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This study investigates the effect of programming courses on the computational thinking (CT) skills of elementary school students and the learning effectiveness of students from different backgrounds who are studying programming. We designed a OwlSpace programming course into an elementary school curriculum. Students in fourth and fifth grades were taught the fundamentals of programming. We measured and analyzed the effectiveness of their CT skills and self-efficacy in CT. The researchers analyzed the changes in the CT of different gender, different grade, and different past experience students in programming courses and then made specific recommendations for information technology teachers and related units. The results demonstrate that students learned and improved their CT skills by taking OwlSpace programming course. Additionally, gender, grade, and past experience are found to have no impact on the students' learning that means the course can improve students ability without limited any characteristics.

While ChatGPT has recently become very popular, AI has a long history and philosophy. This paper intends to explore the promises and pitfalls of the Generative Pre-trained Transformer (GPT) AI and potentially future technologies by adopting a speculative methodology. Speculative future narratives with a specific focus on educational contexts are provided in an attempt to identify emerging themes and discuss their implications for education in the 21st century. Affordances of (using) AI in Education (AIEd) and possible adverse effects are identified and discussed which emerge from the narratives. It is argued that now is the best of times to define human vs AI contribution to education because AI can accomplish more and more educational activities that used to be the prerogative of human educators. Therefore, it is imperative to rethink the respective roles of technology and human educators in education with a future-oriented mindset.

Teachers' conceptions of assessment are a significant indicator of teacher assessment literacy. This study contextualized pre-service teachers' conceptions of assessment in Chinese second language education. An exploratory factor analysis generated eight first-order factors and the following confirmatory factor analysis found a hierarchical model, reflecting a noticeable influence of prior learning experiences and official assessment regimes on conceptions. A follow-up latent profile analysis showed three profiles. Improvement-oriented was the most prevalent profile, but more than 40% of the participants were categorized as negative. The study substantiated the need to develop an integrative and balanced understanding of assessment in teacher education to prepare pre-service teachers for teaching in international contexts.

Abstract Although early solid diet supplementation is a common practice to improve the growth and development in goat kids, its biological mechanism how solid diet induces rumen microbiota and epithelial development is still unknow. In this study, rumen fermentation parameters, 16S rRNA sequencing for rumen content and epithelial microbiota, transcriptomics and proteomics of epithelium were determined to classify the effects of solid diet supplementation. Here, we classified the changes of goat phenotypes (i.e., growth performance, rumen fermentation and development) and linked them to the changes of rumen microbiota, transcriptome and expressed proteins. The mechanism of solid diet improving rumen development was elucidated preliminarily. Moreover, different roles between the rumen content and epithelial microbiota were identified. Thess datasets expands our understanding of the association between the early diet intervention and rumen development, providing the useful information how nutrient strategy affects rumen function and subsequently improves the host growth. The generated data provides insights in the importance of rumen niche microbiota and microbe-host interactions, which benefits future studies.

Abstract Background Associations between Helicobacter pylori infection and lifestyle factors vary greatly by geographic location. This study aims to evaluate the prevalence of Helicobacter pylori infection in the Hunan cohort of central China and analyze the associations between Helicobacter pylori infection and lifestyle factors in different occupations. Methods This was a cross-sectional study. Participants who received an annual physical examination were invited. Helicobacter pylori infection was detected by the 13 C-urea breath test. Self-reported physical examination questionnaires were used to analyze participants’ demographic information, diet, exercise status, and sleep situations. Results 23254 participants finished this study. The Helicobacter pylori infection rate in the Hunan area was 25.8%, with the lowest prevalence in students (8.5%) and the highest prevalence in business managers (29.9%). The risk factors for Helicobacter pylori infection were marital status (divorced or married) (OR:1.16, 95%CI:1.090–1.234), overeating (OR:1.105, 95%CI: 1.001–1.220), and consumption of eggs (OR:1.047, 95%CI:1.004–1.092), animal viscera (OR: 1.077, 95%CI:1.014–1.144) and coffee (OR:1.074, 95%CI:1.019–1.132). Participants’ education level (OR:0.911, 95%CI:0.881-0942), consumption of midnight snack (OR:0.926, 95%CI:0.877–0.977), and vegetable (OR:0.927, 95%CI: 0.884–0.972) were protective factors against Helicobacter pylori infection. Whether participants exercised regularly or had sleep problems had no significant effect on Helicobacter pylori infection. Different professionals showed significant differences in the rates of overeating, eating three meals on time, midnight snack, and consuming coffee, eggs, animal viscera, and vegetables > 3 times/week (P values

Abstract Background Tuberculosis (TB) is a major cause of death worldwide, and Chinese TB burden ranked the second globally. Chinese primary healthcare (PHC) sectors implement the TB Control Program (TCP) to improve active case finding, referral, treatment adherence, and health education. This study aimed to identify barriers and enablers of TCP implementation in high TB burden regions of West China. Methods We conducted a representative study using mixed-methods in 28 counties or districts in Chongqing Municipality and Guizhou Province of West China from October 2021 to May 2022. Questionnaire surveys and semi-structured in-depth interviews were conducted with 2720 TB healthcare workers (HCWs) and 20 interviewees in PHC sectors. Descriptive statistical analysis was used to investigate TB HCWs’ characteristics, and path analysis model was utilized to analyze the impact of associated factors on TCP implementation. Thematic framework analysis was developed with the guide of the adapted Consolidated Framework for Implementation Research (CFIR) on factors of TCP implementation. Results This study found that 84.6% and 94.1% of community and village HCWs had low professional titles. Based on the results of multiple regression analysis and correlation analysis, lower TB core knowledge scores (-0.09) were identified as barriers for TCP implementation in community PHC sectors, and low working satisfaction (-0.17) and low working willingness (-0.10) are barriers for TPC implementation in village PHC sectors. The results of in-depth interviews reported barriers in all domains and enablers in four domains of CFIR. There were identified 19 CFIR constructs associated with TCP implementation, including 22 barriers such as HCWs’ heavy workload, and 12 enablers such as HCWs’ passion towards TCP planning. Conclusions With the guide of the CFIR framework, complex factors (barriers and enablers) of TCP implementation in PHC sectors of West China were explored, which provided important evidences to promote TB program in high TB burden regions. Further implementation studies to translate those factors into implementation strategies are urgent needed. Graphical Abstract

