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Abstract Strong early growth vigor is an essential target in both direct seeded rice breeding and high-yielding rice breeding for rice varieties with relatively short growth duration in the double-cropping region. Shoot dry weight (SDW) is one of the important traits associated with early growth vigor, and breeders have been working to improve this trait. Finding stable QTLs or functional genes for SDW is crucial for improving the early growth vigor by implementing molecular breeding in rice. Here, a genome-wide association analysis revealed that the QTL for SDW, qSDW-5, was stably detected in the three cultivation methods commonly used in production practice. Through gene-based haplotype analysis of the annotated genes within the putative region of qSDW-5, and validated by gene expression and knockout transgenic experiments, LOC_Os05g09520, which is identical to the reported GW5/GSE5 controlling grain width (GW) and thousand grain weight (TGW) was identified as the causal gene for qSDW-5. Five main haplotypes of LOC_Os05g09520 were identified in the diverse international rice collection used in this study and their effects on SDW, GW and TGW were analyzed. Phenotypic comparisons of the major haplotypes of LOC_Os05g09520 in the three subpopulations (indica, japonica and aus) revealed the same patterns of wider GW and higher TGW along with higher SDW. Furtherly, the haplotype analysis of 138 rice varieties/lines widely used in southern China showed that 97.8% of the cultivars/lines carry Hap2 LOC_Os05g09520 . These results not only provide a promising gene source for the molecular breeding of rice varieties with strong early growth vigor, but also elucidate the effect of the LOC_Os05g09520 haplotypes on SDW, GW, and TGW in rice. Importantly, this study provides direct genetic evidence that these three traits are significantly correlated, and suggests a breeding strategy for developing high-yielding and slender grain-shaped indica cultivars with strong early growth vigor.

Abstract Background Spinal muscular atrophy (SMA) is a progressive neurodegenerative disorder that can be treated with intrathecal nusinersen, an antisense oligonucleotide. In addition to efficacy, safety is a determining factor in the success of any therapy. Here, we aim to assess the safety of nusinersen therapy in paediatric patients with SMA. Methods Laboratory data of paediatric patients with SMA who received nusinersen between October 2019 and May 2022 were retrospectively analysed. Results During the observation period, 46 infants and children aged 2.9 months to 13.6 years received a total of 213 nusinersen doses without safety concerns. Inflammatory markers were stable throughout the study. International normalized ratio was increased by 0.09 per injection. Urea levels were increased by 0.108 mmol/L, and cystatin C decreased by 0.029 mg/L per injection. There were no significant changes in platelet count, activated partial thrombin time, creatinine levels or liver enzyme levels during treatment. The cerebrospinal fluid (CSF) leukocyte count remained stable, and total protein increased by 24.038 mg/L per injection. Conclusion Our data showed that nusinersen therapy is generally safe in children with SMA. Laboratory monitoring did not identify any persistent or significantly abnormal findings. CSF protein should be monitored to gain more insights.

Objective To analyze the predictive value of cardiovascular magnetic resonance (CMR) myocardial perfusion imaging combined with CT fractional flow reserve(CT-FFR) parameters in predicting cardiovascular adverse events in obstructive coronary heart disease. Methods A prospective study was conducted in 180 patients with obstructive coronary heart disease (coronary artery stenosis ≥ 50%) who were treated in the Second Affiliated Hospital of Hebei North University from June 2018 to June 2022. All patients underwent CT angiography and CMR myocardial perfusion imaging, and the occurrence of cardiovascular adverse events within 1 year was collected by on-site follow-up or telephone follow-up. Univariate and multivariate logistic regression models were used to analyze the influencing factors of cardiovascular adverse events; ROC curves were used to assess the predictive efficacy of different prediction models for the occurrence of cardiovascular adverse events. Results A total of 45 patients developed cardiovascular adverse events (observation group), and the remaining 135 patients were controls. Compared with the control group, the age, male ratio, smoking patient ratio, total cholesterol level, diabetes mellitus ratio, hyperlipidemia ratio, first-pass perfusion time and myocardial delayed enhancement signal value of the observation group increased, while the CT-FFR and maximum slope(Slopemax) index decreased, and the differences were statistically significant (P

Background Tumor necrosis factor receptor superfamily 25 (TNFRSF25) is a T-cell co-stimulatory receptor. Expression of its ligand, TNF-like cytokine 1A (TL1A), on mouse tumor cells has been shown to promote tumor regression. This study aimed to develop TNFRSF25 agonists (both antibodies (Abs) and TL1A proteins) and to investigate their potential antitumor effects.Methods Anti-mouse TNFRSF25 (mTNFRSF25) Abs and multimeric TL1A proteins were generated as TNFRSF25 agonists. Their agonism was assessed in luciferase reporter and T-cell co-stimulation assays, and their antitumor effects were evaluated in syngeneic mouse tumor models. TNFRSF25 expression within the tumor microenvironment and the effects of an anti-mTNFRSF25 agonistic Ab on tumor-infiltrating T cells were evaluated by flow cytometry. Cell depletion assays were used to identify the immune cell types that contribute to the antitumor effect of the anti-mTNFRSF25 Ab. The Fc gamma receptor (FcγR) dependence of TNFRSF25 agonists was assessed in an in vivo T-cell expansion model and a mouse tumor model using Fc variants and FcγR-deficient mice.Results TNFRSF25 agonists exhibited antitumor effects in syngeneic mouse tumor models without causing observed side effects. We identified an anti-mTNFRSF25 agonistic Ab, 1A6-m1, which exhibited greater antitumor activity than a higher affinity anti-TNFRSF25 Ab which engages an overlapping epitope with 1A6-m1. 1A6-m1 activated CD8+ T cells and antigen-specific T cells, leading to tumor regression; it also induced long-term antitumor immune memory. Although activating TNFRSF25 by 1A6-m1 expanded splenic regulatory T (Treg) cells, it did not influence intratumoral Treg cells. Moreover, 1A6-m1’s antitumor effects required the engagement of both inhibitory FcγRIIB and activating FcγRIII. Replacing 1A6-m1’s CH1-hinge region with that of human IgG2 (h2) conferred enhanced antitumor effects. Finally, we also generated multimeric human and mouse TL1A fusion proteins as TNFRSF25 agonists, and they co-stimulated CD8+ T cells and reduced tumor growth, even in the absence of Fc-FcγR interactions.Conclusion Our data demonstrates the potential of activating TNFRSF25 by Abs and multimeric TL1A proteins for cancer immunotherapy and provides insights into their development astherapeutics.

Using agricultural wastes in asphalt pavements presents a promising solution to enhance pavement performance and utilize agricultural wastes simultaneously. In the paper, the fibers are made from recycled cotton stalks. Chemical modifiers are chosen to enhance the adherence of fiber asphalt binders. Different modified fibers are added to the SBR-modified emulsified asphalt. The modified asphalt binders are then utilized to prepare asphalt mixtures. Comparative studies on construction performance, road performance, and durability were carried out. Results showed that water consumption and bitumen aggregate ratio at the micro-surfacing were increased after adding fiber. Fibers with low hygroscopicity, rough surface, and high asphalt absorption rate had better adhesion properties. The long-term performance of a micro-surfacing mixture was most remarkably improved by the CH3COOH-modified cotton straw fibers, demonstrating a 10.07 % drop in rutting depth, a 9.13 % decrease in abrasion value, and a 41.13 % gain in shear resistance compared to the micro-surfacing mixtures with unmodified fibers. The study concluded that modified fiber micro-surfacing asphalt mixes are more suitable for seasonal frozen regions than the conventional mixes. The findings offer a theory foundation for the future development of cotton straw fibers in road engineering.

