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Abstract Aberrant RNA editing has emerged as a pivotal factor in the pathogenesis of hepatocellular carcinoma (HCC), but the impact of RNA co-editing within HCC remains underexplored. We used a multi-step algorithm to construct an RNA co-editing network in HCC, and found that HCC-related RNA editings are predominantly centralized within the network. Furthermore, five pairs of risk RNA co-editing events were significantly correlated with the overall survival in HCC. Based on presence of risk RNA co-editings resulted in the categorization of HCC patients into high-risk and low-risk groups. Disparities in immune cell infiltrations were observed between the two groups, with the high-risk group exhibiting a greater abundance of exhausted T cells. Additionally, seven genes associated with risk RNA co-editing pairs were identified, whose expression effectively differentiates HCC tumor samples from normal ones. Our research offers an innovative perspective on the etiology and potential therapeutics for HCC.

Abstract Background Sows commonly experience insulin resistance in late gestation and lactation, causing lower feed intake and milk production, which can lead to higher mortality rates in newborn piglets. The probiotic Lactobacillus rhamnosus GG (LGG) is known to improve insulin resistance. However, whether supplementing LGG can improve insulin sensitivity in sows and enhance lactation performance, particularly the early survival of offspring remains unclear. Hence, we explored the effects and mechanisms of supplementing LGG during late gestation and lactation on sow insulin sensitivity, lactation performance, and offspring survival. In total, 20 sows were randomly allocated to an LGG (n = 10) and control group (n = 10). Results In sows, LGG supplementation significantly improved insulin sensitivity during late gestation and lactation, increased feed intake, milk production and colostrum lactose levels in early lactation, and enhanced newborn piglet survival. Moreover, LGG treatment significantly reshaped the gut microbiota in sows, notably increasing microbiota diversity and enriching the relative abundance of insulin sensitivity-associated probiotics such as Lactobacillus, Bifidobacterium, and Bacteroides. Serum metabolite and amino acid profiling in late-gestation sows also revealed decreased branched-chain amino acid and kynurenine serum levels following LGG supplementation. Further analyses highlighted a correlation between mitigated insulin resistance in late pregnancy and lactation by LGG and gut microbiota reshaping and changes in serum amino acid metabolism. Furthermore, maternal LGG enhanced immunity in newborn piglets, reduced inflammation, and facilitated the establishment of a gut microbiota. Conclusions We provide the first evidence that LGG mitigates insulin resistance in sows and enhances offspring survival by modulating the gut microbiota and amino acid metabolism.

Abstract Background Dietary fiber (DF) consumption was reported to improve insulin sensitivity, change the tryptophan metabolism, and alter the gut microbiota. Herein, this study aimed to investigate the effects of DF consumption on insulin sensitivity, tryptophan metabolism, and gut microbiota composition in sows during late pregnancy, and explore the relationship between tryptophan metabolites and insulin sensitivity regulated by DF supplementation. Results Twelve sows were randomly assigned to two dietary treatment groups (six/group): the low-fiber (LF) group, which was fed a basal diet, and the high-fiber (HF) group, which was fed the basal diet supplemented with 22.60 g/kg inulin and 181.60 g/kg cellulose. During late pregnancy, meal test, glucose tolerance test, and insulin challenge test were used to investigate the insulin sensitivity of sows, using the percutaneous brachiocephalic vein catheterization technique. High DF consumption resulted in improved insulin sensitivity, especially during the second and third trimesters, and promoted serotonin production from tryptophan. Additionally, plasma serotonin concentration was positively correlated with the insulin sensitivity index during late pregnancy. Moreover, DF consumption elevated fecal short-chain fatty acid (SCFA) concentrations, altered fecal microbial diversity, and increased the abundances of Rikenellaceae_RC9_gut_group, Alloprevotella, Parabacteroides, Roseburia, and Sphaerochaeta, which were positively correlated to plasma serotonin concentration. Conclusions DF consumption improved insulin sensitivity during late pregnancy in sows, which improved microbial diversity in fecal samples and increased fecal SCFA concentrations, resulting in a positive correlation with plasma serotonin level.

Abstract With the recent advances in smartphones and Internet technologies, ride‐hailing services (such as Uber and Didi) have emerged and changed the travel modes that residents use. An important issue within this area is how ride‐hailing services influence public transit usage. The majority of the research regarding this topic has focused on situations in large cities and has not reached a unanimous consensus among scholars. In particular, the role of ride‐hailing services in small‐ and medium‐sized cities may be different from the role of these services in large cities. In this paper, we choose 22 small‐ and medium‐sized cities in China as samples with a research time window spanning from 2011 to 2016 to examine the impact of the introduction of ride‐hailing services on public transit usage. The results of the synthetic control method, as well as other robustness checks, show that (1) the introduction of ride‐hailing services to China's small‐ and medium‐sized cities significantly increases public transit usage; (2) the effect of the introduction of ride‐hailing services on public transit usage in small‐ and medium‐sized cities is “proactive” for approximately 1 year; and (3) the positive effect of ride‐hailing services on public transit usage in small‐ and medium‐sized cities weakens over time. This study enriches the literature on the impact of ride‐hailing services on the urban transportation system by specifically taking small‐ and medium‐sized cities as the research scope. The above findings are of great significance to the urban transport department's formulation of ride‐hailing policies and the operation layout of public transit operators in small‐ and medium‐sized cities.

[Introduction] As a new form of nuclear energy utilization that is green and clean, nuclear fusion is regarded as the "ultimate energy" of mankind in the future and also as an inevitable route for China's energy development. In thermonuclear fusion power plants, China Fusion Engineering Test Reactors (CFETR) have periodic and pulse energy output, while turbine generator units operate stably and continuously. Therefore, an energy storage island is required between a nuclear island and a conventional island for energy storage buffering. To realize such a buffering function, a suitable operation mode needs to be selected for the energy storage system.[Method] The coupling and decoupling operation of the nuclear island and conventional island corresponded to different operation modes of the energy storage island. Based on the power output characteristics of CFETR, different operation mode schemes were analyzed and compared from aspects such as system configuration, equipment design and operation control. [Result] The results show that the decoupling operation mode of a nuclear island and conventional island is superior in terms of power generation efficiency, maturity of equipment design technology and operation control of generator units, so it is recommended to adopt the decoupling operation mode for the energy storage system in a thermonuclear fusion power plant. [Conclusion] Most of the decoupling operation mode schemes for the energy storage system adopt mature technologies, so they can be put into commercial applications on a large scale and provide support for the commercial design of thermonuclear fusion power plants.

[Introduction] In order to adapt to the periodic output characteristics of CFETR fusion reactors, the fusion power plant adopts a helium-molten salt energy storage-water (steam) power cycle three-circuit system. The parameters and thermal scheme of the three-circuit steam cycle have a significant impact on the investment and power generation benefit of the power generation island. High parameters and complex thermal schemes can improve cycle efficiency but increase initial investment; low parameters and simple thermal schemes have lower cycle efficiency but significantly reduce initial investment. Therefore, the selection of steam parameters and thermal schemes for the three-circuit system should comprehensively consider power generation efficiency and initial investment and should be selected based on the principle of optimal comprehensive economy. [Method] Based on the simulation software Ebsilon, modeling and simulation were carried out in this study to examine the performance of the thermal cycle under different regeneration schemes and different main steam and reheat parameters. By calculating different thermal schemes and parameter combinations, the total efficiency and output power under each operating condition were obtained, and the investment in the main equipment of the three-circuit system and its variation with parameters were analyzed. [Result] Taking into account the total investment and returns of the energy storage island and the conventional island, it is recommended to adopt a thermal scheme with 9-stage regeneration, and main steam parameters of 12.4 MPa, and 540 ℃. [Conclusion] The three-circuit steam parameters and thermal scheme proposed in the study have reference value for subsequent research on fusion power generation technology and engineering design.

