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Abstract Given the growing emphasis on energy efficiency, environmental sustainability, and agricultural demand, there’s a pressing need for decentralized and scalable ammonia production. Converting nitrate ions electrochemically, which are commonly found in industrial wastewater and polluted groundwater, into ammonia offers a viable approach for both wastewater treatment and ammonia production yet limited by low producibility and scalability. Here we report a versatile and scalable solution-phase synthesis of high-entropy single-atom nanocages (HESA NCs) in which Fe and other five metals-Co, Cu, Zn, Cd, and In-are isolated via cyano-bridges and coordinated with C and N, respectively. Incorporating and isolating the five metals into the matrix of Fe resulted in Fe-C5 active sites with a minimized symmetry of lattice as well as facilitated water dissociation and thus hydrogenation process. As a result, the Fe-HESA NCs exhibited a high selectivity toward NH3 from the electrocatalytic reduction of nitrate with a Faradaic efficiency of 93.4% while maintaining a high yield rate of 81.4 mg h−1 mg−1.

Abstract Background and purpose Garlic is used as an important medicinal food for treatment of many diseases, however, the association between garlic consumption and dyslipidemia have yielded inconsistent results. So we carried this meta-analysis to explore the blood lipid-lowering effects of garlic. Methods Databases such as PubMed, Scopus, Web of science, Embase, Cochrane Library were systematically searched until June 2024. Heterogeneity among studies was examined using Q and I2 statistics. Also subgroup analysis were conducted to explore the potential heterogeneity. Combined weighted mean differences (WMD) with their 95% confidence interval (CI) were calculated using a random-effects model. The GRADE approach was used to evaluate the overall certainty of the evidence in the meta-analyses. Results A total of 21 RCTs studies involved association between garlic consumption and blood lipids level of dyslipidemia patients were included in the meta-analysis. The pooled results showed that garlic consumption significantly reduced total cholesterol (TC)(WMD = -0.64mmol/L, 95%CI = -0.75 −-0.54, P 50 years compared to those aged ≤ 50 years. And garlic oil greatly reduced TC and LDL-C compared with garlic power. Finally, sensitivity analysis and publication bias showed that the results were reliable. Conclusions Evidence from this meta-analysis suggested that garlic consumption could be effective in reducing the risk of dyslipidemia and preventing CVDs. Particularly the older people were more susceptible to the protective effects of garlic.

Abstract The characteristic features of the rheumatoid arthritis (RA) microenvironment are synovial inflammation and hyperplasia. Therefore, there is a growing interest in developing a suitable therapeutic strategy for RA that targets the synovial macrophages and fibroblast-like synoviocytes (FLSs). In this study, we used graphene oxide quantum dots (GOQDs) for loading anti-arthritic sinomenine hydrochloride (SIN). By combining with hyaluronic acid (HA)-inserted hybrid membrane (RFM), we successfully constructed a new nanodrug system named HA@RFM@GP@SIN NPs for target therapy of inflammatory articular lesions. Mechanistic studies showed that this nanomedicine system was effective against RA by facilitating the transition of M1 to M2 macrophages and inhibiting the abnormal proliferation of FLSs in vitro. In vivo therapeutic potential investigation demonstrated its effects on macrophage polarization and synovial hyperplasia, ultimately preventing cartilage destruction and bone erosion in the preclinical models of adjuvant-induced arthritis and collagen-induced arthritis in rats. Metabolomics indicated that the anti-arthritic effects of HA@RFM@GP@SIN NPs were mainly associated with the regulation of steroid hormone biosynthesis, ovarian steroidogenesis, tryptophan metabolism, and tyrosine metabolism. More notably, transcriptomic analyses revealed that HA@RFM@GP@SIN NPs suppressed the cell cycle pathway while inducing the cell apoptosis pathway. Furthermore, protein validation revealed that HA@RFM@GP@SIN NPs disrupted the excessive growth of RAFLS by interfering with the PI3K/Akt/SGK/FoxO signaling cascade, resulting in a decline in cyclin B1 expression and the arrest of the G2 phase. Additionally, considering the favorable biocompatibility and biosafety, these multifunctional nanoparticles offer a promising therapeutic approach for patients with RA. Graphical abstract

Chimonobambusa utilis is a unique edible bamboo species valued for its economic and nutritional benefits. However, its existence in natural habitats is at risk due to environmental shifts and human interventions. This research utilised the maximum entropy model (MaxEnt) to predict potential habitats for Ch. utilis in China, identifying key environmental factors influencing its distribution and analysing changes in suitable habitats under future climate conditions. The results show that the results of the MaxEnt model have high prediction accuracy, with an AUC (Area Under the receiver operating characteristic Curve) value of 0.997. Precipitation in the driest month (Bio14), altitude (Alt) and isothermality (Bio03) emerged as the primary environmental factors influencing the Ch. utilis distribution. Currently, the suitable habitats area for Ch. utilis is 10.55 × 104 km2. Projections for the 2050s and 2090s indicate potential changes in suitable habitats ranging from -3.79% to 10.52%. In general, the most suitable habitat area will decrease and shrink towards higher latitude areas in the future. This study provides a scientific basis for the introduction, cultivation and conservation of Ch. utilis.

Abstract Background Because spontaneous remission is common in IMN, and there are adverse effects of immunosuppressive therapy, it is important to assess the risk of progressive loss of renal function before deciding whether and when to initiate immunosuppressive therapy. Therefore, this study aimed to establish a risk prediction model to predict patient prognosis and treatment response to help clinicians evaluate patient prognosis and decide on the best treatment regimen. Methods From September 2019 to December 2020, a total of 232 newly diagnosed IMN patients from three hospitals in Liaoning Province were enrolled. Logistic regression analysis selected the risk factors affecting the prognosis, and a dynamic online nomogram prognostic model was constructed based on extreme gradient boost, random forest, logistic regression machine learning algorithms. Receiver operating characteristic and calibration curves and decision curve analysis were utilized to assess the performance and clinical utility of the developed model. Results A total of 130 patients were in the training cohort and 102 patients in the validation cohort. Logistic regression analysis identified four risk factors: course ≥ 6 months, UTP, D-dimer and sPLA2R-Ab. The random forest algorithm showed the best performance with the highest AUROC (0.869). The nomogram had excellent discrimination ability, calibration ability and clinical practicability in both the training cohort and the validation cohort. Conclusions The dynamic online nomogram model can effectively assess the prognosis and treatment response of IMN patients. This will help clinicians assess the patient’s prognosis more accurately, communicate with the patient in advance, and jointly select the most appropriate treatment plan.

Abstract Intron retention (IR) is the most common alternative splicing event in Arabidopsis. An increasing number of studies have demonstrated the major role of IR in gene expression regulation. The impacts of IR on plant growth and development and response to environments remain underexplored. Here, we found that IR functions directly in gene expression regulation on a genome-wide scale through the detainment of intron-retained transcripts (IRTs) in the nucleus. Nuclear-retained IRTs can be kept away from translation through this mechanism. COP1-dependent light modulation of the IRTs of light signaling genes, such as PIF4, RVE1, and ABA3, contribute to seedling morphological development in response to changing light conditions. Furthermore, light-induced IR changes are under the control of the spliceosome, and in part through COP1-dependent ubiquitination and degradation of DCS1, a plant-specific spliceosomal component. Our data suggest that light regulates the activity of the spliceosome and the consequent IRT nucleus detainment to modulate photomorphogenesis through COP1.

Abstract One-dimensional (1D) olivine iron phosphate (FePO4) is widely proposed for electrochemical lithium (Li) extraction from dilute water sources, however, significant variations in Li selectivity were observed for particles with different physical attributes. Understanding how particle features influence Li and sodium (Na) co-intercalation is crucial for system design and enhancing Li selectivity. Here, we investigate a series of FePO4 particles with various features and revealed the importance of harnessing kinetic and chemo-mechanical barrier difference between lithiation and sodiation to promote selectivity. The thermodynamic preference of FePO4 provides baseline of selectivity while the particle features are critical to induce different kinetic pathways and barriers, resulting in different Li to Na selectivity from 6.2 × 102 to 2.3 × 104. Importantly, we categorize the FePO4 particles into two groups based on their distinctly paired phase evolutions upon lithiation and sodiation, and generate quantitative correlation maps among Li preference, morphological features, and electrochemical properties. By selecting FePO4 particles with specific features, we demonstrate fast (636 mA/g) Li extraction from a high Li source (1: 100 Li to Na) with (96.6 ± 0.2)% purity, and high selectivity (2.3 × 104) from a low Li source (1: 1000 Li to Na) with (95.8 ± 0.3)% purity in a single step.

