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Abstract T helper cells, particularly T follicular helper (TFH) cells, are essential for the neutralizing antibody production elicited by pathogens or vaccines. However, in immunocompromised individuals, the inefficient support from TFH cells could lead to limited protection after vaccine inoculation. Here we showed that the conjugation of inducible T cell costimulatory (ICOS) onto the nanoparticle, together with immunogen, significantly enhanced the immune response of the vaccines specific for SARS-CoV-2 or human immunodeficiency virus type-1 (HIV-1) in TFH-deficient mice. Further studies indicated that ICOSL on B cells was triggered by ICOS binding, subsequently activated the PKCβ signaling pathway, and enhanced the survival and proliferation of B cells. Our findings revealed that the stimulation of ICOS-ICOSL interaction by adding ICOS on the nanoparticle vaccine significantly substitutes the function of TFH cells to support B cell response, which is significant for the immunocompromised people, such as the elderly or HIV-1-infected individuals.

Abstract Glaesserella parasuis is usually a benign swine commensal in the upper respiratory tract, but virulent strains can cause systemic infection characterized by pneumonia, meningitis, and fibrinous polyserositis. The intensive pulmonary inflammatory response following G. parasuis infection is the main cause of lung injury and death in pigs. Vaccination has failed to control the disease due to the lack of extended cross-protection. Accumulating evidence indicates that the heme-binding protein A (HbpA) is a potential virulence determinant and a promising antigen candidate for the development of a broader range of vaccines. However, it is not yet known whether HbpA contributes to G. parasuis virulence or has any potential immune protective effects against G. parasuis. Here, we show that HbpA can induce the transcription and secretion of proinflammatory cytokines (IL-6, TNF-α, and MCP-1) in porcine alveolar macrophages (PAM, 3D4/31). The HbpA protein is recognized by Toll-like receptors 2 and 4 on 3D4/21 macrophages, resulting in the activation of MAP kinase and NF-κB signalling cascades and the transcription and secretion of proinflammatory cytokines. HbpA contributes to virulence and bacterial pulmonary colonization in C57BL/6 mice and plays a role in adhesion to host cells and evasion of the bactericidal effect of pulmonary macrophages. In addition, mice immunized with HbpA were partially protected against challenge by G. parasuis SC1401. The results suggest that HbpA plays an important role in the pathogenesis of disease caused by G. parasuis and lay a foundation for the development of a subunit or chimeric anti-G. parasuis vaccine.

Abstract Introduction The diagnosis and care of children and adolescents with neurodevelopmental disorders presents a public health crisis in China. Attention deficit hyperactivity disorder (ADHD) is one of the most frequent conditions. Many Chinese children and adolescents with ADHD are underdiagnosed and undertreated. This study aimed to evaluate the awareness and attitude parents have about ADHD, and investigated potential factors influencing ADHD medical visit status among school-aged children in Shanghai. Methods A random cluster sampling method was used, and four primary schools in Shanghai were selected. One class was randomly selected from each grade, including students and their parents. Parents completed the Swanson, Nolan, and Pelham Version IV Questionnaire (SNAP-IV) parent form and questionnaire concerning ADHD awareness, knowledge, attitude and status of ADHD medical visit. Descriptive analysis was conducted on the overall results and logistic regression analysis was performed to explore the influencing factors of ADHD medical visit. Results We received 617 valid questionnaires. There were 313 boys (50.7%) and 304 girls (49.2%), with a median age of 8 years old (p25 = 7, p75 = 9). 42.4% parents believed they had some knowledge about ADHD, and 73.5% of them thought ADHD was a neurologically based disorder or neurological condition by nature. Parental ADHD information came from the following sources: Internet/TV (n = 458, 74.2%), families/friends (n = 267, 43.2%), print publication (n = 208, 33.7%), psychiatrists/pediatricians (n = 192, 31.1%), schools/teachers (n = 186, 30.1%) and other ADHD patients (n = 48, 7.7%). When children had ADHD-like behaviors, most parents (61.5%) educated children to behave themselves, 59.1% parents tried to get help from psychiatrists/pediatricians, 55.5% of them would ask psychologist for help. In terms of the ADHD prevalence, the SNAP-IV positive screen rate was 4.3% (n = 27). Only 33.3% (9/27) of parents went to the hospital for consultation and treatment. Multivariate logistic regression model showed that parental knowledge about ADHD (OR = 13.67, 95%CI: 1.72, 144.39, P = 0.01) was significantly correlated with the medical visit. Parents with sufficient knowledge of ADHD tend to visit hospital for help when they thought their children had ADHD related symptoms. Conclusions The majority of parents accepted ADHD as a neurodevelopmental disorder by nature, but some parents still had certain misunderstandings about ADHD. The main source of information for parents to obtain information about ADHD was through the TV/Internet. Parents’ perceptions and knowledge were key to whether children received appropriate treatment for their ADHD. However, medical visits to address ADHD among school-aged children were still lower than expected. Government and healthcare institutes should work to improve ADHD public awareness and to help patients and their families gain access to mental health resources.

Abstract Background Increasing evidence suggests that long noncoding RNAs (lncRNAs) play important regulatory roles in biological processes and are dysregulated in numerous tumors. The lncRNA GRASLND functions as an oncogene in many cancers, but its role in skin cutaneous melanoma (SKCM) requires further investigation. Methods SiRNA transfection, wound − healing and transwell assays were performed to evaluate the effect of GRASLND on cellular function. Results The present study demonstrated that GRASLND expression is increased in SKCM tissues and cell lines. The high expression of GRASLND was correlated with poor prognosis and immunotherapy outcomes. Knockdown of GRASLND significantly inhibited cell migration and invasion. In addition, we found that miR-218-5p directly binds to its binding site on GRASLND, and GRASLND and miR-218-5p demonstrate mutual inhibition. Furthermore, the miR-218-5p inhibitor partially eliminated the knockdown of GRASLND and inhibited its expression. We also demonstrated that GRASLND acts as a miR-218-5p sponge that positively regulates STAM2 expression in SKCM cells. Conclusion In summary, these data suggest that GRASLND functions by regulating miR-218-5p/STAM2 expression, suggesting an important role for the lncRNA‒miRNA–mRNA functional network and a new potential therapeutic target for SKCM.

Abstract Extremely large magnetoresistance (XMR) is highly applicable in spintronic devices such as magnetic sensors, magnetic memory, and hard drives. Typically, XMR is found in Weyl semimetals characterized by perfect electron–hole symmetry or exceptionally high electric conductivity and mobility. Our study explores this phenomenon in a recently developed graphene moiré system, which demonstrates XMR owing to its topological structure and high-quality crystal formation. We investigate the electronic properties of three-dimensional intertwined twisted graphene spirals (TGS), manipulating the screw dislocation axis to achieve a rotation angle of 7.3°. Notably, at 14 T and 2 K, the magnetoresistance of these structures reaches 1.7 × 107%, accompanied by a metal–insulator transition as the temperature increases. This transition becomes noticeable when the magnetic field exceeds a minimal threshold of approximately 0.1 T. These observations suggest the possible existence of complex, correlated states within the partially filled three-dimensional Landau levels of the 3D TGS system. Our findings open up possibilities for achieving XMR by engineering the topological structure of 2D layered moiré systems.