Abstract Background Mitochondrial diseases (MDs) can be caused by single nucleotide variants (SNVs) and structural variants (SVs) in the mitochondrial genome (mtDNA). Presently, identifying deletions in small to medium-sized fragments and accurately detecting low-percentage variants remains challenging due to the limitations of next-generation sequencing (NGS). Methods In this study, we integrated targeted long-range polymerase chain reaction (LR-PCR) and PacBio HiFi sequencing to analyze 34 participants, including 28 patients and 6 controls. Of these, 17 samples were subjected to both targeted LR-PCR and to compare the mtDNA variant detection efficacy. Results Among the 28 patients tested by long-read sequencing (LRS), 2 patients were found positive for the m.3243 A > G hotspot variant, and 20 patients exhibited single or multiple deletion variants with a proportion exceeding 4%. Comparison between the results of LRS and NGS revealed that both methods exhibited similar efficacy in detecting SNVs exceeding 5%. However, LRS outperformed NGS in detecting SNVs with a ratio below 5%. As for SVs, LRS identified single or multiple deletions in 13 out of 17 cases, whereas NGS only detected single deletions in 8 cases. Furthermore, deletions identified by LRS were validated by Sanger sequencing and quantified in single muscle fibers using real-time PCR. Notably, LRS also effectively and accurately identified secondary mtDNA deletions in idiopathic inflammatory myopathies (IIMs). Conclusions LRS outperforms NGS in detecting various types of SNVs and SVs in mtDNA, including those with low frequencies. Our research is a significant advancement in medical comprehension and will provide profound insights into genetics.

Abstract Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.

Long memory in test statistics can either originate from fractional integration or be spuriously induced by a short memory process with a structural break. This research estimated and detected long memory from the two causes by simulations and empirical analysis. The simulation results showed that fractional integration and structural break processes could demonstrate long memory properties. The 2ELW estimator was stable for fractional integration but not stable for time series with structural breaks. The modified W statistic based on 2ELW was efficient in discriminating fractional integration and structural breaks. Moreover, we found that six volatility time series of stock indexes and individual stocks in the Chinese market experience significant long memory and structural breaks, and the fractional differencing parameter is overestimated without controlling structural breaks.

Ti and its alloys have been widely applied in various fields of national economy due to their excellent combinations of specific mechanical properties and outstanding corrosion behavior. Among Ti alloys, Ti–1Al–8V–5Fe (Ti-185) alloy is a metastable and low-cost β-Ti alloy, and owns extremely outstanding mechanical performance. In the paper, to overcome the issue of β flecks associated with Fe segregation in conventional ingot metallurgy process, Ti-185 alloy was prepared by electrostatic levitation (ESL) technique at various supercoolings, and its solidification behavior and dendrite growth were systematically analyzed. Moreover, the thermophysical parameters of liquid Ti-185 alloy were tested, and the microstructure, hardness and compressive property were compared to that of cast ingot. Results shown that the maximum supercooling of 311 K in the liquid Ti-185 alloy can be achieved, and a noticeable recalescence phenomenon appears during ESL process. The density and the ratio of specific heat to emissivity of liquid Ti-185 alloy increases linearly with temperature decreasing. Once the crystal nucleus is formed, the nonfacted interface will advance promptly. Moreover, the dendritic growth velocity (v) exhibits an exponential relationship with the supercooling (ΔT), and can be depicted as the equation of v = 1.59·ΔT1.65 mm s−1. Additionally, at a supercooling of 229 K or above, single crystal can be formed using ESL technique. Furthermore, the microhardness, elastic modulus and compressive strength of as-levitated Ti-185 alloy are hardly affected by the supercooling, but the plasticity of as-levitated sample is obviously higher than that of as-cast one.

Frictional sliding creates distinct microstructural and chemical discontinuities between the subsurface layer and base materials, which dictate the friction and wear properties. Traditional methods for lowering friction and wear in metals primarily rely on strategies that lower the interfacial shear strength between the contacting discontinuities. Contrary to conventional wisdom, we propose an alternative strategy: introducing tribo-induced or pre-designed heterostructures to suppress tribo-induced strain localization, thus yielding superior tribological properties unachievable with their conventional homogeneous counterparts. Citing recent experimental examples, this review explores the multiscale heterogeneities contributing low friction and wear, by interlinking surface deformation mechanisms and applied tribological conditions.

Transparent Gd2O3 ceramics with a cubic crystal structure were successfully synthesized for the first time. The Gd2O3 ceramics subjected to hot isostatic press (HIP) at 1070 ℃ consisted of uniform grains of 2–3 μm, and only a few residual pores could be detected inside the materials. X-ray diffraction (XRD) shows that the obtained polycrystalline materials have a cubic crystal structure, and the transmission polarized light observation shows that there is no birefringence inside the materials, indicating inherent optical properties of the cubic crystal structure. The optical absorption edge is 640 nm (optical band gap: 2.1 eV), and the transmittance in the visible to near-infrared region is 72%, which is close to the theoretical transmittance calculated from Fresnel loss. Verdet constant of this material is almost wavelength-independent, and it is diamagnetic since it has the opposite polarity to that of common paramagnetic materials.

Abstract Background The specific pathogenesis of UC is still unclear, but it has been clear that defects in intestinal barrier function play an important role in it. There is a temporary lack of specific drugs for clinical treatment. Astragaloside IV (AS-IV) is one of the main active ingredients extracted from Astragalus root and is a common Chinese herbal medicine for the treatment of gastrointestinal diseases. This study aimed to determine whether AS-IV has therapeutic value for DSS or LPS-induced intestinal epithelial barrier dysfunction in vivo and in vitro and its potential molecular mechanisms. Methods The intestinal tissues from UC patients and colitis mice were collected, intestinal inflammation was observed by colonoscopy, and mucosal barrier function was measured by immunofluorescence staining. PI3K/AKT signaling pathway activator YS-49 and inhibitor LY-29 were administered to colitic mice to uncover the effect of this pathway on gut mucosal barrier modulation. Then, network pharmacology was used to screen Astragaloside IV (AS-IV), a core active component of the traditional Chinese medicine Astragalus membranaceus. The potential of AS-IV for intestinal barrier function repairment and UC treatment through blockade of the PI3K/AKT pathway was further confirmed by histopathological staining, FITC-dextran, transmission electron microscopy, ELISA, immunofluorescence, qRT-PCR, and western blotting. Finally, 16 S rRNA sequencing was performed to uncover whether AS-IV can ameliorate UC by regulating gut microbiota homeostasis. Results Mucosal barrier function was significantly damaged in UC patients and murine colitis, and the activated PI3K/AKT signaling pathway was extensively involved. Both in vivo and vitro showed that the AS-IV-treated group significantly relieved inflammation and improved intestinal epithelial permeability by inhibiting the activation of the PI3K/AKT signaling pathway. In addition, microbiome data found that gut microbiota participates in AS-IV–mediated intestinal barrier recovery as well. Conclusions Our study highlights that AS-IV exerts a protective effect on the integrality of the mucosal barrier in UC based on the PI3K/AKT pathway, and AS-IV may serve as a novel AKT inhibitor to provide a potential therapy for UC. Graphical abstract

Abstract Background Nutritional deficiencies (ND) continue to threaten the lives of millions of people around the world, with children being the worst hit. Nevertheless, no systematic study of the epidemiological features of child ND has been conducted so far. Therefore, we aimed to comprehensively assess the burden of pediatric ND. Methods We analyzed data on pediatric ND between 1990 and 2019 from the Global Burden of Disease study (GBD) 2019 at the global, regional, and national levels. In addition, joinpoint regression models were used to assess temporal trends. Results In 2019, the number of prevalent cases of childhood malnutrition increased to 435,071,628 globally. The global age-standardized incidence, prevalence, and DALY rates showed an increasing trend between 1990 and 2019. Meanwhile, the burden of child malnutrition was negatively correlated with sociodemographic index (SDI). Asia and Africa still carried the heaviest burden. The burden and trends of child malnutrition varied considerably across countries and regions. At the age level, we found that malnutrition was significantly more prevalent among children

Abstract Background To identify independent factors of cognitive frailty (CF) and construct a nomogram to predict cognitive frailty risk in patients with lung cancer receiving drug therapy. Methods In this cross‐sectional study, patients with lung cancer undergoing drug therapy from October 2022 to July 2023 were enrolled. The data collected includes general demographic characteristics, clinical data characteristics and assessment of tools for cognitive frailty and other factors. Logistic regression was harnessed to determine the influencing factors, R software was used to establish a nomogram model to predict the risk of cognitive frailty. The enhanced bootstrap method was employed for internal verification of the model. The performance of the nomogram was evaluated by using calibration curves, the area under the receiver operating characteristic curve, and decision curve analysis. Results A total of 372 patients were recruited, with a cognitive frailty prevalence of 56.2%. Age, education background, diabetes mellitus, insomnia, sarcopenia, and nutrition status were identified as independent factors. Then, a nomogram model was constructed and patients were classified into high‐ and low‐risk groups with a cutoff value of 0.552. The internal validation results revealed good concordance, calibration and discrimination. The decision curve analysis presented prominent clinical utility. Conclusions The prevalence of cognitive frailty was higher in lung cancer patients receiving drug therapy. The nomogram could identify the risk of cognitive frailty intuitively and simply in patients with lung cancer, so as to provide references for early screening and intervention for cognitive frailty at the early phases of drug treatment.

