarkers for treating of both diseases. From a clinical perspective, clinicians should be vigilant about the possibility of gouty lumbar spinal stenosis with tophi in young patients presenting with back pain, hyperuricemia, and elevated inflammatory markers. A combined surgical and pharmacological treatment plan has a favorable prognosis. Investigating the mechanisms of action of core genes may provide new insights for treatment, ultimately leading to the development of comprehensive and personalized diagnostic and therapeutic strategies.

Abstract Doxorubicin, a representative drug of the anthracycline class, is widely used in cancer treatment. However, Doxorubicin-induced cardiotoxicity (DIC) presents a significant challenge in its clinical application. Mitochondrial dysfunction plays a central role in DIC, primarily through disrupting mitochondrial dynamics. This study aimed to investigate the impact of Rnd3 (a Rho family GTPase 3) on DIC, with a focus on mitochondrial dynamics. Cardiomyocyte-specific Rnd3 transgenic mice (Rnd3-Tg) and Rnd3LSP/LSP mice (N-Tg) were established for in vivo experiments, and adenoviruses harboring Rnd3 (Ad-Rnd3) or negative control (Ad-Control) were injected in the myocardium for in vitro experiments. The DIC model was established using wild-type, N-Tg, and Rnd3-Tg mice, with subsequent intraperitoneal injection of Dox for 4 weeks. The molecular mechanism was explored through RNA sequencing, immunofluorescence staining, co-immunoprecipitation assay, and protein-protein docking. Dox administration induced significant mitochondrial injury and cardiac dysfunction, which was ameliorated by Rnd3 overexpression. Further, the augmentation of Rnd3 expression mitigated mitochondrial fragmentation which is mediated by dynamin-related protein 1 (Drp1), thereby ameliorating the PANoptosis (pyroptosis, apoptosis, and necroptosis) response induced by Dox. Mechanically, the interaction between Rnd3 and Rho-associated kinase 1 (Rock1) may impede Rock1-induced Drp1 phosphorylation at Ser616, thus inhibiting mitochondrial fission and dysfunction. Interestingly, Rock1 knockdown nullified the effects of Rnd3 on cardiomyocytes PANoptosis, as well as Dox-induced cardiac remodeling and dysfunction elicited by Rnd3. Rnd3 enhances cardiac resilience against DIC by stabilizing mitochondrial dynamics and reducing PANoptosis. Our findings suggest that the Rnd3/Rock1/Drp1 signaling pathway represents a novel target for mitigating DIC, and modulating Rnd3 expression could be a strategic approach to safeguarding cardiac function in patients undergoing Dox treatment. The graphical abstract illustrated the cardioprotective role of Rnd3 in DIC. Rnd3 directly binds to Rock1 in cytoplasm and ameliorates mitochondrial fission by inhibiting Drp1 phosphorylation at ser616, thereby alleviating PANoptosis (apoptosis, pyroptosis, and necroptosis) in DIC.

Abstract Aging increases the risk for Alzheimer’s disease (AD), driving pathological changes like amyloid-β (Aβ) buildup, inflammation, and oxidative stress, especially in the prefrontal cortex (PFC). We present the first subcellular-resolution spatial transcriptome atlas of the human prefrontal cortex (PFC), generated with Stereo-seq from six male AD cases at varying neuropathological stages and six age-matched male controls. Our analyses revealed distinct transcriptional alterations across PFC layers, highlighted disruptions in laminar structure, and exposed AD-related shifts in layer-to-layer and cell-cell interactions. Notably, we identified genes highly upregulated in stressed neurons and nearby glial cells, where AD diminished stress-response interactions that promote Aβ clearance. Further, cell-type-specific co-expression analysis highlighted three neuronal modules linked to neuroprotection, protein dephosphorylation, and Aβ regulation, with all modules downregulated as AD progresses. We identified ZNF460 as a transcription factor regulating these modules, offering a potential therapeutic target. In summary, this spatial transcriptome atlas provides valuable insight into AD’s molecular mechanisms.

Abstract Background Major depressive disorder (MDD) is a recurrent and persistent mental illness. However, there is a lack of research that distinguishes the severity of comorbid anxiety disorders in MDD, and insufficient evidence exists regarding the prevalence of MDD patients with comorbid moderate-to-severe anxiety in the Chinese population. Methods The study included 1718 MDD patients (894 with moderate-to-severe anxiety symptoms and 824 without moderate-to-severe anxiety symptoms). Clinical symptoms and development were assessed using the Hamilton Depression Rating Scale-17 (HAMD-17), Hamilton Anxiety Rating Scale-14 (HAMA-14), Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression (CGI). The blood pressure and thyroid hormone levels were measured. Results We found that the incidence of MDD patients with moderate-to-severe anxiety symptoms was 52.04%. The prevalence of recent suicide attempts in MDD comorbid moderate-to-severe anxiety patients was 31.8%, which was 4.24 times higher than that in patients without moderate-to-severe anxiety. Additionally, suicide attempters had elevated levels of thyroid stimulating hormone (TSH), anti-thyroglobulin (TgAb), thyroid peroxidases antibody (TPOAb), systolic blood pressure (SBP), and diastolic blood pressure (DBP) compared to non-suicide attempters. We further identified CGI score, TSH, TPOAb, and DBP as influential factors for recent suicide attempts in MDD individuals who had moderate-to-severe anxiety symptoms. These indexes could distinguish between suicide attempts and non-suicide attempts in MDD patients with moderate-to-severe anxiety symptoms. Conclusions Our findings mainly indicated a high prevalence of recent suicide attempts in MDD patients with moderate-to-severe anxiety. Several clinical correlates, thyroid hormones, and blood pressure might contribute to recent suicide attempts in MDD patients with moderate-to-severe anxiety symptoms.

Abstract Background This study aimed to establish a model for predicting the difficulty of mandibular third molar extraction based on a Bayesian network to meet following requirements: (1) analyse the interaction of the primary risk factors; (2) output quantitative difficulty-evaluation results based on the patient’s personal situation; and (3) identify key surgical points and propose surgical protocols to decrease complications. Methods Relevant articles were searched to identify risk factors. Clinical knowledge and experience were used to analyse the risk factors to establish the Bayesian network. First, the qualitative mechanism knowledge, including the effect of risk factors on the extraction difficulty and the causal relationships between risk factors, was analysed to establish the framework of the Bayesian network. Then, the quantitative knowledge, including the occurrence probability of the parent nodes and the conditional probability table of the nodes with causal relationships, was given by the surgeon experience and calculated using the Dempster-Shafer evidence theory. According to the framework and likelihoods and relationships of risk factors, the Bayesian network model was established. Results This Bayesian network model analysed the weight by sensitivity of each risk factor and expressed the interaction relationship among risk factors as well as the effect of risk factors on extraction difficulty quantitatively. This Bayesian network model showed quantitative analysis results for extraction difficulty and key risk factors. The Bayesian network model revealed that the relationship to the inferior alveolar nerve, surgeon experience and patient anxiety were the most important risk factors for extraction difficulty. By integrating these patient-specific risk factors across the entire surgical process, this model could be used during preoperative planning to identify high-risk cases and to optimize resource allocation; during intraoperative management to tailor surgical techniques; and during postoperative follow-up to establish targeted follow-up protocols for high-risk patients. Moreover, this Bayesian network model can flexibly improve inclusion factors and conditional probabilities with the development of relevant research and expert opinions, as well as change states and probabilities of relevant nodes based on actual clinical conditions. Conclusions A model for predicting the difficulty of mandibular third molar extraction was established based on a Bayesian network.