Abstract Materials with field-tunable polarization are of broad interest to condensed matter sciences and solid-state device technologies. Here, using hydrogen (H) donor doping, we modify the room temperature metallic phase of a perovskite nickelate NdNiO3 into an insulating phase with both metastable dipolar polarization and space-charge polarization. We then demonstrate transient negative differential capacitance in thin film capacitors. The space-charge polarization caused by long-range movement and trapping of protons dominates when the electric field exceeds the threshold value. First-principles calculations suggest the polarization originates from the polar structure created by H doping. We find that polarization decays within ~1 second which is an interesting temporal regime for neuromorphic computing hardware design, and we implement the transient characteristics in a neural network to demonstrate unsupervised learning. These discoveries open new avenues for designing ferroelectric materials and electrets using light-ion doping.

Abstract Callicarpa kwangtungensis Chun (CK) is a common remedy exhibits anti-inflammatory properties and has been used in Chinese herbal formulations, such as KangGongYan tablets. It is the main component of KangGongYan tablets, which has been used to treat chronic cervicitis caused by damp heat, red and white bands, cervical erosion, and bleeding. However, the anti-inflammatory effects of CK water extract remains unknown. This study assessed the anti-inflammatory effects of CK in vivo and in vitro, characterized its main components in the serum of rats and verified the anti-inflammatory effects of serum containing CK. Nitric oxide (NO), tumour necrosis factor α (TNF-α) and interleukin-6 (IL-6) release by RAW264.7 cells was examined by ELISA and Griess reagents. Inflammation-related protein expression in LPS-stimulated RAW264.7 cells was measured by western blotting. Furthermore, rat model of foot swelling induced by λ-carrageenan and a collagen-induced arthritis (CIA) rat model were used to explore the anti-inflammatory effects of CK. The components of CK were characterized by LC–MS, and the effects of CK-containing serum on proinflammatory factors levels and the expression of inflammation-related proteins were examined by ELISA, Griess reagents and Western blotting. CK suppressed IL-6, TNF-α, and NO production, and iNOS protein expression in LPS-stimulated RAW264.7 cells. Mechanistic studies showed that CK inhibited the phosphorylation of ERK, P38 and JNK in the MAPK signaling pathway, promoted the expression of IκBα in the NF-κB signaling pathway, and subsequently inhibited the expression of iNOS, thereby exerting anti-inflammatory effects. Moreover, CK reduced the swelling rates with λ-carrageenan induced foot swelling, and reduced the arthritis score and incidence in the collagen-induced arthritis (CIA) rat model. A total of 68 compounds in CK water extract and 31 components in rat serum after intragastric administration of CK were characterized. Serum pharmacological analysis showed that CK-containing serum suppressed iNOS protein expression and NO, TNF-α, and IL-6 release. CK may be an anti-inflammatory agent with therapeutic potential for acute and chronic inflammatory diseases, especially inflammatory diseases associated with MAPK activation.

Abstract Targeting ferroptosis-related pathway is a potential strategy for treatment of lung cancer (LC). Consequently, exploration of ferroptosis-related markers is important for treating LC. We collected LC clinical data and mRNA expression profiles from TCGA and GEO database. Ferroptosis-related genes (FRGs) were obtained through FerrDB database. Expression analysis was performed to obtain differentially expressed FRGs. Diagnostic and prognostic models were constructed based on FRGs by LASSO regression, univariate, and multivariate Cox regression analysis, respectively. External verification cohorts GSE72094 and GSE157011 were used for validation. The interrelationship between prognostic risk scores based on FRGs and the tumor immune microenvironment was analyzed. Immunocytochemistry, Western blotting, and RT-qPCR detected the FRGs level. Eighteen FRGs were used for diagnostic models, 8 FRGs were used for prognostic models. The diagnostic model distinguished well between LC and normal samples in training and validation cohorts of TCGA. The prognostic models for TCGA, GSE72094, and GSE157011 cohorts significantly confirmed lower overall survival (OS) in high-risk group, which demonstrated excellent predictive properties of the survival model. Multivariate Cox regression analysis further confirmed risk score was an independent risk factor related with OS. Immunoassays revealed that in high-risk group, a significantly higher proportion of Macrophages_M0, Neutrophils, resting Natural killer cells and activated Mast cells and the level of B7H3, CD112, CD155, B7H5, and ICOSL were increased. In conclusion, diagnostic and prognostic models provided superior diagnostic and predictive power for LC and revealed a potential link between ferroptosis and TIME.

Background/Aims: This study aimed to analyze the trends in mortality attributed to hepatitis B and C around the Western Pacific region from 1990 to 2019. Methods: We used data from the Global Burden of Disease Study for a systematic analysis. The deaths related to hepatitis B and C were analyzed by age, sex, year, risk factors, geographical location, and Socio-demographic Index (SDI). Results: From 1990 to 2019, the annual total deaths from hepatitis B decreased from 0.266 to 0.210 million and those from hepatitis C increased from 0.119 to 0.142 million in the Western Pacific region. The age-standardized mortality rate (ASMR) of hepatitis B and C decreased by 63.5% and 48.0%, respectively. The declines in the ASMR related to hepatitis B and C were only detected in 12 and two Western Pacific countries, respectively. As the major risk factors, the contribution of alcohol use to hepatitis B deaths was 52% and drug use to hepatitis C was 80%. In males and females, the ASMR attributed to hepatitis B decreased by 61% and 71%, respectively, and the ASMR attributed to hepatitis C decreased by 43% and 55%, respectively. The association between SDI and ASMRs suggested that hepatitis B and C, respectively, showed an overall decline and stable trends as the SDI improved in the Western Pacific region. Conclusions: Although the mortality rate from hepatitis B and C decreased from 1990 to 2019, notable variation was observed among 27 Western Pacific countries. Efforts targeting hepatitis B and C prevention and treatment are still required in this region, especially for the pandemic countries.

Abstract Purpose To evaluate the perioperative clinical outcomes of en bloc resection and anterior column reconstruction for thoracolumbar spinal tumors. Methods This study conducted a retrospective analysis of prospective data collection of 86 consecutive patients, including 40 males and 46 females, with an average age of 39 years (ranged from 10 to 71 years). There were 35 cases of a malignant primary tumor,42 cases of an aggressive benign tumor, and nine cases of metastases. The main lesions were located in 65 cases of thoracic spine, 17 cases of lumbar spine, and 4 cases of thoracolumbar spine. Tumors involved one level in 45 patients, two levels in 12 patients, three levels in 21 patients, four levels in five patients, five levels in two patients, and six levels in one patient. Results According to the Weinstein-Boriani-Biagini surgical staging system, all patients achieved en bloc resections, including 74 cases of total en bloc spondylectomy and 12 cases of sagittal resections. The mean surgical time was 559 min (210–1208 min), and the mean total blood loss was 1528 ml (260–5500 ml). A total of 122 complications were observed in 62(72.1%) patients, of which 18(20.9%) patients had 25 major complications and one patient (1.2%) died of complications. The combined approach (P = 0.002), total blood loss (P = 0.003), staged surgery (P = 0.004), previous surgical history (P = 0.045), the number of involved vertebrae (P = 0.021) and lumbar location (P = 0.012) were statistically significant risk factors for major complication. When all above risk factors were incorporated in multivariate analysis, only the combined approach (P = 0.052) still remained significant. Conclusions En bloc resection and anterior column reconstruction is accompanied by a high incidence of complications, especially when a combined approach is necessary.