Abstract Graft availability from donation after circulatory death (DCD) is significantly limited by ischaemia reperfusion (IR) injury. Effective strategies to mitigate IR injury in DCD grafts are essential to improve graft quality and expand the donor pool. In this study, liver grafts from DCD pigs were preserved in the University of Wisconsin (UW) solution saturated with 0.1 nM dexmedetomidine (Dex) and various concentrations of noble gases Argon (Ar) and/or Xenon (Xe) at 4 °C for 24 or 72 h. The combined 50% Ar and Dex provided maximum protection to liver grafts by reducing morphological damage, apoptosis, necroptosis, ferroptosis, hepatocyte glycogen depletion, reticulin framework collapse, iron deposition, and oxidative stress. In vitro, human liver Hep G2 cells were preserved in the UW solution saturated with 0.1 nM Dex and 50% Ar in combination at 4 °C for 24 h, followed by recovery in medium at 37 °C for up to 48 h to mimic clinical IR injury. This treatment significantly increased the expression of anti-oxidative stress proteins by promoting the translocation of thioredoxin-interacting protein (TXNIP) to mitochondria, thereby inhibiting ferroptosis, increasing plasma membrane integrity, and maintaining cell viability.In summary, The combination of 0.1 nM Dex and 50% Ar may be a promising strategy to reduce ferroptosis and other form cell death, and preserve liver grafts.

Abstract We study a correspondence between gravitational shockwave geometry and its fluid description near a Rindler horizon in Minkowski spacetime. Utilizing the Petrov classification that describes algebraic symmetries for Lorentzian spaces, we establish an explicit mapping between a potential fluid and the shockwave metric perturbation, where the Einstein equation for the shockwave geometry is equivalent to the incompressibility condition of the fluid, augmented by a shockwave source. Then we consider an Ansatz of a stochastic quantum source for the potential fluid, which has the physical interpretation of shockwaves created by vacuum energy fluctuations. Under such circumstance, the Einstein equation, or equivalently, the incompressibility condition for the fluid, becomes a stochastic differential equation. By smearing the quantum source on a stretched horizon in a Lorentz invariant manner with a Planckian width (similarly to the membrane paradigm), we integrate fluctuations near the Rindler horizon to find an accumulated effect of the variance in the round-trip time of a photon traversing the horizon of a causal diamond.

The transition to a green economy is essential for sustainable development, yet the reliance on fossil fuels poses a significant challenge. This study investigates the impact of fossil fuel consumption on green economic development and examines circular economy innovations as a potential solution. Focusing on the period from 2000 to 2022, we employ the CS-ARDL model to analyze data from twelve developing countries in Latin America. Our analysis reveals that fossil fuel consumption continues to impede green development, while circular economy innovations substantially mitigate this negative impact. The findings show that countries with higher adoption rates of circular economy practices exhibit better performance in green economic indicators, improved resource efficiency, and reduced environmental degradation. The policy implication is that developing countries should prioritize circular economy innovations to balance the adverse effects of fossil fuels and promote sustainable economic growth.

This systematic study on the international research trends in carbon neutrality underscores its critical role in combating global warming and advancing sustainable development. By leveraging the “Web of Science Core Collection” databases and employing CiteSpace software for visual analysis, we examined 2223 research papers to track the influence and trends of key countries, institutions, and authors. Our results reveal a significant increase in publication volume, indicating a robust development potential for carbon neutrality research. The study also identifies environmental science, environmental research, and energy and fuel science as central interdisciplinary hubs, highlighting the importance of cross-disciplinary collaboration. Notably, China leads in publication output but has room for improvement in citation impact, suggesting a need for enhanced research quality and international visibility. The study's findings are instrumental for guiding future research directions, policy-making, and interdisciplinary cooperation, particularly in the fields of environmental science and energy, to accelerate progress towards carbon neutrality and global climate governance.

Equitable access to parks, in alignment with resident needs, is crucial for promoting social equity, justice, and sustainable urban development. However, existing methodologies for evaluating park accessibility often overlook the effect of park popularity and resident choices. To address this limitation, this study introduces an improved two-step floating catchment area (2SFCA) method. This enhanced approach incorporates real-time user data to measure park popularity and employs the Huff model to determine the probability of residents selecting a specific park. By integrating these factors, the study offers a more accurate and robust assessment of park accessibility for residents in Jiangnan Main City, a central district in Nanjing’s urban core. The study utilizes the Gini index and Lorenz curve to appraise the demographic equity of park distribution in the study area. In addition, bivariate spatial autocorrelation analysis is employed to analyze the spatial patterns of park supply and demand. The findings indicate a spatial trend characterized by high accessibility in central locations and reduced accessibility in peripheral areas. Additionally, the northern section exhibits greater accessibility compared to the southern part. The calculated Gini index indicates that the top 10% of the population enjoys access to nearly 36% of the parks, highlighting a significant imbalance. In addition, a spatial mismatch is evident, with significant dislocation between parks and residential areas observed in approximately 29% of residential communities. Simulations conducted in the study demonstrate a marginal improvement in park spatial equity when accounting for park popularity and resident choice. These results emphasize the importance of incorporating these factors in park planning and management strategies. The study advocates for park planning that prioritizes equity and a balance between supply and demand. Moreover, it emphasizes the need for tailored strategies that cater to the unique characteristics of different urban areas.

Background: The predictive value of growth differentiation factor-15 (GDF-15) in coronary microvascular dysfunction (CMD) following primary percutaneous coronary intervention (PPCI) in ST-segment elevation myocardial infarction (STEMI) patients is unclear. Methods: This study continuously recruited STEMI patients treated with PPCI at the Chest Pain Center of Qilu Hospital of Shandong University from April 2023 to December 2023. Blood samples were taken before PPCI and the level of circulating GDF-15 was measured by enzyme-linked immunosorbent assay (ELISA), and the patients were divided into CMD and Control group according to angiographic microvascular resistance (AMR) (cut-off value 2.50 mmHg*s/cm). The differences in GDF-15 expression levels between the two groups were compared, and the predictive value of GDF-15 for CMD was systematically evaluated. Results: A total of 134 patients, with an average age of 59.78 ± 12.69 years and 75.37 % being male, were included in this study. Multivariable logistic regression revealed a significant association between GDF-15 and CMD (adjusted OR = 2.505, 95 % CI: 1.661–3.779, P

Abstract This paper investigates the impact of economic policy uncertainty (EPU) on the dividend policy of listed companies, alongside its underlying mechanisms. Based on a panel data compilation from 4421 Chinese listed companies spanning 2007 to 2021, the research demonstrates that EPU significantly increases the cash dividends of listed companies. Our findings resolve endogeneity issues and are robust to different variable definitions. The influence is more significant among smaller, non-state-owned companies, as well as those with lower equity concentration and lower financial constraints. We further find that EPU heightens investors’ demand for dividends, increases agency costs, and reduces business growth opportunities to improve companies’ dividend distribution tendency. Moreover, we find that increasing dividend payout when EPU increases is aligned with shareholders’ wealth maximization objective.

