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Abstract Nucleotide excision repair (NER) is vital for genome integrity. Yet, our understanding of the complex NER protein machinery remains incomplete. Combining cryo-EM and XL-MS data with AlphaFold2 predictions, we build an integrative model of the NER pre-incision complex(PInC). Here TFIIH serves as a molecular ruler, defining the DNA bubble size and precisely positioning the XPG and XPF nucleases for incision. Using simulations and graph theoretical analyses, we unveil PInC’s assembly, global motions, and partitioning into dynamic communities. Remarkably, XPG caps XPD’s DNA-binding groove and bridges both junctions of the DNA bubble, suggesting a novel coordination mechanism of PInC’s dual incision. XPA rigging interlaces XPF/ERCC1 with RPA, XPD, XPB, and 5′ ssDNA, exposing XPA’s crucial role in licensing the XPF/ERCC1 incision. Mapping disease mutations onto our models reveals clustering into distinct mechanistic classes, elucidating xeroderma pigmentosum and Cockayne syndrome disease etiology.

Abstract Transcription factor IIH (TFIIH) is a protein assembly essential for transcription initiation and nucleotide excision repair (NER). Yet, understanding of the conformational switching underpinning these diverse TFIIH functions remains fragmentary. TFIIH mechanisms critically depend on two translocase subunits, XPB and XPD. To unravel their functions and regulation, we build cryo-EM based TFIIH models in transcription- and NER-competent states. Using simulations and graph-theoretical analysis methods, we reveal TFIIH’s global motions, define TFIIH partitioning into dynamic communities and show how TFIIH reshapes itself and self-regulates depending on functional context. Our study uncovers an internal regulatory mechanism that switches XPB and XPD activities making them mutually exclusive between NER and transcription initiation. By sequentially coordinating the XPB and XPD DNA-unwinding activities, the switch ensures precise DNA incision in NER. Mapping TFIIH disease mutations onto network models reveals clustering into distinct mechanistic classes, affecting translocase functions, protein interactions and interface dynamics.

Abstract The forkhead box transcription factor A2 (FOXA2) is a transcription factor and plays a key role in embryonic development, metabolism homeostasis and tumor cell proliferation; however, its regulatory potential in CRC is not fully understood. Here, it is found that FOXA2 expression is markedly up‐regulated in tumor samples of CRC patients as compared with the normal tissues, which is closely associated with the worse survival in patients with CRC. Notably, a positive correlation between FOXA2 and nuclear factor erythroid 2‐related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) gene expression is observed in CRC patients. Mechanistically, FOXA2 depletion weakens the activation of Nrf2 pathway and decreases GPX4 level in CRC cells, thereby leading to ferroptosis, which is further supported by bioinformatic analysis. More intriguingly, the E3 ubiquitin ligase tripartite motif containing 36 (TRIM36) is identified as a key suppressor of FOXA2, and it is observed that TRIM36 can directly interact with FOXA2 and induce its K48‐linked polyubiquitination, resulting in FOXA2 protein degradation in vitro. Taken together, all the studies demonstrate that FOXA2 mediated by TRIM36 promotes CRC progression by inhibiting the Nrf2/GPX4 ferroptosis signaling pathway, thus providing a new therapeutic target for CRC treatment.

Here the authors provide models of RNA polymerase II bound to the yeast CSB ortholog Rad26 in different nucleotide states; explain how Rad26 domain motions help the polymerase progress past DNA lesions; and interpret the effects of CSB-associated disease mutations.

Summary: Many acute and chronic diseases affect the distal lung alveoli. Alveolar epithelial cell (AEC) lines are needed to better model these diseases. We used de-identified human remnant transplant lungs to develop a method to establish AEC lines. The lines grow well in 2-dimensional (2D) culture as epithelial monolayers expressing lung progenitor markers. In 3-dimensional (3D) culture with fibroblasts, Matrigel, and specific media conditions, the cells form alveolar-like organoids expressing mature AEC markers including aquaporin 5 (AQP5), G-protein-coupled receptor class C group 5 member A (GPRC5A), and surface marker HTII280. Single-cell RNA sequencing of an AEC line in 2D versus 3D culture revealed increased cellular heterogeneity and induction of cytokine and lipoprotein signaling in 3D organoids. Our approach yields lung progenitor lines that retain the ability to differentiate along the alveolar cell lineage despite long-term expansion and provides a valuable system to model and study the distal lung in vitro.

