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Abstract Background The hippocampus, with its complex subfields, is linked to numerous neuropsychiatric traits. While most research has focused on its global structure or a few specific subfields, a comprehensive analysis of hippocampal substructures and their genetic correlations across a wide range of neuropsychiatric traits remains underexplored. Given the hippocampus’s high heritability, considering hippocampal and subfield volumes (HASV) as endophenotypes for neuropsychiatric conditions is essential. Methods We analyzed MRI-derived volumetric data of hippocampal and subfield structures from 41,525 UK Biobank participants. Genome-wide association studies (GWAS) on 24 HASV traits were conducted, followed by genetic correlation, overlap, and Mendelian randomization (MR) analyses with 10 common neuropsychiatric traits. Polygenic risk scores (PRS) based on HASV traits were also evaluated for predicting these traits. Results Our analysis identified 352 independent genetic variants surpassing a significance threshold of 2.1 × 10−9 within the 24 HASV traits, located across 93 chromosomal regions. Notably, the regions 12q14.3, 17q21.31, 12q24.22, 6q21, 9q33.1, 6q25.1, and 2q24.2 were found to influence multiple HASVs. Gene set analysis revealed enrichment of neural differentiation and signaling pathways, as well as protein binding and degradation. Of 240 HASV-neuropsychiatric trait pairs, 75 demonstrated significant genetic correlations (P

Due to overactive inflammation and hindered angiogenesis, self-healing of diabetic wounds (DW) remains challenging in the clinic. Platelet-derived exosomes (PLT-Exos), a novel exosome capable of anti-inflammation and pro-angiogenesis, show great potential in DW treatment. However, previous administration of exosomes into skin wounds is topical daub or intradermal injection, which cannot intradermally deliver PLT-Exos into the dermis layer, thus impeding its long-term efficacy in anti-inflammation and pro-angiogenesis. Herein, a dissolvable microneedle-based wound dressing (PLT-Exos@ADMMA-MN) was developed for transdermal and long-term delivery of PLT-Exos. Firstly, a photo-crosslinking methacrylated acellular dermal matrix-based hydrogel (ADMMA-GEL), showing physiochemical tailorability, fast-gelling performance, excellent biocompatibility, and pro-angiogenic capacities, was synthesized as a base material of our dressing. For endowing the dressing with anti-inflammation and pro-angiogenesis, PLT-Exos were encapsulated into ADMMA-GEL with a minimum effective concentration determined by our in-vitro experiments. Then, in-vitro results show that this dressing exhibits excellent properties in anti-inflammation and pro-angiogenesis. Lastly, in-vivo experiments showed that this dressing could continuously and transdermally deliver PLT-Exos into skin wounds to switch local macrophage into M2 phenotype while stimulating neovascularization, thus proving a low-inflammatory and pro-angiogenic microenvironment for DW healing. Collectively, this study provides a novel wound dressing capable of suppressing inflammation and stimulating vascularization for DW treatment.

Abstract The tumor microenvironment (TME) plays an important role in the occurrence and progression of Acute Myeloid Leukemia (AML). Single-cell sequencing has enabled researchers to explore the correlation between TME subgroups and tumor prognosis, distinguish the existence of drug-resistant subgroups of tumor cells, and unravel the complexity of the AML cellular heterogeneity. We used bone marrow immune cell enrichment analysis from public databases to screen prognostic genes, construct prognostic models, and validate their prognostic significance on independent external datasets and patient samples. A total of 18,251 single cells were obtained to establish prognostic scoring models for 10 key genes including CCL5, ETLS2, and IL2RA.The AML cases were divided into two groups: high-risk and low-risk. The low-risk group exhibited a higher survival rate than the high-risk group. The areas under curves (AUC) of 1-, 3- and 5-year survival curves in the TCGA and GEO training sets were greater than 0.8 and 0.6, respectively, indicating effective prediction. The model’s prognostic efficacy was confirmed across multiple validation sets. It demonstrated increased expression of ETS2, CCL5, and IL2RA in AML samples compared to controls, which was associated with decreased overall survival (OS). This prognostic scoring model based on tumor immune infiltration provides a reference for developing novel treatment strategies for recurrent/refractory AML.

Abstract Background The accuracy of traditional knee MR imaging in diagnosing anterior cruciate ligament tears, especially partial tears, is relatively low, which may lead to misdiagnosis and missed diagnosis. This study aimed to assess the diagnostic performance of a novel imaging method, high-resolution oblique coronal MRI at an optimal flexed-knee Angle, for ACL tears. Methods 50 healthy volunteers were scanned with a scan-assisted device for the optimal flexion angle of ACL. For 92 knee trauma patients selected strictly according to inclusion and exclusion criteria, conventional extended-knee scans (control group) and high-resolution oblique coronal scans based on the optimal flexed-knee angle (experimental group) were conducted. Two observers rated ACL visibility blindly on a 5-point scale. Arthroscopy-defined outcomes determined diagnostic metrics for each method and sensitivity, specificity, positive predictive value, negative predictive value and accuracy were calculated. Results The average optimal flexion angle for healthy volunteers was approximately 30° (30.3° ± 5.0°). Imaging demonstrated complete visualization of the ACL in 96.7% of images in the experimental group versus 12.0% in the control group. The diagnostic indicators of the experimental group surpassed those of the control group: sensitivity (94.9% vs. 76.3%), specificity (97.0% vs. 81.8%), positive predictive value (98.2% vs. 88.2%), negative predictive value(91.4% vs. 65.9%), and accuracy (95.7% vs. 78.3%). ROC analysis indicated superior diagnostic performance in the experimental group, with an AUC of 0.945 compared with 0.776 for the control group (p

Abstract Background Dysregulation of enhancer transcription occurs in multiple cancers. Enhancer RNAs (eRNAs) are transcribed products from enhancers that play critical roles in transcriptional control. Characterizing the genetic basis of eRNA expression may elucidate the molecular mechanisms underlying cancers. Methods Initially, a comprehensive analysis of eRNA quantitative trait loci (eRNAQTLs) was performed in The Cancer Genome Atlas (TCGA), and functional features were characterized using multi-omics data. To establish the first eRNAQTL profiles for colorectal cancer (CRC) in China, epigenomic data were used to define active enhancers, which were subsequently integrated with transcription and genotyping data from 154 paired CRC samples. Finally, large-scale case-control studies (34,585 cases and 69,544 controls) were conducted along with multipronged experiments to investigate the potential mechanisms by which candidate eRNAQTLs affect CRC risk. Results A total of 300,112 eRNAQTLs were identified across 30 different cancer types, which exert their influence on eRNA transcription by modulating chromatin status, binding affinity to transcription factors and RNA-binding proteins. These eRNAQTLs were found to be significantly enriched in cancer risk loci, explaining a substantial proportion of cancer heritability. Additionally, tumor-specific eRNAQTLs exhibited high responsiveness to the development of cancer. Moreover, the target genes of these eRNAs were associated with dysregulated signaling pathways and immune cell infiltration in cancer, highlighting their potential as therapeutic targets. Furthermore, multiple ethnic population studies have confirmed that an eRNAQTL rs3094296-T variant decreases the risk of CRC in populations from China (OR = 0.91, 95%CI 0.88–0.95, P = 2.92 × 10−7) and Europe (OR = 0.92, 95%CI 0.88–0.95, P = 4.61 × 10−6). Mechanistically, rs3094296 had an allele-specific effect on the transcription of the eRNA ENSR00000155786, which functioned as a transcriptional activator promoting the expression of its target gene SENP7. These two genes synergistically suppressed tumor cell proliferation. Our curated list of variants, genes, and drugs has been made available in CancereRNAQTL ( http://canernaqtl.whu.edu.cn/#/ ) to serve as an informative resource for advancing this field. Conclusion Our findings underscore the significance of eRNAQTLs in transcriptional regulation and disease heritability, pinpointing the potential of eRNA-based therapeutic strategies in cancers.