Abstract Background The MADS-box gene family is widely distributed in the plant kingdom, and its members typically encoding transcription factors to regulate various aspects of plant growth and development. In particular, the MIKC-type MADS-box genes play a crucial role in the determination of floral organ development and identity recognition. As a type of androdioecy plant, Chionanthus retusus have unique gender differentiation. Manifested as male individuals with only male flowers and female individuals with only bisexual flowers. However, due to the lack of reference genome information, the characteristics of MIKC-type MADS-box genes in C. retusus and its role in gender differentiation of C. retusus remain largely unknown. Therefore, it is necessary to identify and characterize the MADS-box gene family within the genome of the C. retusus. Results In this study, we performed a genome-wide identification and analysis of MIKC-type MADS-box genes in C. retusus (2n = 2x = 46), utilizing the latest reference genome, and studied its expression pattern in individuals of different genders. As a result, we identified a total of 61 MIKC-type MADS-box genes in C. retusus. 61 MIKC-type MADS-box genes can be divided into 12 subfamilies and distributed on 18 chromosomes. Genome collinearity analysis revealed their conservation in evolution, while gene structure, domains and motif analysis indicated their conservation in structure. Finally, based on their expression patterns in floral organs of different sexes, we have identified that CrMADS45 and CrMADS60 may potentially be involved in the gender differentiation of C. retusus. Conclusions Our studies have provided a general understanding of the conservation and characteristics of the MIKC-type MADS-box genes family in C. retusus. And it has been demonstrated that members of the AG subfamily, CrMADS45 and CrMADS60, may play important roles in the gender differentiation of C. retusus. This provides a reference for future breeding efforts to improve flower types in C. retusus and further investigate the role of MIKC-type MADS-box genes in gender differentiation.

Abstract Background Rheumatoid arthritis (RA) is a systemic autoimmune disease, and depression is a most frequent comorbid condition associated with RA. Studies have shown that inflammation plays a vital role in the pathophysiology of depression and RA. Mediterranean diet (MED) has been proved to be a healthy anti-inflammatory dietary pattern. This study aims to explore the association between the adherence to Mediterranean diet (aMED) and depression in RA patients. Methods In this study, RA patients aged ≥ 20 years old were extracted from the National Health and Nutrition Examination Survey (NAHNES) database. Dietary intake information was obtained from 24-h dietary recall interview. Covariates included sociodemographic information, lifestyles, laboratory parameters, and the history of diseases and medications were included. The weighted univariable and multivariable logistic regression models were used to assess the association between aMED and depression. Subgroup analysis was conducted to further explore the association between MED components and depression. Results Totally 1,148 patients were included, of whom 290 (25.26%) had depression. After adjusted all covariates, high aMED was associated with the lower odds of depression in RA patients (OR = 0.53, 95%CI: 0.29–0.97). Among MED components, higher consumption of vegetables (OR = 0.54, 95%CI: 0.34–0.84) and cereals (OR = 0.63, 95%CI: 0.39–0.99) contributed more to decrease the odds of depression. Conclusion Greater aMED may have potential benefits for improving mental health in RA patients. Future large-scale cohort studies are needed to explore the association between aMED and depression in RA patients.

ObjectiveThis study focuses on the quasi-static pressure characteristics of a confined cabin in a water mist environment. MethodsFirst, on the basis of the theoretical model of quasi-static pressure in a confined cabin in adiabatic ideal gas, two new assumptions are added to establish a theoretical model of quasi-static pressure in a confined cabin in a water mist environment. Internal explosion experiments in a confined cabin with and without water mist are then performed with the charge as an independent variable, and the quasi-static pressure is measured and used to verify the mitigation effect of water mist on quasi-static pressure and obtain its empirical formula.Results Combined with the theoretical model and experimental data analysis, it is concluded that the ability of water mist to reduce quasi-static pressure increases with the increase in charge-volume ratio, but the increase rate gradually decreases. Both the theoretical formulas of the afterburning correction term and empirical formulas can be used to estimate the quasi-static pressure peak in the cabin.ConclusionsThe experimental results verify the mitigation effect of water mist on quasi-static pressure. The experimental data of this paper and others shows good agreement with the empirical formula of the quasi-static pressure peak of an internal explosion in a water mist environment, and can be used to estimate the quasi-static pressure peak.

Large ships and submarines are the main equipment and mobile platforms supporting three-dimensional naval space operations. However, with the increasing damage power and strike accuracy of warheads, plus the diversity of destroying elements, their living environment is facing increasingly severe threats. It is thus necessary to work on the damage and protection of naval vessels subjected to blast loading. The blast-induced damage and protection of naval vessels is an interdisciplinary issue that involves the integration of explosion mechanics, fluid mechanics, structural mechanics, materials science and other disciplines in which many challenges are yet to be addressed. In view of some of the key issues involved, this paper systematically summarizes the research progress on blast load characteristics, damage mechanisms and protection technologies and equipment at home and abroad in recent years. The shortcomings of the current research are pointed out and the development trends of ship explosion damage and protection are predicted. This study can provide valuable references for future research on the efficient damage and protection of naval vessels.

Abstract Background Relapse remains a challenge after transplantation in pediatric patients with hematological malignancies. Myeloablative regimens used for disease control are associated with acute and long-term adverse effects. We used a CD45RA-depleted haploidentical graft for adoptive transfer of memory T cells combined with NK-cell addback and hypothesized that maximizing the graft-versus-leukemia (GVL) effect might allow for reduction in intensity of conditioning regimen. Methods In this phase II clinical trial (NCT01807611), 72 patients with hematological malignancies (complete remission (CR)1: 25, ≥ CR2: 28, refractory disease: 19) received haploidentical CD34 + enriched and CD45RA-depleted hematopoietic progenitor cell grafts followed by NK-cell infusion. Conditioning included fludarabine, thiotepa, melphalan, cyclophosphamide, total lymphoid irradiation, and graft-versus-host disease (GVHD) prophylaxis consisted of a short-course sirolimus or mycophenolate mofetil without serotherapy. Results The 3-year overall survival (OS) and event-free-survival (EFS) for patients in CR1 were 92% (95% CI:72–98) and 88% (95% CI: 67–96); ≥ CR2 were 81% (95% CI: 61–92) and 68% (95% CI: 47–82) and refractory disease were 32% (95% CI: 11–54) and 20% (95% CI: 6–40). The 3-year EFS for all patients in morphological CR was 77% (95% CI: 64–87) with no difference amongst recipients with or without minimal residual disease (P = 0.2992). Immune reconstitution was rapid, with mean CD3 and CD4 T-cell counts of 410/μL and 140/μL at day + 30. Cumulative incidence of acute GVHD and chronic GVHD was 36% and 26% but most patients with acute GVHD recovered rapidly with therapy. Lower rates of grade III-IV acute GVHD were observed with NK-cell alloreactive donors (P = 0.004), and higher rates of moderate/severe chronic GVHD occurred with maternal donors (P = 0.035). Conclusion The combination of a CD45RA-depleted graft and NK-cell addback led to robust immune reconstitution maximizing the GVL effect and allowed for use of a submyeloablative, TBI-free conditioning regimen that was associated with excellent EFS resulting in promising long-term outcomes in this high-risk population. The trial is registered at ClinicalTrials.gov (NCT01807611).