The paper focuses on the failure process and mechanism of the concrete gravity dam considering different nonlinear models under strong earthquakes. By taking a typical monolith of a concrete gravity dam as a case study, a comparative analysis of the failure process and mechanism of the dam considering the plastic damage model and the dynamic contact model, respectively, is performed using the seismic overload method. Moreover, the ultimate seismic capacity of the dam is evaluated for both of the nonlinear models. It is found that the ultimate seismic capacity of the dam is slightly different, but the failure process has significant distinctions in each model. And, the damage model is recommended when the conditions permit.

Lung cancer is the leading cause of cancer-related death and lung adenocarcinoma is its most common subtype. Although genetic alterations have been identified as drivers in subsets of lung adenocarcinoma, they do not fully explain tumor development. Epigenetic alterations have been implicated in the pathogenesis of tumors. To identify epigenetic alterations driving lung adenocarcinoma, we used an improved version of the Tracing Enhancer Networks using Epigenetic Traits method (TENET 2.0) in primary normal lung and lung adenocarcinoma cells. We found over 32,000 enhancers that appear differentially activated between normal lung and lung adenocarcinoma. Among the identified transcriptional regulators inactivated in lung adenocarcinoma vs. normal lung, NKX2-1 was linked to a large number of silenced enhancers. Among the activated transcriptional regulators identified, CENPA, FOXM1, and MYBL2 were linked to numerous cancer-specific enhancers. High expression of CENPA, FOXM1, and MYBL2 is particularly observed in a subgroup of lung adenocarcinomas and is associated with poor patient survival. Notably, CENPA, FOXM1, and MYBL2 are also key regulators of cancer-specific enhancers in breast adenocarcinoma of the basal subtype, but they are associated with distinct sets of activated enhancers. We identified individual lung adenocarcinoma enhancers linked to CENPA, FOXM1, or MYBL2 that were associated with poor patient survival. Knockdown experiments of FOXM1 and MYBL2 suggest that these factors regulate genes involved in controlling cell cycle progression and cell division. For example, we found that expression of TK1, a potential target gene of a MYBL2-linked enhancer, is associated with poor patient survival. Identification and characterization of key transcriptional regulators and associated enhancers in lung adenocarcinoma provides important insights into the deregulation of lung adenocarcinoma epigenomes, highlighting novel potential targets for clinical intervention.

There are various uncertainties in the design, construction, and operation of dams. These uncertainties have an important impact on the seismic response and seismic safety evaluation of concrete dams. In this research, a typical nonoverflow monolith of a concrete gravity dam is selected as a case study for the sliding stability analysis. Based on the analysis and demonstration of parameter sensitivity of friction coefficients and cohesion and their influence on the deep antisliding stability of the dam-foundation system, the probabilistic seismic analysis of a gravity dam-foundation system is carried out through Monte Carlo analysis with a large sample number. Damage levels are defined based on the sliding instability failure mode along with the corresponding threshold values of the damage index. Thus, seismic fragility analysis is investigated, and seismic fragility curves are obtained for the vulnerability assessment under earthquake hazards. The overall seismic stability of the gravity dam is evaluated, which provides the basis for the seismic safety evaluation in the probabilistic framework.

Objective: To explore the sociocultural factors influencing depression in Chinese infertile women in Hunan Province. Methods: A cross-sectional study was carried out. A total of 211 Chinese infertile women completed demographic details, a disease-related information questionnaire, a self-rating depression scale (SDS) and a social support rating scale (SSRS). Results: One hundred and seven (50.71%) of the participants were classified as depressed according to the self-rating depression scale. The average SDS index score was 50.06 ± 10.59. Using analysis of variance (ANOVA), Pearson correlation and a multivariable regression analysis, the results showed family type, feelings of discrimination, social support, feelings of shame and reproductive pressures were influential factors in depression among Chinese infertile women. Conclusion: Sociocultural factors influence depression levels in Chinese female infertile patients. The unique aspects of Chinese culture may have a negative mental impact on the patients, and cultural factors should be taken into consideration in the development of coping strategies for Chinese infertile women.