Abstract Strong seedling vigor is imperative to achieve stable seedling establishment and enhance the competitiveness against weeds in rice direct seeding. Shoot length (SL) is one of the important traits associated with seedling vigor in rice, but few genes for SL have been cloned so far. In the previous study, we identified two tightly linked and stably expressed QTLs for SL, qSL-1f and qSL-1d by genome-wide association study, and cloned the causal gene (LOC_Os01g68500) underlying qSL-1f. In the present study, we identify LOC_Os01g66100 (i.e. the semidwarf gene SD1), a well-known gene controlling plant height (PH) at the adult-plant stage, as the causal gene underlying qSL-1d through gene-based haplotype analysis and knockout transgenic verification. By measuring the phenotypes (SL and PH) of various haplotypes of the two genes and their knockout lines, we found SD1 and LOC_ Os01g68500 controlled both SL and PH, and worked in the same direction, which provided the directly genetic evidence for a positive correlation between SL and PH combined with the analysis of SL and PH in the diverse natural population. Moreover, the knockout transgenic experiments suggested that SD1 had a greater effect on PH compared with LOC_ Os01g68500, but no significant difference in the effect on SL. Further investigation of the pyramiding effects of SD1 and LOC_Os01g68500 based on their haplotype combinations suggested that SD1 may play a dominant role in controlling SL and PH when the two genes coexist. In this study, the effect of SD1 on SL at the seedling stage is validated. In total, two causal genes, SD1 and LOC_ Os01g68500, for SL are cloned in our studies, which controlled both SL and PH, and the suitable haplotypes of SD1 and LOC_ Os01g68500 are beneficial to achieve the desired SL and PH in different rice breeding objectives. These results provide a new clue to develop rice varieties for direct seeding and provide new genetic resources for molecular breeding of rice with suitable PH and strong seedling vigor.

In order to explore the impact of container structure on the motion characteristics of granular media in vertical vibrating grinding equipment, ADAMS-EDEM coupling simulation was used to simulate the motion characteristics of granular media during the vibrating polishing process. Firstly, the influence of container structure on particle motion characteristics is analyzed from the perspective of particle motion trajectory and velocity vector. Secondly, the influence of container structure on particle velocity and particle force is comprehensively judged from the depth direction and radial direction. Finally, the effectiveness of the simulation is verified through dynamic force test experiments. The experimental results show that the island-like structure aids the tumbling movement of particles but hinders circumferential movement. The movement of particles in the container with islands is more violent, and the average force of particles is greater than that of islands. The existence of the island structure does not change the basic law that the particle force gradually increases with depth, but it amplifies the force increase, particularly evident in the island container. However, the existence of the island structure basically does not change the trend of a gradual increase in particle force in the radial direction. The rationality of the simulation is verified by both sets of experiments.

Abstract Cancer cells develop multiple strategies to evade T cell-mediated killing. On one hand, cancer cells may preferentially rely on certain amino acids for rapid growth and metastasis. On the other hand, sufficient nutrient availability and uptake are necessary for mounting an effective T cell anti-tumor response in the tumor microenvironment (TME). Here we demonstrate that tumor cells outcompete T cells for cystine uptake due to high Slc7a11 expression. This competition induces T-cell exhaustion and ferroptosis, characterized by diminished memory formation and cytokine secretion, increased PD-1 and TIM-3 expression, as well as intracellular oxidative stress and lipid-peroxide accumulation. Importantly, either Slc7a11 deletion in tumor cells or intratumoral cystine supplementation improves T cell anti-tumor immunity. Mechanistically, cystine deprivation in T cells disrupts glutathione synthesis, but promotes CD36 mediated lipid uptake due to dysregulated cystine/glutamate exchange. Moreover, enforced expression of glutamate-cysteine ligase catalytic subunit (Gclc) promotes glutathione synthesis and prevents CD36 upregulation, thus boosting T cell anti-tumor immunity. Our findings reveal cystine as an intracellular metabolic checkpoint that orchestrates T-cell survival and differentiation, and highlight Gclc as a potential therapeutic target for enhancing T cell anti-tumor function.

Abstract Tamoxifen (TAM) is the frontline therapy for estrogen receptor-positive (ER+) breast cancer in premenopausal women that interrupts ER signaling. As tumors with elevated heterogeneity, amounts of ER-negative (ER−) cells are present in ER+ breast cancer that cannot be directly killed by TAM. Despite complete remissions have been achieved in clinical practice, the mechanism underlying the elimination of ER− cells during TAM treatment remains an open issue. Herein, we deciphered the elimination of ER− cells in TAM treatment from the perspective of the bystander effect. Markable reductions were observed in tumorigenesis of ER− breast cancer cells by applying both supernatants from TAM-treated ER+ cells and a transwell co-culture system, validating the presence of a TAM-induced bystander effect. The major antitumor protein derived from ER+ cells, peptidyl-prolyl cis-trans isomerase B (PPIB), is the mediator of the TAM-induced bystander effect identified by quantitative proteomics. The attenuation of ER− cells was attributed to activated BiP/eIF2α/CHOP axis and promoted endoplasmic reticulum stress (ERS)-induced apoptosis, which can also be triggered by PPIB independently. Altogether, our study revealed a novel TAM-induced bystander effect in TAM treatment of ER+ breast cancer, raising the possibility of developing PPIB as a synergistic antitumor agent or even substitute endocrine therapy.

The concept of human-centric lighting is gradually emerging. People no longer only consider the lighting function of light, but also begin to pay attention to the comfort and health of light. In this article, we perform an investigation on the circadian regulation of four-primary light-emitting diode (LED) based displays for the people with various ages from 1 year old to 100 years old. The double-Gaussian function is used to mimic the spectral power distribution of monochromatic LED. The main figures of merit of LED display performance are color gamut of Rec. 2020, luminous efficacy of radiation, correlated color temperature (CCT), and also non-visual parameters, such as circadian stimulus and melanopic efficacy of luminous radiation provided by Commission Internationale de l'Eclairage (CIE) standard. Then, the genetic algorithm is adopted for performing the spectral optimization of four-primary LED display while many constraint conditions are set, such as CCT values (2700 K and 6500 K), CCT tolerance, and color distance (Duv < 0.01) in the CIE 1960 UCS color space. Related results of visual and non-visual characteristics are also compared with those of three-primary LED displays. This work would pave a way for the development of healthy four-primary LED display in consideration of various ages of people.

Previous studies have demonstrated a bidirectional relationship between inflammation and depression. Activation of the nucleotide-binding oligomerization domain, leucine-rich repeat, and NLR family pyrin domain-containing 3 (NLRP3) inflammasomes is closely related to the pathogenesis of various neurological diseases. In patients with major depressive disorder, NLRP3 inflammasome levels are significantly elevated. Understanding the role that NLRP3 inflammasome-mediated neuroinflammation plays in the pathogenesis of depression may be beneficial for future therapeutic strategies. In this review, we aimed to elucidate the mechanisms that lead to the activation of the NLRP3 inflammasome in depression as well as to provide insight into therapeutic strategies that target the NLRP3 inflammasome. Moreover, we outlined various therapeutic strategies that target the NLRP3 inflammasome, including NLRP3 inflammatory pathway inhibitors, natural compounds, and other therapeutic compounds that have been shown to be effective in treating depression. Additionally, we summarized the application of NLRP3 inflammasome inhibitors in clinical trials related to depression. Currently, there is a scarcity of clinical trials dedicated to investigating the applications of NLRP3 inflammasome inhibitors in depression treatment. The modulation of NLRP3 inflammasomes in microglia holds promise for the management of depression. Further investigations are necessary to ascertain the efficacy and safety of these therapeutic approaches as potential novel antidepressant treatments.

AbstractCombined chemical-biological methods play an important role in ecological restoration. However, it is still unknown whether the addition of calcium peroxide (CaO2) can promote the growth of Pontederia cordata (P. cordata) and the improvement of water quality. Effects of different levels of added CaO2 (0, 0.2, 0.4, 0.6, 0.8, 1, and 2 kg/m2) on P. Cordata growth and water quality were investigated. CaO2 promoted germination and tillering and increased the leaf number (p

ABSTRACTThis study aimed to provide data for the clinical features of invasive pneumococcal disease (IPD) and the molecular characteristics of Streptococcus pneumoniae isolates from paediatric patients in China. We conducted a multi-centre prospective study for IPD in 19 hospitals across China from January 2019 to December 2021. Data of demographic characteristics, risk factors for IPD, death, and disability was collected and analysed. Serotypes, antibiotic susceptibility, and multi-locus sequence typing (MLST) of pneumococcal isolates were also detected. A total of 478 IPD cases and 355 pneumococcal isolates were enrolled. Among the patients, 260 were male, and the median age was 35 months (interquartile range, 12–46 months). Septicaemia (37.7%), meningitis (32.4%), and pneumonia (27.8%) were common disease types, and 46 (9.6%) patients died from IPD. Thirty-four serotypes were detected, 19F (24.2%), 14 (17.7%), 23F (14.9%), 6B (10.4%) and 19A (9.6%) were common serotypes. Pneumococcal isolates were highly resistant to macrolides (98.3%), tetracycline (94.1%), and trimethoprim/sulfamethoxazole (70.7%). Non-sensitive rates of penicillin were 6.2% and 83.3% in non-meningitis and meningitis isolates. 19F-ST271, 19A-ST320 and 14-ST876 showed high resistance to antibiotics. This multi-centre study reports the clinical features of IPD and demonstrates serotype distribution and antibiotic resistance of pneumococcal isolates in Chinese children. There exists the potential to reduce IPD by improved uptake of pneumococcal vaccination, and continued surveillance is warranted.