Autoantibodies against apolipoprotein A-I (ApoA-I) are associated with cardiovascular disease risks. We aimed to examine the 4-hydroxy-2-nonenal (HNE) modification of ApoA-I in coronary artery disease (CAD) and evaluate the potential risk of autoantibodies against their unmodified and HNE-modified peptides. We assessed plasma levels of ApoA-I, HNE-protein adducts, and autoantibodies against unmodified and HNE-peptide adducts, and significant correlations and odds ratios (ORs) were examined. Two novel CAD-specific HNE-peptide adducts, ApoA-I251–262 and ApoA-I70–83, were identified. Notably, immunoglobulin G (IgG) anti-ApoA-I251–262 HNE, IgM anti-ApoA-I70–83 HNE, IgG anti-ApoA-I251–262, IgG anti-ApoA-I70–83, and HNE-protein adducts were significantly correlated with triglycerides, creatinine, or high-density lipoprotein in CAD with various degrees of stenosis (70%). The HNE-protein adduct (OR = 2.208-fold, p = 0.020) and IgM anti-ApoA-I251–262 HNE (2.046-fold, p = 0.035) showed an increased risk of progression from >30% stenosis in CAD. HNE-protein adducts and IgM anti-ApoA-I251–262 HNE may increase the severity of CAD at high and low levels, respectively.

Background The diagnostic accuracy of preoperative radiologic findings in predicting the tumor characteristics and clinical outcomes of papillary thyroid microcarcinoma (PTMC) was evaluated across all risk groups. Methods In total, 939 PTMC patients, comprising both low-risk and non-low-risk groups, who underwent surgery were enrolled. The preoperative tumor size and lymph node metastasis (LNM) were evaluated by ultrasonography within 6 months before surgery and compared with the postoperative pathologic findings. Discrepancies between the preoperative and postoperative tumor sizes were analyzed, and clinical outcomes were assessed. Results The agreement rate between radiological and pathological tumor size was approximately 60%. Significant discrepancies were noted, including an increase in tumor size in 24.3% of cases. Notably, in 10.8% of patients, the postoperative tumor size exceeded 1 cm, despite being initially classified as 0.5 to 1.0 cm based on preoperative imaging. A postoperative tumor size >1 cm was associated with aggressive pathologic factors such as multiplicity, microscopic extrathyroidal extension, and LNM, as well as a higher risk of distant metastasis. In 30.1% of patients, LNM was diagnosed after surgery despite not being suspected before the procedure. This group was characterized by smaller metastatic foci and lower risks of distant metastasis or recurrence than patients with LNM detected both before and after surgery. Conclusion Among all risk groups of PTMCs, a subset showed an increase in tumor size, reaching 1 cm after surgery. These cases require special consideration due to their association with adverse clinical outcomes, including an elevated risk of distant metastasis.

Abstract Psoriasis is an immune-mediated skin disease associated with neurogenic inflammation, but the underlying molecular mechanism remains unclear. We demonstrate here that acid-sensing ion channel 3 (ASIC3) exacerbates psoriatic inflammation through a sensory neurogenic pathway. Global or nociceptor-specific Asic3 knockout (KO) in female mice alleviates imiquimod-induced psoriatic acanthosis and type 17 inflammation to the same extent as nociceptor ablation. However, ASIC3 is dispensable for IL-23-induced psoriatic inflammation that bypasses the need for nociceptors. Mechanistically, ASIC3 activation induces the activity-dependent release of calcitonin gene-related peptide (CGRP) from sensory neurons to promote neurogenic inflammation. Botulinum neurotoxin A and CGRP antagonists prevent sensory neuron-mediated exacerbation of psoriatic inflammation to similar extents as Asic3 KO. In contrast, replenishing CGRP in the skin of Asic3 KO mice restores the inflammatory response. These findings establish sensory ASIC3 as a critical constituent in psoriatic inflammation, and a promising target for neurogenic inflammation management.

Abstract Recently, the significant benefits of cancer immunotherapy for most cancers have been demonstrated in clinical and preclinical studies. However, the efficacy of these immunotherapies for gliomas is limited, owing to restricted drug delivery and insufficient immune activation. As drug carriers, exosomes offer the advantages of low toxicity, good biocompatibility, and intrinsic cell targeting, which could enhance glioma immunotherapy efficacy. However, a review of exosome-based drug delivery systems for glioma immunotherapy has not been presented. This review introduces the current problems in glioma immunotherapy and the role of exosomes in addressing these issues. Meanwhile, preparation and application strategies of exosome-based drug delivery systems for glioma immunotherapy are discussed, especially for enhancing immunogenicity and reversing the immunosuppressive tumor microenvironment. Finally, we briefly describe the challenges of exosome-based drug delivery systems in clinical translation. We anticipate that this review will guide the use of exosomes as drug carriers for glioma immunotherapy. Graphical Abstract

Abstract Objective This study aims to examine the impact of PE/PPE gene mutations on the transmission of Mycobacterium tuberculosis (M. tuberculosis) in China. Methods We collected the whole genome sequencing (WGS) data of 3202 M. tuberculosis isolates in China from 2007 to 2018 and investigated the clustering of strains from different lineages. To evaluate the potential role of PE/PPE gene mutations in the dissemination of the pathogen, we employed homoplastic analysis to detect homoplastic single nucleotide polymorphisms (SNPs) within these gene regions. Subsequently, logistic regression analysis was conducted to analyze the statistical association. Results Based on nationwide M. tuberculosis WGS data, it has been observed that the majority of the M. tuberculosis burden in China is caused by lineage 2 strains, followed by lineage 4. Lineage 2 exhibited a higher number of transmission clusters, totaling 446 clusters, of which 77 were cross-regional clusters. Conversely, there were only 52 transmission clusters in lineage 4, of which 9 were cross-regional clusters. In the analysis of lineage 2 isolates, regression results showed that 4 specific gene mutations, PE4 (position 190,394; c.46G > A), PE_PGRS10 (839,194; c.744 A > G), PE16 (1,607,005; c.620T > G) and PE_PGRS44 (2,921,883; c.333 C > A), were significantly associated with the transmission of M. tuberculosis. Mutations of PE_PGRS10 (839,334; c.884 A > G), PE_PGRS11 (847,613; c.1455G > C), PE_PGRS47 (3,054,724; c.811 A > G) and PPE66 (4,189,930; c.303G > C) exhibited significant associations with the cross-regional clusters. A total of 13 mutation positions showed a positive correlation with clustering size, indicating a positive association. For lineage 4 strains, no mutations were found to enhance transmission, but 2 mutation sites were identified as risk factors for cross-regional clusters. These included PE_PGRS4 (338,100; c.974 A > G) and PPE13 (976,897; c.1307 A > C). Conclusion Our results indicate that some PE/PPE gene mutations can increase the risk of M. tuberculosis transmission, which might provide a basis for controlling the spread of tuberculosis.