Objective: To translate the English version of Infertility Self-Efficacy Scale into Chinese and to validate the psychometric properties of the Chinese version of the Infertility Self-Efficacy Scale (CISE). Method(s): Participants were recruited from the Gynecology Department of two city hospitals. Five main processes were involved in the formation of CISE [1]: scale translation based on expert consultation [2]; pre-test questionnaire development with infertile women's feedback (N = 20) [3]; factor structure assessed by exploratory and confirmatory factor analysis (N = 177) [4]; assessment of reliability by internal consistency (N = 177) and test-retest reliability (N = 21); and [5] assessment of convergent validity with Self-rating Anxiety Scale, Self-rating Depression Scale, and Simplified Coping Style Questionnaire (N = 177). Results: This study established a 16-item CISE. Factor analyses confirmed a one-component solution, which explained 54.59% of total variances and showed an acceptable model fit. Cronbach's α and test-retest correlation coefficients for the scale were 0.94 and 0.84, respectively. The CISE score was significantly correlated with anxiety (r = −0.47), depression (r = −0.60), positive coping style (r = 0.37), and certain negative coping style items. Conclusion: This 16-item CISE is a reliable and valid measure to evaluate perceived self-efficacy among a sample of Chinese women who underwent infertility treatment.

Integrins are transmembrane proteins that have important roles in cell adhesion and signalling. Here the authors design a therapeutic protein that binds integrin αvβ3, has anti-angiogenic activity, and reduces tumour growth in xenograft models, while being seemingly well tolerated.

While conventional high-resolution techniques in structural biology are challenged by the size and flexibility of many biological assemblies, recent advances in low-resolution techniques such as cryo-electron microscopy (cryo-EM) and small angle X-ray scattering (SAXS) have opened up new avenues to define the structures of such assemblies. By systematically combining various sources of structural, biochemical and biophysical information, integrative modeling approaches aim to provide a unified structural description of such assemblies, starting from high-resolution structures of the individual components and integrating all available information from low-resolution experimental methods. In this review, we describe integrative modeling approaches, which use complementary data from either cryo-EM or SAXS. Specifically, we focus on the popular molecular dynamics flexible fitting (MDFF) method, which has been widely used for flexible fitting into cryo-EM maps. Second, we describe hybrid molecular dynamics, Rosetta Monte-Carlo and minimum ensemble search (MES) methods that can be used to incorporate SAXS into pseudoatomic structural models. We present concise descriptions of the two methods and their most popular alternatives, along with select illustrative applications to protein/nucleic acid assemblies involved in DNA replication and repair.

Transcription initiation by RNA Polymerase I (Pol I) depends on the Core Factor (CF) complex to recognize the upstream promoter and assemble into a Pre-Initiation Complex (PIC). Here, we solve a structure of Saccharomyces cerevisiae Pol I-CF-DNA to 3.8 Å resolution using single-particle cryo-electron microscopy. The structure reveals a bipartite architecture of Core Factor and its recognition of the promoter from −27 to −16. Core Factor’s intrinsic mobility correlates well with different conformational states of the Pol I cleft, in addition to the stabilization of either Rrn7 N-terminal domain near Pol I wall or the tandem winged helix domain of A49 at a partially overlapping location. Comparison of the three states in this study with the Pol II system suggests that a ratchet motion of the Core Factor-DNA sub-complex at upstream facilitates promoter melting in an ATP-independent manner, distinct from a DNA translocase actively threading the downstream DNA in the Pol II PIC.

Human flap endonuclease 1 (FEN1) and related structure-specific 5’nucleases precisely identify and incise aberrant DNA structures during replication, repair and recombination to avoid genomic instability. Yet, it is unclear how the 5’nuclease mechanisms of DNA distortion and protein ordering robustly mediate efficient and accurate substrate recognition and catalytic selectivity. Here, single-molecule sub-millisecond and millisecond analyses of FEN1 reveal a protein-DNA induced-fit mechanism that efficiently verifies substrate and suppresses off-target cleavage. FEN1 sculpts DNA with diffusion-limited kinetics to test DNA substrate. This DNA distortion mutually ‘locks’ protein and DNA conformation and enables substrate verification with extreme precision. Strikingly, FEN1 never misses cleavage of its cognate substrate while blocking probable formation of catalytically competent interactions with noncognate substrates and fostering their pre-incision dissociation. These findings establish FEN1 has practically perfect precision and that separate control of induced-fit substrate recognition sets up the catalytic selectivity of the nuclease active site for genome stability.