Abstract Background Among the most common forms of cancer worldwide, breast cancer posed a serious threat to women. Recent research revealed a lack of oxygen, known as hypoxia, was crucial in forming breast cancer. This research aimed to create a robust signature with hypoxia-related genes to predict the prognosis of breast cancer patients. The function of hypoxia genes was further studied through cell line experiments. Materials and methods In the bioinformatic part, transcriptome and clinical information of breast cancer were obtained from The Cancer Genome Atlas(TCGA). Hypoxia-related genes were downloaded from the Genecards Platform. Differentially expressed hypoxia-related genes (DEHRGs) were identified. The TCGA filtered data was evenly split, ensuring a 1:1 distribution between the training and testing sets. Prognostic-related DEHRGs were identified through Cox regression. The signature was established through the training set. Then, it was validated using the test set and external validation set GSE131769 from Gene Expression Omnibus (GEO). The nomogram was created by incorporating the signature and clinicopathological characteristics. The predictive value of the nomogram was evaluated by C-index and receiver operating characteristiccurve. Immune microenvironment and mutation burden were also examined. In the experiment part, the function of the two most significant hypoxia-related genes were further explored by cell-line experiments. Results In the bioinformatic part, 141 up-regulated and 157 down-regulated DEHRGs were screened out. A prognostic signature was constructed containing nine hypoxia genes (ALOX15B, CA9, CD24, CHEK1, FOXM1, HOTAIR, KCNJ11, NEDD9, PSME2) in the training set. Low-risk patients exhibited a much more favorable prognosis than higher-risk ones (P

Abstract Background and Objective Tebipenem pivoxil (TP) is a carbapenem and is applied against pneumonia, otitis media, and sinusitis. This study compared the pharmacokinetics (PK) and safety of a test (T) preparation and reference (R) preparation of TP in healthy Chinese adults. Methods This study was a single-center, randomized, open, single-dose (fasting/postprandial) oral administration, two-agent, two-sequence, two-cycle, crossover bioequivalence trial. A total of 60 participants were enrolled (24 fasting and 36 postprandial). All participants were randomly assigned to the TR sequence and RT sequence. Subsequently, they switched T sequences or R sequences 7 days later. PK blood samples were collected according to the protocol, plasma TP concentration was determined by liquid chromatography-mass spectrometry, main PK parameters were calculated based on a non-compartment model, and adverse events were recorded during the test. Results In the feeding arm, the geometric mean ratio of maximum concentration (C max) was 89.84% (90% confidence interval 84.33–95.70), the geometric mean ratio of area under the plasma concentration–time curve from time 0 to last time of quantifiable concentration (AUC0–t ) was 86.80% (83.62–90.10), and the geometric mean ratio of area under the plasma concentration–time curve from time 0 to infinity time of quantifiable concentration (AUC0–∞) was 86.90% (83.73–90.20), which were within the acceptable range of bioequivalence (80–125%). In the fasting arm, the geometric mean ratio of C max was 96.07% (89.62–102.99), the geometric mean ratio of AUC0–t was 93.09% (90.47–95.78), and the geometric mean ratio of AUC0–∞ was 93.09% (90.48–95.77), which was within the acceptable range of bioequivalence (80–125%). Hence, the T preparation and R preparation of TP had bioequivalence in the fasting arm and feeding arm of the clinical trial. In addition, all adverse events were mild, and no severe adverse events were noted. Conclusion Preparations T and R of TP were bioequivalent in the fasting and postprandial groups in clinical trials, and TP was safe.

Abstract Tricarboxylic acid cycle (TCA cycle) plays an important role for aerobic growth of heterotrophic bacteria. Theoretically, eliminating TCA cycle would decrease carbon dissipation and facilitate chemicals biosynthesis. Here, we construct an E. coli strain without a functional TCA cycle that can serve as a versatile chassis for chemicals biosynthesis. We first use adaptive laboratory evolution to recover aerobic growth in minimal medium of TCA cycle-deficient E. coli. Inactivation of succinate dehydrogenase is a key event in the evolutionary trajectory. Supply of succinyl-CoA is identified as the growth limiting factor. By replacing endogenous succinyl-CoA dependent enzymes, we obtain an optimized TCA cycle-deficient E. coli strain. As a proof of concept, the strain is engineered for high-yield production of four separate products. This work enhances our understanding of the role of the TCA cycle in E. coli metabolism and demonstrates the advantages of using TCA cycle-deficient E. coli strain for biotechnological applications.

Abstract Ion trapping has been found to be responsible for the performance degradation in electrochromic oxide thin films, and a detrapping procedure was proved to be effective to rejuvenate the degraded films. Despite of the studies on ion trapping and detrapping, its dynamics remain largely unknown. Moreover, coloration mechanisms of electrochromic oxides are also far from clear, limiting the development of superior devices. Here, we visualize ion trapping and detrapping dynamics in a model electrochromic material, amorphous WO3. Specifically, formation of orthorhombic Li2WO4 during long-term cycling accounts for the origin of shallow traps. Deep traps are multiple-step-determined, composed of mixed W4+-Li2WO4, amorphous Li2WO4 and W4+-Li2O. The non-decomposable W4+-Li2WO4 couple is the origin of the irreversible traps. Furthermore, we demonstrate that, besides the typical small polaron hopping between W5+ ↔ W6+ sites, bipolaron hopping between W4+ ↔ W6+ sites gives rise to optical absorption in the short-wavelength region. Overall, we provide a general picture of electrochromism based on polaron hopping. Ion trapping and detrapping were demonstrated to also prevail in other cathodic electrochromic oxides. This work not only provides the ion trapping and detrapping dynamics of WO3, but also open avenues to study other cathodic electrochromic oxides and develop superior electrochromic devices with great durability.

Abstract Epitaxial growth is a fundamental step required to create devices for the semiconductor industry, enabling different materials to be combined in layers with precise control of strain and defect structure. Patterning the growth substrate with a mask before performing epitaxial growth offers additional degrees of freedom to engineer the structure and hence function of the semiconductor device. Here, we demonstrate that conditions exist where such epitaxial lateral overgrowth can produce complex, three-dimensional structures that incorporate cavities of deterministic size. We grow germanium on silicon substrates patterned with a dielectric mask and show that fully-enclosed cavities can be created through an unexpected self-assembly process that is controlled by surface diffusion and surface energy minimization. The result is confined cavities enclosed by single crystalline Ge, with size and position tunable through the initial mask pattern. We present a model to account for the observed cavity symmetry, pinch-off and subsequent evolution, reflecting the dominant role of surface energy. Since dielectric mask patterning and epitaxial growth are compatible with conventional device processing steps, we suggest that this mechanism provides a strategy for developing electronic and photonic functionalities.

Abstract Background Increasing evidence is appearing that ozone has adverse effects on health. However, the association between long-term ozone exposure and lung function is still inconclusive. Objectives To investigate the associations between long-term exposure to ozone and lung function in Chinese young adults. Methods We conducted a prospective cohort study among 1594 college students with a mean age of 19.2 years at baseline in Shandong, China from September 2020 to September 2021. Lung function indicators were measured in September 2020 and September 2021, including forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), forced expiratory flow at the 25th, 50th, and 75th percentile of the FVC (FEF25, FEF50, and FEF75) and mean flow rate between 25% and 75% of the FVC (FEF25-75) were measured. Daily 10 km×10 km ozone concentrations come from a well-validated data-fusion approach. The time-weighted average concentrations in 12 months before the lung function test were defined as the long-term ozone exposure. The associations between long-term ozone exposure and lung function indicators in Chinese young adults were investigated using a linear mixed effects model, followed by stratified analyses regarding sex, BMI and history of respiratory diseases. Results Each interquartile range (IQR) (8.9 µg/m3) increase in long-term ozone exposure were associated with a -204.3 (95% confidence interval (CI): -361.6, -47.0) ml/s, -146.3 (95% CI: -264.1, -28.4) ml/s, and − 132.8 (95% CI: -239.2, -26.4) ml/s change in FEF25, FEF50, and FEF25-75, respectively. Stronger adverse associations were found in female participants or those with BMI ≥ 24 kg/m2 and history of respiratory diseases. Conclusion Long-term exposure to ambient ozone is associated with impaired small airway indicators in Chinese young adults. Females, participants with BMI ≥ 24 kg/m2 and a history of respiratory disease have stronger associations.