Acid mine drainage(AMD) from coal mines contains elevated concentrations of heavy metals and sulfates, rendering it highly corrosive and posing a persistent threat to both the ecological environment and human health. Consequently, it has emerged as a pervasive environmental predicament in the coal mining process. This review presents an overview of the formation mechanism, detrimental effects, and chemical characteristics of AMD in coal mines. Furthermore, it summarizes traditional AMD end treatment methods in recent years, analyzes and compares practical application cases of AMD end treatment in China, and introduces emerging AMD end treatment methods. The reaction mechanisms, advantages, disadvantages of traditional active treatments (neutralization, adsorption, membrane technology), as well as passive treatments (constructed wetlands, limestone ditch drainage), are discussed extensively. Moreover, the applicability of each treatment method is evaluated. However, these methods still have certain limitations. The active method is constrained by the continuous supply of chemicals and energy as well as high maintenance costs. On the other hand, the passive approach is limited by long treatment cycles and the need for timely system renovation. According to the actual application cases, the treatment ideas and optimization methods of domestic AMD end treatment methods are summarized. In order to address these challenges in acid mine drainage treatment within coal mines, this review introduces magnetic nanoparticle materials and a novel collaborative treatment method, providing a fresh perspective. The findings of this study highlight the ongoing necessity to enhance existing technologies and develop new ones to improve the overall effectiveness of acid mine drainage treatment. Relying solely on a single technology proves difficult in meeting discharge standards for acid mine drainage treatment; therefore, adopting a multi-technology collaborative approach based on complementary advantages becomes imperative. Furthermore, during the process of AMD treatment，the approach of “source reduction + end treatment” can be adopted to improve the effectiveness of AMD treatment, resource recovery and reuse can help reduce treatment costs while promoting sustainable management.

Nigrospora osmanthi strain Z1 is a potential bioherbicide for the biological control of water lettuce, one of the most common invasive weeds. Here, the first high-quality genome assembly of N. osmanthi was obtained by a combination of PacBio and Illumina sequencing technologies. Twelve contigs representing the nuclear genome and one mitochondrial DNA were generated, with a total length of 45.94 Mb, an N50 equal to 6.99 Mb, and a GC content of 57.91%; 9 of the 12 nuclear contigs represented chromosomes from telomere to telomere characterized by telomeric-like repeats. A total of 11,051 genes were predicted using a combination of gene prediction tools, including 336 noncoding RNAs, 1,298 genes encoding secretory proteins, 1,735 genes encoding carbohydrate-active enzymes, 1,955 fungal virulence factors, and 50 putative secondary metabolite gene clusters. This complete genome sequence can serve as a valuable resource for future comparative genomic studies of the fungus Nigrospora for effective application in the biocontrol of invasive species and the discovery of fungal secondary metabolites. [Figure: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Abstract As an emerging type of pluripotent stem cells, chemically induced pluripotent stem cells (CiPSCs) avoid the risks of genomic disintegration by exogenous DNAs from viruses or plasmids, providing a safer stem cell source. To verify CiPSCs’ capacity to differentiate into retinal organoids (ROs), we induced CiPSCs from mouse embryonic fibroblasts by defined small-molecule compounds and successfully differentiated the CiPSCs into three-dimensional ROs, in which all major retinal cell types and retinal genes were in concordance with those in vivo. We transplanted retinal photoreceptors from ROs into the subretinal space of retinal degeneration mouse models and the cells could integrate into the host retina, establish synaptic connections, and significantly improve the visual functions of the murine models. This proof-of-concept study for the first time demonstrated that CiPSCs could differentiate into ROs with a full spectrum of retinal cell types, and provided new insights into chemical approach-based retinal regeneration for degenerative diseases.

ObjectiveWith the growth in the demand for natural oil and gas and the technological progress of their production, the oil and gas well depths have been constantly setting new records. The increase in the depth corresponds to sharply increasing in-situ stress, leading to increasingly severe damage to the casing of ultradeep oil and gas wells. To enhance the bearing capacity of the casing under high in-situ stress, high-strength casing with a large wall thickness is typically employed, a measure which has been proved, however, less effective. MethodsThis study established a finite element model of the casing-cement sheath-formation system to corroborate the presence of arching effects in the casing system and the protective effect of flexible cement sheath on the casing. Based on this, the impacts of different formations were investigated, along with the material parameters and thickness of cement sheath on the mechanisms behind the stress transfer in the system through a series of parametric analysis. Results and Conclusions The findings indicate that flexible cement for well cementing enabled the formation near the casing to bear in-situ stress by allowing limited deformations of the formation, thereby reducing the load on the casing. In contrast, rigid cement for well cementing bore in-situ stress by restricting the deformations of formations near the casing, thereby sharing the in-situ stress with the casing. In the force system applied to the flexible cement for well cementing, a smaller elastic modulus of the flexible cement corresponded to a lower casing stress, suggesting an active arching effect. In contrast, in the force system applied to the rigid cement for well cementing, a higher elastic modulus of the rigid cement was associated with a lower casing stress, hinting at a passive arching effect. However, active arching effects exhibited a much higher decreasing amplitude of stress than passive arching effects. Therefore, active arching effects produced more effective protection for the casing, especially in hard formations. Additionally, the Poisson's ratio and thickness of cement sheath also affected the casing stress, while their impacts were smaller than those of the elastic modulus of the cement sheath. Therefore, this study proposes application of the flexible cement for well cementing depends on the presence of the arching effects in formations, that is, the presence of shear strength in formations rather than their hardness.

Abstract The charring tissue generated by the high temperature during microwave ablation can affect the therapeutic effect, such as limiting the volume of the coagulation zone and causing rejection. This paper aimed to prevent tissue carbonization while delivering an appropriate thermal dose for effective ablations by employing a treatment protocol with real-time bioelectrical impedance monitoring. Firstly, the current field response under different microwave ablation statuses is analyzed based on finite element simulation. Next, the change of impedance measured by the electrodes is correlated with the physical state of the ablated tissue, and a microwave ablation carbonization control protocol based on real-time electrical impedance monitoring was established. The finite element simulation results show that the dielectric properties of biological tissues changed dynamically during the ablation process. Finally, the relative change rule of the electrical impedance magnitude of the ex vivo porcine liver throughout the entire MWA process and the reduction of the central zone carbonization were obtained by the MWA experiment. Charring tissue was eliminated without water cooling at 40 W and significantly reduced at 50 W and 60 W. The carbonization during MWA can be reduced according to the changes in tissue electrical impedance to optimize microwave thermal ablation efficacy.