Object: Adipose-derived mesenchymal stem cells (ADSCs) have received significant attention in the field of cartilage tissue repair. Angelica sinensis polysaccharide (ASP) can enhance both the proliferation and differentiation of mesenchymal stem cells. Therefore, we intend to explore the effect of ASP on chondrogenic differentiation of ADSCs in vitro, and elucidate the underlying mechanisms. Method: ADSCs were treated with different concentrations of ASP to determine the optimal concentration. The chondrogenic differentiation of ADSCs was evaluated using Alcian blue staining, qRT-PCR, western blot, and IF staining. Transcriptome sequencing was performed to identify the expression profiles of ADSCs before and after ASP treatment, followed by bioinformatic analyses including differential expression analysis, enrichment analysis, and construction of PPI networks to identify differentially expressed genes (DEGs) associated with ASP and chondrogenic differentiation. Result: Surface markers of isolated rat-derived ADSCs were identified by CD44+CD90+CD45-CD106-, and exhibited the capacity for lipogenic, osteogenic, and chondrogenic differentiation. With increasing concentration of ASP treatment, there was an upregulation in the activity and acidic mucosubstance of ADSCs. The levels of Aggrecan, COL2A1, and Sox9 showed an increase in ADSCs after 28 days of 80 µg/ml ASP treatment. Transcriptome sequencing revealed that ASP-associated DEGs regulate extracellular matrix synthesis, immune response, inflammatory response, and cell cycle, and are involved in the NF-κB, AGE-RAGE, and calcium pathways. Moreover, Edn1, Frzb, Mdk, Nog, and Sulf1 are hub genes in DEGs. Notably, ASP upregulated MDK levels in ADSCs, while knockdown of MDK mitigated ASP-induced elevations in acidic mucosubstance, chondrogenic differentiation-related markers (Aggrecan, COL2A1, and Sox9), and the activity of the PI3K/AKT pathway. Conclusion: ASP enhances the proliferation and chondrogenic differentiation of ADSCs by activating the MDK-mediated PI3K/AKT pathway.

Objective We explored correlations between the Dietary Inflammatory Index (DII) and fracture risk in older adults. Methods We systematically searched MEDLINE, PubMed, Science Direct, Scopus, and CNKI for all relevant epidemiological studies published through October 16, 2023. Because observational studies were included in the meta-analysis, we used a random-effects model to pool the study-specific effect sizes and 95% confidence intervals (CIs). We assessed study quality using the Newcastle–Ottawa scale. This meta-analysis was registered in PROSPERO. Results Eight studies with 462,986 participants were included, with five cohort studies, two cross-sectional studies, and one case–control study. An analysis of heterogeneity among the eight included studies resulted in I 2 = 87.1%, indicating significant between-study heterogeneity; hence, the random-effects model was adopted to generate the combined effect size. We found that the DII was positively associated with fracture (relative risk: 1.188, 95% CI: 1.043–1.354). This result was further confirmed in leave-one-out sensitivity analysis. Conclusions Our study provides evidence suggesting that diets high in pro-inflammatory components might increase the fracture risk among older people. Decreased consumption of pro-inflammatory foods and increased consumption of anti-inflammatory foods are suggested to prevent adverse fracture outcomes. More prospective studies involving both sexes are warranted to verify the results.

Abstract Hyperuricemia as one of the key factors for gout, and quercetin could reduce the uric acid (UA) content. However, the mechanism of quercetin reduces UA content is still uncovered. Herein, we found quercetin can reduce UA content, induce antioxidant enzyme activity, inhibit the enzyme activity of xanthine oxidase (XOD) in hyperuricemia mice. Moreover, the UA reabsorption was also significantly reduced in the kidney and the kidney inflammation was alleviated by quercetin in hyperuricemia mice. Meanwhile, the protein level of ATP‐binding cassette super‐family G member 2 (ABCG2) was markedly induced and the protein levels of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) were significantly repressed by quercetin in hyperuricemia mice and HK‐2 cells and by quercetin‐3‐O‐glucuronide in HK‐2 cells. Additionally, the docking mode indicated that quercetin is stable bound to the active site of XOD. Overall, the data reveal that quercetin alleviates hyperuricemia by repressing the activity of XOD, reducing the UA absorption via enhancing ABCG2 expression, and repressing URAT1 and GLUT9 expression.

Objective Assessing excess deaths from benchmarks across causes of death during the first wave of the COVID-19 pandemic and identifying morbidities most frequently mentioned alongside COVID-19 deaths in the death record.Methods Descriptive study of death records between 11 March 2020 and 27 July 2020, from the New York City Bureau of Vital Statistics. Mortality counts and percentages were compared with the average for the same calendar period of the previous 2 years. Distributions of morbidities from among forty categories of conditions were generated citywide and by sex, race/ethnicity and four age groups. Causes of death were assumed to follow Poisson processes for Z-score construction.Results Within the study period, 46 563 all-cause deaths were reported; 132.9% higher than the average for the same period of the previous 2 years (19 989). Of those 46 563 records, 19 789 (42.5%) report COVID-19 as underlying cause of death. COVID-19 was the most prevalent cause across all demographics, with respiratory conditions (prominently pneumonia), hypertension and diabetes frequently mentioned morbidities. Black non-Hispanics had greater proportions of mentions of pneumonia, hypertension, and diabetes. Hispanics had the largest proportion of COVID-19 deaths (52.9%). Non-COVID-19 excess deaths relative to the previous 2-year averages were widely reported.Conclusion Mortality directly due to COVID-19 was accompanied by significant increases across most other causes from their reference averages, potentially suggesting a sizable COVID-19 death undercount. Indirect effects due to COVID-19 may partially account for some increases, but findings are hardly dispositive. Unavailability of vaccines for the time period precludes any impact over excess deaths. Respiratory and cardiometabolic-related conditions were most frequently reported among COVID-19 deaths across demographic characteristics.

Abstract Background Cue exposure therapy is used to treat alcohol dependence. However, its effectiveness is controversial due to the limitations of the clinical treatment setting. Virtual reality technology may improve the therapeutic effect. The aim of this study is to explore whether virtual reality-based cue exposure therapy can reduce the psychological craving and physiological responses of patients with alcohol dependence. Methods Forty-four male alcohol-dependent patients were recruited and divided into the study group (n = 23) and the control group (n = 21) according to a random number table. The control group received only conventional clinical treatment for alcohol dependence. The study group received conventional clinical treatment with the addition of VR cue exposure (treatment). The primary outcome was to assess psychological craving and physiological responses to cues of patients before and after treatment. Results After virtual reality-based cue exposure therapy, the changes in VAS and heart rate before and after cue exposure in the study group were significantly lower than those in the control group (P 0.05). The changes in VAS and heart rate before and after cue exposure in the study group were significantly lower than those before treatment (P 0.05). The changes in VAS, heart rate, skin conductance and respiration before and after cue exposure in the control group were not significantly different from those before treatment (P > 0.05). Conclusion Virtual reality-based cue exposure therapy can reduce the psychological craving and part of the physiological responses of alcohol-dependent patients during cue exposure in the short term and may be helpful in the treatment of alcohol dependence. Trial registration The study protocol was registered at the China Clinical Trial Registry on 26/02/2021 ( www.chictr.org.cn ; ChiCTR ID: ChiCTR2100043680).