Objective To ensure the smooth implementation of urban rail transit station entry/exit pipe jacking construction project, it is essential to study the impact of ground settlement and explore settlement control measures for its engineering through urban roads. Method With reference to the long-distance bus station entry/exit pipe jacking engineering on Jinan Rail Transit R2 Line , and based on the description of project geological conditions and key difficulties, a 3D numerical calculation model for large profile pipe jacking engineering through urban roads with dense underground pipelines is established. Land subsidence curves at different distances from the excavation face and settlement curves at different depths of the soil layer are obtained. A comparison is made between the simulated vertical displacement values of land monitoring points above the pipe central axis and the field-measured values changing with excavation distances. Corresponding construction optimization measures are proposed, and the optimization effects are analyzed and verified based on field-measured data. Result & Conclusion During the jacking process, as the distance from pipe central axis increases, the land subsidence gradually decreases. With increasing depth, the deep layer displacement of the soil layer gradually increases, and the settlement curve gradually transitions from ′stout and short′ to ′slender and tall′. Factors such as significant fluctuations in soil chamber pressure and frictional disturbance between the pipe and the stratum on-site lead to an outcome of the maximum simulated settlement, which is slightly less than the maximum field-measured settlement, posing certain discrepancy. By adopting measures such as controlling excavation speed and rational grouting for reducing friction, the subsequent construction settlement control effect is evident, with a maximum land subsidence of 18.18 mm, and the deformation is within construction allowable range.

Cobalt (Co)-catalytic reduction of CO2 to CO is a key step in the reverse water–gas shift reaction. Here, dynamic behaviors of activation and reduction of CO2 and its products on clean and H2-adsorbed Co(0001) single-crystal surfaces probed in situ by ultrahigh vacuum − Fourier transform infrared spectroscopy (UHV-FTIRS) are reported for the first time. The physisorbed CO2 at low temperatures exists only at the top sites of terraces and diffuses to active sites for dissociation as annealing. Two active sites of the preferential B5 site at steps and hollow site on terraces are identified. The activated CO2 instantly dissociates to CO and O, and the produced CO at step sites migrates to more stable top sites of terraces at higher or room temperature. The pre-adsorbed H2 on Co(0001) remarkably accelerates CO2 dissociation via transferring more electrons to the 2πu anti-bonding orbital of CO2. The dissociated O and H atoms form hydroxyl groups at the hollow sites of terraces. The occupation of active sites by the O atoms or hydroxyl groups reduces the CO2 dissociation rate. Our work provides the direct experimental evidences for a fundamental understanding activation and reduction of CO2 on Co(0001) and thus is conducive to rational design and synthesis of efficient and highly selective Co-based catalysts.

Heart failure (HF) has emerged as the most pressing health concerns globally, and extant clinical therapies are accompanied by side effects and patients have a high burden of financial. The protein products of nuclear factor erythroid 2-related factor 2 (Nrf2) target genes have a variety of cardioprotective effects, including antioxidant, metabolic functions and anti-inflammatory. By evaluating established preclinical and clinical research in HF to date, we explored the potential of Nrf2 to exert unique cardioprotective functions as a novel therapeutic receptor for HF. In this review, we generalize the progression, structure, and function of Nrf2 research in the cardiovascular system. The mechanism of action of Nrf2 involved in HF as well as agonists of Nrf2 in natural compounds are summarized. Additionally, we discuss the challenges and implications for future clinical translation and application of pharmacology targeting Nrf2. It's critical to developing new drugs for HF.

This study investigated the synergistic potential of an oncolytic herpes simplex virus armed with interleukin 12 (VT1092M) in combination with immune checkpoint inhibitors for enhancing antitumor responses. The potential of this combination treatment to induce systemic antitumor immunity was assessed using bilateral subcutaneous tumor and tumor re-challenge mouse models. The antitumor efficacy of various OV and ICI treatment combinations and the underlying mechanisms were explored through diverse analytical techniques, including flow cytometry and RNA sequencing. Using VT1092M, either alone or in combination with an anti-PD-L1 antibody, significantly reduced the sizes of both the injected and untreated abscopal tumors in a bilateral tumor mouse model. The combination therapy demonstrated superior antitumor efficacy to the other treatment conditions tested, which was accompanied by an increase in T cell numbers and CD8+ T cell activation. Results from the survival and tumor re-challenge experiments showed that the combination therapy elicited long-term, tumor-specific immune responses, which were associated with tumor clearance and prolonged survival. Immune cell depletion assays identified CD8+ T cells as the crucial mediators of systemic antitumor immunity during combination therapy. In conclusion, the combination of VT1092M and PD-L1 blockade emerged as a potent inducer of antitumor immune responses, surpassing the efficacy of each monotherapy. This synergistic approach holds promise for achieving robust and sustained antitumor immunity, with potential implications for preventing tumor metastasis in patients with cancer.

Background: As a political, economic, and cultural exchange channel between ancient China and countries in Asia, Europe, and Africa, the Silk Road has promoted political, trade, and cultural exchanges between China and foreign countries in Chinese history and also promoted the development of traditional Chinese medicine. Methods: This article summarizes the introduction of medicinal materials from the Han to Qing Dynasties, spanning approximately 2000 years. Results: A total of 235 types of medicinal plant materials were imported. An analysis of 178 medicinal herbs of known origin, belonging to 72 families revealed their effectiveness in treating 20 diseases. The maximum number of medicinal herbs used to treat gastrointestinal and digestive disorders (GAS) was 122. The applications and origin of exotic medicinal materials, including draconis sanguis and olibanum have changed during the development of the Silk Road. Imported medicinal materials are affected by five factors, including local demand, adaptability, cultural exchange, scarcity, and medical theory. Five modes for introducing medicinal materials include the onshore Silk Road, the maritime Silk Road, diplomatic envoys and gifts, overseas Chinese, cultural exchange, and medical integration. The application of exotic medicinal materials expands the resources and application fields of traditional Chinese medicine, enriching the theory of traditional Chinese medicine. Conclusion: Traditional Chinese medicinal compounds introduced to China through the ancient Silk Road not only promoted their integration into foreign medicine but also had long-lasting impacts to date and over a wide range, thereby considerably affecting the pharmaceutical and general healthcare industries.

Abstract. Background:. Cerebrovascular disease (CVD) ranks among the foremost factors responsible for mortality on a global scale. The mortality patterns of CVDs and temporal trends in China need to be well-illustrated and updated. Methods:. We collected mortality data on patients with CVD from Chinese Center for Disease Control and Prevention's Disease Surveillance Points (CDC-DSP) system. The mortality of CVD in 2020 was described by age, sex, residence, and region. The temporal trend from 2013 to 2019 was evaluated using joinpoint regression, and estimated rates of decline were extrapolated until 2030 using time series models. Results:. In 2019, the age-standardized mortality in China (ASMRC) per 100,000 individuals was 113.2. The ASMRC for males (137.7/105) and rural areas (123.0/105) were both higher when stratified by gender and urban/rural residence. The central region had the highest mortality (126.5/105), the western region had a slightly lower mortality (123.5/105), and the eastern region had the lowest mortality (97.3/105). The age-specific mortality showed an accelerated upward trend from aged 55–59 years, with maximum mortality observed in individuals over 85 years of age. The age-standardized mortality of CVD decreased by 2.43% (95% confidence interval, 1.02–3.81%) annually from 2013 to 2019. Notably, the age-specific mortality of CVD increased from 2013 to 2019 for the age group of over 85 years. In 2020, both the absolute number of CVD cases and the crude mortality of CVD have increased compared to their values in 2019. The estimated total deaths due to CVD were estimated to reach 2.3 million in 2025 and 2.4 million in 2030. Conclusion:. The heightened focus on the burden of CVD among males, rural areas, the central and western of China, and individuals aged 75 years and above has emerged as a pivotal determinant in further decreasing mortalities, consequently presenting novel challenges to strategies for disease prevention and control.