SUMMARY Regions in the 8q24 gene desert contribute significantly to the risk of prostate cancer and other adult cancers. This region contains several DNA regions with enhancer activity in cultured cells. One such segment, histone acetylation peak 10 (AcP10), contains a risk single nucleotide polymorphism (SNP) that is significantly associated with the pathogenesis of colorectal, prostate and other cancers. The mechanism by which AcP10 influences cancer risk remains unknown. Here we show that AcP10 contains a sequence that is highly conserved across terrestrial vertebrates and is capable in transgenic mice of directing reporter gene expression to a subset of prostate lumenal epithelial cells. These cells include a small population of Nkx3.1-positive cells that persist even after androgen ablation. Castration-resistant Nkx3.1-positive (CARN) cells were shown by others to function both as stem cells and cells of origin of prostate cancer. Our results thus provide a mechanism by which AcP10 could influence prostate cancer risk.

Genome-wide association studies (GWAS) have revolutionized the field of cancer genetics, but the causal links between increased genetic risk and onset/progression of disease processes remain to be identified. Here we report the first step in such an endeavor for prostate cancer. We provide a comprehensive annotation of the 77 known risk loci, based upon highly correlated variants in biologically relevant chromatin annotations--we identified 727 such potentially functional SNPs. We also provide a detailed account of possible protein disruption, microRNA target sequence disruption and regulatory response element disruption of all correlated SNPs at r(2) ≥ 0.88%. 88% of the 727 SNPs fall within putative enhancers, and many alter critical residues in the response elements of transcription factors known to be involved in prostate biology. We define as risk enhancers those regions with enhancer chromatin biofeatures in prostate-derived cell lines with prostate-cancer correlated SNPs. To aid the identification of these enhancers, we performed genomewide ChIP-seq for H3K27-acetylation, a mark of actively engaged enhancers, as well as the transcription factor TCF7L2. We analyzed in depth three variants in risk enhancers, two of which show significantly altered androgen sensitivity in LNCaP cells. This includes rs4907792, that is in linkage disequilibrium (r(2) = 0.91) with an eQTL for NUDT11 (on the X chromosome) in prostate tissue, and rs10486567, the index SNP in intron 3 of the JAZF1 gene on chromosome 7. Rs4907792 is within a critical residue of a strong consensus androgen response element that is interrupted in the protective allele, resulting in a 56% decrease in its androgen sensitivity, whereas rs10486567 affects both NKX3-1 and FOXA-AR motifs where the risk allele results in a 39% increase in basal activity and a 28% fold-increase in androgen stimulated enhancer activity. Identification of such enhancer variants and their potential target genes represents a preliminary step in connecting risk to disease process.

Breast Cancer (BCa) genome-wide association studies revealed allelic frequency differences between cases and controls at index single nucleotide polymorphisms (SNPs). To date, 71 loci have thus been identified and replicated. More than 320,000 SNPs at these loci define BCa risk due to linkage disequilibrium (LD). We propose that BCa risk resides in a subgroup of SNPs that functionally affects breast biology. Such a shortlist will aid in framing hypotheses to prioritize a manageable number of likely disease-causing SNPs. We extracted all the SNPs, residing in 1 Mb windows around breast cancer risk index SNP from the 1000 genomes project to find correlated SNPs. We used FunciSNP, an R/Bioconductor package developed in-house, to identify potentially functional SNPs at 71 risk loci by coinciding them with chromatin biofeatures. We identified 1,005 SNPs in LD with the index SNPs (r(2)≥0.5) in three categories; 21 in exons of 18 genes, 76 in transcription start site (TSS) regions of 25 genes, and 921 in enhancers. Thirteen SNPs were found in more than one category. We found two correlated and predicted non-benign coding variants (rs8100241 in exon 2 and rs8108174 in exon 3) of the gene, ANKLE1. Most putative functional LD SNPs, however, were found in either epigenetically defined enhancers or in gene TSS regions. Fifty-five percent of these non-coding SNPs are likely functional, since they affect response element (RE) sequences of transcription factors. Functionality of these SNPs was assessed by expression quantitative trait loci (eQTL) analysis and allele-specific enhancer assays. Unbiased analyses of SNPs at BCa risk loci revealed new and overlooked mechanisms that may affect risk of the disease, thereby providing a valuable resource for follow-up studies.