In order to study the effects of GABA-rich germinated adzuki bean on blood glucose level and intestinal flora in T2DM mice. C57BL/6J mice were used as subjects to construct T2DM model by high fat diet+STZ injection. Different doses of GABA-rich germinated adzuki bean were used to treat T2DM mice for 6 weeks and 16S rRNA sequencing technique was used to identify the microbial structure and distribution in the cecal contents of T2DM mice. The results showed that different doses of GABA-rich adzuki bean dietary intervention could significantly reduce the FBG value of T2DM mice, and the FBG value of high dose GABA-rich adzuki bean (TF3) group was 8.36±0.78 mmol/L, which was 54.09%, lower than that of model group (M). In addition, TF3 diet induced significant changes in intestinal flora abundance in T2DM mice. Firmicutes abundance at gate level was 35.96%, which decreased by 53.17% compared with M model group, and Bacteroidetes and Verrucomicrobia abundance were significantly up-regulated. In summary, the improvement of glucose and lipid metabolism by TF3 diet was significantly correlated with the abundance of dominant bacteria in Bacteroidetes and Verrucomicrobia, suggesting that high dose of GABA-rich adzuki bean diet could alleviate hyperglycemia symptoms in T2DM mice through beneficial bacteria, which provided reference for further explaining the relationship between T2DM and intestinal flora.

Abstract Given the insidious and high-fatality nature of cardiovascular diseases (CVDs), the emergence of fluoride as a newly identified risk factor demands serious consideration alongside traditional risk factors. While vascular smooth muscle cells (VSMCs) play a pivotal role in the progression of CVDs, the toxicological impact of fluoride on VSMCs remains largely uncharted. In this study, we constructed fluorosis model in SD rats and A7R5 aortic smooth muscle cell lines to confirm fluoride impaired VSMCs. Fluoride aggravated the pathological damage of rat aorta in vivo. Then A7R5 were exposed to fluoride with concentration ranging from 0 to 1200 μmol/L over a 24-h period, revealing a dose-dependent inhibition of cell proliferation and migration. The further metabolomic analysis showed alterations in metabolite profiles induced by fluoride exposure, notably decreasing organic acids and lipid molecules level. Additionally, gene network analysis underscored the frequency of fluoride's interference with amino acids metabolism, potentially impacting the tricarboxylic acid (TCA) cycle. Our results also highlighted the ATP-binding cassette (ABC) transporters pathway as a central element in VSMC impairment. Moreover, we observed a dose-dependent increase in osteopontin (OPN) and α-smooth muscle actin (α-SMA) mRNA level and a dose-dependent decrease in ABC subfamily C member 1 (ABCC1) and bestrophin 1 (BEST1) mRNA level. These findings advance our understanding of fluoride as a CVD risk factor and its influence on VSMCs and metabolic pathways, warranting further investigation into this emerging risk factor.

The yield strength of metallic materials is commonly estimated using linear superposition methods, but this method has limited adaptability to new materials. The mapping relationship between input and output in machine learning methods is difficult to quantify. This study employs a rapid screening method to identify the key strengthening mechanisms that influence the yield strength of typical homogeneous and heterogeneous metallic materials. A non-linear physical neural information network model is developed to describe the yield strength of heterogeneous structures, capturing the main parameters contributing to yield strength from selected physical quantity data. By considering the non-linear strengthening mechanisms arising from interactions among multiple strengthening mechanisms in heterogeneous metal structures, the microstructure and mechanical properties of eutectic high-entropy alloys are optimized through warm rolling and short-time annealing. By inducing microstructural spheroidization and introducing nanoscale precipitates, significant coupling effects of multiple strengthening mechanisms are achieved for eutectic high-entropy alloys. As a result, the yield strength increases by approximately 2.5 times, while plasticity remains nearly unchanged. Transmission electron microscopy, scanning electron microscopy, and electron backscatter diffraction observations provide evidence for the sources of these coupling effects. This study offers guidance for accelerating material design and exploring the physical relationship between microstructure and mechanical properties.

Selective laser melting (SLM) has been proved to be a promising additive manufacturing technique for production of high-performance metal matrix composites (MMCs) with unique microstructures. In this study, the SiC- reinforced 316L MMCs were prepared by SLM and the effects of SiC addition on the densification, microstructure evolution, mechanical properties and tribological behavior were systematically investigated. The SiC/316L MMCs fabricated by SLM were close to full density with high relative density over than 99.7%. The grains were significantly refined, and dislocation density was greatly enhanced with the addition of SiC particles. Tensile tests show that tensile strength of the specimens increased by 81.8% from 707 to 1285 MPa and yield strength increased by 72.7% from 543 to 938 MPa with the addition of SiC. In addition, the tribological behavior of MMCs with SiC addition are much superior to the pure 316L. The underlying strengthening mechanisms are discussed. The findings provide a new perspective on ceramic particles reinforced stainless steel MMCs with unique microstructure and excellence performance.

Abstract Background The talocrural joint and the subtalar joint are the two major joints of the ankle-joint complex. The position and direction of the exosuit force line relative to these two joint axes can influence ankle motion. We aimed to understand the effects of different force-lines on ankle multidimensional motion. Methods In this article, three assistance force line schemes for ankle exosuits were proposed: perpendicular to the talocrural joint axis (PT), intersecting with the subtalar joint axis (IS), and parallel to the triceps surae (PTS). A theoretical model was proposed to calculate the exosuit’s assistance moment. Seven participants completed four experimental tests of ankle plantarflexion, including three passive motions assisted by the PT, PTS and IS schemes, and one active motion without exosuit assistance (Active). Results The simulation results demonstrated that all three exosuits were able to produce significant moments of ankle plantarflexion. Among these, the PT scheme exhibited the highest moments in all dimensions, followed by the PTS and IS schemes. The experimental findings confirmed the effectiveness of all three exosuit schemes in assisting ankle plantarflexion. Additionally, as the assistive force lines approached the subtalar joint, there was a decrease in ankle motion assisted by the exosuits in non-plantarflexion directions, along with a reduction in the average distance of ankle angle curves relative to active ankle motion. Furthermore, the linear correlation coefficients between inversion and plantarflexion, adduction and plantarflexion, and adduction and inversion gradually converged toward active ankle plantarflexion motion. Conclusions Our research indicates that the position of the exosuit force line to the subtalar joint has a significant impact on ankle inversion and adduction. Among all three schemes, the IS, which has the closest distance to the subtalar joint axes, has the greatest kinematic similarity to active ankle plantarflexion and might be a better choice for ankle assistance and rehabilitation.