Abstract With the rapid development of semiconductors, the number of materials needed to be polished sharply increases. The material properties vary significantly, posing challenges to chemical mechanical polishing (CMP). Accordingly, the study aimed to classify the material removal mechanism. Based on the CMP and atomic force microscopy results, the six representative metals can be preliminarily classified into two groups, presumably due to different material removal modes. From the tribology perspective, the first group of Cu, Co, and Ni may mainly rely on the mechanical plowing effect. After adding H2O2, corrosion can be first enhanced and then suppressed, affecting the surface mechanical strength. Consequently, the material removal rate (MRR) and the surface roughness increase and decrease. By comparison, the second group of Ta, Ru, and Ti may primarily depend on the chemical bonding effect. Adding H2O2 can promote oxidation, increasing interfacial chemical bonds. Therefore, the MRR increases, and the surface roughness decreases and levels off. In addition, CMP can be regulated by tuning the synergistic effect of oxidation, complexation, and dissolution for mechanical plowing, while tuning the synergistic effect of oxidation and ionic strength for chemical bonding. The findings provide mechanistic insight into the material removal mechanism in CMP.

The objective of this study is to explore the mechanism of action at the contact interface between gears and particles in spindle barrel finishing, using the Discrete Element Method (DEM) for simulation. The motion of the particles in the vicinity of the gear and the contact particles on the tooth surface is first described. Then the effects of gear embedment depth, gear and roller speed on relative particle motion velocity and tooth contact force are investigated. Finally, the simulation results are verified by experiments. The results show that the action of spindle barrel finishing on the gear tooth face is cyclical in nature. Contact force on the upper and lower tooth surfaces of the gear is not uniform, and the contact force on the upper tooth surface is 1.5 to 1.8 times that on the lower tooth surface. Increasing the gear embedment depth mainly affects the contact force between the particles and the tooth surface. A 75% increase in embedment depth leads to a 76% rise in tooth surface contact force. Similarly, increasing the gear and drum speed mainly affects the relative movement speed between particles and the tooth surface. A 150% increase in gear and drum speed results in a 148% increase in the relative movement speed of particles in contact with the tooth surface. Increasing the embedment depth of the gear can reduce the processing variability of the gear tooth surface along the axial direction. After increasing the embedment depth from 80 mm to 140 mm, the roughness of the upper and lower tooth surfaces along the axial direction decreases from 17% and 36% to 62% and 55%, respectively. However, the processing variability along the tooth profile direction does not change significantly by changing the speed and embedment depth.

Abstract Background Tuberculosis (TB) has been regarded as ‘a relentless scourge’, increasing morbidity and mortality and burdening vulnerable populations. Poor adherence to TB treatment and ineffective traditional interventions hinders TB control. A novel TB approach called ‘electronic monitors’, equipping medication boxes with daily audio or visual reminders for electronically monitoring medication intake, seems promising in improving adherence and health outcomes and overcoming the weaknesses of traditional interventions. However, no review has systematically examined and synthesized the influencing factors of implementing electronic monitors. Implementation research offers the means to analyse the influencing factors of the implementation and its process, fitting well with the aim of this review. Therefore, the widely recognized Consolidated Framework for Implementation Research (CFIR), which offers a common taxonomy for evaluating intervention implementation, will be adopted to systematically identify barriers and facilitators of the electronic monitors for improving adherence and health outcomes in patients with TB. Methods and analysis The systematic review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Literature research will be conducted in five electronic databases (Ovid MEDLINE, CINAHL, EMBASE, Cochrane Library and Web of Science) to identify the barriers and facilitators of implementing electronic monitors in patients with TB. The CFIR will be used as a guide for categorizing and synthesizing the barriers and facilitators. Study screening, data extraction, quality appraisal and data analysis will be conducted by two independent reviewers. The use of additional reviewers will solve any disagreements between the two reviewers. Discussion Given the increased prominence of TB epidemiology and the adherence problem of electronic monitors, there is a solid rationale for synthesizing the existing studies via the CFIR. The findings and conclusion of this review will lay bare the achievements and effectiveness of implementing electronic monitors, as well as the attendant gaps and limitations. Further strategies for facilitating the implementation of electronic monitors will also be explored. This review will be of essential significance for research and practice, supporting future academic research initiatives centred on patients with TB and aiding electronic monitor design in lowering the morbidity and mortality associated with TB disease. Trial registration number: PROSPERO: CRD42023395747.

Abstract Background Mitochondrial dysfunction leading to disturbances in energy metabolism has emerged as one of the risk factors in the pathogenesis of depression. Numerous studies have identified alterations in the content of mitochondrial DNA (mtDNA) in peripheral blood and cerebrospinal fluid of individuals with depression. Researchers have sought to establish a clear association between mtDNA and depression. Consequently, we conducted a comprehensive meta-analysis to assess the existing evidence regarding the impact of mtDNA on depression. Methods This study conducted a thorough search of the following databases up to March 13, 2023: PubMed, Embase, the Cochrane Library, the Web of Science, Wanfang Database, SINOMED, the China Science and Technology Journal Database, and China National Knowledge Infrastructure. The meta-analysis was carried out using RevMan (version 5.4) and Stata (version 16.0) software. In addition, publication bias was assessed with funnel plots, Begg’s test and Egger’s test. Results Our analysis included data from 10 articles, including 12 studies for further examination. A total of 1400 participants were included in this study, comprising 709 (including 300 males and 409 females) patients with depression and 691 (including 303 males and 388 females) healthy controls. The average age of depressed patients was (42.98 ± 2.55) years, and the average age of healthy people was (41.71 ± 2.6) years. The scales used to assess outcomes are Hamilton-rating scale for Depression(4 articles), Montgomery-Asberg Depression Rating Scale(3 articles), and Mini-Internatioal Neuropsychiatric Interview (1 articles). The meta-analysis revealed significantly higher levels of mtDNA in circulating blood samples and skin fibroblasts of individuals with depression in comparison to healthy controls [standardized mean difference(SMD) = 0.42, 95% confidence intervals(CI): 0.16, 0.67]. Conclusions Our study concludes that there is a significant (p

Abstract The powerful CRISPR genome editing system is hindered by its off-target effects, and existing computational tools achieved limited performance in genome-wide off-target prediction due to the lack of deep understanding of the CRISPR molecular mechanism. In this study, we propose to incorporate molecular dynamics (MD) simulations in the computational analysis of CRISPR system, and present CRISOT, an integrated tool suite containing four related modules, i.e., CRISOT-FP, CRISOT-Score, CRISOT-Spec, CRISORT-Opti for RNA-DNA molecular interaction fingerprint generation, genome-wide CRISPR off-target prediction, sgRNA specificity evaluation and sgRNA optimization of Cas9 system respectively. Our comprehensive computational and experimental tests reveal that CRISOT outperforms existing tools with extensive in silico validations and proof-of-concept experimental validations. In addition, CRISOT shows potential in accurately predicting off-target effects of the base editors and prime editors, indicating that the derived RNA-DNA molecular interaction fingerprint captures the underlying mechanisms of RNA-DNA interaction among distinct CRISPR systems. Collectively, CRISOT provides an efficient and generalizable framework for genome-wide CRISPR off-target prediction, evaluation and sgRNA optimization for improved targeting specificity in CRISPR genome editing.

Abstract Purpose While coronavirus disease 2019 (COVID-19) has emerged as a global pandemic, millions of patients with COVID-19 have recovered and returned to their families and work, although the key factors of sequela-free survival remain unknown. Here we determine key factors associated with sequela-free survival of patients with COVID-19. Methods Sequela-free survival is defined as having none of the long-term sequelae measured with the Activity of Daily Living (ADL) Scale, modified Medical Research Council (mMRC) Dyspnoea Scale, New York Heart Association (NYHA) classification, Self-rating Depression Scale (SDS), Carcinologic Handicap Index (CHI) and Modified Telephone Interview for Cognitive Status (TICS-M). Multivariable logistic regression was used to examine the key factors of sequela-free survival. Results The follow-up period for the 464 patients was 10 August to 30 September 2020. Of these, 424 patients completed the assessment of all scales. 30.2% (128 of 424) were categorised as sequela-free at follow-up. The most common sequelae were psychosocial problems (254 [57.7%]), respiratory function abnormality (149 [32.6%]) and cardiac function abnormality (98 [21.5%]). Risk factors associated with COVID-19 sequelae were anaemia on admission, longer duration from the onset of symptoms to admission and increasing of age, whereas anaemia treatment was a protective factor against sequelae. A haemoglobin level of

The CoCrFeNiMn high-entropy alloy and TiB2p/CoCrFeNiMn high-entropy composite (HEC) were manufactured by Selective laser melting. For the CoCrFeNiMn, a coarse epitaxial columnar microstructure with strong crystallographic textures was generated. While in the TiB2p/CoCrFeNiMn, TiB2 particles are distributed in the significantly refined dendrites and nearly equiaxial grains, and phase transformation occurs to form σ phase. TiB2 and σ phase construct a strong interface relationship with the matrix. TiB2p/CoCrFeNiMn HEC has extremely high microhardness (329 ± 2 HV) and excellent wear resistance (coefficients of friction 0.31 ± 0.02). The wear mechanism of the HEC was studied refer to the microstructure, composition and hardness.IMPACT STATEMENTTiB2-reinforced CoCrFeNiMn-based high-entropy composite is successfully fabricated by Selective laser melting, which exhibits exceptional hardness and the best wear resistance.