Objective Re‐resection of spinal giant cell tumors is an exceedingly difficult procedure. Moreover, the prognosis of patients with en bloc resection or intralesional excision for re‐resection has rarely been reported. This study aimed to compare the prognostic value of en bloc resection with that of intralesional excision in patients undergoing re‐resection for giant cell tumors of the spine. Methods This retrospective analysis evaluated patients who underwent revision surgeries for relapse of giant cell tumors of the spine at our center between January 2005 and January 2021. Local progression‐free survival represents the duration between en bloc resection or intralesional excision and tumor recurrence. Neurological recovery, survival rates, local control, and complications were evaluated. The Kaplan–Meier estimator was used for survival analysis. Results A total of 22 patients (nine men and 13 women) with a mean age of 34.1 (range 19–63) years were included. Significant statistical differences were found in the local tumor recurrence rate between patients treated with en bloc resection and those treated with intralesional excision (p

Abstract To investigate the short-term effects and differences between exercise alone and exercise combined with self-mobilization training on chronic non-specific neck pain (CNSNP). Thirty subjects who met the criteria were recruited and randomly assigned to the exercise training group, the exercise combined with cervical self-mobilization training group (ECCM), and the exercise combined with cervicothoracic self-mobilization training group (ECCTM). The exercise training group received 6 weeks of deep neck flexor under biofeedback and scapular stability training, and the other two groups received 6 weeks of cervical self-mobilization and cervicothoracic self-mobilization, respectively, in addition to exercise training. Neck pain, cervical range of motion (ROM), neck disability, strength and endurance of deep neck flexor and quality of life were assessed before and after 6 weeks of training. The study results showed that all the three training programs for 6 weeks increased the strength and endurance of deep neck flexor, increased cervical ROM, reduced pain, and improved neck function (P

Abstract Charge ordering (CO), characterized by a periodic modulation of electron density and lattice distortion, has been a fundamental topic in condensed matter physics, serving as a potential platform for inducing novel functional properties. The charge-ordered phase is known to occur in a doped system with high d-electron occupancy, rather than low occupancy. Here, we report the realization of the charge-ordered phase in electron-doped (100) SrTiO3 epitaxial thin films that have the lowest d-electron occupancy i.e., d 1-d 0. Theoretical calculation predicts the presence of a metastable CO state in the bulk state of electron-doped SrTiO3. Atomic scale analysis reveals that (100) surface distortion favors electron-lattice coupling for the charge-ordered state, and triggering the stabilization of the CO phase from a correlated metal state. This stabilization extends up to six unit cells from the top surface to the interior. Our approach offers an insight into the means of stabilizing a new phase of matter, extending CO phase to the lowest electron occupancy and encompassing a wide range of 3d transition metal oxides.

Recently mRNA methylation modification has been extensively examined, including N6-methyladenosine (m6A), N5-methylcytidine (m5C) and N1-methyladenosine (m1A). The dynamic reversible biological processes of mRNA methylation modification include the participations of "Writer", "Eraser" and "Reader". Abnormal methylation may lead to the occurrence and development of acute kidney injury (AKI) and chronic kidney disease (CKD). And mRNA methylation modification shall become a practical biomarker for diagnosing and monitoring kidney diseases.

Background Cardiovascular disease (CVD) is the leading cause of mortality in type 2 diabetes mellitus (T2DM) patients. Shrunken pore syndrome (SPS) is defined as eGFRcystatin C/eGFRcreatinine ratio 0.85, eGFRcystatin C/eGFRcreatinine≤0.85 increased FRS risk (OR = 1.95, 95%CI = 1.18–3.21, p 0.85 (OR = 1.86, 95%CI = 1.08–3.21, p = 0.03).Conclusions In the current study, no significant association between SPS and FRS was identified. However, lower eGFRcystatin C/eGFRcreatinine and eGFRcystatin C/eGFRcreatinine≤0.85 were associated with a significantly increased CVD risk in T2DM.

ABSTRACTCeftazidime-avibactam (CZA) resistance is a huge threat in the clinic; however, the underlying mechanism responsible for high-level CZA resistance in Pseudomonas aeruginosa (PA) isolates remains unknown. In this study, a total of 5,763 P. aeruginosa isolates were collected from 2010 to 2022 to investigate the ceftazidime-avibactam (CZA) high-level resistance mechanisms of Pseudomonas aeruginosa (PA) isolates in China. Fifty-six PER-producing isolates were identified, including 50 isolates carrying blaPER-1 in PA, and 6 isolates carrying blaPER-4. Of these, 82.1% (46/56) were classified as DTR-PA isolates, and 76.79% (43/56) were resistant to CZA. Importantly, blaPER-1 and blaPER-4 overexpression led to 16-fold and >1024-fold increases in the MICs of CZA, respectively. WGS revealed that the blaPER-1 gene was located in two different transferable IncP-2-type plasmids and chromosomes, whereas blaPER-4 was found only on chromosomes and was carried by a class 1 integron embedded in a Tn6485-like transposon. Overexpression of efflux pumps may be associated with high-level CZA resistance in blaPER-1-positive strains. Kinetic parameter analysis revealed that PER-4 exhibited a similar kcat/Km with ceftazidime and a high (∼3359-fold) IC50 value with avibactam compared to PER-1. Our study found that overexpression of PER-1 combined with enhanced efflux pump expression and the low affinity of PER-4 for avibactam contributes to high-level resistance to CZA. Additionally, the Tn6485-like transposon plays a significant role in disseminating blaPER. Urgent active surveillance is required to prevent the further spread of high-level CZA resistance in DTR-PA isolates.

Objective To explore independent influencing factors for clinical efficacy of roxadustat in hemodialysis patients.Methods Hemodialysis patients treated with roxadustat were enrolled. The plasma trough concentrations of roxadustat were measured using liquid chromatography–tandem mass spectrometry (LC–MS/MS). A multiple logistic regression model was established to determine the factors that affect clinical efficacy of roxadustat in patients undergoing hemodialysis.Results A total of 67 hemodialysis patients were enrolled in the study. The results showed that age, blood trough concentration of roxadustat, and baseline hemoglobin (Hb) level were independent factors of clinical efficacy of roxadustat (OR = 1.06, p = .025 for age; OR = 1.001, p = .037 for plasma concentration; and OR = 0.941, p = .003 for baseline Hb), with an AUC score of 0.859.Conclusions Age, blood trough concentration of roxadustat, and baseline Hb level were independent influencing factors of the response to roxadustat in hemodialysis patients.

ABSTRACT: Heat stress (HS) brings great challenges to the poultry industry. Vitamin B6 (VB6) is an essential micro-nutrient for animals to maintain normal physiological functions and possesses antioxidant and anti-inflammatory properties. This study aimed to explore the effect of VB6 on alleviating HS-induced intestinal barrier impairment in broilers. A total of 250 broilers (609.76 ± 0.34 g) were randomly allocated to 5 groups with 5 replicate cages of 10 birds each. The broilers in thermoneutral (TN) group were raised in thermoneutral conditions (23 ± 1°C) and fed with a basal diet. The birds in other four groups were housed under cycle high temperature (34 ± 1°C for 8 h/d) from d 21 to 35 and fed with the basal diet (HS group) or basal diet supplemented with 6, 12, or 24 mg/kg VB6 (HB-6, HB-12, HB-24 groups). The results showed that HS reduced the growth performance, increased ileum inflammatory cytokines levels, and impaired the gut barrier function (P < 0.05). Compared to the HS group, final body weight, average daily gain, and average daily feed intake, and the feed conversion ratio were improved by VB6 supplementation. The diamine oxidase, interleukin (IL)-1β, tumor necrosis factor-α, IL-18, IL-10, and interferon-γ levels were reduced by VB6 supplementation (P < 0.05). Moreover, VB6 supplementation linearly or quadratically enhanced villus height and villus height-to-crypt depth ratio of duodenum and jejunum, and decreased crypt depth of duodenum and ileum. The mRNA expression of Occlaudin, ZO1, Mucin2, Mucin4, E-cadhein, and β-catenin were increased by VB6 treatment (P < 0.05). Furthermore, dietary VB6 altered the diversity and community of gut microbiota (P < 0.05). A total of 83 differential metabolites associated with the amelioration of VB6 were identified, which were primarily enriched in glycerophospholipid metabolism, caffeine metabolism, and glutathione metabolism pathway. Collectively, VB6 may improve the growth performance and intestinal barrier function of heat-stressed broilers by regulating the ileal microbiota and metabolic homeostasis.