Abstract Metabolic changes precede malignant histology. However, it remains unclear whether detectable characteristic metabolome exists in esophageal squamous cell carcinoma (ESCC) tissues and biofluids for early diagnosis. Here, we conduct NMR- and MS-based metabolomics on 1,153 matched ESCC tissues, normal mucosae, pre- and one-week post-operative sera and urines from 560 participants across three hospitals, with machine learning and WGCNA. Aberrations in ‘alanine, aspartate and glutamate metabolism’ proved to be prevalent throughout the ESCC evolution, consistently identified by NMR and MS, and reflected in 16 serum and 10 urine metabolic signatures in both discovery and validation sets. NMR-based simplified panels of any five serum or urine metabolites outperform clinical serological tumor markers (AUC = 0.984 and 0.930, respectively), and are effective in distinguishing early-stage ESCC in test set (serum accuracy = 0.994, urine accuracy = 0.879). Collectively, NMR-based biofluid screening can reveal characteristic metabolic events of ESCC and be feasible for early detection (ChiCTR2300073613).

Abstract Uric acid (UA) is associated with non-alcoholic fatty liver disease (NAFLD). However, it is unclear whether UA plays a predictive role in NAFLD prognosis. This study aimed to explore the relationship between UA levels and mortality in NAFLD patients without severe renal disease. Data were obtained from the Third National Health and Nutrition Examination Survey (NHANES). Time-dependent Cox regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for mortality. Overall, 2493 individuals with NAFLD and estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 were included in this study. The median follow-up period was 26.58 years. Patients were divided into high and low-UA groups according to UA levels. Time-independent Cox regression showed that UA level was not an independent risk factor for mortality in NAFLD patients without decreased eGFR (P > 0.05). After matching for age and sex using the propensity score matching method, UA remained not independently associated with death in NAFLD patients (P > 0.05). Similar results were found for cardiovascular-related and cancer-related deaths. Although UA is closely related to NAFLD, UA levels are not independently associated with the long-term survival of patients with NAFLD without decreased eGFR.

Abstract Background Remnant cholesterol (RC) is recognized as a risk factor for diabetes mellitus (DM). Although iron status has been shown to be associated with cholesterol metabolism and DM, the association between RC, iron status, and DM remains unclear. We examined the relationship between RC and iron status and investigated the role of iron status in the association between RC and DM. Methods A total of 7308 patients were enrolled from the China Health and Nutrition Survey. RC was calculated as total cholesterol minus low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. Iron status was assessed as serum ferritin (SF) and total body iron (TBI). DM was ascertained by self-reported physician diagnosis and/or antidiabetic drug use and/or fasting plasma glucose ≥ 126 mg/dL and/or glycated haemoglobin ≥ 6.5%. General linear models were used to evaluate the relationships between RC and iron status. Restricted cubic splines were used to assess the association between RC and DM. Mediation analysis was used to clarified the mediating role of iron status in the association between the RC and DM. Results The average age of the participants was 50.6 (standard deviation = 15.1) years. Higher RC was significantly associated with increased SF (β = 73.14, SE = 3.75, 95% confidence interval [CI] 65.79–80.49) and TBI (β = 1.61, SE = 0.08, 95% CI 1.44–1.78). J-shape relationships were found in the association between RC levels with DM, as well as iron status with DM. Significant indirect effects of SF and TBI in the association between RC and DM were found, with the index mediated at 9.58% and 6.37%, respectively. Conclusions RC has a dose–response relationship with iron status. The association between RC and DM was mediated in part by iron status. Future studies are needed to confirm these findings and further clarify the underlying mechanism.

Recent years have seen increasing academic interest in exploring the correlation between temperature and crime. However, it is uncertain whether similar long-term trends or seasonality (rather than causal effect) of temperature and crime is the major reason for the observed correlation between them. To explore whether there is still a correlation between temperature and crime when long-term trends and seasonal cycles are filtered out, we use the Kalman filter to decompose the time series of temperature and crimes, and then the fast Fourier transform is used to calculate the exact circle of their seasonality separately. Based on that, the box-plot method and linear regression are used to explore the correlation between temperature residuals and crime residuals. The results show that more than half of the crime types have similar seasonal cycles (approximately 1 year) to that of temperature. Moreover, the daily residual analyses show that temperature residuals have a positive correlation with assault and robbery residuals in all cities, whose average slopes are more than 0.1. The other four types of crimes vary greatly from case to case. The temperature residuals show a weak correlation with the residuals of some crime types.

ObjectiveThe artificial bee colony (ABC) algorithm has such characteristics as few control parameters, strong local optimization ability and fast convergence speed. However, when solving path optimization problems, it can easily fall into local optimal solutions. In order to solve the problem of pipeline routing in a ship pipeline system, an improved artificial bee colony (IABC) algorithm is proposed. MethodBased on the traditional artificial bee colony algorithm, the crossover operation of genetic operators is introduced into the update mechanism of following bees, and an adaptive strategy is adopted for the crossover probability of the crossover operator. The crossover operation on the population is used to find new solutions in the global range. The way scout bees search for new paths is improved from updating the points that the path passes to updating the "road sections" in the path. This paper proposes an artificial bee colony co-evolution algorithm for solving the optimization of branch pipeline paths. ResultsCompared with the standard artificial bee colony algorithm, the improved algorithm can improve the path layout effect by 32.3%–37.4% and the convergence speed by 17.7%–29.9%. ConclusionThe improved artificial bee colony algorithm proposed herein has higher solution quality, faster convergence speed and better stability than the traditional artificial bee colony algorithm for a single pipe or branch pipe.

Abstract Ketogenic diet (KD) alleviates refractory epilepsy and reduces seizures in children. However, the metabolic/cell biologic mechanisms by which the KD exerts its antiepileptic efficacy remain elusive. Herein, we report that KD-produced β-hydroxybutyric acid (BHB) augments brain gamma-aminobutyric acid (GABA) and the GABA/glutamate ratio to inhibit epilepsy. The KD ameliorated pentetrazol-induced epilepsy in mice. Mechanistically, KD-produced BHB, but not other ketone bodies, inhibited HDAC1/HDAC2, increased H3K27 acetylation, and transcriptionally upregulated SIRT4 and glutamate decarboxylase 1 (GAD1). BHB-induced SIRT4 de-carbamylated and inactivated glutamate dehydrogenase to preserve glutamate for GABA synthesis, and GAD1 upregulation increased mouse brain GABA/glutamate ratio to inhibit neuron excitation. BHB administration in mice inhibited epilepsy induced by pentetrazol. BHB-mediated relief of epilepsy required high GABA level and GABA/glutamate ratio. These results identified BHB as the major antiepileptic metabolite of the KD and suggested that BHB may serve as an alternative and less toxic antiepileptic agent than KD.