ABSTRACTSpaceborne photon-counting light detection and ranging (LiDAR) have been extensively applied in shallow-water bathymetry. The density of underwater topographic photons (UTP) varies and is discontinuous due to sunlight noise, beam intensity, and seabed reflectivity, which differ from the land photon distribution due to the attenuation of water. Therefore, a general method for extracting and grading UTP is still lacking. We propose an active contour method combined with a variable convolution kernel method to calculate the photon range by considering the energy contributions of adjacent photons. Adaptive parameters under different observation conditions were determined to obtain the optimal convolution kernel using a kernel ridge regression model. This implies that the number of photons contained in the buffer zone was largest after the extracted UTP was fitted to a curve. Quantitative and qualitative verifications proved that the method performed well under different conditions. The photons obtained by the energy functional and the curve obtained by the fitting method were then used to grade the photons. Finally, an online developed UTP dataset and extraction framework were proposed to provide an applicable method for current and subsequent spaceborne photon-counting LiDAR.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread worldwide. SARS-CoV-2 is prone to mutation, resulting in variants with increased transmissibility, pathogenicity, and immune escape capabilities, posing a significant global threat. To effectively monitor new coronavirus infections, it is necessary to develop diverse detection technologies that are accurate, sensitive, or field-usable for variant identification. This article describes the principles of nucleic acid amplification-based detection techniques for SARS-CoV-2 variants and their applications variant identification and differentiation. It also discusses the advantages and disadvantages of these methods and provides a reference for the accurate identification and efficient detection of SARS-CoV-2 variants.

Abstract Background Cancer survivors face many challenges in long-term health management, including malnutrition, systemic inflammation, and sleep issues, which significantly affect their survival and quality of life. Methods A prospective cohort study was derived from the National Health and Nutrition Examination Survey from 2005–2018 harboring 1,908 cancer survivors (weighted population, 11,453,293), of whom 688 deaths (220 from cancer mortality, 468 from non-cancer mortality). The Advanced Lung Cancer Inflammation Index (ALI) was used as a measure of nutritional status and systemic inflammation in cancer patients. Weighted multivariable Cox proportional hazards regression models were utilized to explore the independent and combined effects of ALI and sleep quality on mortality outcomes. Results The participants with a high ALI were more likely to be female, aged 40 to 64 years, non-Hispanic white, and have a higher BMI. We observed that elevated ALI levels were associated with decreased risks of all-cause mortality (Hazard ratio [HR] = 0.601, 95% Confidence interval [CI] = 0.521–0.695, P

Abstract The binding of viruses to host-entry factor receptors is an essential step for viral infection. Many studies have shown that macrophages can internalize viruses and degrade them in lysosomes for clearance in vivo. Inspired by these natural behaviors and using SARS-CoV-2 as a testbed, we harvest lysosomes from activated macrophages and anchor the protein-receptor ACE2 as bait, thus constructing a lysosomal “TRAP” (lysoTRAP) that selectively captures, internalizes, and eventually degrades SARS-CoV-2. Through experiments with cells, female mice, female hamsters, and human lung organoids, we demonstrate that lysoTRAP effectively clears SARS-CoV-2. Importantly, unlike therapeutic agents targeting SARS-CoV-2 spike protein, lysoTRAP remains effective against nine pseudotyped variants and the authentic Omicron variant, demonstrating its resistance to SARS-CoV-2 mutations. In addition to the protein-receptor ACE2, we also extend lysoTRAP with the saccharide-receptor sialic acid and verify its excellent antiviral effect against H1N1, highlighting the flexibility of our “TRAP” platform in fighting against various viruses.

Abstract Background Sphingosine-1-phosphate receptor 1 (S1PR1) is considered to be closely related to a variety of malignant tumors, but the role and mechanism of S1PR1 in lung adenocarcinoma are not fully understood. In this study, we aim to explore the role and downstream signaling pathways of S1PR1 in the malignant biological functions of lung adenocarcinoma (LUAD). Methods Bioinformatics analysis, RT-qPCR, western blot and immunohistochemistry (IHC) were was used to investigate the expression of S1PR1 in LUAD. The prognosis of S1PR1 was also analyzed. CCK-8 assay, colony formation assay, scratch assay, transwell migration and invasion assay, cell adhesion assay were performed to examine the effect of S1PR1 on LUAD. RNA sequencing was employed to analyze the DEGs in LUAD cells overexpressing S1PR1. Enrichment pathway analysis using KEGG, GO, and GSEA was conducted to predict potential signaling pathways and downstream targets. chromatin immunoprecipitation (ChIP) and dual luciferase reporter assay were performed to verify the direct regulation between FOXA1 and the target genes. Then FOXA1 overexpression were performed to functional rescue experiments. miRNA-30c-5p was identified as a microRNA regulating FOXA1 by dual luciferase reporter assay. The downstream signaling pathways of S1PR1 was detected to clarify the specific pathways to regulates miR-30c-5p. Results S1PR1 is significantly decreased in LUAD and is positively correlated with the prognosis. Overexpression of S1PR1 inhibits the proliferation, migration, invasion and adhesion function of LUAD cells by suppressing the expression of COL5A1, MMP1, and SERPINE1. FOXA1 is a key transcription factor regulating the expression of MMP1, COL5A1 and SERPINE1. S1PR1 inhibits the expression of FOXA1 through p-STAT1/miR-30c-5p, thereby suppressing the malignant function of LUAD cells. Conclusions The expression of S1PR1 is downregulated in LUAD, which is positively correlated with prognosis. S1PR1 regulates the malignant function of LUAD cells by inhibiting the expression of COL5A1, MMP1 and SERPINE1 through the p-STAT1/miR-30c-5p/FOXA1 signaling pathway.

Abstract The electrocatalytic reduction of nitrogenous waste offers a sustainable approach to producing nitrogen-containing chemicals. The selective synthesis of high-value hydroxylamine (NH2OH) is challenging due to the instability of NH2OH as an intermediate. Here, we present a rational electrocatalyst design strategy for promoting NH2OH electrosynthesis by suppressing the competing pathways of further reduction. We screen zinc phthalocyanines (ZnPc) with a high energy barrier for NH2OH reduction by regulating their intrinsic activity. Additionally, we discover that carbon nanotube substrates exhibit significant NH3-producing activity, which can be effectively inhibited by the high coverage of ZnPc molecules. In-situ characterizations reveal that NH2OH and HNO are generated as intermediates in nitrate reduction to NH3, and NH2OH can be enriched in the ZnPc electrode. In the H-cell, the optimized ZnPc catalyst demonstrates a Faradaic efficiency (FE) of 53 ± 1.7% for NH2OH with a partial current density exceeding 270 mA cm−2 and a turnover frequency of 7.5 ± 0.2 s−1. It also enables the rapid electrosynthesis of cyclohexanone oxime from nitrite with a FE of 64 ± 1.0%.

Contradiction between ultrafast nucleation and deposition rates of lithium (Li) crystals at high rate and heterogeneity of Li+ flux resulting from concentration polarization has compromised the performance of Li metal anodes especially at high areal capacity and current density. Here, multifunctional protective layer consisting of MoO3 nanobelt films (MoO3-NF) is introduced on the surface of Li by a simple rolling method. The strong binding energy between Li and MoO3 guides the homogeneous nucleation and deposition of Li, while the nanobelt networks provide effective ion channels for uniform distribution of the Li+ flux. Because of the novel multifunctional protective layer, the MoO3-NF@Li anodes demonstrate a remarkable stability for 800 h with ultralow overpotential of 159 mV at extreme harsh conditions of 60 mA·h/cm2 and 60 mA/cm2. MoO3-NF@Li||LiNi0.6Co0.2Mn0.2O2 full-cells can run 100 cycles with a superior capacity retention of 84.2% under practical test conditions, demonstrating great potential for high output and energy-density metal batteries.