BackgroundThe therapeutic effectiveness of immune checkpoint inhibitors (ICIs) in bladder cancer varies among individuals. Identifying reliable predictors of response to these therapies is crucial for optimizing patient outcomes.MethodsThis retrospective study analyzed 348 bladder cancer patients treated with ICIs, with additional validation using data from 248 patients at our institution who underwent PD-L1 immunohistochemical staining. We examined patient smoking history, clinicopathological characteristics, and immune phenotypes. The main focus was the correlation between smoking history and immunotherapy outcomes. Multivariate logistic and Cox proportional hazard regressions were used to adjust for confounders.ResultsThe study cohort comprised 348 bladder cancer patients receiving ICIs. Among them, 116 (33.3%) were never smokers, 197 (56.6%) were former smokers (median pack-years = 28), and 35 (10.1%) were current smokers (median pack-years = 40). Analysis revealed no statistically significant difference in overall survival across different smoking statuses (objective response rates were 11.4% for current smokers, 17.2% for never smokers, and 22.3% for former smokers; P = 0.142, 0.410, and 0.281, respectively). However, a notable trend indicated a potentially better response to immunotherapy in former smokers compared to current and never smokers. In the validation cohort of 248 patients from our institution, immunohistochemical analysis showed that PD-L1 expression was significantly higher in former smokers (55%) compared to current smokers (37%) and never smokers (47%). This observation underscores the potential influence of smoking history on the tumor microenvironment and its responsiveness to ICIs.ConclusionIn conclusion, our study demonstrates the importance of incorporating smoking history in predicting the response to immunotherapy in bladder cancer patients, highlighting its role in personalized cancer treatment approaches. Further research is suggested to explore the comprehensive impact of lifestyle factors on treatment outcomes.

In this paper, we present an improved analysis of the top-quark pair production via the process e+e−→γ⁎→tt¯ near the threshold region up to next-to-next-to-next-to-leading order (N3LO) QCD corrections. Near the threshold region, the top-quark velocity v tends to zero, leading to Coulomb singularity. To achieve a reasonable prediction in the threshold region, we reconstruct the analytical expression for the Coulomb-terms up to N3LO accuracy by using the PSLQ algorithm, whose numerical values agree well with the previous N3LO-level calculations. It is found that the N3LO series still has sizable renormalization scale dependence, and to improve the precision of the series, we apply the Principle of Maximum Conformality to eliminate such scale dependence. After that, the Coulomb part is resummed into a Sommerfeld-Gamow-Sakharov factor, which finally leads to a much more reasonable behavior near the threshold region.

Introduction: Celastrol (Cel) is a widely used main component of Chinese herbal medicine with strong anti-inflammatory, antiviral and antitumor activities. In the present study, we aimed to elucidate the cellular molecular protective mechanism of Cel against diabetes-induced inflammation and endothelial dysfunction.Methods: Type 2 diabetes (T2DM) was induced by db/db mice, and osmotic pumps containing Cel (100 μg/kg/day) were implanted intraperitoneally and were calibrated to release the drug for 28 days. In addition, human umbilical vein endothelial cells (HUVECs) were cultured in normal or high glucose and palmitic acid-containing (HG + PA) media in the presence or absence of Cel for 48 h.Results: Cel significantly ameliorated the hyperglycemia-induced abnormalities in nuclear factor (erythroid-derived 2)-like protein 2 (Nrf2) pathway activity and alleviated HG + PA-induced oxidative damage. However, the protective effect of Cel was almost completely abolished in HUVECs transfected with short hairpin (sh)RNA targeting Nrf2, but not by nonsense shRNA. Furthermore, HG + PA reduced the phosphorylation of AMP-activated protein kinase (AMPK), the autophagic degradation of p62/Kelch-like ECH-associated protein 1 (Keap1), and the nuclear localization of Nrf2. However, these catabolic pathways were inhibited by Cel treatment in HUVECs. In addition, compound C (AMPK inhibitors) and AAV9-sh-Nrf2 reduced Cel-induced Nrf2 activation and angiogenesis in db/db mice.Discussion: Taking these findings together, the endothelial protective effect of Cel in the presence of HG + PA may be at least in part attributed to its effects to reduce reactive oxygen species (ROS) and inflammation through p62/Keap1-mediated Nrf2 activation.

Research on understory plant diversity and its response to environmental factors helps in the sustainable development of plantation forests. We investigated the characteristics of understory plant diversity in Eucalyptus plantation forests located in Dongfang, Ding'an, Tunchang, and Lingao on Hainan Island by leveraging the plot survey method, and analyzing how the understory plant diversity in these Eucalyptus plantation forests responds to environmental factors. The results showed that a total of 124 plant species belonging to 62 families and 112 genera were recorded in the sampled plots of the Dongfang, Ding’an, Tunchang, and Lingao regional sites on Hainan Island, among which species of Fabaceae and Poaceae comprised the largest number of plants. The number of species and plant diversity indices of the shrub layer and herb layer in Eucalyptus plantation forests varied at different sites, The richest understory vegetation in Tunchang, located in the center of Hainan Island, and the highest α-diversity whether gauged by species or phylogenetically. The similarity of the understory plant community species was greatest between Ding’an and Tunchang, whereas the difference in composition was largest between Dongfang and the other three sites. Phylogenetically, the understory plant community at Ding’an had the most distant affinities among species, whereas that at Tunchang had the closest affinities among species. The results of the Mantel test and redundancy analysis revealed differing correlations between plant diversity in the shrub layer versus herb layer and various environmental factors. In particular, elevation and annual average temperature are the two main factors influencing plant diversity in the shrub layer, and soil available nitrogen and annual average sunshine duration are the two main factors influencing plant diversity in the herb layer. Variance decomposition showed that the combined effect of soil, climate, and topography factors is the main driver shaping plant diversity in the shrub layer of the understory in Eucalyptus plantation forests, while the combined effect of climate and soil factors is the main one determining plant diversity in their herb layer.

BackgroundChildren with autoimmune hepatitis (AIH) often present with symptoms similar to those of other liver diseases. This study consists of a comparison between the clinical and histological characteristics of AIH and those of other four AIH-like liver diseases [i.e., drug-induced liver injury (DILI), gene deficiency, infectious liver disease and other etiology of liver disease], as well as an evaluation of the AIH scoring system's diagnostic performance.MethodsAll children with AIH-like liver disease at our center from January 2013 to December 2022 were included. The clinical and histological characteristics of the AIH group were retrospectively analyzed and compared with those of the other four groups.ResultsA total of 208 children were included and divided into AIH group (18 patients), DILI group (38 patients), gene deficiency group (44 patients), infectious liver disease group (74 patients), and other etiology group (34 patients). The antinuclear antibodies (ANA) ≥ 1:320 rate was significantly higher in the AIH compared to the other four groups after multiple testing correction (p 0.73) and the revised systems (AUC > 0.93) for AIH have good diagnostic performance, with the latter being superior (p

Background & Aims: Approximately 10 million people live with chronic HCV infection in China, and less than 20% of people with HCV were diagnosed. We aim to determine the cost-effectiveness of one-time HCV screening compared with no screening in the Chinese population from the healthcare system perspective. Methods: A decision-tree plus Markov model was adopted to project chronic hepatitis C (CHC) prevalence, probability of complications, quality-adjusted life years (QALYs), and costs in the Chinese general population undiagnosed for CHC for different screening strategies. Once CHC was diagnosed, pan-genotypic direct-acting antiviral agent treatment was administered regardless of fibrosis. The population was simulated in a model spanning a lifetime. Input parameters were obtained from published literature. The incremental cost-effectiveness ratio between screening and no screening was estimated. The one-time Chinese gross domestic product per capita in 2021 ($12,558/QALY) was used as the willingness-to-pay threshold. Results: Universal screening in the population aged 3–80 years led to the lowest probability of complications, which yielded a 62% reduction of excess mortality. Compared with no screening, implementing screening and treatment for HCV in populations aged 3–80 years resulted in the greatest marginal QALYs (15.2 per 1,000 population) with an increase in total costs of $109,136. Calculating the incremental cost-effectiveness ratio yields a value of $9,503/QALY (95% uncertainty interval $3,738–$22,566). The robustness of the model was demonstrated through various sensitivity analyses. If the CHC prevalence was over 0.3%, screening could be cost-effective. Conclusions: HCV screening for Chinese people aged 3–80 years may be a cost-effective intervention to reduce the disease burden related to HCV infection. This strategy should certainly be implemented. Impact and implications: This study found that screening Chinese people aged 3–80 years yielded the greatest health benefits and was a cost-effective alternative. The findings indicated that national efforts eliminating HCV should be invested and strengthened in China. The results of this study are important because they provide strong evidence that universal screening can be a cost-effective way to reduce the burden of HCV in China. These findings are important for policymakers, physicians, patients, caregivers, and the public because they promote awareness and inform decision-making for HCV prevention and treatment.