Abstract Objective Cemiplimab, a novel PD-1 inhibitor, exhibits significant antitumor activity against advanced non-small cell lung cancer (NSCLC). However, the cost-effectiveness of this drug for the treatment remains unclear. This study aimed to assess the cost-effectiveness of cemiplimab plus chemotherapy compared to chemotherapy for the treatment of advanced NSCLC, from the perspective of the United States payer. Methods A partitioned survival approach was developed to project the disease progression of NSCLC. Overall survival (OS) and progression-free survival (PFS) data were obtained from the EMPOWER lung 3 trial and extrapolated to estimate long-term survival outcomes. Direct medical costs and utility data were collected. The primary outcome measure, the incremental cost-utility ratio (ICUR), was used to evaluate the cost-effectiveness of cemiplimab plus chemotherapy regimen. One-way sensitivity analyses (OWSA) and probabilistic sensitivity analyses (PSA) were conducted to assess the robustness of the results. Results In the base-case analysis, the ICUR for cemiplimab plus chemotherapy versus chemotherapy alone was estimated to be $395,593.8 per quality-adjusted life year (QALY). OWSA revealed that the results were sensitive to Hazard ratio value, utility of PFS, and cost of cemiplimab. PSA demonstrated that cemiplimab plus chemotherapy exhibited 0% probability of cost-effectiveness.In hypothetical scenario analysis, the ICUR of two regimens was $188.803.3/QALY. OWSA revealed that the results were sensitive to the discount rate, utility, and cost of cemiplimab. PSA indicated that cemiplimab plus chemotherapy achieved at least an 11.5% probability of cost-effectiveness. Conclusion Our cost-effectiveness analysis suggests that, at its current price, cemiplimab plus chemotherapy regimen is unlikely to be a cost-effective option compared with chemotherapy alone for advanced NSCLC patients, based on a threshold of $150,000 per QALY, from the perspective of the US payer.

Abstract Background Intrauterine growth retardation (IUGR) affects intestinal growth, morphology, and function, which leads to poor growth performance and high mortality. The present study explored whether maternal dietary methyl donor (MET) supplementation alleviates IUGR and enhances offspring’s growth performance by improving intestinal growth, function, and DNA methylation of the ileum in a porcine IUGR model. Methods Forty multiparous sows were allocated to the control or MET diet groups from mating until delivery. After farrowing, 8 pairs of IUGR and normal birth weight piglets from 8 litters were selected for sampling before suckling colostrum. Results The results showed that maternal MET supplementation tended to decrease the IUGR incidence and increased the average weaning weight of piglets. Moreover, maternal MET supplementation significantly reduced the plasma concentrations of isoleucine, cysteine, urea, and total amino acids in sows and newborn piglets. It also increased lactase and sucrase activity in the jejunum of newborn piglets. MET addition resulted in lower ileal methionine synthase activity and increased betaine homocysteine S-methyltransferase activity in the ileum of newborn piglets. DNA methylation analysis of the ileum showed that MET supplementation increased the methylation level of DNA CpG sites in the ileum of newborn piglets. Down-regulated differentially methylated genes were enriched in folic acid binding, insulin receptor signaling pathway, and endothelial cell proliferation. In contrast, up-regulated methylated genes were enriched in growth hormone receptor signaling pathway and nitric oxide biosynthetic process. Conclusions Maternal MET supplementation can reduce the incidence of IUGR and increase the weaning litter weight of piglets, which may be associated with better intestinal function and methylation status.

Epithelial-to-mesenchymal transition (EMT), a process by which epithelial cells acquire mesenchymal cell characteristics, is well recognized for its critical role in development, wound healing, tissue fibrosis, and cancer progression. During wound healing, keratinocytes undergo a partially reversible EMT process to promote migration and re-epithelialization. In this paper, we review the regulatory roles of key signaling pathways (TGF-β, Wnt/β-catenin, Notch) and core transcription factors (Snail, Slug, Twist) in EMT, explore the parallels between re-epithelialization and EMT, and outline recent therapeutic advances and future developments targeting EMT in wound healing. In addition, we call for the adoption of the term “epithelial-mesenchymal plasticity” (EMP) to more accurately describe the dynamic processes that occur during keratinocyte migration and re-epithelialization.

BackgroundThe purpose of this systematic review and meta-analysis is to evaluate the potential significance of radiomics, derived from preoperative magnetic resonance imaging (MRI), in detecting deep stromal invasion (DOI), lymphatic vascular space invasion (LVSI) and lymph node metastasis (LNM) in cervical cancer (CC).MethodsA rigorous and systematic evaluation was conducted on radiomics studies pertaining to CC, published in the PubMed database prior to March 2024. The area under the curve (AUC), sensitivity, and specificity of each study were separately extracted to evaluate the performance of preoperative MRI radiomics in predicting DOI, LVSI, and LNM of CC.ResultsA total of 4, 7, and 12 studies were included in the meta-analysis of DOI, LVSI, and LNM, respectively. The overall AUC, sensitivity, and specificity of preoperative MRI models in predicting DOI, LVSI, and LNM were 0.90, 0.83 (95% confidence interval [CI], 0.75-0.89) and 0.83 (95% CI, 0.74-0.90); 0.85, 0.80 (95% CI, 0.73-0.86) and 0.75 (95% CI, 0.66-0.82); 0.86, 0.79 (95% CI, 0.74-0.83) and 0.80 (95% CI, 0.77-0.83), respectively.ConclusionMRI radiomics has demonstrated considerable potential in predicting DOI, LVSI, and LNM in CC, positioning it as a valuable tool for preoperative precision evaluation in CC patients.

BackgroundThe safety and efficacy of dual antiplatelet therapy (DAPT) in ischemic stroke patients with intracranial artery stenosis (ICAS) remain contentious.AimsThis study evaluates DAPT’s effectiveness and safety for these patients.MethodsThis review was reported following PRISMA 2020 guidelines. A comprehensive search was conducted in PubMed, Embase, Cochrane Library, ClinicalTrials.gov, CNKI, WanFang, VIP, and SinoMed up to June 20, 2023, for randomized controlled trials comparing efficacy and safety of DAPT against single antiplatelet therapy (SAPT) in ischemic stroke patients with ICAS. The primary outcome was a composite of ischemic and bleeding events. Secondary outcomes included stroke (cerebral infarction and hemorrhage), ischemic events, and cerebral infarction. Safety outcomes assessed were bleeding events, cerebral hemorrhage, and mortality. Risk ratios (RRs) with 95% confidence intervals (CIs) were synthesized using Review Manager 5.4.ResultsAnalysis of 21 randomized controlled trials involving 3,591 patients revealed that DAPT significantly lowered the rate of ischemic and bleeding events (RR = 0.52; 95% CI: 0.46–0.59, p

Pectin is a proven prebiotic and widely used in human health products. This study aims to assess the impact of dietary pectin supplementation during gestation on sow vaginal microbiota and the offspring's intestinal composition. Thirty sows were randomly allocated to two groups and fed a standard diet (CON) or a standard diet supplemented with 3 g/kg pectin (PEC). Blood, feces, and vaginal swab samples from the sows and blood, intestines issue, and colonic content samples from the offspring were collected and analyzed. The results indicate that the relative abundance of vaginal Lactobacillus was notably enhanced in the PEC group and fecal β-glucuronidase (β-G) activity and plasma 17β-estradiol (E2) concentration were also significantly increased in the PEC group. Newborn piglets were found to host different microbial communities as well. At the phylum level, Proteobacteria dominated in the CON group, and Firmicutes was predominant in the PEC group. Newborn piglets in the PEC group had a lower interleukin-6 (IL-6) concentration in their plasma. The expression of intestinal cytokines of offspring was improved as well. Villus height and villus height/crypt depth (V/C) in the PEC group were extremely higher than those in the CON group. In conclusion, dietary pectin supplementation can be of benefit to both sows and newborn piglets.