Global navigation satellite system-reflection (GNSS-R) sea surface altimetry based on satellite constellation platforms has become a new research direction and inevitable trend, which can meet the altimetric precision at the global scale required for underwater navigation. At present, there are still research gaps for GNSS-R altimetry under this mode, and its altimetric capability cannot be specifically assessed. Therefore, GNSS-R satellite constellations that meet the global altimetry needs to be designed. Meanwhile, the matching precision prediction model needs to be established to quantitatively predict the GNSS-R constellation altimetric capability. Firstly, the GNSS-R constellations altimetric precision under different configuration parameters is calculated, and the mechanism of the influence of orbital altitude, orbital inclination, number of satellites and simulation period on the precision is analyzed, and a new multilayer feedforward neural network weighted joint prediction model is established. Secondly, the fit of the prediction model is verified and the performance capability of the model is tested by calculating the R2 value of the model as 0.9972 and the root mean square error (RMSE) as 0.0022, which indicates that the prediction capability of the model is excellent. Finally, using the novel multilayer feedforward neural network weighted joint prediction model, and considering the research results and realistic costs, it is proposed that when the constellation is set to an orbital altitude of 500 km, orbital inclination of 75° and the number of satellites is 6, the altimetry precision can reach 0.0732 m within one year simulation period, which can meet the requirements of underwater navigation precision, and thus can provide a reference basis for subsequent research on spaceborne GNSS-R sea surface altimetry.

Colorectal cancer is one of the most common cancers and the main causes of mortality around the world and Oxaliplatin is a first-line chemotherapy agent for treatment of CRC. However, the dense collagen network in tumors stroma significantly reduces the penetration and efficacy of Oxaliplatin. Therefore, research strategies to further sensitize CRC cells to Oxaliplatin are urgently needed. In this study, we showed that Semen Raphani exhibited a strong synergy with Oxaliplatin to inhibit CRC tumor growth by remodeling tumor stroma and depredate collagen. Further research found that ATG9A mediated autophagy is critical for the collagen degradation induced by Semen Raphani, this process may be mediated by the degradation of collagen transcription factor STAT3 by autophagy. Taken together, our study is the first to evaluate the synergy of Semen Raphani and Oxaliplatin in CRC and to assess new opportunities for remodeling stroma as a promising approach for future chemotherapy sensitization.

A pure nickel film and a carbon/nickel (C/Ni) composite film were produced using radio frequency magnetron sputtering. The structure of the films was regulated by adjusting the sputtering power and the time allocation of sputtering nickel and graphite targets. Furthermore, a scanning electron microscope, an x-ray diffractometer, and a Raman spectrometer were employed for sample characterization. The results demonstrated that the thickness of the pure nickel film and C/Ni composite film with a total deposition time of 60 s was between 44.96 and 65.31 nm. The nickel film exhibited preferential growth along the crystal plane (111), and the structure of carbon materials was in the second stage of the three-stage model known as “amorphization trajectory of graphite.” The prepared films’ electromagnetic interference shielding effectiveness (EMI SE) in the X-band was investigated using a vector network analyzer. It was observed that the C/Ni composite film with a thickness of 44.96 nm demonstrated a superior EMI SE with a maximum value reaching 21 dB. The EMI SE of the C/Ni composite film can reach the same performance and even exceed that of the pure nickel film obtained at the power of 200 W for 60 s in certain frequency segments. In conclusion, the pure nickel film can be replaced by C/Ni composite film prospectively due to their excellent EMI SE along with advantages such as reduced thickness, lighter weight, and lower cost.

Abstract Since the 1950s, observations and climate models show an amplification of sea surface temperature (SST) seasonal cycle in response to global warming over most of the global oceans except for the Southern Ocean (SO), however the cause remains poorly understood. In this study, we analyzed observations, ocean reanalysis, and a set of historical and abruptly quadrupled CO2 simulations from the Coupled Model Intercomparison Project Phase 6 archive and found that the weakened SST seasonal cycle over the SO could be mainly attributed to the intensification of summertime westerly winds. Under the historical warming, the intensification of summertime westerly winds over the SO effectively deepens ocean mixed layer and damps surface warming, but this effect is considerably weaker in winter, thus weakening the SST seasonal cycle. This wind‐driven mechanism is further supported by our targeted coupled model experiments with the wind intensification effects being removed.

While strides in cancer treatment continue to advance, the enduring challenges posed by cancer metastasis and recurrence persist as formidable contributors to the elevated mortality rates observed in cancer patients. Among the multifaceted factors implicated in tumor recurrence and metastasis, cancer stem cells (CSCs) emerge as noteworthy entities due to their inherent resistance to conventional therapies and heightened invasive capacities. Characterized by their notable abilities for self-renewal, differentiation, and initiation of tumorigenesis, the eradication of CSCs emerges as a paramount objective. Recent investigations increasingly emphasize the pivotal role of post-translational protein modifications (PTMs) in governing the self-renewal and replication capabilities of CSCs. This review accentuates the critical significance of several prevalent PTMs and the intricate interplay of PTM crosstalk in regulating CSC behavior. Furthermore, it posits that the manipulation of PTMs may offer a novel avenue for targeting and eliminating CSC populations, presenting a compelling perspective on cancer therapeutics with substantial potential for future applications.

Lichen sclerosus et atrophicus (LSA) is a chronic inflammatory skin lesion with an undefined cause. It is more commonly found in the genital area, particularly in adolescents, premenopausal women and postmenopausal women. LSA is difficult to treat and often recurs. The primary treatment for LSA involves the administration of potent topical corticosteroids. Dupilumab is increasingly being used for the treatment of itching in non-atopic dermatitis patients but there are few reports on its use for the treatment of LSA. Here, we present a case of LSA in a 61-year-old woman with extensive vulvar itching. Over four months of dupilumab therapy, significant therapeutic effects were observed, including vulvar skin thinning and pruritus relief without adverse reactions.

Abstract Cancer metastasis is the leading cause of mortality in patients with hepatocellular carcinoma (HCC). To meet the rapid malignant growth and transformation, tumor cells dramatically increase the consumption of nutrients, such as amino acids. Peptide transporter 1 (PEPT1), a key transporter for small peptides, has been found to be an effective and energy‐saving intracellular source of amino acids that are required for the growth of tumor cells. Here, the role of PEPT1 in HCC metastasis and its underlying mechanisms is explored. PEPT1 is upregulated in HCC cells and tissues, and high PEPT1 expression is associated with poor prognosis in patients with HCC. PEPT1 overexpression dramatically promoted HCC cell migration, invasion, and lung metastasis, whereas its knockdown abolished these effects both in vitro and in vivo. Mechanistic analysis revealed that high PEPT1 expression increased cellular dipeptides in HCC cells that are responsible for activating the MAP4K4/G3BP2 signaling pathway, ultimately facilitating the phosphorylation of G3BP2 at Thr227 and enhancing HCC metastasis. Taken together, these findings suggest that PEPT1 acts as an oncogene in promoting HCC metastasis through dipeptide‐induced MAP4K4/G3BP2 signaling and that the PEPT1/MAP4K4/G3BP2 axis can serve as a promising therapeutic target for metastatic HCC.