Objective Although mini‐plate fixation is an attractive treatment option for distal radius metaphyseal diaphysis junction (DRMDJ) fractures in children, the benefits of minimally invasive fixation (MIF) with pre‐bent elastic stable intramedullary nails (MIF) remain underexplored. Therefore, this study aimed to evaluate the clinical efficacy of MIF administration in children with DRMDJ fractures. Methods This retrospective study enrolled 40 patients with DRMDJ fractures who underwent MIF or mini‐plate fixation from January 2016 to January 2021. Radiographic parameters, such as palmar inclination and ulnar deflection angle, were examined postoperatively to assess the anatomical reduction of the wrist joint. Clinical outcomes, including the range of wrist flexion and back extension, were examined to analyze the recovery of the wrist range of motion. Additionally, the Gartland–Werley scoring system was used to assess the recovery status of wrist function and healing condition. The student t‐test and χ2 test were used to compare differences among groups. Results All included patients successfully underwent the operation and were followed up for 12–24 months. Patients in the MIF group had a smaller surgical incision length (0.49 ± 0.06 cm) compared to those in the mini‐plate fixation group (4.41 ± 0.73 cm) (t = 22.438, p = 0.000). Palmar inclination and ulnar deflection were within the normal range in patients of both groups, and the fractures were successfully anatomically reduced. Moreover, wrist flexion and back extension in the MIF group and mini‐plate group were (72.50° ± 0.64° vs. 70.18° ± 0.56°) and (59.55° ± 1.75° vs. 60.04° ± 1.37°), and differences were statistically significant (t = 2.708, p = 0.010 and t = 0.885, p = 0.382, respectively). Furthermore, MIF treatment resulted in a higher proportion of excellent Gartland–Werley scores (94.44%) than mini‐plate fixation (86.36%) (p = 0.390). In addition, one case in the mini‐plate fixation group experienced re‐fracture following the removal of the internal fixation, and the fracture healed after reduction and cast fixation. All patients achieved satisfactory bone healing without other complications. Conclusion Compared with mini‐plate fixation, MIF has the advantages of small incision length, superior range of motion of thr wrist joint, and better maintenance of the physiological radian, providing a promising approach for clinical and surgical treatment of DRMDJ fractures.

Leak detection has significant implications for the long-term stable operation of water distribution networks (WDNs). This study presented a novel leak detection method by calculating the angular variance between a pressure vector and other vectors in the database, to evaluate the presence of an anomaly in a network. The top priority for this method was to establish a reliable dataset collected from the pressure sensors, which is generated by EPANET 2.2. Numerous node water demand data in normal conditions were generated by the Monte Carlo method, and leak conditions with various leak flows were simulated by creating leak holes in the pipes. Through learning the composite normal and abnormal data in a certain proportion, the angle-based outlier detection model was employed to identify abnormal events. This angle-based method was applied in an actual WDN and the identification performance for anomalies was compared with that of previous detection methods. The results indicated that the novel method proposed in this study could significantly improve the accuracy and efficiency of leak detection compared to the threshold-based and distance-based detection methods. HIGHLIGHTS The proposed method for leak detection in the WDN combines the hydraulic model with outlier detection.; Numerous normal and leak scenarios are simulated by the hydraulic model to calculate residuals.; A clustering algorithm is used to determine the optimal locations of pressure sensors.; The performance of the proposed method is compared with the distance-based method in the literature.;

As an important member of IL-1 family, interleukin 36 (IL-36) is a key regulator of inflammation. Its proinflammatory agonists are composed of IL-36α, IL-36β and IL-36γ while its antagonists include IL-36Ra and IL-38. And co-receptor of IL-36 subfamily is IL-36 receptor (IL-36R). An imbalance of IL-36 agonists and antagonists may lead to the development of skin diseases, intestinal diseases, lung diseases and tumors. In recent years, many studies have confirmed that IL-36 is correlated closely with the occurrence and development of kidney diseases. This review focused on the structure, biological function, regulatory mechanism and role of IL-36 in kidney disease

Abstract Approximately 30% of early-stage lung adenocarcinoma patients present with disease progression after successful surgical resection. Despite efforts of mapping the genetic landscape, there has been limited success in discovering predictive biomarkers of disease outcomes. Here we performed a systematic multi-omic assessment of 143 tumors and matched tumor-adjacent, histologically-normal lung tissue with long-term patient follow-up. Through histologic, mutational, and transcriptomic profiling of tumor and adjacent-normal tissue, we identified an inflammatory gene signature in tumor-adjacent tissue as the strongest clinical predictor of disease progression. Single-cell transcriptomic analysis demonstrated the progression-associated inflammatory signature was expressed in both immune and non-immune cells, and cell type-specific profiling in monocytes further improved outcome predictions. Additional analyses of tumor-adjacent transcriptomic data from The Cancer Genome Atlas validated the association of the inflammatory signature with worse outcomes across cancers. Collectively, our study suggests that molecular profiling of tumor-adjacent tissue can identify patients at high risk for disease progression.

Abstract Background Gain-of-function mutations in STING1 (also known as TMEM173) which result in constitutive activation of STING, have been reported to cause STING-associated vasculopathy with onset in infancy (SAVI). Although a wider spectrum of associated manifestations and perturbations in disease onset have been observed since its description, the genotype-phenotype correlations are not definite, and there is no established treatment protocol for SAVI. Case presentation Herein, we report a kindred, heterozygous STING mutation (p.V155M) in which the 2-year-old proband suffered from severe interstitial lung disease (ILD) while her father was initially misdiagnosed with connective tissue disease associated with ILD at an adult age. Baricitinib was initiated after the diagnosis of SAVI in the proband combined with steroids, and during the 14-month follow-up, the respiratory symptoms were improved. However, as the improvement of laboratory indicators was limited, especially in autoimmune indices, and the lung CT images remained unaltered, it seems that JAK1/2 inhibition was unsatisfactory in completely controlling the inflammation of the disease in our study. Conclusions Baricitinib was shown to elicit some effect on the ILD but failed to control the inflammation of the disease completely. Further exploration of JAK inhibitors or other therapeutic strategies are needed to more optimally treat this inflammatory disease.

Abstract Electrocatalytic CO2 reduction into value-added multicarbon products offers a means to close the anthropogenic carbon cycle using renewable electricity. However, the unsatisfactory catalytic selectivity for multicarbon products severely hinders the practical application of this technology. In this paper, we report a cascade AgCu single-atom and nanoparticle electrocatalyst, in which Ag nanoparticles produce CO and AgCu single-atom alloys promote C-C coupling kinetics. As a result, a Faradaic efficiency (FE) of 94 ± 4% toward multicarbon products is achieved with the as-prepared AgCu single-atom and nanoparticle catalyst under ~720 mA cm−2 working current density at −0.65 V in a flow cell with alkaline electrolyte. Density functional theory calculations further demonstrate that the high multicarbon product selectivity results from cooperation between AgCu single-atom alloys and Ag nanoparticles, wherein the Ag single-atom doping of Cu nanoparticles increases the adsorption energy of *CO on Cu sites due to the asymmetric bonding of the Cu atom to the adjacent Ag atom with a compressive strain.

The discharge mode has a great influence on the energy consumption of electric vehicles, especially at cold environment, soak in cold environment will lead to the decrease of the temperature of the vehicle/battery, resulting in the increase of energy consumption. In this paper, a segmented driving energy consumption test method was designed according to the real road discharge low of private vehicle, and the continuous and segmented energy consumption tests were carried out on the laboratory drum under −10 °C. From the perspective of energy flow, the differences of driving energy consumption, air conditioner energy consumption and brake energy recovery under the two test methods are analyzed. Results shown that soak in cold environment will cause the energy consumption of driving and air conditioner to increase by 5.5% and 43.8%, respectively, and also lead to a 17.1% decrease in brake recovery energy.