Objectives: Rapid antigen test (RAT) and polymerase chain reaction (PCR) using nasopharyngeal (NP) or oropharyngeal (OP) swab specimens are the two main testing techniques used for laboratory diagnosis of influenza in clinical practice. However, performance variations have been observed not only between techniques, but also between different specimens. This study evaluated the differences in performance between specimens and testing techniques to identify the best combination in clinical practice. Methods: Both NP and OP samples from suspected influenza patients collected in the 2023/4–2023/5 Flu-season in Xiamen, China, were tested for RAT and quantitative PCR. The testing performance of the different specimens and testing techniques were recorded and evaluated. Results: Compared to PCR, RAT showed 58.9 % and 10.3 % sensitivity for NP and OP swabs, respectively. The Limit of Detection (LoD) was 28.71 the Median Tissue Culture Infectious Dose (TCID50)/mL. Compared with PCR using NP swabs, PCR with OP swabs showed 89.5 % sensitivity and 95.4 % specificity. Conclusions: There were no significant differences in performance between the specimens when PCR was used to test for influenza. However, a decrease in sensitivity was observed when the RAT was used, regardless of the specimen type. Therefore, to avoid false-negative results, PCR may be a better choice when OP swabs are used as specimens. In contrast, NP swabs should be the recommended specimens for RAT.

Identification of novel therapeutic targets for type 2 diabetes is a key area of contemporary research. In this study, we screened differentially expressed genes in type 2 diabetes through the GEO database and sought to identify the key virulence factors for type 2 diabetes through a transcription factor regulatory network. Our findings may help identify new therapeutic targets for type 2 diabetes. Data pertaining to the humoral (whole blood) gene expression profile of diabetic patients were obtained from the NCBI’s GEO Datasets database and gene sets with differential expression were identified. Subsequently, the TRED transcriptional regulatory element database was integrated to build a gene regulatory network for type 2 diabetes. Functional analysis (GO-Analysis) and Pathway-analysis of differentially expressed genes were performed using the DAVID database and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Finally, gene-disease correlation analysis was performed using the DAVID online annotation tool. A total of 236 pathogenic genes, four transcription factors related to the pathogenic genes, and 261 corresponding target genes were identified. A transcription factor-target gene regulatory network for type 2 diabetes was constructed. Most of the key factors of the transcription factor-target gene regulatory network for type 2 diabetes were found closely related to the immune metabolic system and the functions of cell proliferation and transformation.

Key Clinical Message Atrial fibrillation is closely associated with thrombotic events. In non‐valvular atrial fibrillation, 90% of thrombi are formed by the left atrial appendage. Left atrial appendage occlusion (LAAC) can effectively prevent the detachment of left atrial appendage thrombus during atrial fibrillation, thereby reducing the risk of long‐term disability or death caused by thromboembolic events. However, the identification and management of complications in LAAC are also very important. Abstract The efficacy and safety of left atrial appendage occlusion (LAAC) in preventing non‐valvular atrial fibrillation stroke have been confirmed by multiple randomized controlled and registered studies, and have been recommended by several guidelines for stroke prevention in patients with atrial fibrillation at high‐risk of stroke. We reported an 80‐year‐old male patient with persistent atrial fibrillation. The patient underwent left atrial appendage closure surgery due to high risk of embolism and bleeding. On the second day after surgery, echocardiography showed displacement of the left atrial appendage occluder. Immediately perform removal of left atrial appendage occlude and left atrial appendage occlusion on the same day, and the patient was discharged on the fifth day after surgery without any special circumstances. This case demonstrates the feasibility and important clinical significance of using interventional surgery to remove the left atrial appendage occluder after displacement in clinical practice.

Stylocarotid artery syndrome (SAS) is a rare variant of Eagle’s syndrome that may lead to transient ischemic attack or stroke. The underlying pathophysiological mechanism involves compression of the internal carotid artery by an elongated styloid process (ESP), potentially resulting in vascular occlusion or dissection. An ESP exceeding 2.5 cm is deemed elongated, with a length of 3.0 cm considered clinically significant. Although the prevalence of ESP ranges from 4.0% to 7.3%, symptomatic cases are rare; symptoms are present in only approximately 4.0% of individuals with an ESP. Unlike the typical symptoms of Eagle’s syndrome, SAS may not cause pharyngeal discomfort, the sensation of a foreign body in the throat, dysphagia, or facial pain. This absence of characteristic symptoms as well as the development of central nervous system symptoms often leads patients to seek care from neurologists instead of otolaryngologists, increasing the likelihood of misdiagnosis or underdiagnosis. We herein report a unique case of ischemic stroke caused by SAS and present a literature review on cases of SAS-associated ischemic stroke published in the past decade. The reporting of this study conforms to the CARE guidelines.

Background: With the growing use of nitrogen-containing pesticides in agriculture, their residues in the environment have raised significant public health concerns.Objective: This study aimed to develop a novel PPy-DBSA/IT-SPME coating to enhance the detection efficiency of polar nitrogen-containing pesticides in water matrices.Methods: The preparation conditions were optimized, including pyrrole concentration at 7.0 mol/L, DBSA concentration at 0.014 mol/L, oxidant concentration at 0.35 mol/L, and a coating cycle repeated 10 times. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was employed for detection.Results: The novel coating effectively adsorbed 19 different categories of polar nitrogen-containing pesticides, including sulfonylureas, triazolopyrimidines, diphenyl ether herbicides, benzoylurea insecticides, and phenylurea herbicides, with unadsorbed rates below 10%. The analytical method achieved an average recovery rate of 61.92% to 115.21%, with an RSD below 5.0%. Detection and quantification limits ranged from 0.012 to 0.524 μg/L and 0.127 to 5.243 μg/L, respectively.Conclusion: The developed method is green, efficient, simple, and cost-effective. It offers an environmentally friendly and user-friendly approach for the detection of polar nitrogen-containing pesticide residues, demonstrating good recovery and precision. This method holds potential for wide application in environmental monitoring and food safety.

Abstract Background Overlapping cases of systemic lupus erythematosus (SLE) and primary biliary cirrhosis (PBC) are rare and have not yet been fully proven to be accidental or have a common genetic basis. Methods Two-sample bidirectional Mendelian randomization (MR) analysis was applied to explore the potential causal relationship between SLE and PBC. The heterogeneity and reliability of MR analysis were evaluated through Cochran’s Q-test and sensitivity test, respectively. Next, transcriptome overlap analysis of SLE and PBC was performed using the Gene Expression Omnibus database to identify the potential mechanism of hub genes. Finally, based on MR analysis, the potential causal relationship between hub genes and SLE or PBC was validated again. Results The MR analysis results indicated that SLE and PBC were both high-risk factors for the occurrence and development of the other party. On the one hand, MR analysis had heterogeneity, and on the other hand, it also had robustness. Nine hub genes were identified through transcriptome overlap analysis, and machine learning algorithms were used to verify their high recognition efficiency for SLE patients. Finally, based on MR analysis, it was verified that there was no potential causal relationship between the central gene SOCS3 and SLE, but it was a high-risk factor for the potential risk of PBC. Conclusion The two-sample bidirectional MR analysis revealed that SLE and PBC were high-risk factors for each other, indicating that they had similar genetic bases, which could to some extent overcome the limitation of insufficient overlap in case samples of SLE and PBC. The analysis of transcriptome overlapping hub genes provided a theoretical basis for the potential mechanisms and therapeutic targets of SLE with PBC overlapping cases.