We describe a case of a female patient with acute lymphoblastic leukemia treated with high-dose systemic methotrexate and intrathecal methotrexate for leukemic relapse of the central nervous system. She developed complete bilateral lower-limb paralysis that was not attributable to any other cause. She was treated with folic acid, vitamin B12, methionine, S-adenosylmethionine, leucovorin, and dextromethorphan. After a 3-month period of paraplegia, she began to slowly recover motor function. She can now ambulate with assistance and continues to improve. There is a paucity of literature on methotrexate-induced subacute combined degeneration, which is typically described as irreversible. In addition to reporting our unique case, we review the published literature and call for more awareness and research in this area.

Abstract Background BRAF non-V600 mutation occupies a relatively small but critical subset in colorectal cancer (CRC). However, little is known about the biological functions and impacts of BRAF class III mutation in CRC. Here, we aim to explore how D594A mutation impacts on biological behaviors and immune related signatures in murine CRC cells. Methods BRAF V600E (class I), G469V (class II) and D594A (class III) mutant cell lines were established based on MC38 cells. The biological behaviors of cells were evaluated in respect of cell growth, cell proliferation, cell apoptosis, cell migration and invasion by the methods of colony-forming assay, CCK-8 assay, Annexin V/PI staining and transwell assay. The concentrations of soluble cytokines were detected by ELISA. The membrane expression of immuno-modulatory molecules and the pattern of tumor infiltrating lymphocyte were evaluated by flow cytometry. The molecular mechanism was explored by RNA sequencing. Immunohistochemistry (IHC) staining was used for the detection of CD8α in tumor tissues. qRT-PCR and western blot were performed to assess the mRNA and protein expression. Anti-PD-L1 treatment and cytokines neutralization experiments were conducted in in vivo models. Results D594A mutant cells displayed lower grade malignancy characteristics than V600E (class I) and G469V (class II) mutant cells. Meanwhile, D594A mutation led to evident immuno-modulatory features including upregulation of MHC Class I and PD-L1. In vivo experiments displayed that the frequency of infiltrated CD8+ T cells was significantly high within D594A mutant tumors, which may provide potential response to anti-PD-L1 therapy. RNA sequencing analysis showed that D594A mutation led to enhanced expression of ATF3 and THBS1, which thus facilitated CXCL9 and CXCL10 production upon IFN-γ treatment. In addition, CXCL9 or CXCL10 neutralization reduced the infiltration of CD8+ T cells into THBS1-overexpressing tumors. Conclusions D594A mutant CRC exhibited lower aggressiveness and immune-activated phenotype. ATF3-THBS1-CXCL9/CXCL10 axis mediated functional CD8+ T cells infiltration into the microenvironment of D594A mutant CRC. Our present study is helpful to define this mutation in CRC and provide important insights in designing effective immunotherapeutic strategies in clinic.

Phytoplankton plays a key role in the stabilization of aquatic ecosystems. However, there is a lack of research on the structure of phytoplankton communities and their influencing factors in shallow lakes in Southeast Hubei. In this study, four typical lakes were selected in the summer of 2019, and the phytoplankton community structure and its drivers were investigated for each lake. The results showed that the number of phytoplankton species, dominant species, biomass, and abundance varied among lakes. A comprehensive trophic level index (TLI) assessment showed that Lake Xiandao was oligotrophic, Lake Baoan was light eutrophic, and Lake Wang and Lake Ci were moderate eutrophic. The Shannon–Wiener, Margalef, and Pielou indices showed that the phytoplankton communities of Lake Wang and Lake Ci are less stable, and the water bodies are more severely contaminated. In contrast, the communities of the Lake Baoan and Lake Xiandao are more stable and have superior water quality. A redundancy analysis (RDA) indicated that the primary variables influencing phytoplankton community structures were pH and water temperature (WT) (Lake Ci); permanganate index (CODMn) and pH (Lake Xiandao); WT and total nitrogen (TN) (Lake Wang); and WT and total phosphorus (TP) (Lake Baoan).

Surface treatment processes such as mass finishing play a crucial role in enhancing the quality of machined parts across industries. However, accurate measurement of the velocity field of granular media in mass finishing presents significant challenges. Existing measurement methods suffer from issues such as complex and expensive equipment, limited to single-point measurements, interference with the flow field, and lack of universality in different scenarios. This study addresses these issues by proposing a single-camera-based method with deep learning to measure the three-dimensional velocity field of granular flow. We constructed a complete measurement system and analyzed the accuracy and performance of the proposed method by comparing the measurement results with those of the traditional DIC algorithm. The results show that the proposed method is very accurate in measuring spatial displacement, with an average error of less than 0.07 mm and a calculation speed that is 1291.67% of the traditional DIC algorithm under the same conditions. Additionally, experiments in a bowl-type vibratory finishing machine demonstrate the feasibility of the proposed method in capturing the three-dimensional flow of granular media. This research not only proposed a novel method for three-dimensional reconstruction and velocity field measurement using a single-color camera, but also demonstrated a way to combine deep learning with traditional optical techniques. It is of great significance to introduce deep learning to improve traditional optical techniques and apply them to practical engineering measurements.

The wild strawberry (Fragaria vesca L.; F. vesca) represents a resilient and extensively studied model organism. While the AP2/ERF gene family plays a pivotal role in plant development, its exploration within F. vesca remains limited. In this study, we characterized the AP2/ERF gene family in wild strawberries using the recently released genomic data (F. vesca V6.0). We conducted an analysis of the gene family expansion pattern, we examined gene expression in stem segments and leaves under cold conditions, and we explored its functional attributes. Our investigation revealed that the FvAP2/ERF family comprises 86 genes distributed among four subfamilies: AP2 (17), RAV (6), ERF (62), and Soloist (1). Tandem and segmental duplications significantly contributed to the growth of this gene family. Furthermore, predictive analysis identified several cis-acting elements in the promoter region associated with meristematic tissue expression, hormone regulation, and resistance modulation. Transcriptomic analysis under cold stress unveiled diverse responses among multiple FvAP2/ERFs in stem segments and leaves. Real-time fluorescence quantitative reverse transcription PCR (RT-qPCR) results confirmed elevated expression levels of select genes following the cold treatment. Additionally, overexpression of FvERF23 in Arabidopsis enhanced cold tolerance, resulting in significantly increased fresh weight and root length compared to the wild-type control. These findings lay the foundation for further exploration into the functional roles of FvAP2/ERF genes.