A three-dimensional magnetic probe system has been designed and implemented at the Space Plasma Environment Research Facility (SPERF). This system has been developed to measure the magnetic field with high spatial and temporal resolution, enabling studies of fundamental processes in space physics, such as magnetic reconnection at the Earth’s magnetopause, on the basis of SPERF. The system utilizes inductive components as sensors, arranged in an array and soldered onto a printed circuit board (PCB), achieving a spatial resolution of 2.5 mm. The system’s electrical parameters have been measured, and its amplitude–frequency response characteristics have been simulated. The system has demonstrated good performance with response capabilities below 50 kHz. The experimental setup and results are discussed, highlighting the system’s effectiveness in accurately measuring weak magnetic signals and its suitability for magnetic reconnection experiments.

The human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor and tumor-associated antigen abnormally expressed in various types of cancer, including breast, ovarian, and gastric cancer. HER2 overexpression is highly correlated with increased tumor aggressiveness, poorer prognosis, and shorter overall survival. Consequently, multiple HER2-targeted therapies have been developed and approved; however, only a subset of patients benefit from these treatments, and relapses are common. More potent and durable HER2-targeted therapies are desperately needed for patients with HER2-positive cancers. In this study, we developed a lipid nanoparticle (LNP)-based therapy formulated with mRNA encoding a novel HER2-CD3-Fc bispecific antibody (bsAb) for HER2-positive cancers. The LNPs efficiently transfected various types of cells, such as HEK293S, SKOV-3, and A1847, leading to robust and sustained secretion of the HER2-CD3-Fc bsAb with high binding affinity to both HER2 and CD3. The bsAb induced potent T-cell-directed cytotoxicity, along with secretion of IFN-λ, TNF-α, and granzyme B, against various types of HER2-positive tumor cells in vitro, including A549, NCI-H460, SKOV-3, A1847, SKBR3, and MDA-MB-231. The bsAb-mediated antitumor effect is highly specific and strictly dependent on its binding to HER2, as evidenced by the gained resistance of A549 and A1847 her2 knockout cells and the acquired sensitivity of mouse 4T1 cells overexpressing the human HER2 extracellular domain (ECD) or epitope-containing subdomain IV to the bsAb-induced T cell cytotoxicity. The bsAb also relies on its binding to CD3 for T-cell recruitment, as ablation of CD3 binding abolished the bsAb’s ability to elicit antitumor activity. Importantly, intratumoral injection of the HER2-CD3-Fc mRNA-LNPs triggers a strong antitumor response and completely blocks HER2-positive tumor growth in a mouse xenograft model of human ovarian cancer. These results indicate that the novel HER2-CD3-Fc mRNA-LNP-based therapy has the potential to effectively treat HER2-positive cancer.

Rejuvenation refers to the transition from the state of mature to juvenile. Many ancient Cinnamomum camphora have aged and died due to climatic and anthropic factors. Vegetative propagation can protect valuable germplasm resources. In this study, a 2000-year-old ancient C. camphora and its 2-year-old cutting plantlets were selected as experimental materials. The results indicated that the number of leaves with palisade tissue (Pal) cell layers was different between samples, with two layers in the rejuvenated leaves (RLs) and one layer in the mature leaves (MLs) and young leaves (YLs). Indole-3-acetic acid (IAA), isopentenyladenine (iP) and isopentenyladenosine (iPR) concentrations were significantly higher in RLs than in MLs and YLs, but the abscisic acid (ABA) concentration was lower. Targeted metabolome analysis identified 293 differentially accumulated metabolites (DAMs). Meanwhile, a total of 5241 differentially expressed genes (DEGs) were identified by transcriptome sequencing. According to the KEGG analysis, there were seven important enriched pathways in the MLs, RLs and YLs, including plant hormone signal transduction (57 DEGs), plant–pathogen interaction (56 DEGs) and MAPK signaling pathway–plant (36 DEGs). KEGG enrichment conjoint analyses of DEGs and DAMs identified 16 common pathways. Integrated analyses of cytological, hormone, metabolome and transcriptome elements can provide a research basis in regard to the rejuvenation regulatory mechanism of ancient C. camphora.

Few studies have focused on the evaluation of vaccine effectiveness (VE) in mainland China. This study was to characterize the VE including the frequent symptoms, laboratory indices, along with endotracheal intubation, hospital length of stay (LoS), and survival status. This retrospective cohort study included patients with COVID-19 admitted to our hospital. Statistical comparisons of continuous variables were carried out with an independent Student’s t-test or Mann-Whitney U test. For categorical variables, the Chi-square test and Fisher exact test were used. Multivariable regression analysis was performed to adjust the confounding factors such as age, gender, body mass index (BMI), residential area, smoking status, the Charlson comorbidity index (CCI) score, followed by investigating the effects of vaccination on critical ill prevention, reduced mortality and endotracheal intubation, LoS and inspired oxygen. This study included 549 hospitalized patients with COVID-19, including 222 (40.43 %) vaccinated participants and 327 (59.57 %) unvaccinated counterparts. There was no obvious difference between the two groups in typical clinical symptoms of COVID-19, clinical laboratory results and mortality. Multivariable analysis showed that COVID-19 vaccine obviously reduced LoS by 1.2 days (lnLoS = -0.14, 95 %CI[-0.24,-0.04]; P = 0.005) and decreased fraction of inspired oxygen by 40 % (OR: 0.60; 95 %CI[0.40,0.90]; P = 0.013) after adjusting age, gender, BMI, residential area, smoking status and CCI score. In contrast, vaccination induced reduction in the critically ill, mortality, and endotracheal intubation compared with the unvaccinated counterparts, but with no statistical differences. Vaccinated patients hospitalized with COVID-19 have a reduced LoS and fraction of inspired oxygen compared to unvaccinated cases in China.

Background Patients with poor prognosis of pulmonary cryptococcosis (PC) are prone to other complications such as meningeal infection, recurrence or even death. Therefore, this study aims to analyze the influencing factors in the poor prognosis of patients with PC, so as to build a predictive nomograph model of poor prognosis of PC, and verify the predictive performance of the model. Methods This retrospective study included 410 patients (78.1%) with improved prognosis of PC and 115 patients (21.9%) with poor prognosis of PC. The 525 patients with PC were randomly divided into the training set and validation set according to the ratio of 7:3. The Least Absolute Shrinkage and Selection Operator (LASSO) algorithm was used to screen the demographic information, including clinical characteristics, laboratory test indicators, comorbidity and treatment methods of patients, and other independent factors that affect the prognosis of PC. These factors were included in the multivariable logistic regression model to build a predictive nomograph. The receiver operating characteristic curve (ROC), calibration curve and decision curve analysis (DCA) were used to verify the accuracy and application value of the model. Results It was finally confirmed that psychological symptoms, cytotoxic drugs, white blood cell count, hematocrit, platelet count, CRP, PCT, albumin, and CD4/CD8 were independent predictors of poor prognosis of PC patients. The area under the curve (AUC) of the predictive model for poor prognosis in the training set and validation set were 0.851 (95% CI: 0.818-0.881) and 0.949, respectively. At the same time, calibration curve and DCA results confirmed the excellent performance of the nomogram in predicting poor prognosis of PC. Conclusion The nomograph model for predicting the poor prognosis of PC constructed in this study has good prediction ability, which is helpful for improving the prognosis of PC and further optimizing the clinical management strategy.