ObjectivePropofol and etomidate are the most commonly used sedative agents in procedural sedation, each with its own advantages and disadvantages. However, there remains considerable controversy regarding the optimal ratio for the mixture of these two drugs, warranting further investigation. Therefore, this study aims to investigate the optimal ratio for combining propofol and etomidate during gastroscopy.MethodsThis study is a prospective, double-blinded, randomized controlled clinical trial. One hundred and sixty-two patients from July 2019 to December 2022 were evenly classified into three groups using a random number table as follows: (1) P group (propofol); (2) EP1 group (5 mL etomidate +10 mL propofol); (3) EP2 group (10 mL etomidate +10 mL), 54 patients per group. The medications, including a pre-sedation dose of 50 μg/kg dezocine followed by sedatives, ceasing when the patient’s eyelash reflex vanished, indicating adequate sedation. Mean arterial pressure (MAP), heart rate (HR), and peripheral oxygen saturation (SpO2) measurements taken before anesthesia (T1), immediately after the administration of sedatives (T2), immediately gastroscopic insertion (T3) and immediately recovery (T4) were determined. Additional, perioperative related outcomes and adverse events were also recorded.ResultsThe EP2 group exhibited a higher MAP at T2 compared to the P and EP1 groups (p

BackgroundCongenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD) syndrome (OMIM #616266) is an autosomal dominant hereditary disease that can lead to the congenital contracture of the limbs and face, hypotonia, and developmental delay. In addition, it may result in growth retardation and present various clinical symptoms, such as brain atrophy, a small pituitary gland, musculoskeletal abnormalities, abnormal breathing, abdominal hernia, and abnormal facial features. Herein, we describe a novel de novo missense genetic variant in the sodium leak channel, non-selective (NALCN) gene that is associated with CLIFAHDD syndrome.Case descriptionThis study describes a patient with varus deformities in both feet, deviation of the ulnar side of the fingers, and severe hypotonia. This patient was subsequently confirmed to have CLIFAHDD syndrome through genetic testing, which also revealed a novel missense de novo genetic variant in the NALCN gene (c.3553G > A, p.Ala1185Thr).ConclusionsOur findings further enrich the known variant spectrum of the NALCN gene and may expand the range of clinical options for treating NALCN-related disorders.

PurposeThe aim of this study was to evaluate the bioequivalence of two formulations of rupatadine (10-mg tablets) under fasting and fed conditions in healthy Chinese subjects.MethodsA total of 72 subjects were randomly assigned to the fasting cohort (n = 36) and fed cohort (n = 36). Each cohort includes four single-dose observation periods and 7-day washout intervals. Blood samples were collected at several timepoints for up to 72 h post-dose. The plasma concentration of rupatadine and the major active metabolites (desloratadine and 3-hydroxydesloratadine) were analyzed by a validated HPLC–MS/MS method. The non-compartmental analysis method was employed to determine the pharmacokinetic parameters. Based on the within-subject standard deviation of the reference formulation, a reference-scaled average bioequivalence or average bioequivalence method was used to evaluate the bioequivalence of the two formulations.ResultsFor the fasting status, the reference-scaled average bioequivalence method was used to evaluate the bioequivalence of the maximum observed rupatadine concentration (Cmax; subject standard deviation > 0.294), while the average bioequivalence method was used to evaluate the bioequivalence of the area under the rupatadine concentration–time curve from time 0 to the last detectable concentration (AUC0-t) and from time 0 to infinity (AUC0-∞). The geometric mean ratio (GMR) of the test/reference for Cmax was 95.91%, and the upper bound of the 95% confidence interval was 95.91%. For AUC0-t and AUC0-∞ comparisons, the GMR and 90% confidence interval (CI) were 98.76% (93.88%–103.90%) and 98.71% (93.93%–103.75%), respectively. For the fed status, the subject standard deviation values of Cmax, AUC0-t, and AUC0-∞ were all

Industrial robots are prone to failure due to harsh working environments, which affects movement accuracy. The fault diagnosis of industrial robots has become an indispensable part of robot collaborative maintenance in intelligent manufacturing. Most existing diagnostic methods only use a single data source, and the diagnostic accuracy will be affected due to signal acquisition errors and noise interference. This paper proposes a multi-source data fusion and channel attention convolutional neural network (MD-CA-CNN) for fault diagnosis of multi-joint industrial robots. The network takes the time domain data and time-frequency domain data of the vibration signal, torque signal, and current signal of the six joints of the robot as input. Then, we realize the diagnosis of the faults by using a Softmax Classifier layer after the two parts of feature extraction and feature fusion. In addition, a channel attention mechanism is developed. It acts on the two parts of feature extraction and feature fusion, respectively. It assigns weights to different source data and weights to time-domain and time-frequency domain features. Finally, we established a test bench to compare the proposed method with the deep learning algorithm that only uses multi-data source fusion, the deep learning algorithm that only uses a single data source, and the commonly used machine learning algorithm. The results show that the MD-CA-CNN model proposed in this paper has the highest accuracy and stability, reaching 95.8% $\pm ~0.39$ %, which verifies the method’s effectiveness.

Traditional collaborative filtering-based grade prediction methods overly rely on students’ historical grades and overlook the content correlation between courses, resulting in lower accuracy in predicting student grades. This paper proposes a grade prediction method that combines the educational domain knowledge graph with collaborative filtering, gathering course semantic information and constructing a course knowledge graph as auxiliary information for grade prediction. Through experimentation, it has been demonstrated that the integration of the educational knowledge graph and collaborative filtering in the grade prediction method uncovers more semantic relationships between courses, thereby improving the accuracy of predicting grades for related courses. The Root Mean Square Error (RMSE) and Mean Absolute Error (MAE) metrics show a decrease when compared to collaborative filtering and K-means algorithms.The method in this paper allows for more personalized learning and recommendation in the knowledge-rich field of education with semantic richness.

Abstract Background Periodontitis is a highly prevalent oral disease characterized by bacterium-induced periodontal inflammation and alveolar bone destruction. Osteoblast function is impaired in periodontitis with a global proteome change. METTL3 is the pivotal methyltransferase of N 6-methyladenosine (m6A) that is recently proved to exert a crucial role in osteoblast differentiation. This study aims to investigate the role of METTL3 in osteoblast ribosome biogenesis in periodontitis progression. Results METTL3 was knocked down in osteoblasts, and the downregulated genes were enriched in ribosome and translation. METTL3 knockdown inhibited ribosome biogenesis and oxidative phosphorylation in LPS-stimulated osteoblasts, whereas METTL3 overexpression facilitated ribosomal and mitochondrial function. Mechanistically, METTL3 mediated osteoblast biological behaviors by activating Wnt/β-catenin/c-Myc signaling. METTL3 depletion enhanced the mRNA expression and stability of Dkk3 and Sostdc1 via YTHDF2. In periodontitis mice, METTL3 inhibitor SAH promoted alveolar bone loss and local inflammatory status, which were partially rescued by Wnt/β-catenin pathway activator CHIR-99021 HCl. Conclusions METTL3 promoted ribosome biogenesis and oxidative phosphorylation by activating Wnt/β-catenin/c-Myc signaling in LPS-treated osteoblasts and alleviated the inflammatory alveolar bone destruction in periodontitis mice.