The mechanisms by which MAP kinases recognize and phosphorylate substrates are not completely understood. Efforts to understand the mechanisms have been compromised by the lack of MAPK-substrate structures. While MAPK-substrate docking is well established as a viable mechanism for bringing MAPKs and substrates into close proximity the molecular details of how such docking promotes phosphorylation is an unresolved issue. In the present study computer modeling approaches, with restraints derived from experimentally known interactions, were used to predict how the N-terminus of Ets-1 associates with ERK2. Interestingly, the N-terminus does not contain a consensus-docking site ((R/K)(2-3)-X(2-6)-Φ(A)-X-Φ(B), where Φ is aliphatic hydrophobic) for ERK2. The modeling predicts that the N-terminus of Ets-1 makes important contributions to the stabilization of the complex, but remains largely disordered. The computer-generated model was used to guide mutagenesis experiments, which support the notion that Leu-11 and possibly Ile-13 and Ile-14 of Ets-1 1-138 (Ets) make contributions through binding to the hydrophobic groove of the ERK2 D-recruiting site (DRS). Based on the modeling, a consensus-docking site was introduced through the introduction of an arginine at residue 7, to give the consensus (7)RK-X(2)-Φ(A)-X-Φ(B) (13). This results in a 2-fold increase in k(cat)/K(m) for the phosphorylation of Ets by ERK2. Similarly, the substitution of the N-terminus for two different consensus docking sites derived from Elk-1 and MKK1 also improves k(cat)/K(m) by two-fold compared to Ets. Disruption of the N-terminal docking through deletion of residues 1-23 of Ets results in a 14-fold decrease in k(cat)/K(m), with little apparent change in k(cat). A peptide that binds to the DRS of ERK2 affects K(m), but not k(cat). Our kinetic analysis suggests that the unstructured N-terminus provides 10-fold uniform stabilization of the ground state ERK2•Ets•MgATP complex and intermediates of the enzymatic reaction.

Multiple discrete regions at 8q24 were recently shown to contain alleles that predispose to many cancers including prostate, breast, and colon. These regions are far from any annotated gene and their biological activities have been unknown. Here we profiled a 5-megabase chromatin segment encompassing all the risk regions for RNA expression, histone modifications, and locations occupied by RNA polymerase II and androgen receptor (AR). This led to the identification of several transcriptional enhancers, which were verified using reporter assays. Two enhancers in one risk region were occupied by AR and responded to androgen treatment; one contained a single nucleotide polymorphism (rs11986220) that resides within a FoxA1 binding site, with the prostate cancer risk allele facilitating both stronger FoxA1 binding and stronger androgen responsiveness. The study reported here exemplifies an approach that may be applied to any risk-associated allele in non-protein coding regions as it emerges from genome-wide association studies to better understand the genetic predisposition of complex diseases.

Abstract Gastric cancer (GC) is a common malignant tumor, which originated from the epithelial cells of the stomach. It has the characteristics of high incidence and poor prognosis. Therefore, it is urgent to find new prognostic markers for the diagnosis and treatment of GC. Download gene expression matrix and clinical data from TCGA database and GSE84437 dataset. Through independent prognostic analysis and clinical correlation analysis, 74 prognostic related genes (PRG) were screened out. A PPI network was established for PRG to identify four key genes (KG), namely LMOD1, CRYAB, VCL and MYL9. Survival analysis showed that patients with high expression of KG had poor prognosis. Multivariate Cox regression analysis showed that KG was an independent prognostic factor. TCGA database verifies the importance and significance of KG as a prognostic indicator. Functional enrichment analysis showed that KG was mainly involved in cell adhesion molecules, adhesion spots and PI3K/AKT signaling pathway. KG may be a potential therapeutic target for gastric cancer.