Preimplantation genetic testing for monogenic diseases (PGT-M) can be used to select embryos that do not develop disease phenotypes or carry disease-causing genes for implantation into the mother’s uterus, to block disease transmission to the offspring, and to increase the birth rate of healthy newborns. However, the traditional PGT-M technique has some limitations, such as its time consumption, experimental procedural complexity, and the need for a complete family or reference embryo to construct the haplotype. In this study, proband-independent haplotyping based on NGS-based long-read sequencing (Phbol-seq) was used to effectively construct haplotypes. By targeting the mutation sites of single gene disease point mutations and small fragment deletion carriers, embryos carrying parental disease-causing mutations were successfully identified by linkage analysis. The efficiency of embryo resolution was then verified by classical Sanger sequencing, and it was confirmed that the construction of haplotype and SNP linkage analysis by Phbol-seq could accurately and effectively detect whether embryos carried parental pathogenic mutations. After the embryos confirmed to be nonpathogenic by Phbol-seq-based PGT-M and confirmed to have normal copy number variation by Phbol-seq-based PGT-A were transplanted into the uterus, gene detection in amniotic fluid of the implanted embryos was performed, and the results confirmed that Phbol-seq technology could accurately distinguish normal genotype embryos from genetically modified carrier embryos. Our results suggest that Phbol-seq is an effective strategy for accurately locating mutation sites and accurately distinguishing between embryos that inherit disease-causing genes and normal embryos that do not. This is critical for Phbol-seq-based PGT-M and could help more single-gene disease carriers with incomplete families, de novo mutations or suspected germline mosaicism to have healthy babies with normal phenotypes. It also helps to reduce the transmission of monogenic genetic diseases in the population.

BackgroundThis investigation aimed to examine the epidemiological characteristics of children with liver disease hospitalized for the first time between June 2012 and May 2022 in a tertiary hospital.MethodsThe study retrospectively recruited children aged between 29 days and 18 years who had been hospitalized for liver disease. Clinical characteristics were categorized by age and etiology, and time trends were assessed using linear regression analysis.ResultsA total of 4,313 children were recruited, with a median age of 0.7 (0.2–4.5) years, and 54.5% of the cases were in the 0–1 years age group. Infection was the primary cause of liver disease (30.0%), followed by undiagnosed cases (25.8%), biliary obstructive disease (15.9%), inherited metabolic liver disease (13.9%), and non-alcoholic fatty liver disease (NAFLD) (3.2%). Genetic diagnoses were established in 43.9% (478/1,088) of patients. The percentage of NAFLD demonstrated an upward trend from 1.2% in 2012 to 12.6% in 2022 (p = 0.006). In contrast, the percentage of cytomegalovirus hepatitis decreased from 13.3% in 2012 to 3.4% in 2022 (p = 0.002).ConclusionsLiver disease in infancy makes up the largest group in pediatric liver disease. Infection remains the leading cause of pediatric liver disease. Hospital admissions for NAFLD in children have increased rapidly over the past decade, while cytomegalovirus hepatitis has declined markedly.

Abstract Among numerous dynamic scheduling strategies for low‐density parity‐check codes, many of them are of high complexity due to repetitive computation and ordering of belief residuals. To address these challenges, two novel approaches are proposed: the derived informed variable‐to‐check residual belief propagation and the derived variable‐node and variable‐to‐check‐edge residual belief propagation for low‐density parity‐check codes. Simulation results show that the derived dynamic scheduling exhibits a substantial gain of approximately 0.15 dB in signal‐to‐noise ratio over the non‐derived one with considerably lower decoding complexity when targeting a bit‐error rate of 10−4.

Sinomenine (SIN), an alkaloid extracted from the Chinese herbal medicine Sinomenium acutum, has great potential in anti-inflammatory, immune regulation, analgesic and sedative, and is already a clinical drug for the treatment of rheumatoid arthritis in China. Our previous studies show SIN inhibits inflammation by regulating ɑ7nAChR, a key receptor of cholinergic anti-inflammatory pathway (CAP), which plays an important role in regulating peripheral and central nervous system inflammation. Growing evidence supports the cholinergic dysregulation and inflammatory responses play the key role in the pathogenesis of AD. The intervention effects of SIN on AD by regulating CAP and homeostasis in brain and gut were analyzed for the first time in the present study using scopolamine-induced AD model mice. Behavioral tests were used to assess the cognitive performance. The neurons loss, cholinergic function, inflammation responses, biological barrier function in the mouse brain and intestinal tissues were evaluated through a variety of techniques, and the gut microbiota was detected using 16SrRNA sequencing. The results showed that SIN significantly inhibited the cognitive decline, dysregulation of cholinergic system, peripheral and central inflammation, biological barrier damage as well as intestinal flora disturbance caused by SCOP in mice. More importantly, SIN effectively regulated CAP to suppress the activation of TLR4/NF-κB and protect the homeostasis in brain and gut to alleviate cognitive impairment.

BackgroundPrediabetes is associated with an increased risk of cardiovascular diseases and all-cause mortality. Rare research in China has evaluated the prevalence of prediabetes among children and adolescents using the HbA1c criterion or the combined FPG-or-HbA1c diagnostic criterion, and researchers paid no attention to the distributions of blood glucose in Shenzhen, especially for juveniles.MethodsWe conducted a school-based cross-sectional study based on the first-year students from 17 primary, middle, and high schools. Prediabetes was defined as FPG of 5.6–6.9 mmol/L or HbA1c of 5.7%–6.4%. The crude and standardized prevalence of prediabetes with 95% confidence interval (95% CI) was estimated.ResultsA total of 7519 participants, aged 6 to 17 years, were included. For all subjects, the crude prevalence (95% CI) of prediabetes was 1.49% (1.21–1.77), 8.72% (8.08–9.36), and 9.80% (9.13–10.47) by the FPG-only, HbA1c-only, and FPG-or-HbA1c criteria, respectively. Based on the 2010 Shenzhen census population, the standardized prevalence was 1.56% (males 1.85%, females 1.19%), 11.05% (males 11.47%, females 10.53%), and 12.19% (males 13.01%, females 11.15%) by the corresponding criteria. The proportion of prediabetes was higher for males than females, and the prevalence decreased with grade for males but increased for females. The association of BMI and prediabetes was U-shaped curve, indicating higher rates of prediabetes for underweight and obesity people.ConclusionThe blood glucose status of children and adolescents in Shenzhen is worrisome, and the early detection and management of prediabetes are imperative.

ABSTRACT This study aims to assess the usefulness of peripheral blood metagenomic next-generation sequencing (mNGS) in diagnosing invasive mucormycosis (IM). We conducted a retrospective analysis of clinical data from 73 patients with mucorales sequences detected by peripheral blood mNGS at the First Affiliated Hospital, Zhejiang University School of Medicine, between February 2021 and December 2022. We examined data on risk factors, clinical symptoms, imaging characteristics, pathogenic findings, clinical diagnoses, and treatment outcomes. Among the 73 patients with mucorales sequences detected by peripheral blood mNGS, 7 cases were confirmed, 12 were probable, 34 were possible, and 20 were false positives, based on the diagnostic criteria for IM. Among the 34 possible cases, patients exhibited risk factors, clinical symptoms, imaging features, and prognoses consistent with IM. In 7 out of the 12 probable cases, the same mucorale nucleic acid was found in peripheral blood mNGS samples collected at an average interval of 8.1 days. In the remaining 20 patients, mucorales nucleic acid was detected in peripheral blood mNGS, but they lacked risk factors or clinical features of mucorales infection and lacked other pathological evidence, leading to a judgment of false positive. The positive predictive value of peripheral blood mNGS for diagnosing invasive mucormycosis in the cases studied was 72.6%. Peripheral blood mNGS testing provides valuable insights for diagnosing invasive mucormycosis. However, it should be used in conjunction with risk factors, clinical features, and other pathogenic test results to make a comprehensive assessment. IMPORTANCE Given the high fatality rates, prompt and accurate identification of the fungal culprit is crucial, emphasizing the need for invasive mucormycosis. Unfortunately, mucormycosis lacks definitive biomarkers, depending primarily on smears, cultures, or pathology, all necessitating invasive specimen collection from the infection site. However, obtaining valid specimens early in critically ill patients poses substantial risks and challenges. Whether peripheral blood metagenomic next-generation sequencing (mNGS) can enhance early mucormycosis diagnosis, especially when direct specimen collection from the infection site is challenging, is warranted. This is a large-scale clinical study conducted to evaluate the utility and clinical impact of mNGS of peripheral blood for the diagnosis of invasive mucormycosis. We believe our study provided both novelty in translational medicine and a great value for the medical community to understand the strengths and limitations of mNGS of peripheral blood as a new diagnostic tool for the diagnosis and management of invasive mucormycosis.