Abstract Colorectal cancer is one of the common malignant tumors with poor prognosis, which is partly due to the lack of an effective biomarker. The purpose of this study is to explore the impact of membrane palmitoylated protein (MPP2) on the prognosis of colorectal cancer patients. We obtained transcriptome data and DNA methylation data of 380 colorectal cancer patients from the Cancer Genome Atlas (TCGA). Then we used a series of bioinformatics analysis methods to reveal the relationship between MPP2 expression, DNA methylation sites, prognosis, immune checkpoint and clinical characteristics of patients. Finally, in vitro experiment and the meta-analysis of thousands of patients further confirmed the impact of MPP2 on the prognosis of colorectal cancer patients and cell migration and proliferation. The expression level of MPP2 is negatively regulated by its DNA methylation sites, which leads to its low expression in colorectal cancer. High expression of MPP2 is an independent prognostic risk factor, which may be a biomarker for colorectal cancer. Moreover, the expression of MPP2 shows a close relationship with immune checkpoint or immune cells infiltration, especially CD4+T cells. In addition, meta-analysis involving 1584 patients from four different data further confirmed that MPP2 was a risk factor for colorectal cancer. Finally, knockdown of MPP2 could significantly inhibit the proliferation of SW480 cells via mTOR signaling pathway. This study was the first to suggest that MPP2 may become a promising biomarker, and has an important role in immune checkpoint or immune cell infiltration in colorectal cancer.

One of the most prevalent disorders that cause blindness worldwide is cataract, and its essence is the visual disorder caused by the opacity of the lens. The significant degree of variation in cataracts and the fact that a variety of factors can impact a patient's lens transparency make it especially crucial to investigate the pathogenesis of cataracts at the molecular level. It has been found that more than 60 genes are linked to the formation of cataracts, and the construction of a transgenic mouse model of cataract similar to the selection of human lens clouding due to a variety of causes has become an important means of studying the pathogenesis of cataract. Therefore, the research on the application of transgenic mice to the molecular pathogenesis of cataracts will be the main topic of this review of the literature.

Abstract Estimating gross primary production (GPP) of terrestrial ecosystems is important for understanding the terrestrial carbon cycle. However, existed nationwide GPP datasets are primarily driven by coarse spatial resolutions (≥500 m) remotely sensed data, which fails to capture the spatial heterogeneity of GPP across different ecosystem types at land surface. This paper introduces a new GPP dataset, Hi-GLASS GPP v1, with a fine spatial resolution (30-m) and monthly temporal resolution from 2016 to 2020 in China. The Hi-GLASS GPP v1 dataset is generated from 30-m Landsat data using a process based light use efficiency model. The Hi-GLASS GPP v1 model integrates a detailed map of maize plantations, a crucial C4 crop in China known for its higher photosynthetic efficiency compared to C3 crops. This inclusion helps correct the underestimation of GPP that typically occurs when all croplands are categorized as C3. The Hi-GLASS GPP v1 dataset demonstrates a robust correlation with GPP data derived from eddy covariance towers, thereby enabling a more accurate assessment of terrestrial carbon sequestration across China.

China is a hotspot of relict plant species that were once widespread throughout the Northern Hemisphere. Recent research has demonstrated that the occurrence of long-term stable refugia in the mountainous regions of central and south-western China allowed their persistence through the late Neogene climate fluctuations. One of these relict lineages is Dipteronia, an oligotypic tree genus with a fossil record extending to the Paleocene. Here, we investigated the genetic variability, demographic dynamics and diversification patterns of the two currently recognized Dipteronia species (Dipteronia sinensis and D. dyeriana). Molecular data were obtained from 45 populations of Dipteronia by genotyping three cpDNA regions, two single copy nuclear genes and 15 simple sequence repeat loci. The genetic study was combined with niche comparison analyses on the environmental space, ecological niche modeling, and landscape connectivity analysis. We found that the two Dipteronia species have highly diverged both in genetic and ecological terms. Despite the incipient speciation processes that can be observed in D. sinensis, the occurrence of long-term stable refugia and, particularly, a dispersal corridor along Daba Shan-west Qinling, likely ensured its genetic and ecological integrity to date. Our study will not only help us to understand how populations of Dipteronia species responded to the tectonic and climatic changes of the Cenozoic, but also provide insight into how Arcto-Tertiary relict plants in East Asia survived, evolved, and diversified.

Abstract Understanding of the mechanisms for genome integrity maintenance can help in developing effective intervention strategies to combat aging. A whole-genome RNAi screen was conducted to identify novel factors involved in maintaining genome stability. The potential target genes identified in the screening are related to the cell cycle, proteasome, and spliceosomes. Unexpectedly, the Golgi protein YIPF2 has been found to play a critical role in maintaining genome stability. The depletion of YIPF2 hinders the process of homologous recombination (HR) repair, which then triggers DNA damage response mechanisms, ultimately leading to cellular senescence. The overexpression of YIPF2 facilitated cellular recovery from DNA damage induced by chemotherapy agents or replicative senescence-associated DNA damage. Our findings indicate that only the intact Golgi apparatus containing YIPF2 provides a protective effect on genome integrity.

Abstract Background Glioblastoma (GBM) is an immunosuppressive, universally lethal cancer driven by glioblastoma stem cells (GSCs). The interplay between GSCs and immunosuppressive microglia plays crucial roles in promoting the malignant growth of GBM; however, the molecular mechanisms underlying this crosstalk are unclear. This study aimed to investigate the role of POSTN in maintaining GSCs and the immunosuppressive phenotype of microglia. Methods The expression of POSTN in GBM was identified via immunohistochemistry, quantitative real-time PCR, and immunoblotting. Tumorsphere formation assay, Cell Counting Kit-8 assay and immunofluorescence were used to determine the key role of POSTN in GSC maintenance. ChIP-seq and ChIP-PCR were conducted to confirm the binding sequences of β-catenin in the promoter region of FOSL1. Transwell migration assays, developmental and functional analyses of CD4+ T cells, CFSE staining and analysis, enzyme-linked immunosorbent assays and apoptosis detection tests were used to determine the key role of POSTN in maintaining the immunosuppressive phenotype of microglia and thereby promoting the immunosuppressive tumor microenvironment. Furthermore, the effects of POSTN on GSC maintenance and the immunosuppressive phenotype of microglia were investigated in a patient-derived xenograft model and orthotopic glioma mouse model, respectively. Results Our findings revealed that POSTN secreted from GSCs promotes GSC self-renewal and tumor growth via activation of the αVβ3/PI3K/AKT/β-catenin/FOSL1 pathway. In addition to its intrinsic effects on GSCs, POSTN can recruit microglia and upregulate CD70 expression in microglia through the αVβ3/PI3K/AKT/NFκB pathway, which in turn promotes Treg development and functionality and supports the formation of an immunosuppressive tumor microenvironment. In both in vitro models and orthotopic mouse models of GBM, POSTN depletion disrupted GSC maintenance, decreased the recruitment of immunosuppressive microglia and suppressed GBM growth. Conclusion Our findings reveal that POSTN plays critical roles in maintaining GSCs and the immunosuppressive phenotype of microglia and provide a new therapeutic target for treating GBM.