Background: In traditional Mongolian or Tibetan medicine in China, Chebulae Fructus (CF) is widely used to process or combine with aconitums to decrease the severe toxicity of aconitums. Researches in this area have predominantly focused on tannins, with few research on other major CF components for cardiotoxicity mitigation. The present study aimed to clarify whether triterpenoids can attenuate the cardiotoxicity caused by mesaconitine (MA) and investigate the mechanism of cardiotoxicity attenuation.Methods: Firstly, the pharmacophore model, molecular docking, and 3D-QSAR model were used to explore the mechanism of CF components in reducing the toxicity of MA mediated by the TRPV1 channel. Then three triterpenoids were selected to verify whether the triterpenoids had the effect of lowering the cardiotoxicity of MA using H9c2 cells combined with MTT, Hoechst 33258, and JC-1. Finally, Western blot, Fluo-3AM, and MTT assays combined with capsazepine were used to verify whether the triterpenoids reduced H9c2 cardiomyocyte toxicity induced by MA was related to the TRPV1 channel.Results: Seven triterpenoids in CF have the potential to activate the TRPV1 channel. And they exhibited greater affinity for TRPV1 compared to other compounds and MA. However, their activity was relatively lower than that of MA. Cell experiments revealed that MA significantly reduced H9c2 cell viability, resulting in diminished mitochondrial membrane potential and nuclear pyknosis and damage. In contrast, the triterpenoids could improve the survival rate significantly and counteract the damage of MA to the cells. We found that MA, arjungenin (AR), and maslinic acid (MSA) except corosolic acid (CRA) upregulated the expression of TRPV1 protein. MA induced a significant influx of calcium, whereas all three triterpenoids alleviated this trend. Blocking the TRPV1 channel with capsazepine only increased the cell viability that had been simultaneously treated with MA, and AR, or MSA. However, there was no significant difference in the CRA groups treated with or without capsazepine.Conclusion: The triterpenoids in CF can reduce the cardiotoxicity caused by MA. The MSA and AR function as TRPV1 agonists with comparatively reduced activity but a greater capacity to bind to TRPV1 receptors, thus antagonizing the excessive activation of TRPV1 by MA.

Summary: Overactivation of osteoclasts due to altered osteoclastogenesis causes multiple bone metabolic diseases. However, how osteoclast differentiation is tightly regulated and involved in multiple pathophysiological states remains mystery. In this study, we noticed that the downregulation of BHLHE41 (basic-helix-loop-helix family member e41) was tightly associated with osteoclast differentiation and osteoporosis. Functionally, the upregulation or downregulation of BHLHE41 suppressed or promoted osteoclast differentiation, respectively, in vitro. A mechanism study indicated that the direct binding of BHLHE41 to the promoter region of NFATc1 that led to its downregulation. Notably, the inhibition of NFATc1 abrogated the enhanced osteoclast differentiation in BHLHE41-knockdown bone marrow macrophages (BMMs). Additionally, upregulation of BHLHE41 impeded bone destruction in OVX mice with osteoporosis. Therefore, our research reveals the mechanism by which BHLHE41 regulates osteoclast differentiation and bone resorption via NFATc1, and targeting BHLHE41 is a potential strategy for the treatment of osteoporosis.

Abstract Purpose To explore the feasibility of individualized elective prophylactic neck irradiation (iEPNI) for optimizing current approach by investigating metastatic lymph nodes (LNs) distribution in nasopharyngeal carcinoma (NPC). Materials and Methods Records of 870 NPC patients without distant metastasis in Hunan Cancer Hospital from January 2019 to December 2019 were reviewed. LNs' locations were identified based on the 2013 guidelines. The intra‐regional lymphatic drainage (IRLD) areas included Station 1st (level VIIa and II), Station 2nd (level III and Va), and Station 3rd (level IV, Vb, and Vc). Other levels were categorized as extra‐regional areas. Results Among the 870 patients, 94.5% cases exhibited LNs metastasis, including unilateral metastasis in 198 patients and bilateral metastasis in 624 patients. In the whole cohort, the most common involved IRLD areas were level IIb (87.1%), VIIa (80.0%), IIa (61.8%), Va (30.6%), IV (21.4%), Vb (8.9%), and Vc (1.1%). Besides, rates of LNs metastasis in Station 1st, 2nd, and 3rd were 94.3%, 61.1%, and 22.9%, respectively. Only four patients (4, 0.5%) revealed skipping metastasis among the three stations. Conclusions Lymph node metastasis follows an organized pattern from Station 1st to 3rd with scarce skipping metastasis. A potential iEPNI strategy of prophylactic neck irradiation to the ipsilateral latter node‐negative station appears promising in NPC patients. Further prospective investigations are warranted to validate the approach.

Summary: The acidic metabolic byproducts within the tumor microenvironment (TME) hinder T cell effector functions. However, their effects on T cell infiltration remain largely unexplored. Leveraging the comprehensive The Cancer Genome Atlas dataset, we pinpoint 16 genes that correlate with extracellular acidification and establish a metric known as the “tumor acidity (TuAci) score” for individual patients. We consistently observe a negative association between the TuAci score and T lymphocyte score (T score) across various human cancer types. Mechanistically, extracellular acidification significantly impedes T cell motility by suppressing podosome formation. This phenomenon can be attributed to the reduced expression of methyltransferase-like 3 (METTL3) and the modification of RNA N6-methyladenosine (m6A), resulting in a subsequent decrease in the expression of integrin β1 (ITGB1). Importantly, enforced ITGB1 expression leads to enhanced T cell infiltration and improved antitumor activity. Our study suggests that modulating METTL3 activity or boosting ITGB1 expression could augment T cell infiltration within the acidic TME, thereby improving the efficacy of cell therapy.

The wind environment quality at the height of pedestrians can significantly affect the thermal comfort and physical and mental health of pedestrians, promote the diffusion of air pollutants and inhibit the formation of urban heat island effect, and has been paid more and more attention in the field of urban and rural planning. This paper takes Jianlan Road commercial pedestrian Street as an example to maximize the thermal comfort of pedestrians. Based on CFD numerical simulation technology and space syntax theory, the pedestrian wind environment of the accessible space of the block is selected for quantitative research. Through numerical simulation, the influence of block spatial form on the wind environment at pedestrian height under the initial condition of uniform air flow is analyzed, and some suggestions are put forward for the optimization of block spatial form. Finally, the block optimization scheme is verified and simulated. The visualization results show that the wind environment quality of the optimized high-accessibility space is significantly improved, the proportion of comfort zone is increased from 58.2% to 86%, and the static wind rate is reduced from 41.8% to 14%. The wind environment optimization effect is obvious.

Abstract Background Catastrophic health expenditure (CHE) is an important indicator of measuring health inequality. Previous studies mainly focused on specific vulnerable populations rather than a wider range of vulnerable areas through panel data. Rural China is often associated with an underdeveloped economy and insufficient health resources. This study aims to update the information on the extent of and trends in the incidence and inequality of CHE among the households of rural China through longitudinal survey data. Methods Data were obtained from three waves of the China Health and Retirement Longitudinal Study (CHARLS): 2013, 2015, and 2018. In total, 2,575 households were included in the analysis. CHE was defined as household health expenditures exceeding 40% of non-food expenditures. Inequality in CHE was measured using the concentration curve and concentration index. The contribution to CHE inequality was decomposed using the concentration index decomposition method. Results The incidence of CHE was 0.2341 (95% CI: 0.22, 0.25) in 2013, 0.2136 (95% CI: 0.20, 0.23) in 2015, and 0.2897 (95% CI: 0.27, 0.31) in 2018 in rural China. The concentration curve lay above the equality line, and the concentration index was negative: −0.1528 (95% CI: −0.1941, −0.1115) in 2013, −0.1010 (95% CI: −0.1442, −0. 0577) in 2015, and −0.0819 (95% CI: −0.1170, −0.0467) in 2018. Economic status, age, and chronic diseases were the main contributors to inequality in CHE. Conclusions The incidence of CHE in rural China displayed an upward trend from 2013 to 2018, although it was not continuous. Furthermore, a strong pro-low-economic inequality in CHE existed in rural China. Mainly economic status, age, and chronic diseases contributed to this pro-low-economic inequality. Health policies to allocate resources and services are needed to satisfy the needs of rural households and provide more accessible and affordable health services. More concern needs to be directed toward households with chronic diseases and older persons to reduce the incidence of CHE and promote health equality.