Abstract Background Neoadjuvant immune checkpoint blockade (ICB) combined with chemoradiotherapy offers high pathologic complete response (pCR) rate for patients with locally advanced esophageal squamous cell carcinomas (ESCC). But the dynamic tumor immune microenvironment modulated by such neoadjuvant therapy remains unclear. Patients and methods A total of 41 patients with locally advanced ESCC were recruited. All patients received neoadjuvant toripalimab combined with concurrent chemoradiotherapy. Matched pre- and post-treatment tissues were obtained for fluorescent multiplex immunohistochemistry (mIHC) and IHC analyses. The densities and spatial distributions of immune cells were determined by HALO modules. The differences of immune cell patterns before and after neoadjuvant treatment were investigated. Results In the pre-treatment tissues, more stromal CD3 + FoxP3 + Tregs and CD86+/CD163 + macrophages were observed in patients with residual tumor existed in the resected lymph nodes (pN1), compared with patients with pCR. The majority of macrophages were distributed in close proximity to tumor nest in pN1 patients. In the post-treatment tissues, pCR patients had less CD86 + cell infiltration, whereas higher CD86 + cell density was significantly associated with higher tumor regression grades (TRG) in non-pCR patients. When comparing the paired pre- and post-treatment samples, heterogeneous therapy-associated immune cell patterns were found. Upon to the treatment, CD3 + T lymphocytes were slightly increased in pCR patients, but markedly decreased in non-pCR patients. In contrast, a noticeable increase and a less obvious decrease of CD86 + cell infiltration were respectively depicted in non-pCR and pCR patients. Furthermore, opposite trends of the treatment-induced alterations of CD8 + and CD15 + cell infiltrations were observed between pN0 and pN1 patients. Conclusions Collectively, our data demonstrate a comprehensive picture of tumor immune landscape before and after neoadjuvant ICB combined with chemoradiotherapy in ESCC. The infiltration of CD86 + macrophage may serve as an unfavorable indicator for neoadjuvant toripalimab combined with chemoradiotherapy.

Abstract Objective It has been reported that in western countries malignancy risk was higher in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) compared with that in the general population. In the current study, we investigated the incidence, spectrum and risk factors of malignancy in Chinese AAV patients. Methods AAV patients diagnosed from 1995 to 2021 in Peking University First Hospital with a follow-up more than 12 months were recruited. Standardized incidence ratios (SIR) were calculated to describe the risk of malignancy, adjusted for sex, age and follow-up time. Results A total of 552 AAV patients were recruited, among which 23 patients had malignancies either preceding or concurrent with AAV diagnosis, and 43 of the remaining 529 patients developed malignancies within 4.3 ± 4.2 years post AAV diagnosis (SIR: 2.24; 95% CI: 1.68–2.99; p

Abstract The post-translational modification of proteins by ubiquitin-like modifiers (UbLs), such as SUMO, ubiquitin, and Nedd8, regulates a vast array of cellular processes. Dedicated UbL deconjugating proteases families reverse these modifications. During bacterial infection, effector proteins, including deconjugating proteases, are released to disrupt host cell defenses and promote bacterial survival. NopD, an effector protein from rhizobia involved in legume nodule symbiosis, exhibits deSUMOylation activity and, unexpectedly, also deubiquitination and deNeddylation activities. Here, we present two crystal structures of Bradyrhizobium (sp. XS1150) NopD complexed with either Arabidopsis SUMO2 or ubiquitin at 1.50 Å and 1.94 Å resolution, respectively. Despite their low sequence similarity, SUMO and ubiquitin bind to a similar NopD interface, employing a unique loop insertion in the NopD sequence. In vitro binding and activity assays reveal specific residues that distinguish between deubiquitination and deSUMOylation. These unique multifaceted deconjugating activities against SUMO, ubiquitin, and Nedd8 exemplify an optimized bacterial protease that disrupts distinct UbL post-translational modifications during host cell infection.

Abstract Pulmonary hypertension (PH) is regarded as cardiovascular disease with an extremely poor prognosis, primarily due to irreversible vascular remodeling. Despite decades of research progress, the absence of definitive curative therapies remains a critical challenge, leading to high mortality rates. Recent studies have shown that serious metabolic disorders generally exist in PH animal models and patients of PH, which may be the cause or results of the disease. It is imperative for future research to identify critical biomarkers of metabolic dysfunction in PH pathophysiology and to uncover metabolic targets that could enhance diagnostic and therapeutic strategies. Metabolomics offers a powerful tool for the comprehensive qualitative and quantitative analysis of metabolites within specific organisms or cells. On the basis of the findings of the metabolomics research on PH, this review summarizes the latest research progress on metabolic pathways involved in processes such as amino acid metabolism, carbohydrate metabolism, lipid metabolism, and nucleotide metabolism in the context of PH.

Abstract To evaluate the predictive and prognostic value of fibroblast growth factor 21 (FGF21) levels in retinal artery occlusion (RAO) patients. In this case–control study, serum FGF21 levels were detected by using the ELISA method. Multivariable logistic regression analyses were performed to evaluate the significance of FGF21 in assessing the risk of developing RAO and its impact on vision and concurrent ischemic stroke. Compared with control group, serum FGF21 levels were significantly higher (median [IQR] = 230.90[167.40,332.20] pg/ml) in RAO patients. Multivariate logistic regression analysis showed that elevated serum FGF21 levels were associated with a higher risk of RAO occurrence (P = 0.025, OR [95%CI] = 9.672 [2.573, 36.359]) after adjustment for multiple confounding factors. Higher serum FGF21 levels were negatively associated with visual acuity improvement (P = 0.029, OR [95%CI] = 0.466[0.235, 0.925]) and positively correlated with concurrent ischemic stroke (P = 0.04, OR [95% CI] = 1.944[1.029, 3.672]) in RAO patients. Elevated serum FGF21 levels could promote the development of RAO and indicate worse visual prognosis and increase the risk of concurrent ischemic stroke, which might help clinicians early diagnose and treat RAO patients.