Abstract Liver ultrasound is widely used in clinical practice due to its advantages of non-invasiveness, non-radiation, and real-time imaging. Accurate segmentation of the liver region in ultrasound images is essential for accelerating the auxiliary diagnosis of liver-related diseases. This paper proposes BACANet, a deep learning algorithm designed for real-time liver ultrasound segmentation. Our approach utilizes a lightweight network backbone for liver feature extraction and incorporates a convolutional attention mechanism to enhance the network's ability to capture global contextual information. To improve early localization of liver boundaries, we developed a selective large kernel convolution module for boundary feature extraction and introduced explicit liver boundary supervision. Additionally, we designed an enhanced attention gate to efficiently convey liver body and boundary features to the decoder to enhance the feature representation capability. Experimental results across multiple datasets demonstrate that BACANet effectively completes the task of liver ultrasound segmentation, achieving a balance between inference speed and segmentation accuracy. On a public dataset, BACANet achieved a DSC of 0.921 and an IOU of 0.854. On a private test dataset, BACANet achieved a DSC of 0.950 and an IOU of 0.907, with an inference time of approximately 0.32 s per image on a CPU processor.

Abstract Background Air pollution, a reversible environmental factor, was significantly associated with the cognitive domains that are impaired in major depressive disorder (MDD), notably processing speed. Limited evidence explores the interactive effect of air pollution and the genetic risk of depression on cognition. This cross-sectional study aims to extend the research by specifically examining how this interaction influences depression-related cognitive impairment and resting-state brain function. Methods Eligible participants were 497 healthy adult volunteers (48.7% males, mean age 24.5) living in Beijing for at least 1 year and exposed to relatively high air pollution from the local community controlling for socioeconomic and genomic. Six months’ ambient air pollution exposures were assessed based on residential addresses using monthly averages of fine particulate matter with a diameter of less than or equal to 2.5 μm (PM2.5). A cross-sectional analysis was conducted using functional magnetic resonance imaging (fMRI) and cognitive performance assessments. The polygenic risk score (PRS) of MDD was used to estimate genetic susceptibility. Results Using a general linear model and partial least square regression, we observed a negative association between resting-state local connectivity in precuneus and PRS-by-PM2.5 interactive effect (P FWE = 0.028), indicating that PM2.5 exposure reduced the spontaneous activity in precuneus in individuals at high genetic risk for MDD. DNA methylation and gene expression of the SLC30A3 gene, responsible for maintaining zinc-glutamate homeostasis, was suggestively associated with this local connectivity. For the global functional connectivity, the polygenic risk for MDD augmented the neural impact of PM2.5 exposure, especially in the frontal-parietal and frontal-limbic regions of the default mode network (P FDR

Abstract Diagnostic pathology, historically dependent on visual scrutiny by experts, is essential for disease detection. Advances in digital pathology and developments in computer vision technology have led to the application of artificial intelligence (AI) in this field. Despite these advancements, the variability in pathologists’ subjective interpretations of diagnostic criteria can lead to inconsistent outcomes. To meet the need for precision in cancer therapies, there is an increasing demand for accurate pathological diagnoses. Consequently, traditional diagnostic pathology is evolving towards “next-generation diagnostic pathology”, prioritizing on the development of a multi-dimensional, intelligent diagnostic approach. Using nonlinear optical effects arising from the interaction of light with biological tissues, multiphoton microscopy (MPM) enables high-resolution label-free imaging of multiple intrinsic components across various human pathological tissues. AI-empowered MPM further improves the accuracy and efficiency of diagnosis, holding promise for providing auxiliary pathology diagnostic methods based on multiphoton diagnostic criteria. In this review, we systematically outline the applications of MPM in pathological diagnosis across various human diseases, and summarize common multiphoton diagnostic features. Moreover, we examine the significant role of AI in enhancing multiphoton pathological diagnosis, including aspects such as image preprocessing, refined differential diagnosis, and the prognostication of outcomes. We also discuss the challenges and perspectives faced by the integration of MPM and AI, encompassing equipment, datasets, analytical models, and integration into the existing clinical pathways. Finally, the review explores the synergy between AI and label-free MPM to forge novel diagnostic frameworks, aiming to accelerate the adoption and implementation of intelligent multiphoton pathology systems in clinical settings.

Highlights Ni3Fe oxide, with an average size of 3.5 ± 1.5 nm, was successfully deposited onto polyaniline (PANI) support through a solvothermal strategy followed by calcination. The catalyst–support interaction between Ni3Fe oxide and PANI can enhance the Ni-O covalency via the interfacial Ni-N bond. Ni3Fe oxide/PANI-assembled Zn-air batteries achieve superior cycling life for over 400 h at 10 mA cm−2 and a low charge potential of around 1.95 V.

Rice (Oryza sativa L.), as one of the most significant food crops worldwide, holds paramount importance for global food security. Throughout its extensive evolutionary journey, rice has evolved a diverse array of defense mechanisms to fend off pest and disease infestations. Notably, labdane-related diterpenoid phytoalexins play a crucial role in aiding rice in its response to both biotic and abiotic stresses. This article provides a comprehensive review of the research advancements pertaining to the chemical structures, biological activities, and biosynthetic pathways, as well as the molecular regulatory mechanisms, underlying labdane-related diterpenoid phytoalexins discovered in rice. This insight into the molecular regulation of labdane-related diterpenoid phytoalexin biosynthesis offers valuable perspectives for future research aimed at improving crop resilience and productivity.

Abstract Diabetic cardiomyopathy (DCM) represents a unique myocardial disease originating from diabetic metabolic disturbances that is characterized by myocardial fibrosis and diastolic dysfunction. While recent research regarding the pathogenesis and treatment of DCM has focused primarily on myocardial cells, nonmyocardial cells—including fibroblasts, vascular smooth muscle cells (VSMCs), endothelial cells (ECs), and immune cells—also contribute significantly to the pathogenesis of DCM. Among various therapeutic targets, fibroblast growth factor 21 (FGF21) has been identified as a promising agent because of its cardioprotective effects that extend to nonmyocardial cells. In this review, we aim to elucidate the role of nonmyocardial cells in DCM and underscore the potential of FGF21 as a therapeutic strategy for these cells.

Abstract The incidence of lung cancer has become the highest among all cancer types globally, also standing as a leading cause of cancer-related deaths. Lung cancer is broadly divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with the latter accounting for 85% of total cases. SRY-box transcription factor 4 (SOX4), a crucial transcription factor, has been found to play a key role in the development of various cancers. However, the association between SOX4 and NSCLC is still unclear. This study investigated the clinical relevance of SOX4 and its potential mechanisms in the progression of NSCLC. Analysis of our NSCLC patient cohort revealed a significant increase in SOX4 levels in cancerous tissues, indicating its role as an independent prognostic indicator for NSCLC. In vitro experiments demonstrated that elevated SOX4 expression facilitated NSCLC cell migration, invasion, and EMT. Functionally, SOX4 drives NSCLC progression by enhancing the transcription and expression of B-cell-specific moloney leukemia virus insertion site 1 (BMI1). The oncogenic impact of SOX4-induced BMI1 expression on NSCLC advancement was validated through both in vivo and in vitro studies. In addition, our findings showed that BMI1 promoted the ubiquitination of histone H2A (H2Aub), leading to decreased zinc finger protein 24 (ZNF24) expression, which subsequently triggered vascular endothelial growth factor A (VEGF-A) secretion in NSCLC cells, thereby promoting NSCLC angiogenesis. Moreover, we evaluated the therapeutic potential of a BMI1 inhibitor in combination with Bevacizumab for NSCLC treatment using orthotopic models. The data presented in our study reveal a previously unrecognized role of the SOX4-BMI1 axis in promoting NSCLC progression and angiogenesis. This research significantly contributes to our knowledge of the interplay between SOX4 and BMI1 in NSCLC, potentially paving the way for the development of targeted therapies for this disease.