Abstract Background Early detection of colorectal neoplasms can reduce the colorectal cancer (CRC) burden by timely intervention for high-risk individuals. However, effective risk prediction models are lacking for personalized CRC early screening in East Asian (EAS) population. We aimed to develop, validate, and optimize a comprehensive risk prediction model across all stages of the dynamic adenoma-carcinoma sequence in EAS population. Methods To develop precision risk-stratification and intervention strategies, we developed three trans-ancestry PRSs targeting colorectal neoplasms: (1) using 148 previously identified CRC risk loci (PRS148); (2) SNPs selection from large-scale meta-analysis data by clumping and thresholding (PRS183); (3) PRS-CSx, a Bayesian approach for genome-wide risk prediction (PRSGenomewide). Then, the performance of each PRS was assessed and validated in two independent cross-sectional screening sets, including 4600 patients with advanced colorectal neoplasm, 4495 patients with non-advanced adenoma, and 21,199 normal individuals from the ZJCRC (Zhejiang colorectal cancer set; EAS) and PLCO (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; European, EUR) studies. The optimal PRS was further incorporated with lifestyle factors to stratify individual risk and ultimately tested in the PLCO and UK Biobank prospective cohorts, totaling 350,013 participants. Results Three trans-ancestry PRSs achieved moderately improved predictive performance in EAS compared to EUR populations. Remarkably, the PRSs effectively facilitated a thorough risk assessment across all stages of the dynamic adenoma-carcinoma sequence. Among these models, PRS183 demonstrated the optimal discriminatory ability in both EAS and EUR validation datasets, particularly for individuals at risk of colorectal neoplasms. Using two large-scale and independent prospective cohorts, we further confirmed a significant dose–response effect of PRS183 on incident colorectal neoplasms. Incorporating PRS183 with lifestyle factors into a comprehensive strategy improves risk stratification and discriminatory accuracy compared to using PRS or lifestyle factors separately. This comprehensive risk-stratified model shows potential in addressing missed diagnoses in screening tests (best NPV = 0.93), while moderately reducing unnecessary screening (best PPV = 0.32). Conclusions Our comprehensive risk-stratified model in population-based CRC screening trials represents a promising advancement in personalized risk assessment, facilitating tailored CRC screening in the EAS population. This approach enhances the transferability of PRSs across ancestries and thereby helps address health disparity. Graphical Abstract

Tumor cells voraciously consume nutrients from their environment to facilitate rapid proliferation, necessitating effective strategies to manage nutrient scarcity during tumor growth and progression. A pivotal regulatory mechanism in this context is the Integrated Stress Response (ISR), which ensures cellular homeostasis under conditions such as endoplasmic reticulum stress, the unfolded protein response, and nutrient deprivation. Within the ISR framework, the kinase GCN2 is critical, orchestrating a myriad of cellular processes including the inhibition of protein synthesis, the enhancement of amino acid transport, autophagy initiation, and angiogenesis. These processes collectively enable tumor survival and adaptation under nutrient-limited conditions. Furthermore, GCN2-mediated pathways may induce apoptosis, a property exploited by specific therapeutic agents. Leveraging extensive datasets from TCGA, GEO, and GTEx projects, we conducted a pan-cancer analysis to investigate the prognostic significance of GCN2 expression across diverse cancer types. Our analysis indicates that GCN2 expression significantly varies and correlates with both adverse and favorable prognoses depending on the type of cancer, illustrating its complex role in tumorigenesis. Importantly, GCN2 also modulates the tumor immune microenvironment, influencing immune checkpoint expression and the functionality of immune cells, thereby affecting immunotherapy outcomes. This study highlights the potential of targeting GCN2 with specific inhibitors, as evidenced by their efficacy in preclinical models to augment treatment responses and combat resistance in oncology. These findings advocate for a deeper exploration of GCN2′s multifaceted roles, which could pave the way for novel targeted therapies in cancer treatment, aiming to improve clinical outcomes.

BackgroundThis study aimed to investigate epidemiologic characteristics of major human infection with avian influenza and explore the factors underlying the spatial distributions, particularly H5N6 and H9N2, as H9N2 could directly infect mankind and contribute partial or even whole internal genes to generate novel human-lethal reassortants such as H5N6. They pose potential threats to public health and agriculture.MethodsThis study collected cases of H5N1, H5N6, H9N2, and H7N9 in China, along with data on ecoclimatic, environmental, social and demographic factors at the provincial level. Boosted regression tree (BRT) models, a popular approach to ecological studies, has been commonly used for risk mapping of infectious diseases, therefore, it was used to investigate the association between these variables and the occurrence of human cases for each subtype, as well as to map the probabilities of human infections.ResultsA total of 1,123 H5N1, H5N6, H9N2, and H7N9 human cases have been collected in China from 2011 to 2024. Factors including density of pig and density of human population emerged as common significant predictors for H5N1 (relative contributions: 5.3, 5.8%), H5N6 (10.8, 6.4%), H9N2 (11.2, 7.3%), and H7N9 (9.4, 8.0%) infection. Overall, each virus has its own ecological and social drivers. The predicted distribution probabilities for H5N1, H5N6, H9N2, and H7N9 presence are highest in Guangxi, Sichuan, Guangdong, and Jiangsu, respectively, with values of 0.86, 0.96, 0.93 and 0.99.ConclusionThis study highlighted the important role of social and demographic factors in the infection of different avian influenza, and suggested that monitoring and control of predicted high-risk areas should be prioritized.

Background Comfort is a primary goal of healthcare. Theory-informed interventions and measurement are essential for comfort enhancement.Objectives To categorise and synthesise the international literature on the application of Kolcaba’s Comfort Theory in research and practice aiming to promote adults’ comfort.Eligibility criteria Papers reporting the application of Kolcaba’s Comfort Theory on adult participants published in English and Chinese.Sources of evidence MEDLINE, CINAHL, APA PsycInfo, Embase, AMED, Web of Science, Scopus, The Cochrane Library, JBI EBP Database, CNKI, Wan Fang; grey literature of Google Scholar, Baidu Scholar and The Comfort Line were searched from January 1991 to January 2024.Chart methods Following the Joanna Briggs Institute guidance and Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist, two reviewers selected papers and extracted data independently using a standardised chart embedded in NVivo software. A thematic synthesis and a descriptive analysis were provided.Results The review included 359 papers. Approximately two-thirds (n=216, 60.2%) had been published since 2017. The majority of papers (n=316, 88.0%) originated from China, the USA, Turkey, Brazil and Portugal. The use of Kolcaba’s Comfort Theory was dominated in a range of hospital settings (n=263) and with participants suffering neoplasms (n=55). Seven categories of theory application were identified: (I) interventions underpinned by Comfort Theory as the theoretical framework, (II) interventions evaluated by instruments derived from Comfort Theory, (III) descriptive or observational studies of services or practices underpinned by Comfort Theory, (IV) surveys using questionnaires derived from Comfort Theory, (V) questionnaires development or adaption based on Comfort Theory, (VI) qualitative studies interpreted by Comfort Theory and (VII) literature reviews and discussion about Comfort Theory use. The most commonly evaluated interventions included music therapy (n=31), position intervention (n=20) and massage (n=19), and the most commonly used questionnaire was General Comfort Questionnaire (n=109).Conclusions Kolcaba’s Comfort Theory has been largely used in interventions and assessments across a wide range of contexts, providing a set of options for practitioners. However, quantifying evidence is needed through further systematic reviews, and continuous development of Comfort Theory is warranted based on the categorisation by this review.

Abstract In this comprehensive genome-wide study, we identified and classified 83 Xylanase Inhibitor Protein (XIP) genes in wheat, grouped into five distinct categories, to enhance understanding of wheat's resistance to Fusarium head blight (FHB), a significant fungal threat to global wheat production. Our analysis reveals the unique distribution of XIP genes across wheat chromosomes, particularly at terminal regions, suggesting their role in the evolutionary expansion of the gene family. Several XIP genes lack signal peptides, indicating potential alternative secretion pathways that could be pivotal in plant defense against FHB. The study also uncovers the sequence homology between XIPs and chitinases, hinting at a functional diversification within the XIP gene family. Additionally, the research explores the association of XIP genes with plant immune mechanisms, particularly their linkage with plant hormone signaling pathways like abscisic acid and jasmonic acid. XIP-7A3, in particular, demonstrates a significant increase in expression upon FHB infection, highlighting its potential as a key candidate gene for enhancing wheat's resistance to this disease. This research not only enriches our understanding of the XIP gene family in wheat but also provides a foundation for future investigations into their role in developing FHB-resistant wheat cultivars. The findings offer significant implications for wheat genomics and breeding, contributing to the development of more resilient crops against fungal diseases.

Highlights A composite thermal interface material with three-dimensional hybrid carbon network-reinforced polydimethylsiloxane was proposed. The cooperative regulation of thermal conductivity and mechanical properties was achieved by controlling the assembly process of micro-nano scale unit carbon materials. The orthotropic continuous carbon structure endowed the composites with in-plane and out-of-plane thermal conductivities of up to 113.61 and 24.37 W m−1 K−1, respectively. The excellent compressibility and adhesion properties cooperatively improved the effective thermal conductivity by more than an order of magnitude.