TiB2 nano-particle reinforced CoCrFeMnNi composite has been additively manufactured by using laser powder bed fusion (LPBF) technique. In comparison with the matrix CoCrFeMnNi sample, the average grain size of the TiB2 doped CoCrFeMnNi (CoCrFeMnNi + TiB2) sample reduces from 26.27 μm to 7.51 μm, appearing a morphological transformation from columnar grains to fine equiaxed grains and fine dendritic grains. Correspondingly, the compressive yield strength (σy) sharply increases from 484.41 ± 57.81 MPa of CoCrFeMnNi HEA to 952.62 ± 38.15 MPa of CoCrFeMnNi + TiB2, and the tensile yield strength increases from 480.27 ± 1.25 MPa to 834.21 ± 15.93 MPa, revealing a substantial enhancement of mechanical properties. The structural analysis unveils that the CoCrFeMnNi + TiB2 sample formed a tetragonal σ phase beside the FCC matrix and TiB2 phases compared with the single FCC phase of CoCrFeMnNi HEA. Especially, atomic resolution scanning transmission electron microscopy discloses that the TiB2 nanoparticles epitaxially grow onto the FCC matrix phase with [01–10]TiB2//[011]FCC orientation relationship. Theoretical calculations indicate that the enhancement mechanism of the CoCrFeMnNi + TiB2 sample should originate from a synergistic strengthening effect which is induced by grain refinement, TiB2 particles, σ phases and dislocations. Our work should provide a new view to utilize the rapid solidification process of LPBF and ceramic nano-particle reinforcement for the enhanced mechanical properties of HEAs with great potential.

Abstract Background Breast cancer (BC) seriously threatens women's health. Aspirin plays a key role in the treatment and prognosis of BC. Objective To explore the effect of low‐dose aspirin on BC radiotherapy through the mechanism of exosomes and natural killer (NK) cells. Methods BC cells were injected into the left chest wall to establish a BC model in nude mice. Tumor morphology and size were observed. Immunohistochemical staining for Ki‐67 was used to observe the proliferation of tumor cells. TUNEL was used to detect the apoptosis of cancer cells. Protein levels of exosomal biogenesis‐ and secretion‐related genes (Rab 11, Rab27a, Rab27b, CD63, and Alix) were detected by Western blot. Flow cytometry was used to detect apoptosis. Transwell assays were used to detect cell migration. A clonogenic assay was used to detect cell proliferation. Exosomes of BT549 and 4T1‐Luc cells were extracted and observed by electron microscopy. After the coculture of exosomes and NK cells, the activity of NK cells was detected by CCK‐8. Results The protein expression of genes related to exosomal genesis and secretion (Rab 11, Rab27a, Rab27b, CD63, and Alix) in BT549 and 4T1‐Luc cells was upregulated under radiotherapy treatment. Low doses of aspirin inhibited exosome release from BT549 and 4T1‐Luc cells and alleviated the inhibitory effect of BC cell exosomes on NK cell proliferation. In addition, knocking down Rab27a reduced the protein levels of exosome‐related and secretion‐related genes in BC cells, further enhancing the promotive effect of aspirin on NK cell proliferation, while overexpressing Rab27a had the opposite effect. Aspirin was combined at a radiotherapeutic dose of 10 Gy to enhance the radiotherapy sensitivity of radiotherapy‐tolerant BC cells (BT549R and 4T1‐LucR). Animal experiments have also verified that aspirin can promote the killing effect of radiotherapy on cancer cells and significantly inhibit tumor growth. Conclusion Low doses of aspirin can inhibit the release of BC exosomes induced by radiotherapy and weaken their inhibition of NK cell proliferation, promoting radiotherapy resistance.

Abstract Many of the currently available COVID-19 vaccines and therapeutics are not effective against newly emerged SARS-CoV-2 variants. Here, we developed the metallo-enzyme domain of angiotensin converting enzyme 2 (ACE2)—the cellular receptor of SARS-CoV-2—into an IgM-like inhalable molecule (HH-120). HH-120 binds to the SARS-CoV-2 Spike (S) protein with high avidity and confers potent and broad-spectrum neutralization activity against all known SARS-CoV-2 variants of concern. HH-120 was developed as an inhaled formulation that achieves appropriate aerodynamic properties for rodent and monkey respiratory system delivery, and we found that early administration of HH-120 by aerosol inhalation significantly reduced viral loads and lung pathology scores in male golden Syrian hamsters infected by the SARS-CoV-2 ancestral strain (GDPCC-nCoV27) and the Delta variant. Our study presents a meaningful advancement in the inhalation delivery of large biologics like HH-120 (molecular weight (MW) ~ 1000 kDa) and demonstrates that HH-120 can serve as an efficacious, safe, and convenient agent against SARS-CoV-2 variants. Finally, given the known role of ACE2 in viral reception, it is conceivable that HH-120 has the potential to be efficacious against additional emergent coronaviruses.

Abstract Molecular interplay between host epigenetic factors and viral proteins constitutes an intriguing mechanism for sustaining hepatitis B virus (HBV) life cycle and its chronic infection. HBV encodes a regulatory protein, HBx, which activates transcription and replication of HBV genome organized as covalently closed circular (ccc) DNA minichromosome. Here we illustrate how HBx accomplishes its task by hijacking Spindlin1, an epigenetic reader comprising three consecutive Tudor domains. Our biochemical and structural studies have revealed that the highly conserved N-terminal 2–21 segment of HBx (HBx2–21) associates intimately with Tudor 3 of Spindlin1, enhancing histone H3 “K4me3-K9me3” readout by Tudors 2 and 1. Functionally, Spindlin1-HBx engagement promotes gene expression from the chromatinized cccDNA, accompanied by an epigenetic switch from an H3K9me3-enriched repressive state to an H3K4me3-marked active state, as well as a conformational switch of HBx that may occur in coordination with other HBx-binding factors, such as DDB1. Despite a proposed transrepression activity of HBx2-21, our study reveals a key role of Spindlin1 in derepressing this conserved motif, thereby promoting HBV transcription from its chromatinized genome.

Echinococcus shiquicus is peculiar to the Qinghai–Tibet plateau of China. Research on this parasite has mainly focused on epidemiological surveys and life cycle studies. So far, limited laboratory studies have been reported. Here, experimental infection of E. shiquicus metacestode in BALB/c mice and Mongolian jirds (Meriones unguiculatus) was carried out to establish alternative laboratory animal models. Intraperitoneal inoculation of metacestode material containing protoscoleces (PSCs) obtained from infected plateau pikas were conducted on BALB/c mice. Furthermore, metacestode material without PSCs deriving from infected BALB/c mice was intraperitoneally inoculated to Mongolian jirds. Experimental animals were dissected for macroscopic and histopathological examination. The growth of cysts in BALB/c mice was infiltrative, and they invaded the murine entire body. Most of the metacestode cysts were multicystic, but a few were unilocular. The cysts contained sterile vesicles, which had no PSCs. The metacestode materials were able to successfully infect new mice. In the jirds model, E. shiquicus cysts were typically formed freely in the peritoneal cavity; the majority of these cysts were free while a small portion adhered loosely to nearby organs. The proportion of fertile cysts was high, and contained many PSCs. The PSCs produced in Mongolian jirds also successfully infected new ones, which confirms that jirds can serve as an alternative experimental intermediate host. In conclusion, a laboratory animal infection was successfully established for E. shiquicus using BALB/c mice and Mongolian jirds. These results provide new models for the in-depth study of Echinococcus metacestode survival strategy, host interactions and immune escape mechanism.

Abstract The unique dumbbell-shape of grass guard cells (GCs) is controlled by their cell walls which enable their rapid responses to the environment. The molecular mechanisms regulating the synthesis and assembly of GC walls are as yet unknown. Here we have identified BZU3, a maize gene encoding UDP-glucose 4-epimerase that regulates the supply of UDP-glucose during GC wall synthesis. The BZU3 mutation leads to significant decreases in cellular UDP-glucose levels. Immunofluorescence intensities reporting levels of cellulose and mixed-linkage glucans are reduced in the GCs, resulting in impaired local wall thickening. BZU3 also catalyzes the epimerization of UDP-N-acetylgalactosamine to UDP-N-acetylglucosamine, and the BZU3 mutation affects N-glycosylation of proteins that may be involved in cell wall synthesis and signaling. Our results suggest that the spatiotemporal modulation of BZU3 plays a dual role in controlling cell wall synthesis and glycosylation via controlling UDP-glucose/N-acetylglucosamine homeostasis during stomatal morphogenesis. These findings provide insights into the mechanisms controlling formation of the unique morphology of grass stomata.