Abstract The Jishishan Ms 6.2 earthquake occurred at 23:59 on December 18, 2023 in Gansu Province, China. We conducted a field survey to assess the hazards and damages caused by the earthquake and its associated geo-activities. Subsequently, we organized a seminar to discuss the possible causes of the destruction of a prehistoric site—Lajia Settlement—dated back to four thousand years B.P. and located only several kilometers away from the epicenter of the Jishishan earthquake. The Jishishan earthquake was unique for its hazard and disaster process, which featured ground shaking and a series of complex geological and geomorphological activities: sediment and soil spray piles, liquefaction, collapse, landslide, and mudflow along water channels. We define this phenomenon as the Jishishan earthquake ripple hazard (JERH). The most recent evidence from the JERH suggests that a prehistoric earthquake similar to the JERH, instead of riverine floods or earthquake-induced landslide dam outburst flood, as previously hypothesized, destroyed the Lajia Settlement.

Abstract Background Lipid-lowering drugs and antihypertensive drugs are commonly combined for cardiovascular disease (CVD). However, the relationship of combined medications with CVD remains controversial. We aimed to explore the associations of genetically proxied medications of lipid-lowering and antihypertensive drugs, either alone or both, with risk of CVD, other clinical and safety outcomes. Methods We divided 423,821 individuals in the UK Biobank into 4 groups via median genetic scores for targets of lipid-lowering drugs and antihypertensive drugs: lower low-density lipoprotein cholesterol (LDL-C) mediated by targets of statins or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lower systolic blood pressure (SBP) mediated by targets of β-blockers (BBs) or calcium channel blockers (CCBs), combined genetically lower LDL-C and SBP, and reference (genetically both higher LDL-C and SBP). Associations with risk of CVD and other clinical outcomes were explored among each group in factorial Mendelian randomization. Results Independent and additive effects were observed between genetically proxied medications of lipid-lowering and antihypertensive drugs with CVD (including coronary artery disease, stroke, and peripheral artery diseases) and other clinical outcomes (ischemic stroke, hemorrhagic stroke, heart failure, diabetes mellitus, chronic kidney disease, and dementia) (P > 0.05 for interaction in all outcomes). Take the effect of PCSK9 inhibitors and BBs on CVD for instance: compared with the reference, PCSK9 group had a 4% lower risk of CVD (odds ratio [OR], 0.96; 95%CI, 0.94–0.99), and a 3% lower risk was observed in BBs group (OR, 0.97; 95%CI, 0.94–0.99), while combined both were associated with a 6% additively lower risk (OR, 0.94; 95%CI, 0.92–0.97; P = 0.87 for interaction). Conclusions Genetically proxied medications of combined lipid-lowering and antihypertensive drugs have an independent and additive effects on CVD, other clinical and safety outcomes, with implications for CVD clinical practice, subsequent trials as well as drug development of polypills.

Abstract Aims The aim of this study is to enhance the accuracy of monitoring and treatment information for patients diagnosed with colorectal cancer (CRC). Methods Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, a cohort of 335,948 eligible CRC patients was included in this investigation. Conditional survival probability and actuarial overall survival were employed as methodologies to investigate the association between clinicopathological characteristics and cancer prognosis. Results Among CRC patients, the 5-year survival rate was 59%, while the 10-year survival rate was 42%. Over time, conditional survival showed a consistent increase, with rates reaching 45% and 48% for individuals surviving 1 and 2 years, respectively. Notably, patients with unfavorable tumor stages exhibited substantial improvements in conditional survival, thereby narrowing the disparity with actuarial overall survival over time. Conclusion This study underscores the significance of time-dependent conditional survival probability, particularly for patients with a poorer prognosis. The findings suggest that long-term CRC survivors may experience improved cancer prognosis over time.

Abstract Background Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of lung cancer patients with mutated EGFR. However, the efficacy of EGFR-TKIs in wild-type EGFR tumors has been shown to be marginal. Methods that can sensitize EGFR-TKIs to EGFR wild-type NSCLC remain rare. Hence, we determined whether combination treatment can maximize the therapeutic efficacy of EGFR-TKIs. Methods We established a focused drug screening system to investigate candidates for overcoming the intrinsic resistance of wild-type EGFR NSCLC to EGFR-TKIs. Molecular docking assays and western blotting were used to identify the binding mode and blocking effect of the candidate compounds. Proliferation assays, analyses of drug interactions, colony formation assays, flow cytometry and nude mice xenograft models were used to determine the effects and investigate the molecular mechanism of the combination treatment. Results Betulinic acid (BA) is effective at targeting EGFR and synergizes with EGFR-TKIs (gefitinib and osimertinib) preferentially against wild-type EGFR. BA showed inhibitory activity due to its interaction with the ATP-binding pocket of EGFR and dramatically enhanced the suppressive effects of EGFR-TKIs by blocking EGFR and modulating the EGFR-ATK-mTOR axis. Mechanistic studies revealed that the combination strategy activated EGFR-induced autophagic cell death and that the EGFR-AKT-mTOR signaling pathway was essential for completing autophagy and cell cycle arrest. Activation of the mTOR pathway or blockade of autophagy by specific chemical agents markedly attenuated the effect of cell cycle arrest. In vivo administration of the combination treatment caused marked tumor regression in the A549 xenografts. Conclusions BA is a potential wild-type EGFR inhibitor that plays a critical role in sensitizing EGFR-TKI activity. BA combined with an EGFR-TKI effectively suppressed the proliferation and survival of intrinsically resistant lung cancer cells via the inhibition of EGFR as well as the induction of autophagy-related cell death, indicating that BA combined with an EGFR-TKI may be a potential therapeutic strategy for overcoming the primary resistance of wild-type EGFR-positive lung cancers. Graphical abstract

Abstract The active Himalayan-Tibetan orogen, where India underthrusts into Asia, is an important geological source of carbon dioxide (CO2) emission into Earth’s atmosphere. However, the extent to which Indian underthrusting could stimulate the mobilization of deeply-sourced carbon and its subsequent emission remains unknown. Here, we use a combination of field observations coupled with in-situ CO2 flux measurements and helium and carbon isotopic data, to study the controls on CO2 origins and fluxes in a 400-kilometre-long rift transecting northern Himalaya and southern Tibet. High diffuse CO2 fluxes sustained by pure crustal fluids are confined to rift segments in the northern Himalaya, while toward southern Tibet, CO2 fluxes become lower but mantle fluid inputs are identified. Such rift-related CO2 degassing profile suggests metamorphic decarbonation and release of carbon-bearing fluids enhanced by the underthrusting Indian lower crust, agreeing well with Himalayan metamorphism and orogen-parallel lithospheric extension. Deep CO2 fluxes from extensional tectonics in northern Himalaya and southern Tibet, primarily of crustal origins, are comparable to mantle CO2 fluxes from global mid-ocean ridges. Our findings demonstrate that geophysical and geo-tectonic responses to continental underthrusting could facilitate massive crustal carbon mobilization and emission, making active collisional orogens globally important carbon sources.