Psoriasis is a chronic inflammatory skin condition characterized by erythematous plaques with white scales. Its pathogenesis is closely linked to oxidative stress and an imbalance in Th1/Th2 immune responses. Current treatments for psoriasis, such as topical agents, systemic therapies and phototherapy, frequently fail to achieve complete remission in clinical settings. Monomethyl fumarate (MMF), which has been approved by the US Food and Drug Administration in 2020 for multiple sclerosis, has demonstrated efficacy in psoriasis management. Additionally, our previous studies have identified aluminum ions as beneficial in psoriasis treatment. This present study investigates the combined therapeutic effects of MMF and aluminum ions and observed that the combination treatment achieves superior efficacy compared to either treatment alone in a psoriasis mouse model through the modulation of the Nrf2/NF-κB signaling pathway, as demonstrated in cellular models. The combination first activates Nrf2 nuclear translocation and induces antioxidant gene expression, followed by the inhibition of NF-κB nuclear translocation and phosphorylation, which reduces Th1 cytokine production and cellular chemotaxis. Concurrently, the treatment elevates Th2 cytokine secretion, thereby increasing the anti-inflammatory response in HaCaT cells. Overall, these findings support the MMF and aluminum ions combination (MMFAL) as a potential therapeutic strategy for psoriasis, effectively diminishing inflammation and oxidative stress.

Abstract The efficiency of nitrate reduction reaction (NO3RR) at low nitrate concentration is predominantly hindered by the poor affinity of nitrate ions and competitive hydrogen evolution reaction (HER), particularly in neutral and acidic media. Here, an innovative strategy to leverage the interfacial electric field (IEF) is introduced to boost the NO3RR performance. By in situ constructing tannic acid‐metal ion (TA‐M2+) crosslinked structure on the electrode surface, the TA‐M2+‐CuO NW/Cu foam sample exhibits an exceptional Faraday efficiency of 99.4% at −0.2 V versus reversible hydrogen electrode (RHE) and 83.9% at 0.0 V versus RHE under neutral and acidic conditions, respectively. The computational studies unveil that the TA‐Cu2+ complex on the CuO (111) plane induces the increasing concentration of nitrate at the interface, accelerating NO3RR kinetics over HER via the IEF effect. This interfacial modulation strategy also contributes the enhanced ammonia production performance when it is employed on commercial electrode materials and flow reactors, exhibiting great potential in practical application. Overall, combined results illustrated multiple merits of the IEF effect, paving the way for future commercialization of NO3RR in the ammonia production industry.

Abstract Nonalcoholic fatty liver disease (NAFLD) encompasses a broad range of conditions, commencing with simple steatosis and progressing to non‐alcoholic steatohepatitis, with the possibility of further deterioration into fibrosis, cirrhosis, and ultimately, hepatocellular carcinoma. Unfortunately, there is currently no approved medication for treating NAFLD‐associated liver steatosis. This underscores the need for improved therapeutic approaches that can modulate lipid metabolism and halt the transition from liver steatosis to chronic liver disease. Our previous studies have demonstrated that apoptotic vesicles (apoVs), which are produced during apoptosis, show great potential in regulating liver homeostasis. However, whether they can ameliorate NAFLD is unknown. In our research, apoVs derived from platelets (PLT‐apoVs) as well as apoVs derived from mesenchymal stem cells (MSC‐apoVs) were used to treat NAFLD. The results showed that PLT‐apoVs exhibited superior effects in diminishing lipid accumulation in liver induced by high‐fat diet than MSC‐apoVs. Through proteomic analysis, we defined and validated apolipoprotein A‐II (APOA2) as a regulator for apoV‐mediated MSC adipogenesis, which could be used as a target to enhance apoV therapeutic potential in the lipid metabolism biomedical field. Owing to the higher expression of APOA2, PLT‐apoVs showed better therapeutic effects than MSC‐apoVs. Our results pave the way to apoV‐based therapy for NAFLD.

IntroductionPublic health interventions increasingly integrate multimodal data sources, such as Electroencephalogram (EEG) data, to enhance monitoring and predictive capabilities for mental health conditions. However, traditional models often face challenges with the complexity and high dimensionality of EEG signals. While recent advancements like Contrastive Language-lmage Pre-training(CLIP) models excel in cross-modal understanding, their application to EEG-based tasks remains limited due to the unique characteristics of EEG data.MethodsIn response, we introduce PH-CLIP (Public Health Contrastive Language-lmage Pretraining), a novel framework that combines CLIP's representational power with a multi-scale fusion mechanism designed specifically for EEG data within mobile health technologies. PH-CLIP employs hierarchical feature extraction to capture the temporal dynamics of EEG signals, aligning them with contextually relevant textual descriptions for improved public health insights. Through a multi-scale fusion layer, PH-CLIP enhances interpretability and robustness in EEG embeddings, thereby supporting more accurate and scalable interventions across diverse public health applications.Results and discussionExperimental results indicate that PH-CLIP achieves significant improvements in EEG classification accuracy and mental health prediction efficiency compared to leading EEG analysis models. This framework positions PH-CLIP as a transformative tool in public health monitoring, with the potential to advance large-scale mental health interventions through integrative mobile health technologies.

Abstract Persistent H. pylori infection triggers the repair program of the mucosa, such as spasmolytic polypeptide‐expressing metaplasia (SPEM). However, the mechanism underlying the initiation of SPEM in gastric tissues by H. pylori remains unclear. Here, an increase in telomerase reverse transcriptase (TERT) protein expression is observed in chief cells upon infection with cagA‐positive H. pylori. Tert knockout significantly ameliorated H. pylori‐induced SPEM and single‐cell RNA sequencing demonstrated that the Wnt/β‐Catenin pathway is suppressed in gastric cells with Tert knockout. Mechanism study revealed that CagA elevated TERT abundance by disrupting the interaction between TERT and its novel E3 ligase, SYVN1. Interestingly, Nitazoxanide effectively relieved SPEM via inhibition of the Wnt/β‐Catenin signaling in vivo. This results clarified the mechanism underlying which CagA activated the TERT/Wnt/β‐Catenin pathway, thus promoting the dedifferentiation of chief cells and the occurrence of SPEM in gastric mucosa. This highlights a molecular basis for targeting CagA‐activated Wnt signaling in chief cells for the treatment of gastric precancerous lesions.