Abstract Background Superficial acral fibromyxoma is a noncancerous, benign tumor of soft tissue with an unidentified origin. Occurrences of abnormalities on the palm are less frequently documented. Case report presentation A 47-year-old East Asian woman presented with a palm tumor on her left knuckle that had been present for 4 months. Four months prior to treatment, a reddish nodule appeared at the site due to continuous friction, but the patient did not pay attention to it. Upon physical examination, a pale-reddish nodule measuring approximately 0.8 × 0.8 cm was observed on the flexion side of the fourth metacarpophalangeal joint of the left hand. The nodule was nearly round, exhibited distinct margins, featured slight surface keratosis, and displayed a collar-like alteration at its periphery. The stroma showed significant fibrous proliferation and a myxoid matrix. The cellular composition consisted primarily of spindle-shaped fibroblasts, which were locally arranged in bundles within the stroma. Sparse slender blood vessels were distributed along with observed red blood cell extravasation. Immunohistochemistry of the tumor showed CD34 (+), CD99 (−), desmin (−), epithelial membrane antigen (−). Extensive resection of the mass was performed. Conclusion A rounded mass on the palm of the hand may be superficial acral fibromyxoma. The optimal approach for treating superficial acral fibromyxoma involves complete surgical removal of the mass followed by postoperative monitoring.

Abstract Messenger RNA (mRNA) therapeutics have garnered considerable attention due to their remarkable efficacy in the treatment of various diseases. The COVID‐19 mRNA vaccine and RSV mRNA vaccine have been approved on the market. Due to the inherent nuclease‐instability and negative charge of mRNA, delivery systems are developed to protect the mRNA from degradation and facilitate its crossing cell membrane to express functional proteins or peptides in the cytoplasm. However, the deficiency in transfection efficiency and targeted biological distribution are still the major challenges for the mRNA delivery systems. In this review, we first described the physiological barriers in the process of mRNA delivery and then discussed the design approach and recent advances in mRNA delivery systems with an emphasis on their tissue/cell‐targeted abilities. Finally, we pointed out the existing challenges and future directions with deep insights into the design of efficient mRNA delivery systems. We believe that a high‐precision targeted delivery system can greatly improve the therapeutic effects and bio‐safety of mRNA therapeutics and accelerate their clinical transformations. This review may provide a new direction for the design of mRNA delivery systems and serve as a useful guide for researchers who are looking for a suitable mRNA delivery system.

BackgroundAlthough an intracranial aneurysm (IA) is widespread and fatal, few drugs can be used to prevent its rupture. This study explored the molecular mechanism and potential targets of IA rupture through bioinformatics methods.MethodsThe gene expression matrices of GSE13353, GSE122897, and GSE15629 were downloaded. Differentially expressed genes (DEGs) were screened using the limma package. Functional enrichment analysis was performed, and a PPI network was constructed. Furthermore, candidate key genes were identified using the least absolute shrinkage and selection operator (LASSO) regression model, support vector machine-recursive feature elimination (SVM-RFE) analysis, and PPI network analysis. ROC analysis was conducted to further verify the diagnostic value of the key genes.ResultsA total of 334 DEGs were screened, including 175 upregulated genes and 159 downregulated genes. Further functional analysis suggested that the DEGs were enriched in inflammation and immune response pathways. Fourteen hub genes were identified using the two algorithms. The PPI networks of the hub genes were analyzed using the Cytoscape plugin CytoNCA to obtain two key genes (IL10 and Integrin α5 (ITGA5)). The ROC curve analysis showed that the AUC values of IL10 and ITGA5 were 0.801, and 0.786, respectively. In addition, the two key genes were significantly positively correlated with macrophages and Treg (T) cells. The immune score and ESTIMATE score of the ruptured IA group were significantly higher than those of the unruptured IA group.ConclusionThe increase in IL-10 and ITGA5 may weaken the vascular wall by promoting inflammation in blood vessels and immune cells, which could have a harmful effect on the rupture of IAs.