Abstract Hypermutated neoantigens in cancers with DNA mismatch repair deficiency (dMMR) are prerequisites for favorable clinical responses to immune-checkpoint blockade (ICB) therapy. However, TMB is not significantly associated with favorable prognosis from Preclinical and clinical studies. It implies that except for TMB, other mechanisms should be needed to contribute to successful cancer immunotherapy. We found that the hyperactivation of PANoptotic effective molecules in dMMR tumor cells caused cell membrane damage, induced ESCRT-mediated membrane repair, and protected tumor cells from the damage caused by Triton X-100, while DNA mismatch repair proficient (pMMR) tumor cells were sensitive to Triton X-100 mediating cell membrane damage due to the lack of ESCRT-mediated membrane repair. There was hyperactivation of GSDMD, GSDME, and p-MLKL in dMMR tumor cells. Co-treatment of IFN-γ and TNF-α induced rapid death of dMMR tumor cells by inducing PANoptosis including pyroptosis, apoptosis, and no necrosis. pMMR tumor cells had defects in the PANoptosis pathway and were resistant to co-treatment of IFN-γ and TNF-α. In conclusion, we can activate immune cells to release IFN-γ and TNF-α to overcome resistance to ICB treatment.

Abstract Background Changes in economy and dietary guidelines brought a great shock to diet quality and meal behaviors, but if these transformations have extended to minerals intake and their sources was still poorly understood. It is essential to evaluate time trends in minerals intake and their sources to inform policy makers. Objective To investigate trends in minerals intake and their sources among U.S. adults. Methods This analysis used dietary data collected by 24-h recalls from U.S. adults (≥ 20 years) in NHANES (1999-March 2020). Minerals intake, age-adjusted percentage of participants meeting recommendations, and minerals sources were calculated among all participants and by population subgroups in each NHANES survey cycle. Weighted linear or logistic regression models were used to examine the statistical significance of time trends. Results A total of 48223 U.S. adults were included in this analysis. From 1999 to March 2020, intake of calcium (from 0.94 to 1.02 g/day), magnesium (from 308.07 to 321.85 mg/day), phosphorus (from 1.24 to 1.30 g/day), and sodium (from 3.24 to 3.26 mg/day) from food and beverages (FB) and dietary supplements (DSs) significantly increased, and intake of iron (from 19.17 to 16.38 mg/day), zinc (from 16.45 to 14.19 mg/day), copper (from 1.79 to 1.38 mg/day), and potassium (from 2.65 to 2.50 g/day) from FB + DSs decreased (all FDR

Abstract Objective To investigate the correlation between higher-order aberrations (HOA) after small incision lenticule extraction (SMILE) and the severity of myopia and astigmatism, along with the relevant factors. These findings will provide valuable insights for decreasing the occurrence of HOA after SMILE and enhancing visual quality. Methods A total of 75 patients (150 eyes) with myopia and astigmatism who underwent SMILE were categorized into four groups based on the severity of myopia and astigmatism: Myopia Group 1 (Group M1, spherical diopter ranged from -1.00 D to -4.00 D), Myopia Group 2 (Group M2, spherical diopter ranged from -4.10 D to -10.00 D), Astigmatism Group 1 (Group A1, cylindrical diopter ranged from 0 D to -1.00 D), and Astigmatism Group 2 (Group A2, cylindrical diopter ranged from -1.10 D to -3.00 D). A comprehensive assessment was performed to examine the association between HOA and various relevant factors, including a detailed analysis of the subgroups. Results Group M1 had significantly lower levels of total eye coma aberration (CA), corneal total HOA (tHOA), internal tHOA, and vertical CA ( $${{\text{Z}}}_{3}^{-1}$$ Z 3 - 1 ) after SMILE than Group M2 (P

Abstract The diagnostic accuracy of clinically significant prostate cancer (csPCa) of Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) is limited by subjectivity in result interpretation and the false positive results from certain similar anatomic structures. We aimed to establish a new model combining quantitative contrast-enhanced ultrasound, PI-RADSv2, clinical parameters to optimize the PI-RADSv2-based model. The analysis was conducted based on a data set of 151 patients from 2019 to 2022, multiple regression analysis showed that prostate specific antigen density, age, PI-RADSv2, quantitative parameters (rush time, wash-out area under the curve) were independent predictors. Based on these predictors, we established a new predictive model, the AUCs of the model were 0.910 and 0.879 in training and validation cohort, which were higher than those of PI-RADSv2-based model (0.865 and 0.821 in training and validation cohort). Net Reclassification Index analysis indicated that the new predictive model improved the classification of patients. Decision curve analysis showed that in most risk probabilities, the new predictive model improved the clinical utility of PI-RADSv2-based model. Generally, this new predictive model showed that quantitative parameters from contrast enhanced ultrasound could help to improve the diagnostic performance of PI-RADSv2 based model in detecting csPCa.

Abstract Background Woody bamboos are the only diverse large perennial grasses in mesic-wet forests and are widely distributed in the understory and canopy. The functional trait variations and trade-offs in this taxon remain unclear due to woody bamboo syndromes (represented by lignified culm of composed internodes and nodes). Here, we examined the effects of heritable legacy and occurrence site climates on functional trait variations in leaf and culm across 77 woody bamboo species in a common garden. We explored the trade-offs among leaf functional traits, the connection between leaf nitrogen (N), phosphorus (P) concentrations and functional niche traits, and the correlation of functional traits between leaves and culms. Results The Bayesian mixed models reveal that the combined effects of heritable legacy (phylogenetic distances and other evolutionary processes) and occurrence site climates accounted for 55.10–90.89% of the total variation among species for each studied trait. The standardized major axis analysis identified trade-offs among leaf functional traits in woody bamboo consistent with the global leaf economics spectrum; however, compared to non-bamboo species, the woody bamboo exhibited lower leaf mass per area but higher N, P concentrations and assimilation, dark respiration rates. The canonical correlation analysis demonstrated a positive correlation (ρ = 0.57, P-value