Abstract Background The general sluggish clearance kinetics of functional inorganic nanoparticles tend to raise potential biosafety concerns for in vivo applications. Renal clearance is a possible elimination pathway for functional inorganic nanoparticles delivered through intravenous injection, but largely depending on the surface physical chemical properties of a given particle apart from its size and shape. Results In this study, three small-molecule ligands that bear a diphosphonate (DP) group, but different terminal groups on the other side, i.e., anionic, cationic, and zwitterionic groups, were synthesized and used to modify ultrasmall Fe3O4 nanoparticles for evaluating the surface structure-dependent renal clearance behaviors. Systematic studies suggested that the variation of the surface ligands did not significantly increase the hydrodynamic diameter of ultrasmall Fe3O4 nanoparticles, nor influence their magnetic resonance imaging (MRI) contrast enhancement effects. Among the three particle samples, Fe3O4 nanoparticle coated with zwitterionic ligands, i.e., Fe3O4@DMSA, exhibited optimal renal clearance efficiency and reduced reticuloendothelial uptake. Therefore, this sample was further labeled with 99mTc through the DP moieties to achieve a renal-clearable MRI/single-photon emission computed tomography (SPECT) dual-modality imaging nanoprobe. The resulting nanoprobe showed satisfactory imaging capacities in a 4T1 xenograft tumor mouse model. Furthermore, the biocompatibility of Fe3O4@DMSA was evaluated both in vitro and in vivo through safety assessment experiments. Conclusions We believe that the current investigations offer a simple and effective strategy for constructing renal-clearable nanoparticles for precise disease diagnosis. Graphical Abstract

Background: Anterior cruciate ligament (ACL) rupture is a common sports injury, which causes knee instability and abnormal joint kinematics. The current ACL graft was single-phasic, and not convenient for the formation of enthesis-like tissue in the bone tunnel, resulting in poor integration of graft-to-bone. Methods: A band-shaped acellular tendon (BAT) was prepared as the core component of the ACL reconstruction graft at first, while sleeve-shaped acellular cartilage (SAC) or sleeve-shaped acellular bone (SAB) was fabricated using a vacuum aspiration system (VAS)-based decellularization protocol. The biocompatibility of the three acellular matrixes was evaluated. Furthermore, a collagen-binding peptide (CBP) derived from the A3 domain of von Willebrand factor was respectively fused into the N-terminal of GDF7, TGFβ3, or BMP2 to synthesize three recombinant growth factors capable of binding collagen (named C-GDF7, C-TGFβ3, or C-BMP2), which were respectively tethered to the BAT, SAC or SAB for improving their inducibilities in stem cell differentiation. An in-vitro experiment was performed to evaluate theirs osteogenic, chondrogenic, and tenogenic inducibilities. Then, C-TGFβ3-tethering SAC (C-TGFβ3@SAC) and C-BMP2-tethering SAB (C-BMP2@SAB) were sequentially surrounded at the bone tunnel part of C-GDF7-tethering BAT (C-GDF7@BAT), thus a sleeve-shaped acellular graft with a triphasic enthesis-like structure in bone tunnel part (named tissue-engineered graft, TE graft) was engineered. Lastly, a canine ACL reconstruction model was used to evaluate the in-vivo performance of this TE graft in enhancing graft-to-bone integration. Results: The BAT, SAC, and SAB well preserved the structure and components of native tendon, cartilage, and bone, showing good biocompatibility. C-GDF7, C-TGFβ3, or C-BMP2 showed a stronger binding ability to BAT, SAC, and SAB. The C-GDF7@BAT, C-TGFβ3@SAC, or C-BMP2@SAB was a controlled delivery system for the scaffold-specific release of GDF7, TGFβ3, and BMP2, thus showing superior tenogenic, chondrogenic, or osteogenic inducibility, respectively. Using a canine ACL reconstruction model, abundant newly-formed bone and connective collagen fibers could be observed at the integration site between TE graft and bone tunnel at postoperative 16 weeks. Meanwhile, the failure load of the reconstructed ACL by TE graft was significantly higher than that of the autograft. Conclusion: The TE graft could be used to reconstruct ruptured ACL and augment graft-to-bone integration, thus demonstrating high potential for clinical translation in ACL reconstruction. Translational potential of this article: The findings of the study indicated that the TE graft could be a novel graft for ACL reconstruction with the ability to augment graft-to-bone integration, which may provide a foundation for future clinical application.

The aim of this study was to investigate the global epidemiological trends in the incidence and deaths of acute respiratory infections (ARIs), encompassing both upper respiratory infections (URIs) and lower respiratory infections (LRIs), from 1990 to 2021. Using data from the Global Burden of Disease study 2021 (GBD 2021), we utilized the average annual percentage change (AAPC) to examine the trends in the age-standardized incidence rate and deaths rate (ASIR and ASDRs) of URIs and LRIs. In 2021, the global ASIR of URIs and LRIs were 166,770.73 (95 % UI: 148,098.16–189,487.93) per 100,000 and 4283.61 (95 % UI: 4057.03–4524.89) per 100,000, respectively. The highest ASIR of URIs occurred in high-sociodemographic index (SDI) regions (232744.64, 95 % UI: 206887.07–261694.81) per 100,000, whereas LRIs occurred in low-SDI regions (9261.1, 95 % UI: 8741.61–9820.86) per 100,000. In 2021, the global ASDRs of URIs and LRIs were 0.28 (95 % UI: 0.09–0.61) per 100,000 and 28.67 (95 % UI: 25.92–31.07) per 100,000, respectively. The highest ASDRs of both URIs and LRIs were observed in low-SDI regions, with 1.1 (95 % UI: 0.08–2.78) per 100,000 and 70.68 (95 % UI: 62.56–78.62) per 100,000, respectively. From 1990 to 2021, the global ASIR for URIs and LRIs decreased, with AAPCs of −0.17 % (95 % CI: 0.17 % to −0.16 %) and −1.28 % (95 % CI: −1.37 % to −1.22 %), respectively. The global ASDRs also decreased (−3.39 % for URIs; −2.46 % for LRIs). However, during the COVID-19 pandemic, the ASIR of URIs increased in many countries, especially in high-SDI regions (rate difference before and during the COVID-19 pandemic in ASIR was 2210.19 per 100,000.) and low-SDI regions (rate difference in ASIR: 111.26 per 100,000). The global incidence and deaths related to ARIs have decreased over the past 32 years. However, it remains a significant public health concern, particularly due to the notable incidence of URIs in high SDI regions and the deaths associated with both URIs and LRIs in low SDI regions. Furthermore, an increase in the incidence of URIs was observed in both high- and low-SDI regions during the COVID-19 pandemic, highlighting the need for increased attention.

In this article, we provided a comprehensive overview and in-depth analysis of global patterns and temporal trends in years lived with disability (YLDs) for musculoskeletal (MSK) disorders in individuals aged ≥70. Data on YLDs for MSK disorders in individuals aged ≥70 were obtained from the Global Burden of Disease 2019. The average annual percentage change (AAPC) was calculated to assess the temporal trends in the YLDs rate of MSK disorders. A Bayesian Age-Period-Cohort model was used to predict the YLDs rate up to the year 2040. In 2019, the global rate of YLDs for MSK disorders in individuals aged ≥70 were 4819.81 (95 % UI: 3402.91 - 6550.77) per 100,000 persons. The YLDs rate of MSK disorders in female was 1.36 times higher than that in male, and was highest in high SDI regions. From 1990 to 2019, the global YLDs rate showed a slightly downward trend (AAPC = −0.04 %, 95 % CI: −0.06 % to −0.03 %), while it significantly increased in high, low-middle, low SDI regions. Tobacco and high body mass index were the primary risk factors worldwide, while in low SDI regions, occupational risks emerged as the predominant factors. Up to 2040, the global YLDs rate of MSK disorders are expected to increase by 1.78 %, with 36.39 %, 20.66 %, 18.96 % and 5.32 % growth in other MSK disorders, rheumatoid arthritis, neck pain and osteoarthritis. MSK disorders are a significant and continuously growing public health concern among older adults. Tailored interventions should be developed for older adults, taking into account the variations across distributions, trends, and risk factors in terms of sex and SDI levels.

Due to the continuous improvement of the computer network communication level and the acceleration of data transmission speed, the hardware configuration of the digital signal processing room on the second floor of this unit has become more intensive, and the power consumption and heat generation have also increased.Although the constant temperature and humidity precision air conditioning system has sufficient theoretical cooling capacity, it uses the conventional diffusion air supply mode of cooling the surroundings first and then cooling the device.In a computer system, there are many local over temperature faults due to the uneven distribution of computer load in many areas, which is very difficult to deal with.The existing air distribution cycle has been unable to meet the cooling requirements of equipment with high energy consumption.The examples of the application of optimization and transformation of airflow organization based on CFD in State Grid’s substation computer room was introduced, it has a certain reference significance for energy saving and consumption reduction in computer rooms design.