Pulmonary tuberculosis (PTB) is a major global health threat. Diagnosing PTB infectiousness is vital for clinical decision-making, but existing etiological examination methods do not meet the requirements for speed, accuracy, and cost effectiveness. Developing deep learning models for infectiousness identification based on computed tomography (CT) volume measurements holds promise for meeting these requirements. However, with limited samples and coarse annotations, the large amount of information in the CT volume poses a challenge for models to distinguish information related to patient-level labels, which often leads to severe model overfitting. In this study, A dual-branch framework is developed for identifying PTB infectiousness using CT volume. To address the issue of imbalance between the CT volume information and the patient-level labels, we propose a method for selecting representative slices to reduce redundant information and adopt a multiple-instance learning framework to improve label supervision. Furthermore, we incorporate multi-view projection information to compensate for the deficiency of global information caused by using single-dimensional slices as the input. Experimental results demonstrate that our strategy effectively mitigates overfitting and achieves desirable performance on an external test set, with an area under the receiver operating characteristic curve of 80.48%. This performance is superior to that obtained for models using the 3D CT volume or 2D projection images alone as the input.

To promote the development of the new energy vehicle industry, China has introduced many subsidy policies. Existing policies rarely consider the difference in market share of new energy vehicle enterprises, but the difference in market share will directly affect consumer demand, and then affect the development of the new energy vehicle industry. Therefore, we consider the difference of the market share and endurance of the new energy vehicle firms at the same time, establishing a Stackelberg model and considering three most common subsidy forms, which are quantity-based subsidies, price-based subsidies, and endurance-based subsidies to derive the optimal differentiated subsidies of the government. The analysis of this paper shows that for the new energy vehicle firms with different market share and endurance, differentiated subsidies can achieve higher social welfare. In addition, for any subsidy form of the sale-based subsidies, price-based subsidies, and endurance-based subsidies, the final cost for consumers will be reduced, and the total sales quantity of the new energy vehicles in the market will increase, but the profits of firms and the sales quantity of one firm could increase or decrease. Lastly, under the assumption of this paper, the optimal price of both firms and social welfare are the same under the three aforementioned subsidy forms.

Abstract Background Age-related hearing loss (ARHL) signifies the bilateral, symmetrical, sensorineural hearing loss that commonly occurs in elderly individuals. Several studies have suggested a higher risk of dementia among patients diagnosed with ARHL. Although the precise causal association between ARHL and cognitive decline remains unclear, ARHL has been recognized as one of the most significant factors that can be modified to reduce the risk of developing dementia potentially. Mild cognitive impairment (MCI) typically serves as the initial stage in the transition from normal cognitive function to dementia. Consequently, the objective of our randomized controlled trial (RCT) is to further investigate whether the use of hearing aids can enhance cognitive function in older adults diagnosed with ARHL and MCI. Methods and design This study is a parallel-arm, randomized controlled trial conducted at multiple centers in Shanghai, China. We aim to enlist a total of 688 older adults (age ≥ 60) diagnosed with moderate-to-severe ARHL and MCI from our four research centers. Participants will be assigned randomly to either the hearing aid fitting group or the health education group using block randomization with varying block sizes. Audiometry, cognitive function assessments, and other relevant data will be collected at baseline, as well as at 6, 12, and 24 months post-intervention by audiologists and trained researchers. The primary outcome of our study is the rate of progression to dementia among the two groups of participants. Additionally, various evaluations will be conducted to measure hearing improvement and changes in cognitive function. Apart from the final study results, we also plan to conduct an interim analysis using data from 12-month follow-up. Discussion In recent years, there has been a notable lack of randomized controlled trials (RCTs) investigating the possible causal relationship between hearing fitting and the improvement of cognitive function. Our findings may demonstrate that hearing rehabilitation can be a valuable tool in managing ARHL and preventing cognitive decline, which will contribute to the development of a comprehensive framework for the prevention and control of cognitive decline. Trial registration Chinese Clinical Trial Registry chictr.org.cn ChiCTR2000036139. Registered on 21 August 2020.

Abstract Background 1H magnetic resonance spectroscopy (1H-MRS) can be used to study neurological disorders because it can be utilized to examine the concentrations of related metabolites. However, the diagnostic utility of different field strengths for temporal lobe epilepsy (TLE) remains unclear. The purpose of this study is to make quantitative comparisons of metabolites of TLE at 1.5T and 3.0T and evaluate their efficacy. Methods Our retrospective collections included the single-voxel 1H-MRS of 23 TLE patients and 17 healthy control volunteers (HCs) with a 1.5T scanner, as well as 29 TLE patients and 17 HCs with a 3.0T scanner. Particularly, HCs were involved both the scans with 1.5T and 3.0T scanners, respectively. The metabolites, including the N-acetylaspartate (NAA), creatine (Cr), and choline (Cho), were measured in the left or right temporal pole of brain. To analyze the ratio of brain metabolites, including NAA/Cr, NAA/Cho, NAA/(Cho + Cr) and Cho/Cr, four controlled experiments were designed to evaluate the diagnostic utility of TLE on 1.5T and 3.0T MRS, included: (1) 1.5T TLE group vs. 1.5T HCs by the Mann-Whitney U Test, (2) 3.0T TLE group vs. 3.0T HCs by the Mann-Whitney U Test, (3) the power analysis for the 1.5T and 3.0T scanner, and (4) 3.0T HCs vs. 1.5T HCs by Paired T-Test. Results Three metabolite ratios (NAA/Cr, NAA/Cho, and NAA/(Cho + Cr) showed the same statistical difference (p

Glaesserella parasuis cytolethal distending toxin (GpCDT) can induce cell cycle arrest and apoptosis. Our laboratory’s previous work demonstrated that GTPase 4b (Rab4b) is a key host protein implicated in GpCDT-induced cytotoxicity. This study investigated the probable involvement of Rab4b in the process. Our study used CRISPR/Cas9 technology to create a Rab4b-knockout cell line. The results showed greater resistance to GpCDT-induced cell cytotoxicity. In contrast, forced Rab4b overexpression increased GpCDT-induced cytotoxicity. Further immunoprecipitation study reveals that GpCDT may bind with Rab4b. In PK-15 cells, GpCDT is transported to the early endosomes and late endosomes, while after knocking out Rab4b, GpCDT cannot be transported to the early endosome via vesicles. Rab4b appears essential for GpCDT-induced cytotoxicity in PK-15 cells.

Under the background of the worsening global food and water crisis, efficient agricultural practices have become increasingly important. This study investigated the impact of different irrigation and cultivation modes on rice growth parameters, gas exchange, rice yield components, and water footprints in Jiangsu, China. Four treatments were employed in a randomized complete block design with three replications: (i) transplanted rice with frequent shallow irrigation (T-FSI), (ii) transplanted rice with rain-catching and controlled irrigation (T-RCCI), (iii) direct-seeded rice with frequent shallow irrigation (D-FSI), (iv) and direct-seeded rice with rain-catching and controlled irrigation (D-RCCI). The results revealed that the D-RCCI treatment significantly improved growth and physiological parameters. The D-FSI treatment drastically increased rice yield whereas T-RCCI increased the stem bending resistance and reduced lodging risk. The water footprint analysis showed significant water savings by optimized management practices. Compared to T-FSI, the T-RCCI, D-FSI, and D-RCCI treatments reduced the blue-green water footprint by 33%, 25%, and 25%, respectively. Additionally, water production efficiency increased by 13%, 106%, and 154% for T-RCCI, D-FSI, and D-RCCI respectively. The water footprint per unit yield of T-RCCI, D-FSI, and D-RCCI treatments was significantly reduced by 12%, 5,3%, and 63% compared to T-FSI. Overall, D-RCCI is the optimal strategy for rice cultivation in Jiangsu province and similar climatic areas due to its positive impact on yield, water savings, and environmental benefits.