ObjectiveThe adherence to plant-based diets has been shown to positively impact longevity by reducing the incidence and severity of lifestyle-related diseases. Previous studies on the association of plant-based dietary pattern, as evaluated by plant-based dietary index (PDI), healthy plant-based dietary index (hPDI) and unhealthy plant-based dietary index (uPDI), with mortality risk have reported inconsistent results. We performed the present meta-analysis to summarize evidence on this association and to quantify the potential dose–response relationship based on all available cohort studies.MethodsA comprehensive literature search and systematic review of relevant articles up to October 2024 was performed in PubMed and Scopus. The summary risk estimates (RR) with 95% confidence interval (CI) for the highest versus the lowest category of PDIs, hPDIs and uPDIs were calculated. Dose–response meta-analysis was also performed for studies reporting categorical risk estimates for at least three quantitative levels of PDIs, hPDIs and uPDIs.ResultsA total of 11 eligible cohort studies (13 datasets) were eventually included in this meta-analysis. Participants in the highest quintile of both the PDI and hPDI had a significantly decreased risk of all-cause mortality (pooled HRPDI = 0.85; 95% CI: 0.80–0.90; pooled HRhPDI = 0.86; 95% CI: 0.81–0.92) compared to participants in the lowest quintile. In contrast, the highest uPDI was associated with an increased risk of mortality (pooled HRuPDI = 1.20; 95% CI: 1.11–1.31). Dose–response meta-analysis showed that there was a non-linear relationship between PDI or hPDI level and all-cause mortality (p = 0.001 and p

Objective The objective of this study is to evaluate the efficacy and safety of jaktinib hydrochloride tablets (jaktinib), a Janus kinase inhibitor, in patients with active radiographic axial spondyloarthritis (r-axSpA).Methods Adults with active r-axSpA who met modified New York criteria and had an inadequate response to non-steroidal anti-inflammatory drugs were randomised 1:1:1 to receive jaktinib 75 mg two times per day, 100 mg two times per day, or placebo. The primary and key secondary endpoints were Assessment of SpondyloArthritis international Society 20 (ASAS 20) and ASAS 40 responses, respectively, at week 16. Safety was evaluated by analysing adverse events.Results A total of 107 patients with active r-axSpA were randomised (jaktinib 75 mg two times per day, n=35; jaktinib 100 mg two times per day, n=36; placebo, n=36). In the ASAS20 response rates, the 100 mg two times per day group had the highest response at 61.1%, followed by the 75 mg two times per day group at 57.1%, and the placebo group had the lowest at 33.3% for the 16 weeks of treatment. The ASAS40 response rates were significantly higher with jaktinib (100 mg two times per day group: 47.2%, 75 mg two times per day group: 37.1%) compared with placebo (13.9%). The incidence of treatment-emergent adverse events in the 75 mg two times per day, 100 mg two times per day and placebo groups was 88.6% versus 94.4% versus 86.1%, respectively, with no statistically significant difference among the three groups. No major adverse cardiovascular events, malignancy, thromboembolism or deaths were reported.Conclusions Jaktinib showed good efficacy and tolerability in the treatment of active r-axSpA, with the 100 mg two times per day showing a trend towards better efficacy.Trial registration number NCT04507659.

Summary: The electroreduction of nitrate has emerged as a promising global strategy for water purification in the face of harmful nitrate in wastewater. However, the usually low concentration of nitrate in wastewater poses a great challenge to this process, thus necessitating more in-depth studies to optimize its efficiency. This perspective article briefly explores the various electrochemical pathways of nitrate reduction, including the conversion of nitrate to ammonia, the conversion of nitrate to dinitrogen, and the C-N coupled reduction process. In addition, the feasibility of the electroreduction method is assessed from the concentration nitrate sources, reactor design, and promising energy sources, while also offering insights into prospective developments for further research.

Chicken is an important economic animal that encounter various stressors including high temperature, high stocking density, bacterial infections and transportation, etc. affecting the poultry production with serious economic loss. To be in response to the varied stimulus, the hypothalamic-pituitary-adrenal (HPA) axis is activated through the controlling of the synthesis and secretion of glucocorticoids (GCs). Present study characterized a novel gene C5H11ORF96, that demonstrated significant upregulation after the DEX injection in chicken, which simulates the stress stimulus. Our results showed that: (1) cC5H11ORF96 cDNA encodes a 120 amino acids protein, which shares high sequence identity with that of birds, mammals, reptiles, frogs and fish; (2) cC5H11ORF96 has a fully conserved RFKTQP motif and high proportion of serine, indicating its multiple potential phosphorylation sites; (3) cC5H11ORF96 is widely expressed in various chicken tissues, with high expression levels in the parathyroid gland, adrenal gland, and pituitary; (4) glucocorticoids (GCs) and stress significantly upregulate C5H11ORF96 mRNA and protein expression in the chicken pituitary and hypothalamus, suggesting its involvement in regulating stress response by influencing the negative feedback of GCs on the HPA axis in chickens. The characterization of the C5H11ORF96 gene in the chicken stress response provides potential targets for stress adaptability and poultry production. Meanwhile, our finding provides essential insights into the physiological functions of C11ORF96 gene in vertebrates.

Introduction Despite the implementation of mechanical thrombectomy, acute ischaemic stroke with large vessel occlusion (AIS-LVO) remains a significant health concern, characterised by substantial morbidity and mortality. Our trial aims to evaluate the efficacy and safety of minocycline in reducing infarct volume and improving functional outcomes in patients undergoing mechanical thrombectomy for anterior circulation AIS-LVO.Methods and analysis The MIST-A trial is a prospective, randomised, open-label, blinded-endpoint trial to be conducted across 12 medical centres. The study will enrol 180 adult patients who have experienced an anterior circulation AIS-LVO and have undergone mechanical thrombectomy. These patients will be randomly divided into two groups: one receiving minocycline in addition to standard care and the other receiving only standard care. The primary efficacy outcome is the change in infarct volume as measured by MRI, from baseline to day 5. The secondary efficacy outcomes include the incidence of intracerebral haemorrhage occurring within 24 hours and the clinical scores between the baseline and follow-up assessments. The primary outcome will be assessed using a mixed-effects model to determine the association between treatment and outcomes.Ethics and dissemination The study is approved by the Ethics Committee of Xijing Hospital (XJLL-KY20222186) and is registered at ClinicalTrials.gov (NCT05487417). This trial is estimated to end in the first quarter of 2025 and study findings are expected to be published in scientific journals that undergo peer review and also to be showcased at scientific conferences.Trial registration number NCT05487417.

Antibiotic resistance is a global health concern that is rapidly spreading among human and animal pathogens. Developing novel antibiotics is one of the most significant approaches to surmount antibiotic resistance. Given the difficult in identifying novel targets, cryptic binding sites provide new pockets for compounds design to combat antibiotic resistance. However, there exists a lack of comprehensive analysis and discussion on the successful utilization of cryptic pockets in overcoming antibiotic resistance. Here, we systematically analyze the crucial role of cryptic pockets in neutralizing antibiotic resistance. First, antibiotic resistance development and associated resistance mechanisms are summarized. Then, the advantages and mechanisms of cryptic pockets for overcoming antibiotic resistance were discussed. Specific cryptic pockets in resistant proteins and successful case studies of designed inhibitors are exemplified. This review provides insight into the discovery of cryptic pockets for drug design as an approach to overcome antibiotic resistance

Abstract Oral diseases affect nearly half of the global population throughout their lifetime causing pain, as estimated by the World Health Organization. Preservation of vital pulp is the therapeutic core as well as a challenge to protect natural teeth. Current bottleneck lies in that the regenerative capacity of injured pulp is undetermined. In this study, we identified a lifelong lineage that is labelled by cathepsin K (Ctsk) contributing to the physiological, reactionary and reparative odontogenesis of mouse molars. Ctsk+ cell‐mediated dentin formation is regulated by nociceptive nerve‐derived Sonic Hedgehog (Shh), especially rapidly responsive to acute injury. Notably, exogenous Shh protein to the injury pulp can preserve Ctsk+ cell capacity of odontogenesis for the nearby crown pulp and even remote root apex growth, alleviating conventionally developmental arrest in youth pulpitis. Exposed to chronical attrition, aged pulp Ctsk+ cells still hold the capacity to respond to acute stimuli and promote reparative odontogenesis, also enhanced by exogenous Shh capping. Therefore, Ctsk+ cells may be one of the lineages for accelerating precision medicine for efficient pulp treatment across ages. Shh application can be a candidate for vital pulp preservation and pulp injury repair by promoting regenerative odontogenesis to a certain extent from young adults to older individuals.