In finishing simulations, achieving accurate results can be challenging due to the minimal amount of material removal and the limited measurement range of surface micro-topography instruments. To overcome these limitations, a novel high-fidelity modeling method combining image mosaic and wavelet decomposition technologies is proposed in this paper. We achieve the stitching of narrow field and high pixel micro morphology images through four steps: image feature extraction, overlapped feature matching, feature fusion, and stitching effect evaluation. On this basis, the wavelet decomposition method is employed to separate detection signals based on their respective frequencies, allowing the establishment of a datum plane and a roughness surface. The point cloud model undergoes a transformation into a continuous geometric model via the Poisson reconstruction algorithm. In the case study, four sample images of an aluminum alloy sheet after barrel finishing were collected using the ZeGage Plus optical profiler. Each image has an actual size of 834.37 μm × 834.37 μm. Subsequently, a comparison was carried out between the physical and simulation experiments. The results clearly indicate that the proposed method has the potential to enhance the accuracy of the finishing simulation by over 30%. The error between the resulting model and the actual surface of the part can be controlled within 1 μm.

Aluminum (Al) and its alloys are widely used in various fields due to their excellent physical properties. Although many efforts have been made to fabricate an Al-based composite, they usually results in a significant decrease in electrical conductivity. Herein, a special layer-structured Al/graphene (Gr)/Al composite was successfully designed and fabricated through a facile method using the ultrasonic spraying of graphene powder with alumina removal and a subsequent vacuum hot-pressing process. The as-obtained Al/Gr/Al composite presents a significantly enhanced electrical conductivity of 66% IACS, which is much higher than that of other reported Al-based composites, while it still maintains similar mechanical properties. This work provides a new strategy for the development of highly conductive Al-based composites, which would be very useful and important for practical applications.

The interplay patterns of amino acid residues are pivotal in determining the tertiary structure and flexibility of proteins, which in turn are intricately linked to their functionality and interactions with other molecules. Here, we introduce ARIP, a novel tool designed to identify contact residues within proteins. ARIP employs a modified version of the dr_sasa algorithm and an atomic overlap weighted algorithm to directly calculate the contact area and volume between atoms based on their van der Waals radius. It also allows for the selection of solvent radii, recognizing that not every atom in proteins can interact with water molecules. The solvent parameters were derived from the analysis of approximately 5000 protein and nucleic acid structures with water molecules determined using X-ray crystallography. One advantage of the modified algorithm is its capability to analyze multiple models within a single PDB file, making it suitable for molecular dynamic capture. The contact volume is symmetrically distributed between the interacting atoms, providing more informative results than contact area for the analysis of intra- and intermolecular interactions and the development of scoring functions. Furthermore, ARIP has been applied to four distinct cases: capturing key residue–residue contacts in NMR structures of P4HB, protein–drug binding of CYP17A1, protein–DNA binding of SPI1, and molecular dynamic simulations of BRD4.

Aqueous two-phase extraction (APTE) stands out as an environmentally friendly technique for the separation of metal ions. The separation of Re (VII) and Mo (VI) in an aqueous solution was investigated using a novel aqueous two-phase system (ATPS) consisting of isodecanol polyoxyethylene ether (E-1006), ammonium sulfate, and water. A phase diagram of this system was developed, and the effects of pH, temperature, extraction time, the concentrations of E-1006 and (NH4)2SO4, and metal ions on the separation of Re (VII) and Mo (VI) were examined. The results show that at pH 7.0, Mo (VI) had almost transformed into the (NH4)2SO4-rich phase, while Re (VI) was extracted into the E-1006-rich phase. The increase in temperature induces a transition of Mo (VI) to the salt-rich phase, which is unfavorable for the extraction of Re (VII). The increase in the concentrations of E-1006 and (NH4)2SO4 has a positive effect on the separation of rhenium and molybdenum. Overall, the ATPS consisting of 200 g/L of E-1006, 200 g/L of (NH4)2SO4, and water yields an extraction efficiency of 97.2% for Re and a high separation factor of 2700 for Re (VII) and Mo (VI) from a mixture of 0.1 g/L of Re (VII) and 5 g/L of Mo (VI) at pH 7.0 and 323.15 K. Separation studies of the simulated leaching solution show that the extraction efficiency for Re (VI) is 99.1% and the separation factor of Re (VII) and Mo (VI) is 5100.

Within a river catchment, the relationship between pollutant load migration and its related factors is nonlinear generally. When neural network models are used to identify the nonlinear relationship, data scarcity and random weight initialization might result in overfitting and instability. In this paper, we propose an averaged weight initialization neural network (AWINN) to realize the multi-index integrated prediction of a pollutant load under data scarcity. The results show that (1) compared with the particle swarm optimization neural network (PSONN) and AdaboostR models that prevent overfitting, AWINN improved simulation accuracy significantly. The R2 in test sets of different pollutant load models reached 0.51–0.80. (2) AWINN is effective in overcoming instability. With more hidden layers, the stability of the models’ outputs was stronger. (3) Sobol sensitivity analysis explained that the main influencing factors of the whole process were the flows of the catchment inlet and outlet, and main factors changed across seasons. The algorithm proposed in this paper can realize stably integrated prediction of pollutant load in the catchment under data scarcity and help to understand the mechanism that influences pollutant load migration.

The NAC (NAM, ATAF1/2, CUC2) family of transcription factors (TFs) is a vital transcription factor family of plants. It controls multiple parts of plant development, tissue formation, and abiotic stress response. We cloned the FvNAC29 gene from Fragaria vesca (a diploid strawberry) for this research. There is a conserved NAM structural domain in the FvNAC29 protein. The highest homology between FvNAC29 and PaNAC1 was found by phylogenetic tree analysis. Subcellular localization revealed that FvNAC29 is localized onto the nucleus. Compared to other tissues, the expression level of FvNAC29 was higher in young leaves and roots. In addition, Arabidopsis plants overexpressing FvNAC29 had higher cold and high-salinity tolerance than the wild type (WT) and unloaded line with empty vector (UL). The proline and chlorophyll contents of transgenic Arabidopsis plants, along with the activities of the antioxidant enzymes like catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD) under 200 mM NaCl treatment or −8 °C treatment, were higher than those activities of the control. Meanwhile, malondialdehyde (MDA) and the reactive oxygen species (ROS) content were higher in the WT and UL lines. FvNAC29 improves transgenic plant resistance to cold and salt stress by regulating the expression levels of AtRD29a, AtCCA1, AtP5CS1, and AtSnRK2.4. It also improves the potential to tolerate cold stress by positively regulating the expression levels of AtCBF1, AtCBF4, AtCOR15a, and AtCOR47. These findings suggest that FvNAC29 may be related to the processes and the molecular mechanisms of F. vesca response to high-salinity stress and LT stress, providing a comprehensive understanding of the NAC TFs.

This study examines the relationship between market volatility conditions and the weekend effect on size and profitability anomalies in the U.S. stock market. The study uses the ICSS model to divide the sample into high- and low-volatility periods. Empirical results indicate that the weekend effect of size and profitability anomalies is significant in low-volatility states and insignificant in high-volatility conditions, and it is consistent across different measures of stock market volatility and subsamples. Additionally, we identify the intra-week patterns of log returns on the VIX index as the driver of the weekend effect on profitability and size anomalies. Our study not only extends the understanding of the weekend effect of long-short anomalies but also provides new evidence on the effectiveness of volatility management in factor investing. It also has important implications for investors, who should consider improving their factor investment strategies based on our results.

Abstract Ferroelectricity in ultrathin two-dimensional (2D) materials has attracted broad interest due to potential applications in nonvolatile memory, nanoelectronics and optoelectronics. However, ferroelectricity is barely explored in materials with native centro or mirror symmetry, especially in the 2D limit. Here, we report the first experimental realization of room-temperature ferroelectricity in van der Waals layered GaSe down to monolayer with mirror symmetric structures, which exhibits strong intercorrelated out-of-plane and in-plane electric polarization. The origin of ferroelectricity in GaSe comes from intralayer sliding of the Se atomic sublayers, which breaks the local structural mirror symmetry and forms dipole moment alignment. Ferroelectric switching is demonstrated in nano devices fabricated with GaSe nanoflakes, which exhibit exotic nonvolatile memory behavior with a high channel current on/off ratio. Our work reveals that intralayer sliding is a new approach to generate ferroelectricity within mirror symmetric monolayer, and offers great opportunity for novel nonvolatile memory devices and optoelectronics applications.