The stator of a flat wire motor is the core component of new energy vehicles. However, detecting quality defects in the coating process in real-time is a challenge. Moreover, the number of defects is large, and the pixels of a single defect are very few, which make it difficult to distinguish the defect features and make accurate detection more difficult. To solve this problem, this article proposes the YOLOv8s-DFJA network. The network is based on YOLOv8s, which uses DSFI-HEAD to replace the original detection head, realizing task alignment. It enhances joint features between the classification task and localization task and improves the ability of network detection. The LEFG module replaces the C2f module in the backbone of the YOLOv8s network that reduces the redundant parameters brought by the traditional BottleNeck structure. It also enhances the feature extraction and gradient flow ability to achieve the lightweight of the network. For this research, we produced our own dataset of stator coating quality regarding flat wire motors. Data augmentation technology (Gaussian noise, adjusting brightness, etc.) enriches the dataset, to a certain extent, which improves the robustness and generalization ability of YOLOv8s-DFJA. The experimental results show that in the performance of YOLOv8s-DFJA compared with YOLOv8s, the mAP@.5 index increased by 6.4%, the precision index increased by 1.1%, the recall index increased by 8.1%, the FPS index increased by 9.8FPS/s, and the parameters decreased by 3 Mb. Therefore, YOLOv8s-DFJA can be better realize the fast and accurate detection of the stator coating quality of flat wire motors.

ObjectiveThis study aims to evaluate the origin of the neonatal gut microbiota on the 14th day and probiotic intervention in the third trimester.MethodsSamples were obtained from a total of 30 pregnant individuals and their offspring, divided into a control group with no intervention and a probiotic group with live combined Bifidobacterium and Lactobacillus tablets, analyzing by 16S rRNA amplicon sequencing of the V4 region to evaluate the composition of them. Non-metric multidimensional scaling and SourceTracker were used to evaluate the origin of neonatal gut microbiota.ResultsWe found that the microbiota in the neonatal gut at different times correlated with that in the maternal microbiota. The placenta had more influence on meconium microbiota. Maternal gut had more influence on neonatal gut microbiota on the 3rd day and 14th day. We also found that the maternal gut, vaginal, and placenta microbiota at full term in the probiotic group did not have a significantly different abundance of Bifidobacterium, Lactobacillus, or Streptococcus. However, some other bacteria changed in the maternal gut and their neonatal gut in the probiotic group.

Abstract Shrub expansion is increasing in grasslands worldwide and has profound effects on biodiversity and ecosystem functions. Shrub expansion has primarily been explained by extrinsic factors such as climate change and human activities, yet the roles of intrinsic shrub demographic population dynamic and shrub–grass interaction remain poorly understood. With a paired mown and exclosure comparison experiment and baseline levels of shrub abundance in a semiarid grassland, we confirmed that long‐term livestock exclusion promotes expansion of two native shrubs, Artemisia sacrorum and Caragana brachypoda. Shrub abundance increased during the livestock exclusion period. Shrub biomass in fenced plots was about 5‐ to 10‐fold greater than in mown plots. Both increase in population density and individual size (especially height) contributed to shrub increase. The mechanism behind this was the divergent effects of litter accumulation on shrubs and grasses. Litter accumulation suppressed grass production, while facilitating shrub recruitment and growth. Our findings highlight the potential role of litter accumulation‐mediated shifts in shrub–grass interactions, which should be incorporated into grazing top‐down control to better predict the restoration outcomes of grassland management changes. The identified internal biotic mechanism raises the possibility that removal of accumulated litter by grazing or mowing may be an alternative way to maintain or restore a grass‐dominated state in shrub expansion areas.

Psoriasis and atopic dermatitis (AD) are prevalent inflammatory skin disorders, each stemming from diverse factors, and characterized by recurring episodes. In certain complex cases, the clinical and pathological features exhibit overlapping and atypical characteristics, making accurate clinical diagnosis and targeted treatment a challenge. Psoriasiform dermatitis is the term used to describe such cases. Moreover, when patients have a history of malignancy, the situation becomes even more intricate, resulting in limited treatment options. Biologic therapies have transformed the management of immune-mediated inflammatory diseases, including psoriasis and AD. Meanwhile, the safety of biologics in special populations, especially among patients with a history of malignancy, should be underlined. The selective Janus kinase 1 (JAK1) inhibitor abrocitinib has been approved for the treatment of AD and has showed satisfying efficacy and safety in the treatment of psoriasis in clinical trials. Although unreported, JAK1 inhibitors are thought to have the potential to increase the risk of potential tumors. Apremilast, an oral phosphodiesterase (PDE)-4 inhibitor, is approved for moderate to severe plaque psoriasis. It has been investigated for its efficacy in AD, and is not contraindicated in malignancy. This report presents three cases of psoriasiform dermatitis in patients with a history of malignancy, showcasing significant improvement following treatment with systemic glucocorticoid, abrocitinib, or apremilast.

ABSTRACT The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a global pandemic, which severely endangers public health. Our and others’ works have shown that the angiotensin-converting enzyme 2 (ACE2)-containing exosomes (ACE2-exos) have superior antiviral efficacies, especially in response to emerging variants. However, the mechanisms of how the virus counteracts the host and regulates ACE2-exos remain unclear. Here, we identified that SARS-CoV-2 nonstructural protein 6 (NSP6) inhibits the production of ACE2-exos by affecting the protein level of ACE2 as well as tetraspanin-CD63 which is a key factor for exosome biogenesis. We further found that the protein stability of CD63 and ACE2 is maintained by the deubiquitination of proteasome 26S subunit, non-ATPase 12 (PSMD12). NSP6 interacts with PSMD12 and counteracts its function, consequently promoting the degradation of CD63 and ACE2. As a result, NSP6 diminishes the antiviral efficacy of ACE2-exos and facilitates the virus to infect healthy bystander cells. Overall, our study provides a valuable target for the discovery of promising drugs for the treatment of coronavirus disease 2019.IMPORTANCEThe outbreak of coronavirus disease 2019 (COVID-19) severely endangers global public health. The efficacy of vaccines and antibodies declined with the rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants. Angiotensin-converting enzyme 2-containing exosomes (ACE2-exos) therapy exhibits a broad neutralizing activity, which could be used against various viral mutations. Our study here revealed that SARS-CoV-2 nonstructural protein 6 inhibited the production of ACE2-exos, thereby promoting viral infection to the adjacent bystander cells. The identification of a new target for blocking SARS-CoV-2 depends on fully understanding the virus-host interaction networks. Our study sheds light on the mechanism by which the virus resists the host exosome defenses, which would facilitate the study and design of ACE2-exos-based therapeutics for COVID-19.