Abstract Background With the advent of the new media era, the understanding of adolescent internet addiction needs to be enriched. It is also necessary to distinguish the related factors of adolescent internet addiction at different levels to clarify the mechanisms of this phenomenon. Methods This study used hierarchical linear model analysis to explore the effects of student-level factors and school-level factors on adolescent internet addiction, along with cross-level moderating effects. A total of 1,912 students between the 4th and 8th grades in China participated in the study. Participants completed the Self-Esteem Scale, Parents Phubbing Scale, Classroom Environment Scale, and the Diagnostic Questionnaire of Internet Addiction. Results Correlational analyses revealed that internet addiction was found to be negatively correlated with both self-esteem and the teacher-student relationship (p

Abstract Background Cancer‐associated fibroblasts (CAFs) play a vital role in facilitating tumor progression through extensive reciprocal interplay with cancer cells. Tumor‐derived extracellular vesicles (EVs) are the critical mediators involved in the crosstalk between cancer cells and stromal cells, contributing to the metastasis of cancers. Yet, the biological mechanisms of tumor‐derived EVs in triggering CAFs phenotype to stimulate the lymph node (LN) metastasis of bladder cancer (BCa) are largely unknown. Here, we aimed to explore the effects and molecular mechanisms of tumor‐derived EV‐mediated CAFs phenotype in regulating BCa LN metastasis. Methods The high‐throughput sequencing was utilized to identify the crucial long non‐coding RNA (lncRNA) associated with CAF enrichment in BCa. The functional role of the transition of fibroblasts to CAFs induced by LINC00665‐mediated EVs was investigated through the in vitro and in vivo assays. Chromatin isolation by RNA purification assays, fluorescence resonance energy transfer assays, cytokine profiling and patient‐derived xenograft (PDX) model were performed to explore the underlying mechanism of LINC00665 in the LN metastasis of BCa. Results We found that CAFs are widely enriched in the tumor microenvironment of BCa, which correlated with BCa lymphangiogenesis and LN metastasis. We then identified a CAF‐associated long non‐coding RNA, LINC00665, which acted as a crucial mediator of CAF infiltration in BCa. Clinically, LINC00665 was associated with LN metastasis and poor prognosis in patients with BCa. Mechanistically, LINC00665 transcriptionally upregulated RAB27B expression and induced H3K4me3 modification on the promoter of RAB27B through the recruitment of hnRNPL. Moreover, RAB27B‐induced EVs secretion endowed fibroblasts with the CAF phenotype, which reciprocally induced LINC00665 overexpression to form a RAB27B‐HGF‐c‐Myc positive feedback loop, enhancing the lymphangiogenesis and LN metastasis of BCa. Importantly, we demonstrated that blocking EV‐transmitted LINC00665 or HGF broke this loop and impaired BCa lymphangiogenesis in a PDX model. Conclusion Our study uncovers a precise mechanism that LINC00665 sustains BCa LN metastasis by inducing a RAB27B‐HGF‐c‐Myc positive feedback loop between BCa cells and fibroblasts, suggesting that LINC00665 could be a promising therapeutic target for patients with LN metastatic BCa.

Abstract Hyoscyamine and scopolamine (HS), two valuable tropane alkaloids of significant medicinal importance, are found in multiple distantly related lineages within the Solanaceae family. Here we sequence the genomes of three representative species that produce HS from these lineages, and one species that does not produce HS. Our analysis reveals a shared biosynthetic pathway responsible for HS production in the three HS-producing species. We observe a high level of gene collinearity related to HS synthesis across the family in both types of species. By introducing gain-of-function and loss-of-function mutations at key sites, we confirm the reduced/lost or re-activated functions of critical genes involved in HS synthesis in both types of species, respectively. These findings indicate independent and repeated losses of the HS biosynthesis pathway since its origin in the ancestral lineage. Our results hold promise for potential future applications in the artificial engineering of HS biosynthesis in Solanaceae crops.

Abstract Lymph node (LN) metastasis is one of the predominant metastatic routes of non-small cell lung cancer (NSCLC) and is considered as a leading cause for the unsatisfactory prognosis of patients. Although lymphangiogenesis is well-recognized as a crucial process in mediating LN metastasis, the regulatory mechanism involving lymphangiogenesis and LN metastasis in NSCLC remains unclear. In this study, we employed high-throughput sequencing to identify a novel circular RNA (circRNA), circTLCD4-RWDD3, which was significantly upregulated in extracellular vesicles (EVs) from LN metastatic NSCLC and was positively associated with deteriorated OS and DFS of patients with NSCLC from multicenter clinical cohort. Downregulating the expression of EV-packaged circTLCD4-RWDD3 inhibited lymphangiogenesis and LN metastasis of NSCLC both in vitro and in vivo. Mechanically, circTLCD4-RWDD3 physically interacted with hnRNPA2B1 and mediated the SUMO2 modification at K108 residue of hnRNPA2B1 by upregulating UBC9. Subsequently, circTLCD4-RWDD3-induced SUMOylated hnRNPA2B1 was recognized by the SUMO interaction motif (SIM) of ALIX and activated ALIX to recruit ESCRT-III, thereby facilitating the sorting of circTLCD4-RWDD3 into NSCLC cell-derived EVs. Moreover, EV-packaged circTLCD4-RWDD3 was internalized by lymphatic endothelial cells to activate the transcription of PROX1, resulting in the lymphangiogenesis and LN metastasis of NSCLC. Importantly, blocking EV-mediated transmission of circTLCD4-RWDD3 via mutating SIM in ALIX or K108 residue of hnRNPA2B1 inhibited the lymphangiogenesis and LN metastasis of NSCLC in vivo. Our findings reveal a precise mechanism underlying SUMOylated hnRNPA2B1-induced EV packaging of circTLCD4-RWDD3 in facilitating LN metastasis of NSCLC, suggesting that EV-packaged circTLCD4-RWDD3 could be a potential therapeutic target against LN metastatic NSCLC.

Abstract Background The use of umbilical cord mesenchymal stem cells (UC-MSCs) is a burgeoning method for the treatment of liver cirrhosis. However, the secretory phenotype and regulatory ability of UC-MSCs are easily affected by their microenvironment. Ensuring a specific microenvironment to enhance the UC-MSCs phenotype is a potential strategy for improving their therapeutic efficacy. The aim of this study was to explore therapeutic UC-MSCs phenotypes for improving liver fibrosis. Methods RNA-sequencing was used to analyze the response pattern of UC-MSCs after exposure to the serum of cirrhotic patients with HBV. Using immunohistochemistry, quantitative polymerase chain reaction, and immunofluorescence techniques, we evaluated the therapeutic effect of UC-MSCs pretreated with interferon alpha 2 (IFN-α2) (pre-MSCs) in an animal model of cirrhosis. Immunoblotting, ELISA, and other techniques were used to analyze the signaling pathways underlying the IFN-induced changes in UC-MSCs. Results UC-MSCs exposed to the serum of patients with hepatitis B-induced cirrhosis showed an enhanced response to type I IFN. The activated type I IFN signal induced the highest secretion of colony-stimulating factor 3 (CSF-3), interleukin (IL)-8, and chemokine (C–C motif) ligand 20 (CCL20) by the UC-MSCs. Pre-MSCs showed a higher therapeutic efficacy than untreated UC-MSCs in an animal model of liver fibrosis. Immunohistochemical analysis revealed that pre-MSCs could recruit neutrophils resulting in an increase in the secretion of matrix metalloprotease 8 that alleviated fibrosis. When neutrophils in animals were depleted, the therapeutic effect of pre-MSCs on fibrosis was inhibited. IFN-α2 altered the secretory phenotype of UC-MSCs by activating phosphorylated signal transducer and activator of transcription 1 and 2 (p-STAT1 and p-STAT2). Conclusions Pre-MSCs exhibited enhanced secretion of CSF-3, IL-8, and CCL20 and recruited neutrophils to alleviate fibrosis. This new strategy can improve cell therapy for liver cirrhosis. Graphical abstract

Background: A two-dimensional (2D) ultrasound examination is the primary technique for follicle monitoring, but 2D ultrasound follicle monitoring has significant inter- and intra-observer variability in the measurement of follicle diameter. The aim of this study was to propose a novel deep learning-based automated model for accurate 2D ultrasound follicle monitoring and validate the reliability and repeatability in clinical practice. Methods: A prospective trial including 300 infertile women undergoing ovulation induction (single follicle cycles) or controlled ovarian hyperstimulation (multiple follicle cycles) was conducted in the reproductive center. After 2D ultrasound image acquisition, the mean diameter of each targeted follicle was measured using an automated model, experts, and a novice. Designating the expert assessment as the gold standard, the reliability and repeatability of the automated model for single and multiple follicle cycles were evaluated using the intraclass correlation coefficient and Bland-Altman plots. Results: A total of 228 and 1065 follicles from single and multiple follicle cycles, respectively, were included. The accurate recognition rate of follicle boundaries using the automated model was 0.931. The inter-observer variability of follicle mean diameter measurements in single and multiple follicle cycles were 0.970 and 0.984 for the automated model and experts, and 0.965 and 0.978 for a novice and experts, respectively. Bland-Altman plots showed that 95% limits of agreement for follicle diameter measurement between the automated model and experts (−2.02 to 2.39 mm and −0.68 to 1.50 mm) was lower than a novice and experts (−1.69 to 2.74 mm and −0.58 to 1.73 mm) for both single and multiple follicle cycles. The intraclass correlation (ICC) of follicle diameters ≥10 mm calculated by the automated model was significantly higher than follicle diameters