Abstract Background Patients with degenerative spinal deformity often experience symptoms that seriously affect their quality of life, such as low back pain and dysfunction. This study aimed to investigate the relationship between paravertebral muscle function and pelvic incidence (PI) and their effect on health-related quality of life (HRQL) in patients with degenerative spinal deformity. Methods A total of 112 patients with degenerative spinal deformity in Southwest Hospital (Chongqing, China) were enrolled. They were divided into groups according to PI angle: high (PI > 60°, n = 37), normal (PI 50°–60°, n = 31), and low (PI 0.05). There was no significant difference in endurance time, SVA, ODI, RMQ, and SF-36 among the three groups. Paravertebral muscle MVE was negatively correlated with PI, SVA, ODI, and RMQ (r = − 0.193, − 0.210, − 0.283, − 0.277, p

Abstract To explore the research status on mechanism of the skid-resistance for asphalt pavement, the related achievements of the rubber friction, the tire–road contact, and the influence factors were reviewed. The rubber friction was reviewed from the mechanism and rubber friction model. The tire-road contact was studied from the modeling methods, the evaluation methods, and the skid-resistance mechanisms at different conditions. The influence factors of skid-resistance were summarized from different designing processes. This review showed that the appropriate contact or evaluation model should be selected according to the required parameters. Although the finite element method is widely used, the accuracy of the model, the boundary conditions, and the load cases need to be further improved. The optimized aggregates and asphalt binders, reasonable gradation, reasonable geometric design, and strict construction quality control are necessary for good initial skid-resistance. Pavement texture as an important factor affecting skid-resistance should be considered in pavement gradation design, especially for wearing layer technology.

Speckle-tracking X-ray imaging is an attractive candidate for dynamic X-ray imaging owing to its flexible setup and simultaneous yields of phase, transmission and scattering images. However, traditional speckle-tracking imaging methods suffer from phase distortion at locations with abrupt changes in density, which is always the case for real samples, limiting the applications of the speckle-tracking X-ray imaging method. In this paper, we report a deep-learning based method which can achieve dynamic X-ray speckle-tracking imaging with high-accuracy phase retrieval. The calibration results of a phantom show that the profile of the retrieved phase is highly consistent with the theoretical one. Experiments of polyurethane foaming demonstrated that the proposed method revealed the evolution of the complicated microstructure of the bubbles accurately. The proposed method is a promising solution for dynamic X-ray imaging with high-accuracy phase retrieval, and has extensive applications in metrology and quantitative analysis of dynamics in material science, physics, chemistry and biomedicine.

Abstract As nonlinear thermal devices, thermal regulators can intelligently respond to temperature and control heat flow through changes in heat transfer capacities, which allows them to reduce energy consumption without external intervention. However, current thermal regulators generally based on high‐quality crystalline‐structure transitions are intrinsically rigid, which may cause structural damage and functional failure under mechanical strain; moreover, they are difficult to integrate into emerging soft electronic platforms. In this study, we develop a flexible, elastic thermal regulator based on the reversible thermally induced deformation of a liquid crystal elastomer/liquid metal (LCE/LM) composite foam. By adjusting the crosslinking densities, the LCE foam exhibits a high actuation strain of 121% with flexibility below the nematic–isotropic phase transition temperature (TNI) and hyperelasticity above TNI. The incorporation of LM results in a high thermal resistance switching ratio of 3.8 over a wide working temperature window of 60°C with good cycling stability. This feature originates from the synergistic effect of fragmentation and recombination of the internal LM network and lengthening and shortening of the bond line thickness. Furthermore, we fabricate a “grid window” utilizing photic‐thermal integrated thermal control, achieving a superior heat supply of 13.7°C at a light intensity of 180 mW/cm2 and a thermal protection of 43.4°C at 1200 mW/cm2. The proposed method meets the mechanical softness requirements of thermal regulator materials with multimode intelligent temperature control.

Abstract The rice-turtle coculture system is the most special rice-fish integrated farming system. In this study, we selected four paddy fields, including a rice monoculture paddy and three rice-turtle paddies with different planting years, to investigate the soil bacterial community composition with Illumina MiSeq sequencing technology. The results indicated that the contents of soil available nitrogen (AN), soil available phosphorus (AP) and soil organic matter (OM) in 9th year of rice-turtle paddy (RT9) were increased by 5.40%, 51.11% and 23.33% compared with rice monoculture paddy (CK), respectively. Significant differences of Acidobacteria, Desulfobacteria, Crenarchaeota were observed among the different rice farming systems. The relative abundance of Methylomonadaceae, Methylococcaceae and Methylophilaceae in RT9 was significantly higher than that in other treatments. RT9 had significantly lower relative abundance of Acidobacteria, but significantly higher relative abundance of Proteobacteria than other treatments. Redundancy analysis showed that soil AN and AP contents were the major factors influencing the abundance of the dominant microbes, wherein Methylomonadaceae, Methylococcaceae and Methylophilaceae were positively correlated with OM. The findings revealed the rice-turtle coculture system in the 9th year had higher soil nutrients and soil bacterial diversity, but there was also a risk of increasing methane emissions.

Abstract Background Mycoplasma ovipneumoniae (M. ovipneumoniae) is one of the main pathogens of sheep pneumonia, causing a series of clinical symptoms, such as depression, anorexia, hyperthermia, cough, dyspnea, and tract secretions. In recent years, the prevalence of M. ovipneumoniae pneumonia has become increasingly serious in sheep farms in Ningxia, China, leading to the death of sheep, and causing significant economic losses. In this study, the pathological organs infected by M. ovipneumoniae were collected to observe histopathological change, to determine the tissue localization of M. ovipneumoniae, and to analyze the cytokine changes, which lays a basis for the diagnosis and pathogenesis of M. ovipneumoniae disease. Results In this study, M. ovipneumoniae was detected in 97 of 105 samples collected from 13 large-scale sheep farms for nucleic acid by PCR. One representative isolate per farm was isolated from 13 farms. The lesions caused by M. ovipneumoniae were mainly in the trachea, bronchus, and lung, including necrosis of tracheal mucosal epithelial cells, disintegration of some epithelial cells, edema of mucosal lamina propria, with inflammatory cell infiltration, cytoplasmic vacuolization of epithelial cells of bronchial mucosa, massive infiltration of inflammatory cells in the alveolar space of lung, necrosis and hyperplasia of alveolar epithelial cells. Immunohistochemical analysis showed that the proportion of M. ovipneumoniae positive area in the lung was the largest, followed by that in the bronchus and trachea. Compared to healthy animals, diseased animals exhibited up-regulated gene expression levels of IL-1β, IL-6, and NF-κB in the trachea, bronchus, and lungs. In contrast, the expression of IL-10, IL-12, and IFN-γ was primarily limited to the trachea and bronchus. The expression of IL-1β showed differential patterns across different lung regions, with variations observed among lung lobes. Additionally, other cytokines consistently showed significant up-regulation specifically in the bronchus. Conclusions M. ovipneumoniae is primarily found in the lungs of infected individuals. NF-κB, an essential transcription factor, is involved in the regulation of IL-1β transcription. IL-12 may enhance the cytotoxic function of natural killer cells during M. ovipneumoniae infection. Those findings demonstrate the distinct expression profiles of cytokines in various anatomical sites throughout disease progression, suggesting the potential role of bronchial tissue as a major site of immune response.

Background Cadonilimab (AK104) is a bispecific IgG-single-chain Fv fragment (ScFv) antibody that binds to PD-1 and CTLA-4. Cadonilimab has shown encouraging anti-tumour activity and a favourable safety profile in several tumour types. In second-line treatment, there is no defined standard of care for patients with extensive-stage small-cell lung cancer (ES-SCLC). Cadonilimab is expected to show substantial clinical efficacy. Objective To assess the antitumor activity and safety of cadonilimab monotherapy or combination with conventional therapy in ES-SCLC patients who failed first-line treatment. Methods In this multicenter, open-label, phase II study, ES-SCLC patients who had failed first-line treatment, also aged 18 years to 70 years with histologically or cytologically confirmed ES-SCLC, and an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0–2 were eligible. Patients will receive cadonilimab 10 mg/kg every three weeks (Q3 W) among 24 months until progressive disease (PD) or adverse events (AE) discovery. The primary endpoint is progression-free survival (PFS). Trial registration NCT05901584.