Summary: Background: Currently, the diagnostic testing for the primary origin of liver metastases (LMs) can be laborious, complicating clinical decision-making. Directly classifying the primary origin of LMs at computed tomography (CT) images has proven to be challenging, despite its potential to streamline the entire diagnostic workflow. Methods: We developed ALMSS, an artificial intelligence (AI)-based LMs screening system, to provide automated liver contrast-enhanced CT analysis for distinguishing LMs from hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), as well as subtyping primary origin of LMs as six organ systems. We processed a CECT dataset between January 1, 2013 and June 30, 2022 (n = 3105: 840 HCC, 354 ICC, and 1911 LMs) for training and internally testing ALMSS, and two additional cohorts (n = 622) for external validation of its diagnostic performance. The performance of radiologists with and without the assistance of ALMSS in diagnosing and subtyping LMs was assessed. Findings: ALMSS achieved average area under the curve (AUC) of 0.917 (95% confidence interval [CI]: 0.899–0.931) and 0.923 (95% [CI]: 0.905–0.937) for differentiating LMs, HCC and ICC on both the internal testing set and external testing set, outperformed that of two radiologists. Moreover, ALMSS yielded average AUC of 0.815 (95% [CI]: 0.794–0.836) and 0.818 (95% [CI]: 0.790–0.842) for predicting six primary origins on both two testing sets. Interestingly, ALMSS assigned origin diagnoses for LMs with pathological phenotypes beyond the training categories with average AUC of 0.761 (95% [CI]: 0.657–0.842), which verify the model's diagnostic expandability. Interpretation: Our study established an AI-based diagnostic system that effectively identifies and characterizes LMs directly from multiphasic CT images. Funding: National Natural Science Foundation of China, Guangdong Provincial Key Laboratory of Medical Image Processing.

In this article, a novel ensemble framework of improved siamese network (SN) is proposed to address the small sample issue that deep learning approaches encounter, as well as to enhance the precision of pipeline leakage detection (PLD) under small sample conditions. Firstly, training samples are input in pairs to the feature extraction network, and a combination of one-dimensional convolution neural network (1DCNN) and long short-term memory (LSTM) network is introduced to extract features of the time-series data, thus enhancing the effectiveness and robustness of feature extraction. Then, an improved relational metric network is designed to measure the similarity of features, to further strengthen the discriminative nature of the whole framework. In addition, the framework has been augmented with a classification network that can be used directly for PLD. The proposed SN-1DCNN-LSTM framework not only increases the number of training samples from the side, but also fully exploits the similarity information and data features between samples, overcoming the problem of instability and overfitting of deep learning models under small sample conditions. Finally, the experimental results verify the validity and superiority of the method under small sample conditions.

Microbiota in pregnant time is vital to healthy of pregnant women and their offspring. However, few study evaluate the composition of the microbiota of health pregnancy, placenta and their newborns at different stages and the origin of the placental microbiota. Samples were obtained from a total of 31 pregnant individuals and their offspring, analyzing by 16S rRNA amplicon sequencing of the V4 region to evaluate the composition and variation of them. We found that the microbiota of pregnant individuals changes in the third trimester. The placental microbiota has its own specific dominant microbiota. The placental microbiota is correlated with the pregnancy microbiota in the gut and vagina at 32–34 weeks but not at full term. The gut microbiota in newborns changes over the first 14 days.

Abstract Background The epithelial-mesenchymal transition (EMT) plays an indispensable role in the development and progression of Endometrial cancer (EC). Nevertheless, little evidence is reported to uncover the functionality and application of EMT-related molecules in the prognosis of EC. This study aims to develop novel molecular markers for prognosis prediction in patients with EC. Methods RNA sequencing profiles of EC patients obtained from The Cancer Genome Atlas (TCGA) database were used to screen differential expression genes (DEGs) between tumors and normal tissues. The Cox regression model with the LASSO method was utilized to identify survival-related DEGs and to establish a prognostic signature whose performance was evaluated by Kaplan–Meier curve, receiver operating characteristic (ROC) and calibration curve. Eventually, functional enrichment analysis and cellular experiments were performed to reveal the roles of prognosis-related genes in EC progression. Results A total of 540 EMT-related DEGs in EC were screened, and subsequently a four-gene risk signature comprising SIRT2, SIX1, CDKN2A and PGR was established to predict overall survival of EC. This risk signature could serve as a meaningfully independent indicator for EC prognosis via multivariate Cox regression (HR = 2.002, 95%CI = 1.433–2.798; P

A long-standing paucity of effective therapies results in the poor outcomes of triple-negative breast cancer brain metastases. Immunotherapy has made progress in the treatment of tumors, but limited by the non-immunogenicity of tumors and strong immunosuppressive environment, patients with TNBC brain metastases have not yet benefited from immunotherapy. Dual immunoregulatory strategies with enhanced immune activation and reversal of the immunosuppressive microenvironment provide new therapeutic options for patients. Here, we propose a cocktail-like therapeutic strategy of microenvironment regulation-chemotherapy-immune synergistic sensitization and construct reduction-sensitive immune microenvironment regulation nanomaterials (SIL@T). SIL@T modified with targeting peptide penetrates the BBB and is subsequently internalized into metastatic breast cancer cells, releasing silybin and oxaliplatin responsively in the cells. SIL@T preferentially accumulates at the metastatic site and can significantly prolong the survival period of model animals. Mechanistic studies have shown that SIL@T can effectively induce immunogenic cell death of metastatic cells, activate immune responses and increase infiltration of CD8+ T cells. Meanwhile, the activation of STAT3 in the metastatic foci is attenuated and the immunosuppressive microenvironment is reversed. This study demonstrates that SIL@T with dual immunomodulatory functions provides a promising immune synergistic therapy strategy for breast cancer brain metastases.

Abstract Background Gastric cancer is a highly heterogeneous disease, which makes it challenging to develop effective targeted therapies. Although the potassium voltage‐gated channel subfamily D (KCND) channels, particularly KCND2 (also known as Kv4.2), have found evidence of involvement in the occurrence and development of various cancers, there are still some limitations in our understanding of KCND2's roles in gastric cancer. Methods We analyzed the correlation between KCND2 expression and clinical features as well as immune infiltration using the Cancer Genome Atlas (TCGA) database. Functional assays of KCND2 were conducted using Cell counting Kit‐8 (CCK8), clone formation assay and cell cycle analysis. Additionally, immunofluorescence, flow cytometry and quantitative real‐time polymerase chain reaction (qRT‐PCR) techniques were used to investigate tumor proliferation and immune cell infiltration at different levels of KCND2 expression in vivo. Results KCND2 was markedly elevated in gastric cancer and its expression appeared to link to different grades, T stages, and N stages. In addition, KCND2 was an independent predictor of prognosis, and its elevated levels in TCGA database revealed a more unfavorable prognosis for patients with gastric cancer. KCND2 strengthened the viability at the cellular level by boosting the proliferation of gastric cancer cells and reducing their death rate. Additionally, it also highlights that KCND2 the abilities of proliferating of gastric cancer cells by stimulating NF‐κB both in cell and animal levels. In addition, the findings provided proof that in animal levels, KCND2 might regulate the immune system by associating with promoting M2 macrophages, which are known to play critical roles in cancer progression. Mechanistically, KCND2 was found to lead to the infiltration of M2 macrophages through activation of NF‐κB, ultimately promoting the advancement of gastric cancer. Conclusion Overall, these findings suggest that KCND2 is likely to be available as an underlying therapeutic target for gastric cancer.