Subtropical Moso bamboo (Phyllostachys edulis) forests have become hot spots for nitrogen (N) deposition in China. However, the effect of long-term N deposition on the structure of soil microbial communities in different horizons of these forests remains unclear. To investigate the influence of extended N deposition on soil bacteria and fungi, a simulated N deposition field study was conducted in Fujian Province with four N deposition levels (0, 20, 40 and 80 kg N hm−2 a−1). The absolute abundances, diversity, community structure, and potential functions of soil bacteria and fungi were investigated after 10 years of simulated N deposition. The results indicated that there was no significant effect of N deposition on the abundance or diversity of soil microbes in either the organic or mineral horizons of Moso bamboo forests. However, under rates of 40 and 80 kg N hm−2 a−1, long-term N deposition altered the structure of the soil bacterial community in the organic horizon. Specifically, there was a 27.75∼36.40 % increase in the relative abundance of Actinobacteria, while that of Acidobacteria decreased by 24.40∼27.52 %. Redundancy analysis (RDA) demonstrated that soil total carbon (TC) was the key variable influencing the bacterial community structure in the organic horizon. Analysis of potential microbial functions showed that in the organic horizon, the rates of chemoheterotrophy significantly decreased under 80 kg N hm−2 a−1. However, N deposition did not noticeably impact the fungal community structure in either soil horizon. Our study suggested that under 10 years of N deposition, only the bacterial community composition and function in the organic horizon was affected, indicating that soil bacteria are more sensitive to N deposition than fungi in subtropical Moso bamboo forests. Therefore, further research is necessary to fully understand the impact of N deposition on fungal community composition in the soil organic horizon and on the microbial community in the mineral horizon of subtropical bamboo forests. This study provides valuable insights for informing future environmental management and conservation strategies.

Ferroptosis is an emerging mode of programmed cell death fueled by iron buildup and lipid peroxidation. Recent evidence points to the function of ferroptosis in the aetiology and development of cancer and other disorders. Consequently, harnessing iron death for disease treatment has diverted the interest of the researchers in the field of basic and clinical research. The ubiquitin-proteasome system (UPS) represents a primary protein degradation pathway in eukaryotes. It involves labelling proteins to be degraded by ubiquitin (Ub), followed by recognition and degradation by the proteasome. Dysfunction of the UPS can contribute to diverse pathological processes, emphasizing the importance of maintaining organismal homeostasis. The regulation of protein stability is a critical component of the intricate molecular mechanism underlying iron death. Moreover, the intricate involvement of the UPS in regulating iron death-related molecules and signaling pathways, providing valuable insights for targeted treatment strategies. Besides, it highlights the potential of ferroptosis as a promising target for cancer therapy, emphasizing the combination between ferroptosis and the UPS. The molecular mechanisms underlying ferroptosis, including key regulators such as glutathione peroxidase 4 (GPX4), cysteine/glutamate transporter (system XC-), and iron metabolism, are thoroughly examined, alongside the role of the UPS in modulating the abundance and activity of crucial proteins for ferroptotic cell death, such as GPX4, and nuclear factor erythroid 2–related factor 2 (NRF2). As a pivotal regulatory system for macromolecular homeostasis, the UPS substantially impacts ferroptosis by directly or indirectly modulating iron death-related molecules or associated signaling pathways. This review explores the involvement of the UPS in regulating iron death-related molecules and signaling pathways, providing valuable insights for the targeted treatment of diseases associated with ferroptosis.

Staphylococcus (S.) aureus infection is a serious, worldwide health concern, particularly in many communities and hospitals. Understanding the S. aureus pathogenetic regulatory network will provide significant insights into diagnostic target screening to improve clinical treatment of diseases caused by S. aureus. We screened differentially expressed genes between normal mice and S. aureus-infected mice. We used the Gene Expression Omnibus (GEO) DataSets database for functional analysis (GO-analysis) and the DAVID and KEGG databases for signaling pathway analyses. We next integrated the gene and pathway analyses with Transcriptional Regulatory Element Database (TRED) to build an antimicrobial resistance gene regulatory network of S. aureus. We performed association analysis of network genes and diseases using DAVID online annotation tools. We identified a total of 437 virulence genes and 15 transcription factors (TFs), as well as 444 corresponding target genes, in the S. aureus TF regulatory network. We screened seven key network nodes (Met, Mmp13, Il12b, Il4, Tnf, Ptgs2, and Ctsl), four key transcription factors (Jun, C3, Spil, and Il6) and an important signaling pathway (TNF). We hypothesized that the cytokine activity and growth factor activity of S. aureus are combinatorically cross-regulated by Met, Mmp13, Il12b, Il4, Tnf, Ptgs2, and Ctsl genes, the TFs Jun, C3, Spi1, and Il6, as well as the immune response, cellular response to lipopolysaccharide, and inflammatory response. Our study provides information and reference values for the molecular understanding of the S. aureus pathogenetic gene regulatory network.

IntroductionChimeric antigen receptor natural killer (CAR-NK) cells have been found to be successful in treating hematologic malignancies and present potential for usage in solid tumors.MethodsIn this study, we created CD276-targeted CAR-expressing NK cells from pluripotent stem cells (iPSC CD276-targeted CAR-NK cells) and evaluated their cytotoxicity against esophageal squamous cell carcinoma (ESCC) using patient-specific organoid (PSO) models comprising of both CD276-positive and CD276-negative adjacent epithelium PSO models (normal control PSO, NC PSO) as well as primary culture of ESCC cell models. In addition, in vitro and in vivo models such as KYSE-150 were also examined. iPSC NK cells and NK-free media were used as the CAR-free and NK-free controls, respectively.ResultsThe positive CD276 staining was specifically detected on the ESCC membrane in 51.43% (54/105) of the patients of all stages, and in 51.35% (38/74) of stages III and IV. The iPS CD276-targeted CAR-NK cells, comparing with the iPS NK cells and the NK-free medium, exhibited specific and significant cytotoxic activity against CD276-positive ESCC PSO rather than CD276-negative NC PSO, and exhibited significant cytotoxicity against CD276-expressing cultured ESCC cells, as well as against CD276-expressing KYSE-150 in vitro and in BNDG mouse xenograft.DiscussionThe efficacy of the iPSC CD276-targeted CAR-NK cells demonstrated by their successful treatment of CD276-expressing ESCC in a multitude of pre-clinical models implied that they hold tremendous therapeutic potential for treating patients with CD276-expressing ESCC.

IntroductionTo analyze public perceptions of active aging in China on mainstream social media platforms to determine whether the “14th Five Year Plan for the Development of the Aging Career and Older Adult Care System” issued by the CPC in 2022 has fully addressed public needs.MethodsThe original tweets posted on Weibo between January 1, 2020, and June 30, 2022, containing the words “aging” or “old age” were extracted. A bidirectional encoder representation from transformers (BERT)-based model was used to generate themes related to this perception. A qualitative thematic analysis and an independent review of the theme labels were conducted by the researchers.ResultsThe findings indicate that public perceptions revolved around four themes: (1) health prevention and protection, (2) convenient living environments, (3) cognitive health and social integration, and (4) protecting the rights and interests of the older adult.DiscussionOur study found that although the Plan aligns with most of these themes, it lacks clear planning for financial security and marital life.