Abstract Background Since coronavirus 2019 (COVID‐19) swept the world, a variety of novel therapeutic and prevention strategies have been developed, among which nirmatrelvir–ritonavir is highly recommended. We intended to assess the effectiveness and safety of nirmatrelvir–ritonavir in the elderly mild‐to‐moderate COVID‐19 population caused by the omicron BA.2.2 variant in real‐world settings. Methods An observational study was conducted retrospectively to review the outcomes of mild‐to‐moderate COVID‐19 patients admitted between April 26 and June 30, 2022. Patients' baseline characteristics were collected and assessed. Participants in the intervention group were administered nirmatrelvir–ritonavir in addition to standard care, whereas those in the control group only received standard care. The primary outcome was the duration between the initial positive reverse‐transcription polymerase chain reaction (RT‐PCR) test and the subsequent conversion to a negative result. Results The analysis included 324 patients who were administered nirmatrelvir–ritonavir and an equal number of control patients. The patient characteristics in both groups were evenly matched. The average duration from the initial positive RT‐PCR to negative conversion was similar in both groups (16.2 ± 5.0 vs. 16.1 ± 6.3 days, p = .83). Control patients exhibited slower conversion in comparison to patients who received nirmatrelvir–ritonavir treatment within 10 days of symptom onset. Conclusions These findings suggest that administering nirmatrelvir–ritonavir within 10 days of symptom onset could potentially reduce the time it takes for SARS‐CoV‐2‐infected patients to negative RT‐PCR results, thereby expanding the current usage guidelines for nirmatrelvir–ritonavir.

The cssR gene (ncgl1578) of Corynebacterium glutamicum encodes a repressor of the TetR (tetracycline regulator) family. Its role in the stress response to antibiotics/heavy metals has been investigated, but how CssR functions in response to phenolic compounds in C. glutamicum has been rarely studied. In this study, we applied transcriptomic analysis, β-galactosidase analysis, qRT-PCR, and EMSAs to analyze the target genes and functions of CssR in response to phenolic compounds. Consistent with the upregulation of genes involved in the degradation of phenolic compounds, the ΔcssR mutant was more resistant to various phenolic compounds than was the wild-type strain. Furthermore, the addition of phenolic compounds induced the expression of corresponding genes (ncgl0283, ncgl1032, ncgl1111, ncgl2920, ncgl2923, and ncgl2952) in vivo. However, the DNA binding activity of CssR to the promoter of phenolic compound-degrading genes was undetected in vitro. Additionally, we also found that CssR indirectly negatively regulates the expression of cell wall/membrane/envelope biogenesis-related genes, which may enhance resistance to stress caused by phenolic compounds. Together, our findings demonstrate that CssR is a key regulator that copes with stress conditions induced by phenolic compounds, thus greatly expanding our understanding of the functions of TetR family transcription factors.

Summary: Subtype interference has a significant impact on the epidemiological patterns of seasonal influenza viruses (SIVs). We used attributable risk percent [the absolute value of the ratio of the effective reproduction number (Rₑ) of different subtypes minus one] to quantify interference intensity between A/H1N1 and A/H3N2, as well as B/Victoria and B/Yamagata. The interference intensity between A/H1N1 and A/H3N2 was higher in southern China 0.26 (IQR: 0.11–0.46) than in northern China 0.17 (IQR: 0.07–0.24). Similarly, interference intensity between B/Victoria and B/Yamagata was also higher in southern China 0.14 (IQR: 0.07–0.24) than in norther China 0.10 (IQR: 0.04–0.18). High relative humidity significantly increased subtype interference, with the highest relative risk reaching 20.59 (95% CI: 6.12–69.33) in southern China. Southern China exhibited higher levels of subtype interference, particularly between A/H1N1 and A/H3N2. Higher relative humidity has a more pronounced promoting effect on subtype interference.

Abstract Left ventricular regional wall thickness (LVRWT) is an independent predictor of morbidity and mortality in cardiovascular diseases (CVDs). To identify specific genetic influences on individual LVRWT, we established a novel deep learning algorithm to calculate 12 LVRWTs accurately in 42,194 individuals from the UK Biobank with cardiac magnetic resonance (CMR) imaging. Genome-wide association studies of CMR-derived 12 LVRWTs identified 72 significant genetic loci associated with at least one LVRWT phenotype (P

Objective: Understanding the global patterns of respiratory syncytial virus (RSV) is crucial for developing effective prevention and control strategies. Methods: Data on RSV-related burden were extracted from the Global Burden of Disease 2019. Joinpoint regression models were used to assess the global temporal trends of RSV and further stratified analyses were conducted according to the Socio-demographic Index (SDI), which is a composite measure of income, education, and total fertility. Age-period-cohort model was used to evaluate age, period, and cohort effects. Results: In 2019, the global age-standardized rate of mortality (ASMR) and disability-adjusted life years (ASR-DALYs) of RSV were 4.79/100,000 (95% uncertainty interval [95% UI]: 1.82/100,000-9.32/100,000) and 218.34/100,000 (95% UI: 92.06/100,000-376.80/100,000), respectively. The burden of RSV was higher in men than women. The highest ASMR (10.26/100,000, 3.80/100,000-20.16/100,000) and ASR-DALYs (478.71/100,000, 202.40/100,000-840.85/100,000) were reported in low-SDI region. Although mortality and DALYs rates in all age groups declined globally, the pace of decline was not uniform across age groups. Mortality rate in the elderly over 70 years surpassed that in children under 5 years in 2019. Conclusion: This study highlights the need for targeted interventions to reduce the burden of RSV, particularly in low-SDI region, and among the elderly over 70 years.

Abstract Genome-wide association studies have identified numerous variants associated with human complex traits, most of which reside in the non-coding regions, but biological mechanisms remain unclear. However, assigning function to the non-coding elements is still challenging. Here we apply Activity-by-Contact (ABC) model to evaluate enhancer-gene regulation effect by integrating multi-omics data and identified 544,849 connections across 20 cancer types. ABC model outperforms previous approaches in linking regulatory variants to target genes. Furthermore, we identify over 30,000 enhancer-gene connections in colorectal cancer (CRC) tissues. By integrating large-scale population cohorts (23,813 cases and 29,973 controls) and multipronged functional assays, we demonstrate an ABC regulatory variant rs4810856 associated with CRC risk (Odds Ratio = 1.11, 95%CI = 1.05–1.16, P = 4.02 × 10−5) by acting as an allele-specific enhancer to distally facilitate PREX1, CSE1L and STAU1 expression, which synergistically activate p-AKT signaling. Our study provides comprehensive regulation maps and illuminates a single variant regulating multiple genes, providing insights into cancer etiology.

Abstract Fusarium head blight (FHB) is a devastating fungal disease that poses a significant threat to wheat production, causing substantial yield losses. Understanding the molecular mechanisms of wheat resistance to FHB is crucial for developing effective disease management strategies. This study aimed to investigate the mechanisms of FHB resistance and the patterns of toxin accumulation in three wheat cultivars, Annong8455, Annong1589, and Sumai3, with different levels of resistance, ranging from low to high respectively, under natural field conditions. Samples were taken at three different grain-filling stages (5, 10, and 15 DPA) for gene expression analysis and phenotypic observation. Results found that toxin concentration was inversely correlated with varietal resistance but not correlated with disease phenotypes, indicating that toxin analysis is a more accurate measure of disease status in wheat ears and grains. Transcriptomic data showed that Sumai3 exhibited a stronger immune response during all stages of grain filling by upregulating genes involved in the active destruction of pathogens and removal of toxins. In contrast, Annong1589 showed a passive prevention of the spread of toxins into cells by the upregulation of genes involved in tyramine biosynthesis at the early stage (5 DPA), which may be involved in cell wall strengthening. Our study demonstrates the complexity of FHB resistance in wheat, with cultivars exhibiting unique and overlapping defense mechanisms, and highlights the importance of considering the temporal and spatial dynamics of gene expression in breeding programs for developing more resistant wheat cultivars.