Abstract Cardiovascular disease remains the leading cause of high mortality in individuals with diabetes mellitus. Endothelial injury is a major contributing factor for vascular dysfunction in diabetes. However, the precise mechanisms underlying endothelial cell injury and their heterogeneity in diabetes remains elusive. In this study, single‐cell sequencing is performed in heart tissues from leptin receptor knock‐out (db/db) diabetic mice at various pathological stages. Through cell cluster identification, differential gene analysis, intercellular communication analysis, pseudo time analysis, and transcription factor analysis, a novel mechanism of cardiac vascular endothelial damage in diabetes is identified. Specifically, a single‐cell transcription map of cardiac vascular endothelial cells is presented in db/db mice. Diverse cellular clusters are found to play vital roles under diabetes‐induced damage, highlighting crucial transcription factors involved in their regulation. In addition, the essential transcription factor Ets1 is found to protect against vascular endothelial injury in db/db mice. In summary, the work provides a comprehensive understanding of the development of diabetic cardiac vascular endothelial damage and the heterogeneity of the cells involved. These findings offer valuable insights into potential treatments and assessments of diabetic cardiovascular endothelial damage.

Smart ageing is the process of leveraging accessible socio-ecological opportunities to proactively build the desired lifestyle and preferred quality of life as people age. Different from other ageing models, smart ageing views the ageing process from a socio-ecological perspective, a process which is shaped by the interplay of social, cultural, economic, political, and technological factors, along with medical ones. Rather than taking a one-size-fits-all approach and pre-emptively defining a “universal” factor that decides the ageing process, smart ageing respects and emphasises individuals’ agency and efficacy in deciding what is important and appropriate to their well-being and designing their own ageing journey. While smart ageing can be a solution to population ageing, ingrained inequality issues like the digital divide can nevertheless hinder its ability to help people age at their own pace and with grace. To shed light on the issue, this paper examines the tsunami of social issues population ageing could unleash, and discusses how the smart ageing model—along with its opportunities and challenges—can help people better navigate their ageing adventure.

The population disease burden caused by extreme temperature events has been increasing. However, research on the long-term effects of extreme temperature events on chronic kidney disease (CKD), as well as the combined effects with individual behaviors and metabolic factors is still lacking. Based on 176,874 participants from the most recent nationally representative surveillance on CKD and validated high spatial resolution (0.1°) remote-sensing products, this study investigated the associations between extreme temperature events in the preceding five years before investigation and CKD (defined by reduced renal function or albuminuria) prevalence. We also investigated the associations between “Life’s Essential 8”, a recognized scale to evaluate overall cardiovascular health (CVH) based on individual behaviors and metabolic indicators and CKD prevalence, as well as its combined effects with extreme temperature events. One additional day of heat waves and cold spells per year was associated with increased ORs of CKD [1.10 (95 % CI: 1.08, 1.11) and 1.07 (95 % CI: 1.05, 1.09), respectively]. Meanwhile, per standard deviation (SD) increment in health behavior score (SD = 16.1), health factor score (SD = 18.4), and overall CVH score (SD = 12.4) were associated with decreased ORs of CKD [0.92 (95 % CI: 0.90, 0.93), 0.60 (95 % CI: 0.59, 0.61), and 0.64 (95 % CI: 0.63, 0.65, respectively]. Relative to higher heat wave & lower CVH score group, the ORs of CKD were 0.87 (95 % CI: 0.84, 0.90), 0.51 (95 % CI: 0.48, 0.53), and 0.42 (95 % CI: 0.40, 0.44) in lower & lower, higher & higher, and lower & higher group, respectively. Our findings underscore the importance of considering the synergistic effects of individual behavioral and metabolic factors for strategies to mitigate the impacts of climate change on CKD.

Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated both efficacy and safety in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients infected with hepatitis B virus (HBV). However, its applicability in individuals with liver cirrhosis remains largely unexplored due to the potential for unpredictable complications. Here, we report three cases (P1, P2, and P3) of relapsed/refractory DLBCL with HBV-related cirrhosis treated with CAR-T cell infusion. P1 and P2 received CAR-T cell infusion following a conditioning regimen of fludarabine and cyclophosphamide (FC) for lymphodepletion, while P3 received the SEAM (semustine, etoposide, cytarabine, and melphalan) regimen and autologous stem cell transplantation bridging CAR-T cell infusion. P1 and P2 achieved rapid complete remission (CR), whereas P3 initially exhibited stable disease a month after CAR-T infusion and subsequently achieved CR after local radiation salvage therapy and lenalidomide maintenance. With a median follow-up of 42 months after CAR-T, the progression-free survival rate was 100%. Notably, during follow-up, these patients experienced complications associated with cirrhosis, including endoscopic variceal bleeding, HBV reactivation, or the diagnosis of hepatic malignancy. Our findings suggest that CAR-T therapy is applicable and effective for the treatment of DLBCL patients with HBV-related cirrhosis, albeit necessitating monitoring for potential hepatic complications.

The Qinghai Lake National Nature Reserve (QLNNR), renowned for its abundant natural resources and diverse ecological habitats, serves as an ideal environment for ticks, thereby increasing the risk of various tick-borne pathogens (TBPs) transmission. This study aimed to investigate the prevalence of TBPs in ticks collected from Przewalski's gazelle and Tibetan sheep within the QLNNR. A total of 313 tick samples were collected from the vicinity of Qinghai Lake. Tick species identification was conducted using both morphological and molecular biology techniques. Polymerase chain reaction (PCR) amplification was performed to detect the presence of spotted fever group (SFG) Rickettsia, Coxiella burnetii, Anaplasma phagocytophilum, Babesia microti, Theileria spp, Borrelia burgdorferi, Brucella spp, and Anaplasma ovis was performed using specific primers. Positive samples were sequenced and analyzed using BLASTn, followed by phylogenetic tree construction. The ticks collected from the Qinghai Lake area were identified as Dermacentor nuttalli. The overall prevalence rates of ticks carrying SFG Rickettsia and C. burnetii were 42.8 % (134/313) and 4.8 % (15/313), respectively. Three SFG Rickettsia species were detected, including R. raoultii 33.9 % (106/313), R. slovaca 3.8 % (12/113) and R. sibirica 7.7 % (24/113), with R. raoultii being the predominant species. The prevalence rates of SFG Rickettsia and C. burnetii in ticks from Tibetan sheep was 44.7 % (115/257) and 4.7 % (12/257), respectively,and in ticks from Przewalski's gazelle were 33.9 % (19/56) and 5.4 % (3/56). Furthermore, the study revealed a positive linear relationship between the abundance of Przewalski's gazelle and the number of ticks, as well as the prevalence of TBPs. The current study has identified Dermacentor nuttalli as the predominant tick vector species within the QLNNR region. The detection of SFG Rickettsia and C. burnetii has augmented our understanding of the epidemiological profile of ticks and TBPs in this area, thereby providing a robust theoretical foundation for the implementation of effective prevention and control strategies against TBPs.