Abstract Objective This study aims to develop a nomogram integrating inflammation (NLR), Prognostic Nutritional Index (PNI), and EBV DNA (tumor burden) to achieve personalized treatment and prediction for stage IVA NPC. Furthermore, it endeavors to pinpoint specific subgroups that may derive significant benefits from S-1 adjuvant chemotherapy. Methods A total of 834 patients diagnosed with stage IVA NPC were enrolled in this study and randomly allocated into training and validation cohorts. Multivariate Cox analyses were conducted to identify independent prognostic factors for constructing the nomogram. The predictive and clinical utility of the nomogram was assessed through measures including the AUC, calibration curve, DCA, and C-indexes. IPTW was employed to balance baseline characteristics across the population. Kaplan-Meier analysis and log-rank tests were utilized to evaluate the prognostic value. Results In our study, we examined the clinical features of 557 individuals from the training cohort and 277 from the validation cohort. The median follow-up period was 50.1 and 49.7 months, respectively. For the overall cohort, the median follow-up duration was 53.8 months. The training and validation sets showed 3-year OS rates of 87.7% and 82.5%, respectively. Meanwhile, the 3-year DMFS rates were 95.9% and 84.3%, respectively. We created a nomogram that combined PNI, NRI, and EBV DNA, resulting in high prediction accuracy. Risk stratification demonstrated substantial variations in DMFS and OS between the high and low risk groups. Patients in the high-risk group benefited significantly from the IC + CCRT + S-1 treatment. In contrast, IC + CCRT demonstrated non-inferior 3-year DMFS and OS compared to IC + CCRT + S-1 in the low-risk population, indicating the possibility of reducing treatment intensity. Conclusions In conclusion, our nomogram integrating NLR, PNI, and EBV DNA offers precise prognostication for stage IVA NPC. S-1 adjuvant chemotherapy provides notable benefits for high-risk patients, while treatment intensity reduction may be feasible for low-risk individuals.

Abstract Rare-earth engineering is an effective way to introduce and tune magnetism in topological kagome materials, which have been acting as a fertile platform to investigate the quantum interactions between geometry, topology, spin, and correlation. Here, we report the synthesis, structure, and physical properties of titanium-based kagome metals RETi3Bi4 (RE = Yb, Pr, and Nd) with various magnetic states. They all crystallize in the orthogonal space group Fmmm (No. 69), featuring distorted titanium kagome lattices and rare-earth zig-zag chains. By changing the rare earth atoms in the zig-zag chains, the magnetism can be tuned from nonmagnetic YbTi3Bi4 to short-range ordered PrTi3Bi4 (T anomaly ~ 8.2 K), and finally to ferromagnetic NdTi3Bi4 (T c ~ 8.5 K). In-situ resistance measurements of NdTi3Bi4 under high pressure further reveal a tunable ferromagnetic ordering temperature. These results highlight RETi3Bi4 as a promising family of kagome metals to explore nontrivial band topology and exotic phases.

Abstract Objective To find the relationship between N6-methyladenosine (m6A) genes and Major Depressive Disorder (MDD). Methods Differential expression of m6A associated genes between normal and MDD samples was initially identified. Subsequent analysis was conducted on the functions of these genes and the pathways they may affect. A diagnostic model was constructed using the expression matrix of these differential genes, and visualized using a nomogram. Simultaneously, an unsupervised classification method was employed to classify all patients based on the expression of these m6A associated genes. Following this, common differential genes among different clusters were computed. By analyzing the functions of the common differential expressed genes among clusters, the role of m6A-related genes in the pathogenesis of MDD patients was elucidated. Results Differential expression was observed in ELAVL1 and YTHDC2 between the MDD group and the control group. ELAVL1 was associated with comorbid anxiety in MDD patients. A linear regression model based on these two genes could accurately predict whether patients in the GSE98793 dataset had MDD and could provide a net benefit for clinical decision-making. Based on the expression matrix of ELAVL1 and YTHDC2, MDD patients were classified into three clusters. Among these clusters, there were 937 common differential genes. Enrichment analysis was also performed on these genes. The ssGSEA method was applied to predict the content of 23 immune cells in the GSE98793 dataset samples. The relationship between these immune cells and ELAVL1, YTHDC2, and different clusters was analyzed. Conclusion Among all the m6A genes, ELAVL1 and YTHDC2 are closely associated with MDD, ELAVL1 is related to comorbid anxiety in MDD. ELAVL1 and YTHDC2 have opposite associations with immune cells in MDD.

In the present work, a novel high-V high-Mn twinning induced plasticity (TWIP) steel for cryogenic storage tank applications was developed. Furthermore, innovative two-stage cooling processes encompassing ultra-fast cooling and the subsequent furnace cooling were proposed. Effects of cooling process on the microstructure and mechanical properties of the experimental steel were investigated. It was observed that with the change in cooling process (the initial temperature of furnace cooling rised gradually), the dwell time of hot-rolled plates above 600 °C was extended. The extension in dwell time facilitated the precipitation of secondary phase particles, leading to the change in average diameter and volume fraction of secondary phase particles. The yield strength increased with the increasing initial temperature of furnace cooling due to the combined effect of small-sized secondary phase particles inside the grains and large-sized ones located at the grain boundaries. The occurrence of intergranular cracking, primarily caused by the presence of large-sized secondary phase particles at the grain boundaries, was the main factor responsible for the significant reduction in total elongation. The small-sized secondary phase particles inside the grains inhibited deformation twinning, while the large-sized ones at the grain boundaries weaken the binding force between grain boundaries, which ultimately resulted in a decrease in cryogenic impact toughness. The implementation of two-stage cooling processes effectively mitigated the trade-off between yield strength and cryogenic impact toughness, offering a novel approach and valuable insights for optimizing the strength and toughness characteristics of cryogenic high-Mn steels.

Abstract Pou6f2 is a genetic connection between central corneal thickness (CCT) in the mouse and a risk factor for developing primary open-angle glaucoma. POU6F2 is also a risk factor for several conditions in humans, including glaucoma, myopia, and dyslexia. Recent findings demonstrate that POU6F2-positive retinal ganglion cells (RGCs) comprise a number of RGC subtypes in the mouse, some of which also co-stain for Cdh6 and Hoxd10. These POU6F2-positive RGCs appear to be novel of ON–OFF directionally selective ganglion cells (ooDSGCs) that do not co-stain with CART or SATB2 (typical ooDSGCs markers). These POU6F2-positive cells are sensitive to damage caused by elevated intraocular pressure. In the DBA/2J mouse glaucoma model, heavily-labeled POU6F2 RGCs decrease by 73% at 8 months of age compared to only 22% loss of total RGCs (labeled with RBPMS). Additionally, Pou6f2 −/− mice suffer a significant loss of acuity and spatial contrast sensitivity along with an 11.4% loss of total RGCs. In the rhesus macaque retina, POU6F2 labels the large parasol ganglion cells that form the magnocellular (M) pathway. The association of POU6F2 with the M-pathway may reveal in part its role in human glaucoma, myopia, and dyslexia.