Background: Measles and rubella are vaccine-preventable diseases targeted for elimination in most World Health Organization regions, and China is considered to have momentum towards measles elimination. Therefore, this study aimed to assess the population immunity levels against measles and rubella in Zhejiang Province in China in order to provide valuable insights for informing future public health measures and contributing to the ongoing global campaign against these diseases. Materials and methods: A cross-sectional serological survey was conducted in 2022. A total of 2740 blood samples were collected from healthy individuals spanning the age range of 0–59 years, representing diverse demographic strata across 11 prefectures in Zhejiang Province in China. The sera were tested for measles and rubella IgG antibodies to determine positivity rates and geometric mean concentrations (GMCs). Results: The overall positivity rate for the measles IgG antibody was 85.3%, with a GMC of 588.30 mIU/mL. The positivity rate for the rubella IgG antibody was 70.9%, and the GMC was 35.30 IU/mL. Measles IgG antibody positivity rates across the 0–11 months, 12–23 months, 24–35 months, 3–5 years, 6–9 years, 10–14 years, 15–19 years, 20–29 years, and 30–59 years age groups were 63.1%, 92.5%, 97.0%, 94.0%, 85.8%, 77.3%, 86.9%, 84.9%, and 88.7%, respectively (trend χ2 = 118.34, p < 0.001). Correspondingly, rubella antibody positivity rates for these same age brackets were 55.9%, 87.9%, 94.7%, 88.2%, 69.9%, 54.2%, 72.6%, 67.5%, and 74.3% (trend χ2 = 199.18, p < 0.001). Both univariate and multivariate analyses consistently demonstrated that age, immunization history, and differing economic levels were significant factors contributing to variations in antibody levels. Conclusions: The seroprevalence of measles and rubella was lower than that required for herd immunity. Periodic vaccination campaigns should be launched to increase immunity.

Fragrance is a valuable trait in rice varieties, with its aroma significantly influencing consumer preference. In this study, we conducted comprehensive metabolome and transcriptome analyses to elucidate the genetic and biochemical basis of fragrance in the Shangsixiangnuo (SSXN) variety, a fragrant indica rice cultivated in Guangxi, China. Through sensory evaluation and genetic analysis, we confirmed SSXN as strongly fragrant, with an 806 bp deletion in the BADH2 gene associated with fragrance production. In the metabolome analysis, a total of 238, 233, 105 and 60 metabolic compounds exhibited significant changes at the seedling (S), reproductive (R), filling (F), and maturation (M) stages, respectively. We identified four compounds that exhibited significant changes in SSXN across all four development stages. Our analyses revealed a significant upregulation of 2-acetyl-1-pyrroline (2AP), the well-studied aromatic compound, in SSXN compared to the non-fragrant variety. Additionally, correlation analysis identified several metabolites strongly associated with 2AP, including ethanone, 1-(1H-pyrrol-2-yl)-, 1H-pyrrole, and pyrrole. Furthermore, Weighted Gene Co-expression Network Analysis (WGCNA) analysis highlighted the magenta and yellow modules as particularly enriched in aroma-related metabolites, providing insights into the complex aromatic compounds underlying the fragrance of rice. In the transcriptome analysis, a total of 5582, 5506, 4965, and 4599 differential expressed genes (DEGs) were identified across the four developmental stages, with a notable enrichment of the common pathway amino sugar and nucleotide sugar metabolism in all stages. In our correlation analysis between metabolome and transcriptome data, the top three connected metabolites, phenol-, 3-amino-, and 2AP, along with ethanone, 1-(1H-pyrrol-2-yl)-, exhibited strong associations with transcripts, highlighting their potential roles in fragrance biosynthesis. Additionally, the downregulated expression of the P4H4 gene, encoding a procollagen-proline dioxygenase that specifically targets proline, in SSXN suggests its involvement in proline metabolism and potentially in aroma formation pathways. Overall, our study provides comprehensive insights into the genetic and biochemical mechanisms underlying fragrance production in rice, laying the foundation for further research aimed at enhancing fragrance quality in rice breeding programs.

Abstract Due to increasing morbidity worldwide, fractures are becoming an emerging public health concern. This study aimed to investigate the effect of metformin on the healing of osteoporotic as well as normal fractures. Type H vessels have recently been identified as a bone-specific vascular subtype that supports osteogenesis. Here, we show that metformin accelerated fracture healing in both osteoporotic and normal mice. Moreover, metformin promoted angiogenesis in vitro under hypoxia as well as type H vessel formation throughout fracture healing. Mechanistically, metformin increased the expression of HIF-1α, an important positive regulator of type H vessel formation, by inhibiting the expression of YAP1/TAZ in calluses and hypoxia-cultured human microvascular endothelial cells (HMECs). The results of HIF-1α or YAP1/TAZ interference in hypoxia-cultured HMECs using siRNA further suggested that the enhancement of HIF-1α and its target genes by metformin is primarily through YAP1/TAZ inhibition. Finally, overexpression of YAP1/TAZ partially counteracted the effect of metformin in promoting type H vessel-induced angiogenesis-osteogenesis coupling during fracture repair. In summary, our findings suggest that metformin has the potential to be a therapeutic agent for fractures by promoting type H vessel formation through YAP1/TAZ inhibition.

Abstract Background Sagittal imbalance is a common cause of low back pain and dysfunction in patients with degenerative spinal deformity (DSD), which greatly affects their quality of life. Strength and endurance are important functional physical indexes for assessing muscle condition. However, the correlation between sagittal parameters and paraspinal muscle strength/endurance is not yet clear. The purpose of this study was to analyze the correlation between strength/endurance of paraspinal muscles and sagittal parameters in patients with DSD. Methods There were 105 patients with DSD and 52 healthy volunteers (control group) enrolled. They were divided into the balance group [sagittal vertical axis (SVA)

Abstract Background Type 2 diabetes mellitus (T2DM) patients have a higher incidence of coronary artery disease than the general population. The aim of this study was to develop a radiomics nomogram of pericoronary adipose tissue (PCAT) based on non-contrast CT to predict haemodynamically significant coronary stenosis in T2DM patients. Methods The study enrolled 215 T2DM patients who underwent non-contrast CT and coronary computed tomography angiography (CCTA). CCTA derived fractional flow reserve (FFRCT) ≤ 0.80 was defined as hemodynamically significant stenosis.1691 radiomics features were extracted from PCAT on non-contrast CT. Minimum redundancy maximum relevance (mRMR) and least absolute shrinkage and selection operator (LASSO) were used to select useful radiomics features to construct Radscore. Logistic regression was applied to select significant factors among Radscore, fat attenuation index (FAI) and coronary artery calcium score (CACS) to construct radiomics nomogram. Results Radscore [odds ratio (OR) = 2.84; P

Abstract Rectal mucinous adenocarcinoma (RMAC) is a rare and aggressive form of rectal cancer. The effectiveness of neoadjuvant radiotherapy (NRT) for RMAC has not been well studied, and the survival benefit remains controversial. The purpose of this work was to determine the prognostic role of NRT in patients with RMAC by propensity-score matching (PSM). A retrospective cohort study using the Surveillance, Epidemiology, and End Results from 2004 to 2015 was performed. In the multivariate analysis before PSM, NRT provided better OS (HR 0.61, 95% CI 0.52–0.71, p

Abstract Background CD2‐associated protein (CD2AP) is a podocyte‐associated gene and its reduced expression is associated with the development of proteinuria and glomerulosclerosis. However, few studies have focused on the correlation between the expression and prognosis of CD2AP in renal clear cell carcinoma (ccRCC). Therefore, we aimed to assess the regulation of CD2AP expression and prognostic value in ccRCC. Methods Multiple databases were employed to examine the expression of CD2AP in ccRCC. RT‐qPCR, Western Blot and immunohistochemistry were used to validate CD2AP expression in different cell lines and tissue samples. Kaplan–Meier analysis and ROC curve analysis were performed on the predictive prognostic performance of CD2AP. COX regression was used to construct CD2AP‐related prognostic models. The TIMER and TISIDB databases were used to analyze the correlation of tumor‐infiltrating immune cells with gene expression, mutations, somatic copy number variation, and immune molecules. Mass spectrometry was used to detect methylation status of the promoter CpG site of CD2AP in multiple cells. Results We found that CD2AP expression was downregulated in ccRCC and its lower expression level was correlation with worse patient prognosis, higher tumor stage and grade and distant metastasis through analysis of databases, ccRCC cell lines and clinical tissue samples. Moreover, database and mass spectrometry techniques identified and validated cg12968598 hypermethylation as one of the key reasons for the downregulation of CD2AP expression. CD2AP expression was also associated with macrophage and neutrophil infiltration. Conclusions Taken together, our results suggest that CD2AP can be used as a diagnostic and prognostic biomarker in ccRCC patients and that DNA hypermethylation plays an important role in reducing CD2AP expression.