Wire arc additive manufacturing offers advantages in producing large metal structures. The current research on GTA-based wire arc additive manufacturing (GTA-WAAM) of magnesium alloys is focused on deformed magnesium alloys, mainly on the Mg-Al alloy system. However, there is little research on GTA-WAAM for casting magnesium alloy. This study investigates the microstructural characteristics and mechanical properties of AZ91D magnesium alloy (AZ91D-Mg) deposited by GTA-WAAM. Single-pass multilayer thin-walled components were successfully fabricated. The results show that equiaxed grains dominate the microstructure of the deposited samples. During the remelting process, the precipitated phases dissolve into the matrix, and they precipitate and grow from the matrix under the thermal effect of the subsequent thermal cycle. The mechanical properties in the vertical and horizontal directions are similar, showing higher overall mechanical properties than the casting parts. The average yield strength is 110.5 MPa, the ultimate tensile strength is 243.6 MPa, and the elongation is 11.7%. The overall hardness distribution in the deposited sample is relatively uniform, and the average microhardness is 59.6 HV0.2.

ObjectiveTo explore and describe the epidemiological and genetic variation characteristics of the influenza A (H1N1) virus in Hangzhou City.MethodsRespiratory throat swab specimens collected from the fever clinic of the 903rd Hospital of the Chinese People’s Liberation Army (PLA) between January and March 2023 were collected. The respiratory pathogen antigens were identified using the colloidal gold method, and those testing positive for influenza A virus antigens were confirmed and subtyped by RT-qPCR. Seventeen H1N1 isolates were selected to amplify hemagglutinin (HA) and neuraminidase (NA) gene sequences via RT-PCR, and sequencing was completed following the identification of the amplified products. The sequenced HA and NA sequences were spliced using DNASTAR software (version 5.0), and a phylogenetic tree was constructed using MEGA software (version 11.0) for genetic characterization.ResultsA total of 2,376 respiratory samples were tested, with 680 cases testing positive for influenza A. Of these, 129 positive cases of influenza A were randomly selected for typing, resulting in the isolation of 112 H1N1 subtypes and 17 H3N2 subtypes. The HA genes of 17 strains of influenza A (H1N1) were randomly selected for amino acid homology comparisons with two vaccine strains recommended by the WHO for 2023 (A/Wisconsin/67/2022 (H1N1) and A/Victoria/4897/2022 (H1N1)). The HA gene results showed identities of 98.24 to 98.65% and 98.41 to 98.82%, respectively, and the NA gene results were 98.79 to 99.15% and 98.94 to 99.29%, respectively. Fourteen amino acid sites were altered in the HA gene of the 17 strains, with some strains contributing to the Sa and Ca antigenic determinants, respectively. Seventeen strains had mutations in the NA gene at sites 13, 50, 200, 339, 382, and 469. The sequenced strains, vaccine strains, and some 2023 domestic representative strains independently formed a branch 6B.1A.5a.2a.ConclusionThe continuous evolutionary mutations of the H1N1 virus genes in Hangzhou City suggest the possibility of the virus escaping from the immune response. This study provides an experimental basis for evaluating the protective effect of the vaccine and formulating preventive measures against influenza in Hangzhou City.

MethodsWe recruited 58 MA-dependent young adult females from a compulsory isolation drug rehabilitation center in Sichuan Province and randomly divided them into an MBRP group (n = 29) and a control group (n = 29) according to their degree of psychological craving. The MBRP group received 2 hours of MBRP training twice a week for 4 weeks, alongside routine treatment at the drug rehabilitation center. Meanwhile, the control group solely received routine treatment at the drug rehabilitation center without any additional interventions. The assessment was conducted before and immediately after the intervention, with the Compulsive Drug Use Scale (OCDUS) used to assess craving and the Five-Factor Mindfulness Scale (FFMQ) used to assess trait mindfulness. Also, a “mental feedback monitoring balance” instrument was used to assess concentration and relaxation during some training sessions. This randomized trial was conducted to evaluate the effectiveness of decreasing psychological craving and increasing trait mindfulness.ResultsAt baseline, there were no significant differences in total or dimension scores for FFMQ or OCDUS between the two groups (all P > 0.05). After the intervention, the repeated measures ANOVA showed a significant time main effect on changes in observing, non-judging, and non-reacting scores (all P < 0.05), and a significant interaction effect between time and group on both FFMQ total score and OCDUS score (P < 0.01 or P < 0.05). Mental feedback monitoring indicated significant improvement in concentration and relaxation after breath meditation exercises (P < 0.05 or P < 0.001). Additionally, the MBRP group showed improved relaxation during the body scan exercise (P < 0.01).ConclusionMBRP training can improve the trait mindfulness of MA addicts and reduce psychological cravings effectively.