The human cytomegalovirus major immediate early gene (CMV) promoter is currently the most preferred promoter for recombinant therapeutic proteins (RTPs) production in CHO cells. To enhance the production of RTPs, five synthetic enhancers including multiple transcription factor regulatory elements (TFREs) were evaluated to enhance recombinant protein level in transient and stably transfected CHO cells. Compared with the control, four elements can enhance the report genes expression under both two transfected states. Further, the function of these four enhancers on human serum albumin (HSA) were investigated. We found that the transient expression can increase by up to 1.5 times, and the stably expression can maximum increase by up to 2.14 times. The enhancement of transgene expression was caused by the boost of their corresponding mRNA levels. Transcriptomics analysis was performed and found that transcriptional activation and cell cycle regulation genes were involved. In conclusion, optimization of enhancers in the CMV promoter could increase the production yield of transgene in transfected CHO cells, which has significance for developing high-yield CHO cell expression system.

Abstract Over the past few decades, there has been a significant interest in the study of essential genes, which are crucial for the survival of an organism under specific environmental conditions and thus have practical applications in the fields of synthetic biology and medicine. An increasing amount of experimental data on essential genes has been obtained with the continuous development of technological methods. Meanwhile, various computational prediction methods, related databases and web servers have emerged accordingly. To facilitate the study of essential genes, we have established a database of essential genes (DEG), which has become popular with continuous updates to facilitate essential gene feature analysis and prediction, drug and vaccine development, as well as artificial genome design and construction. In this article, we summarized the studies of essential genes, overviewed the relevant databases, and discussed their practical applications. Furthermore, we provided an overview of the main applications of DEG and conducted comprehensive analyses based on its latest version. However, it should be noted that the essential gene is a dynamic concept instead of a binary one, which presents both opportunities and challenges for their future development.

IntroductionThe clinical efficacy of CAR-NK cells against CD19-expressing blood cancers has been demonstrated, and they have shown potential for treating solid tumors as well. However, the efficacy of CAR-NK cells for treating human oral tongue squamous cell carcinoma (OTSCC) has not been examined. MethodsWe assessed MUC1 expression in human OTSCC tissue and a cell line using immunohistochemistry and immunofluorescence. We constructed NK cells that express CAR targeted to MUC1 from pluripotent stem cells (iPSC-derived MUC1-targeted CAR-NK cells) and evaluated their effectiveness against OTSCC in vitro using the xCELLigence Real-Time Cell Analysis system and CCK8 assay, and in vivo by measuring xenograft growth daily in BNDG mice treated with MUC1-targeted CAR-NK cells. As controls, we used iPSC-derived NK cells and NK-free media, which were CAR-free and blank, respectively.ResultsMUC1 expression was detected in 79.5% (66/83) of all OTSCC patients and 72.7% (24/33) of stage III and IV. In stage III and IV MUC1 positive OTSCC, 63.6% (21/33) and 48.5% (16/33) patients had a MUC1-positive cancer cell rate of more than 50% and 80%, respectively. The iPSC-derived MUC1-targeted CAR-NK cells exhibited significant cytotoxicity against MUC1-expressing OTSCC cells in vitro, in a time- and dose-dependent manner, and showed a significant inhibitory effect on xenograft growth compared to both the iPSC-derived NK cells and the blank controls. We observed no weight loss, severe hematological toxicity or NK cell-mediated death in the BNDG mice. ConclusionThe MUC1-targeted CAR-NK cells had significant efficacy against human OTSCC, and their promising therapeutic response warrants further clinical trials.

ABSTRACT: Growth performance and carcass traits may be retarded by low nutrient density diets. Organic chromium propionate (CrProp) can improve growth, carcass traits, and meat quality in farmed lambs, white broilers, and fish. Limited data regarding CrProp's impacts on yellow-feathered broilers are available. Eight hundred yellow-feathered male broilers (1-day old) were randomly allocated to 4 dietary groups and reared for 56 d. The trial was a 2 (dietary nutrient density) ×2 (CrProp) factorial arrangement with 4 diets: regular nutrient diet and low nutrient density (LND, reduction in metabolizable energy by 81 kcal and crude protein by 0.43%) diet supplemented with or without 200 mg/kg CrProp. Broilers were euthanized at d 56 after blood collection. The results indicated that the LND diet led to greater average daily feed intake (ADFI) from d 1 to 42 and feed conversion ratio (FCR) from d 22 to 42 (P < 0.05). Supplementation of CrProp improved body weight (BW) from d 1 to 56, average daily gain (ADG), and FCR during d 1 to 42 but reduced ADFI during d 1 to 21, as well as lowered abdominal fat percentage (P < 0.05). Supplementation with CrProp to regular and LND diets reduced ADFI but improved FCR from d 1 to 21 (P < 0.05). The LND diet lowered total antioxidant capacity (T-AOC) concentration and total superoxide dismutase (T-SOD) activity in the jejunal mucosa. CrProp elevated T-AOC levels and glutathione peroxidase activity (GSH-Px, P < 0.05). Dietary CrProp upregulated (P < 0.05) the expression of fatty acid transporter (FABP1) gene and peptide transporter (Pept1) gene. CrProp administration increased jejunal FABP1 expression and lowered cooking loss of breast meat (P < 0.05) in the LND group while reducing shear force (P = 0.009) of broilers treated by regular diet. In summary, CrProp administration to the LND diet can improve growth performance in the starter period and meat quality on d 56, possibly through upregulated nutrient transporter gene expression in the jejunum and enhanced antioxidant capability.

ObjectiveThe aim of this study was to investigate the mold and mycotoxin contamination status of cooked nuts and seeds in China in 2021 and to understand the correlation and risk of mold and mycotoxin contamination in such foods.MethodsSamples of commercially available cooked nuts and seeds were tested for mold contamination. Internal transcribed spacer （ITS） sequencing was used to identify the genus of the contaminating mold in the samples.ResultsOut of the cooked nut and seed samples analyzed， 19.32% （560/2 912） had mold counts > 25 colony-forming units （CFU）/g. The proportion of mold counts > 25 CFU/g was lower in single nuts and seeds （14.74%， 321/2 178） than in mixed nuts and seeds （32.56%， 239/734， P < 0.05）. Among the single nut and seed samples， walnuts （24.10%， 47/195） had the highest proportion of mold counts > 25 CFU/g， followed by almonds， spartan wood， and peanuts at 17.44% （15/86）， 16.81% （20/119）， and 16.22% （73/450）， respectively. All other nuts and seeds had proportions below 15%. Mycotoxin analysis was performed on 26 samples with mold counts > 25 CFU/g， and beauvericin was detected at 16.37 μg/kg in one peanut sample collected from Yunnan Province. ITS amplicon sequencing revealed that the main contaminating genera in cooked nuts and seeds were Aspergillus， Alternaria， and Candida. The detected molds had a certain correlation with mycotoxins.ConclusionHigh levels of mold contamination were detected in cooked nuts and seeds， resulting in a risk of mycotoxin production in the detected foods. Thus， it is necessary to strengthen the genus and species identification and mycotoxin analysis in these types of food to understand the contamination route and the regularity of toxin production and to provide a scientific basis for risk assessment and effective prevention and control measures.

Abstract Background Two studies were designed to determine standard ileal crude protein (CP) and amino acid (AA) digestibility of soybean meal (SBM) from different origins fed to non-pregnant and pregnant sows. Seven solvent-extracted SBMs from soybeans produced in the USA, Brazil, and China were selected. In Exp. 1, eight different diets were created: a nitrogen (N)-free diet and 7 experimental diets containing SBM from different origins as the only N source. Eight non-pregnant, multiparous sows were arranged in an 8 × 8 Latin square design (8 periods and 8 diets). In Exp. 2, the diet formula was the same as in Exp. 1. Eight gestating sows (parity 3) were assigned to 4 different diets in a replicated 4 × 3 Youden square design (three periods and four diets) in mid-gestation and again in late-gestation stages. Results When fed to non-pregnant and late-gestating sows, the standardized ileal digestibility (SID) of CP and most AAs from different SBM were not significantly different (P > 0.05). When fed to mid-gestating sows, the SID values for Arg, His, Lys, Phe, Cys, Gly, Ser, and Tyr in SBM 1 were lower than in SBM 4 and 5 (P