Abstract In order to repair critical‐sized bone defects, various polylactic acid‐glycolic acid (PLGA)‐based hybrid scaffolds are successfully developed as bone substitutes. However, the byproducts of these PLGA‐based scaffolds are known to acidify the implanted site, inducing tiresome acidic inflammation. Moreover, these degradation productions cannot offer an osteo‐friendly microenvironment at the implanted site, matching natural bone healing. Herein, inspired by bone microenvironment atlas of natural bone‐healing process, an osteo‐microenvironment stage‐regulative scaffold (P80/D10/M10) is fabricated by incorporating self‐developed decellularized bone matrix microparticles (DBM‐MPs) and multifunctional magnesium hydroxide nanoparticles (MH‐NPs) into PLGA with an optimized proportion using low‐temperature rapid prototyping (LT‐RP) 3D‐printing technology. The cell experiments show that this P80/D10/M10 exhibits excellent properties in mechanics, biocompatibility, and biodegradability, meanwhile superior stimulations in osteo‐immunomodulation, angiogenesis, and osteogenesis. Additionally, the animal experiments determined that this P80/D10/M10 can offer an osteo‐friendly microenvironment in a stage‐matched pattern for enhanced bone regeneration, namely, optimization of early inflammation, middle neovascularization, and later bone formation. Furthermore, transcriptomic analysis suggested that the in vivo performance of P80/D10/M10 on bone defect repair is mostly attributed to regulating artery development, bone development, and bone remodeling. Overall, this study reveals that the osteo‐microenvironment stage‐regulative scaffold provides a promising treatment for bone defect repair.

At present, GPX4's role in the occurrence and development of diffuse large B lymphoma (DLBCL) is rarely reported. This study's purpose is to explore GPX4's significance in the diagnosis, treatment, and pathological mechanisms of DLBCL. The TIMER 2.0, GEPIA, and GEO databases were used to analyze GPX4's expression levels in DLBCL tissue, peripheral blood, and single cells, and evaluate its potential performance as a therapeutic and diagnostic marker. Cell experiments validate GPX4's role in DLBCL cells. And revealed the potential mechanism of GPX4's action from three aspects: immunity, pathogenic gene expression, and protein interaction. The results indicate that GPX4 can be used as a biomarker for treatment and diagnosis (FC > 1.5, P 0.8, KM-P value

Hepatosplenic T cell lymphoma (HSTCL) is a particularly difficult-to-treat form of lymphoma, with many patients exhibiting primary resistance to chemotherapy. At present, no effective strategy for treating relapsed and refractory HSTCL has been established, with treatment being hampered by questions of how best to overcome chemoresistance to allow patients to attain more durable therapeutic benefits. While there have been marked advances in immunotherapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains one of the primary approaches to curing HSTCL. Of patients who undergo immunochemotherapeutic treatment, many are resistant to conventional chemotherapeutic drugs yet remain sensitive to radiotherapy. We selected to employ a transplant pretreatment regimen consisting of total -body irradiation (TBI) and administered this regimen to two patients with HSTCL. Both patients achieved complete remission (CR) after transplantation, demonstrating extended periods without disease recurrence. We systematic reviewed previously published instances involving allo-HSCT in patients with HSTCL. We have found a total of 67 patients who have received allo-HSCT. In general, age

Acacia confusa is an important species in coastal shelter forests. In order to explore the effects of salt and phosphorus fertilization on leaf photosynthesis and nutrient characteristics of the seedlings. NaCl solutions were configured in the concentrations of 0% (B0), 0.2% (B1), 0.4% (B2), 0.6% (B3) and 0.8% (B4), and superphosphate solutions in the concentrations of 0 g·kg-1(P0), 0.5 g·kg-1(P1), and 1.5 g·kg-1(P2). The photosynthesis and nutrient characteristics of the seedlings were determined after being watered by the six combined solutions of salt-phosphorus coupling fertilization. The results were as follows: (1) Salt stress significantly inhibited the growth and development of the seedlings, and the higher the salt content, the greater the effect. Phosphorus application under low-salt stress was unfavorable to the growth of the seedlings, while phosphorus application under medium-high one significantly slowed down the inhibition of the seedling growth. (2) The greater the salt stress, the higher the effects on the photosynthesis of the seedlings. The stomatal closure degree of phosphorus application increased under low and medium salt stress, which aggravated the effect of salt stress on photosynthesis of the seedlings. Appropriate phosphorus application under high-salt stress could significantly improve the photosynthetic capacity of the seedlings. (3) Salt stress significantly reduced chlorophyll content and caused harm to photosystem II. Phosphorus fertilization on the seedlings under low-salt stress had adverse effects on chlorophyll synthesis. Appropriate fertilization of phosphorus in high-salt stress could increase chlorophyll synthesis, stabilize cell membrane structure, and improve the potential photosynthetic capacity of leaves. (4) Salt stress had strong interference on the contents of Fe, Mn, Na, Cu and other metal elements in leaves. Phosphorus application under salt stress could effectively promote the absorption of some elements by seedlings. In conclusion, phosphorus application after salt stress can improve the photosynthesis and nutrient absorption ability of A. confusa seedlings on the whole. The results provides a theoretical basis for improving the salt tolerance and phosphorus utilization rate of A. confusa, and have guiding significance for the sustainable management of coastal shelter forests.

Artificial coastal protection forests are difficult to manage because of nutrient stress in harsh environment. To explore the effects of salt and phosphorus stress on the seed germination and seedling growth of Casuarina equisetifolia and Acacia confusa, we respectively watered the seeds and seedlings of the two kinds of plants with the solutions of NaCl (salt) and KH2PO4 (phosphorus) in different concentrations, and then determined their growth indicators, respectively. The results were as follows: (1) High salt concentration solutions significantly inhibited seed germination and had a certain effect on the growth of seedlings, however, the effects of salt stress on seed gemination and growth were different. The salt tolerance of Acacia confusa seed germination was higher than that of Casuarina equisetifolia. The biggest relative salt damage rate of Acacia confusa was 23.03% and that of Casuarina equisetifolia was 89.15%. As the concentration of NaCl increased, the germination rate, germination potential, germination index and vitality index of Casuarina equisetifolia and Acacia confusa seeds decreased. And the maximums of the four germination indexes of Casuarina equisetifolia seed were 38.70%, 34.67%, 18.70 and 0.055, and of Acacia confusa seeds were 76.67%, 62.22%, 48.46 and 6.11, respectively. (2) The height and root length of the plants decreased with the increase of salt concentration. The plant heights of Casuarina equisetifolia and Acacia confusa were 12.29 to 6.01 mm and 48.27 to 17.33 mm, and the root lengths were 8.57 to 1.45 mm and 33.41 to 5.88 mm, respectively. The biomass of root, stem and leaf as well as root shoot ratio of Acacia confusa gradually decreased with the increase of salt concentration, but the differences between the treatments of Casuarina equisetifolia were not obvious. 0.6% and 0.4% salt stress were the thresholds for seed germination and seedling growth of the two plants, respectively. (3)The seed and seedling of Acacia confusa were more tolerant to low-phosphorus environment than Casuarina equisetifolia, and there was a difference in the optimum phosphorus concentration between the two. When the phosphorus concentration was 0.1 mmol·L-1, the seed germination rate(49.33%), germination index (23.12%) and vitality index(0.093) of Casuarina equisetifolia, as well as the biomass of root, stem and leaf, all reached the maximum. In the 5 mmol·L-1 treatment, the maximums of germination rate(81.11%), germination potential(62.22%), gemination index(38.23), vitality index(5.07), plant height (54.48 mm) and root length (37.16 mm) of Acacia confusa seeds all appeared, while their germination was inhibited in the treatment of 10 mmol·L-1. Therefore, when sowing the seed of coastal defense forest or planting its seedling, the sowing or planting mode must be selected according to the soil salt and phosphorus contents.

Abstract GEnome-scale Metabolic models (GEMs) are powerful tools to predict cellular metabolism and physiological states in living organisms. However, due to our imperfect knowledge of metabolic processes, even highly curated GEMs have knowledge gaps (e.g., missing reactions). Existing gap-filling methods typically require phenotypic data as input to tease out missing reactions. We still lack a computational method for rapid and accurate gap-filling of metabolic networks before experimental data is available. Here we present a deep learning-based method — CHEbyshev Spectral HyperlInk pREdictor (CHESHIRE) — to predict missing reactions in GEMs purely from metabolic network topology. We demonstrate that CHESHIRE outperforms other topology-based methods in predicting artificially removed reactions over 926 high- and intermediate-quality GEMs. Furthermore, CHESHIRE is able to improve the phenotypic predictions of 49 draft GEMs for fermentation products and amino acids secretions. Both types of validation suggest that CHESHIRE is a powerful tool for GEM curation to reveal unknown links between reactions and observed metabolic phenotypes.

Abstract A growing body of epidemiological evidence suggests that nonalcoholic fatty liver disease (NAFLD) is an independent risk factor for chronic kidney disease (CKD), but the regulatory mechanism linking NAFLD and CKD remains unclear. Our previous studies have shown that overexpression of PDE4D in mouse liver is sufficient for NAFLD, but little is known about its role in kidney injury. Here, liver-specific PDE4D conditional knockout (LKO) mice, adeno-associated virus 8 (AAV8)-mediated gene transfer of PDE4D and the PDE4 inhibitor roflumilast were used to assess the involvement of hepatic PDE4D in NAFLD-associated renal injury. We found that mice fed a high-fat diet (HFD) for 16 weeks developed hepatic steatosis and kidney injury, with an associated increase in hepatic PDE4D but no changes in renal PDE4D. Furthermore, liver-specific knockout of PDE4D or pharmacological inhibition of PDE4 with roflumilast ameliorated hepatic steatosis and kidney injury in HFD-fed diabetic mice. Correspondingly, overexpression of hepatic PDE4D resulted in significant renal damage. Mechanistically, highly expressed PDE4D in fatty liver promoted the production and secretion of TGF-β1 into blood, which triggered kidney injury by activating SMADs and subsequent collagen deposition. Our findings revealed PDE4D might act as a critical mediator between NAFLD and associated kidney injury and indicated PDE4 inhibitor roflumilast as a potential therapeutic strategy for NAFLD-associated CKD.

Objectives: This study aimed to investigate region-specific epidemiologic characteristics of influenza and influenza transmission zones (ITZs). Methods: Weekly influenza surveillance data of 156 countries from 1996 to 2021 were obtained using FluNet. Joinpoint regression was used to describe global influenza virus trends, and clustering analyses were used to classify the ITZs. Results: The global median average positive rate for total influenza virus was 16.19% (interquartile range: 11.62-25.70%). Overall, three major subtypes (influenza H1, H3, and B viruses) showed alternating epidemics. Notably, the proportion of influenza B viruses increased significantly from July 2020 to June 2021, reaching 62.66%. The primary peaks of influenza virus circulation in the north were earlier than those in the south. Global influenza virus circulation was significantly characterized by seven ITZs, including ''Northern America'' (primary peak: week 10), ''Eastern & Southern-Asia'' (primary peak: week 10), ''Europe'' (primary peak: week 11), ''Asia-Europe'' (primary peak: week 12), ''Southern-America'' (primary peak: week 30), ''Oceania-Melanesia-Polynesia'' (primary peak: week 39), and ''Africa'' (primary peak: week 46). Conclusion: Global influenza virus circulation was significantly characterized by seven ITZs that could be applied to influenza surveillance and warning.

Abstract Background Comfort is a primary patient objective and central to patient experience, and thus, maximising comfort is a universal goal for healthcare. However, comfort is a complex concept that is difficult to operationalise and evaluate, resulting in a lack of scientific and standardised comfort care practices. The Comfort Theory developed by Kolcaba has been the most widely known for its systematisation and projection and most of the global publications regarding comfort care were based on this theory. To develop international guidance on theory-informed comfort care, a better understanding about the evidence on the effects of interventions guided by the Comfort Theory is needed. Objectives To map and present the available evidence on the effects of interventions underpinned by Kolcaba’s Comfort theory in healthcare settings. Methods The mapping review will follow Campbell Evidence and Gap Maps guideline and Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews Protocols guidelines. An intervention-outcome framework has been developed based on Comfort Theory and the classification of pharmacological and non-pharmacological interventions via consultation with stakeholders. Eleven electronic databases (MEDLINE, CINAHL, PsycINFO, Embase, AMED, Cochrane Library, JBI Library of Systematic Reviews, Web of Science, Scopus, CNKI and Wan Fang) and grey literature sources (Google Scholar, Baidu Scholar and The Comfort Line) will be searched for primary studies and systematic reviews between 1991 and 2023 written in English and Chinese as the papers regarding Comfort Theory were first published in 1991. Additional studies will be identified by reference list review of included studies. Key authors will be contacted for unpublished or ongoing studies. Two independent reviewers will screen and extract data using piloted forms with discrepancies resolved by discussion with a third reviewer. A matrix map with filters of study characteristics will be generated and presented through software of EPPI-Mapper and NVivo. Discussion More informed use of theory can strengthen improvement programmes and facilitate the evaluation of their effectiveness. Findings from the evidence and gap map will present the existing evidence base for researchers, practitioners and policy-makers and inform further research as well as clinical practices aiming at patients’ comfort enhancement.

An increasing number of studies have shown that the seismic response of shield tunnels differs from that of aboveground structures. While the seismic response of aboveground structures is mainly influenced by the peak acceleration and frequency of the earthquake, the seismic response of shield tunnels is more influenced by the ground displacement due to the surrounding soil layers. In this study, it is not appropriate to follow the seismic concept of aboveground structures. Dynamic time-history analysis is a powerful and effective method to study the seismic response of tunnels in the typical subway in this paper. The analysis results show that the overall levelling of the tunnel will not affect the tunnel too much, and the seismic response of the tunnel is mainly related to the relative displacement of the ground around the tunnel. The analysis results show that the internal force of the tunnel and the tunnel inclination have a good linear relationship, and the tunnel inclination can be used to measure the magnitude of the seismic response of the tunnel. In the seismic design of shield tunnels, the inclination of the tunnel can be taken into account to evaluate the change in the internal forces of the tunnel during earthquakes, which avoids the need for complex dynamic time-history analysis and greatly improves the efficiency of the seismic design of shield tunnels.

Branched-chain amino acid aminotransferases, widely present in natural organisms, catalyze bidirectional amino transfer between branched-chain amino acids and branched-chain α-ketoacids in cells. Branched-chain amino acid aminotransferases play an important role in the metabolism of branched-chain amino acids. In this paper, the interspecific evolution and biological characteristics of branched-chain amino acid aminotransferases are introduced, the related research of branched-chain amino acid aminotransferases in animals, plants, microorganisms and humans is summarized and the molecular mechanism of branched-chain amino acid aminotransferase is analyzed. It has been found that branched-chain amino acid metabolism disorders are closely related to various diseases in humans and animals and plants, such as diabetes, cardiovascular diseases, brain diseases, neurological diseases and cancer. In particular, branched-chain amino acid aminotransferases play an important role in the development of various tumors. Branched-chain amino acid aminotransferases have been used as potential targets for various cancers. This article reviews the research on branched-chain amino acid aminotransferases, aiming to provide a reference for clinical research on targeted therapy for various diseases and different cancers.

Selective internal radiation therapy (SIRT) is used as a locoregional therapy for hepatocellular carcinoma (HCC) to delay the progression of HCC. Thus far, various kinds of radioactive microspheres with different materials and radionuclides have been developed to be utilized in SIRT, but they remain unsatisfactory in some ways. Herein, using a facile method, phosphonated silica microspheres (PSMs) are prepared and further radiolabeled with 177Lu in a rapid and effective manner. The results suggest that the radiolabeling efficiency is higher than 99%, and the specific activity of the product is 10 kBq per microsphere. 177Lu‐PSM exhibits outstanding in vivo radiolabeling stability, excellent antitumor activity, and single‐photon‐emission computed tomography–computed tomography (SPECT/CT) imaging capability. In addition, it is shown that PSM can be produced in large quantities at a relatively low cost. The results indicate that 177Lu‐PSM might hold considerable potential for translation to clinical applications.

Plaque rupture is a critical concern due to its potential for severe outcomes such as cerebral infarction and myocardial infarction, underscoring the urgency of noninvasive early diagnosis. Magnetic resonance imaging (MRI) has gained prominence in plaque imaging, leveraging its noninvasiveness, high spatial resolution, and lack of ionizing radiation. Ultrasmall iron oxides, when modified with polyethylene glycol, exhibit prolonged blood circulation and passive targeting toward plaque sites, rendering them conducive for MRI. In this study, we synthesized ultrasmall iron oxide nanoparticles of approximately 3 nm via high-temperature thermal decomposition. Subsequent surface modification facilitated the creation of a dual-modality magnetic resonance/fluorescence probe. Upon intravenous administration of the probes, MRI assessment of atherosclerotic plaques and diagnostic evaluation were conducted. The application of Flash-3D sequence imaging revealed vascular constriction at lesion sites, accompanied by a gradual signal amplification postprobe injection. T1-weighted imaging of the carotid artery unveiled a progressive signal ratio increase between plaques and controls within 72 h post-administration. Fluorescence imaging of isolated carotid arteries exhibited incremental lesion-to-control signal ratios. Additionally, T1 imaging of the aorta demonstrated an evolving signal enhancement over 48 h. Therefore, the ultrasmall iron oxide nanoparticles hold immense promise for early and noninvasive diagnosis of plaques, providing an avenue for dynamic evaluation over an extended time frame.