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Abstract Water conservation (WC) is a critical ecological service function in the Yellow River Basin (YRB). There is currently a lack of detailed exploration of WC development processes and the impact mechanisms of driving factors at spatiotemporal scales in the YRB. By collecting data on DEM, land use, soil, meteorology, reservoirs, and observed discharge, this study established a large-scale WC model using the soil and water assessment tool (SWAT). The abrupt change test, empirical orthogonal function (EOF), wavelet analysis, hierarchical partitioning analysis (HPA), geodetectors, and aridity index were employed to analyze the multi-spatiotemporal characteristics and driving forces of WC calculated using the water balance method. The results are as follows: (1) The average WC among the YRB was 9.11 mm (74.68 × 108 m3) from 1960 to 2020. Pasture and forests contributed to 48.65% and 22.05% of the average annual WC, respectively. (2) WC exhibited four forms: less/more in the YRB, more in the southeast (northwest), and less in the northwest (southeast). (3) Forests and pastures in land use had higher average WC capacity, while Gansu, Shaanxi, and Qinghai ranked in the top three for average WC among the nine provinces. (4) Precipitation was the major driving force affecting WC variations, with the interaction between precipitation and actual evapotranspiration being the most significant. (5) Drought was a significant cause of negative WC. Protecting and managing crucial WC areas was essential for improving the ecological environment. This research elucidates the driving forces of WC in the YRB, providing scientific support for improving regional WC and promoting sustainable development.

Abstract Background Contrast-induced acute kidney injury (CI-AKI) is manifested by a rapid decline in renal function occurring within 48–72 h in patients exposed to iodinated contrast media (CM). Although intravenous hydration is currently the effective method confirmed to prevent CI-AKI, it has several drawbacks. Some investigations have demonstrated the nephroprotective effects of vagus nerve stimulation (VNS) against kidney ischemia-reperfusion injury, but no direct research has investigated the use of VNS for treating CI-AKI. Additionally, most current VNS treatment applies invasive electrical stimulator implantation, which is largely limited by the complications. Our recent publications introduce the magnetic vagus nerve stimulation (mVNS) system pioneered and successfully used for the treatment of myocardial infarction. However, it remains uncertain whether mVNS can mitigate CI-AKI and its specific underlying mechanisms. Therefore, we herein evaluate the potential therapeutic effects of mVNS on CM-induced nephropathy in rats and explore the underlying mechanisms. Results mVNS treatment was found to significantly improve the damaged renal function, including the reduction of elevated serum creatinine (Scr), blood urea nitrogen (BUN), and urinary N-acetyl-β-D-glucosaminidase (NAG) with increased urine output. Pathologically, mVNS treatment alleviated the renal tissue structure injury, and suppressed kidney injury molecule-1 (KIM-1) expression and apoptosis in renal tubular epithelial cells. Mechanistically, increased circulating plasma exosomal miR-365-3p after mVNS treatment enhanced the autophagy and reduced CM-induced apoptosis in renal tubular epithelial cells by targeting Ras homolog enriched in brain (Rheb). Conclusions In summary, we demonstrated that mVNS can improve CI-AKI through enhanced autophagy and apoptosis inhibition, which depended on plasma exosomal miR-365-3p. Our findings highlight the therapeutic potential of mVNS for CI-AKI in clinical practice. However, further research is needed to determine the optimal stimulation parameters to achieve the best therapeutic effects. Graphical abstract

Abstract Obesity and related diseases pose a major health risk, yet current anti-obesity drugs inadequately addressing clinical needs. Here we show AA005, an annonaceous acetogenin mimic, resists obesity induced by high-fat diets and leptin mutations at non-toxic doses, with the alpha subunit of the mitochondrial trifunctional protein (HADHA) as a target identified through proteomics and in vitro validation. Pharmacokinetic analysis shows AA005 enriches in adipose tissue, prompting the creation of adipose-specific Hadha-deficient mice. These mice significantly mitigate diet-induced obesity, echoing AA005’s anti-obesity effects. AA005 treatment and Hadha deletion in adipose tissues increase body temperature and energy expenditure in high-fat diet-fed mice. The beneficial impact of AA005 on obesity mitigation is ineffective without uncoupling protein 1 (UCP1), essential for thermogenesis regulation. Our investigation shows the interaction between AA005 and HADHA in mitochondria, activating the UCP1-mediated thermogenic pathway. This substantiates AA005 as a promising compound for obesity treatment, targeting HADHA specifically.

Abstract Metal nanoparticles have extraordinary properties, but their integration into mesostructures has been challenging. Producing uniformly dispersed nanoparticles attached to substrates in industrial quantities is difficult. Herein, a “plasmashock” method was developed to synthesize metal nanoparticles anchored on different types of carbonaceous substrates using liquid salt solution precursors. These self-supporting, nanoparticle-loaded carbon fabrics are mechanically robust and have been tested as antibacterial substrates and electrocatalysts for reducing carbon dioxide and nitrite. A piece of silver–carbon nanotube paper with a silver loading of ~0.13 mg cm−2 treated after a few-second plasmashock presents good antibacterial and electrocatalytic properties in wastewater, even after 20 bactericidal immersion cycles, due to the strong bonding of the nanoparticles to the substrate. The results prove the effectiveness of this plasmashock method in creating free-standing functional composite films or membranes.

Background/purpose: Quantitative in vitro research was conducted on the learning process of a dynamic navigation system. This study provides guidance for the promotion and application of dynamic navigation technology in the endodontic apical surgery field. Materials and methods: Standardized models were designed and 3D printed to form the approach operation of endodontic apical surgery. 6 clinicians with no experience in dynamic navigation performed the operation. The distance deviation tolerance was set as 0.6 mm, and the angle deviation tolerance was set as 5°. Fifteen mm deep approach operation was completed using dynamic navigation. Each operator performed 10 consecutive exercises on the models. The positioning deviation and operation time of each operator for each practice were recorded. Based on this, the learning curve of the dynamic navigation of every operator was mapped. The learning difficulty of dynamic navigation was evaluated. Results: The learning curves of all operators reached a stable level after the 7th practice, which can ensure that the distance and angle deviations are maintained within the deviation tolerances (0.6 mm, 5°). Conclusion: Operators with no experience in dynamic navigation technology need practice to master dynamic navigation operations. For this navigation system, operators with no operational experience can master dynamic navigation operations after 7 exercises.

Abstract At present, the research on the influence of surrounding soil deformation induced by tunnel construction under the action of surcharge is generally based on the situation after the tunnel has been built, and less consideration is given to the existence of surface surcharge near the planned route of the tunnel when the tunnel is not built. Therefore, based on the Luochuan tunnel under construction, this study monitors the deformation of shallowly buried loess tunnels under different surcharge conditions and analyzes the influence of varying surcharge conditions on the deformation and stress of the tunnel through numerical simulation to determine the effective range of surface surcharge. The results show that the influence of surcharge load on tunnel stability is the most significant when located at the tunnel axis, and the influence degree increases with the increase of load. The adverse effects of surcharge load mainly occur in the range of 2 times the tunnel diameter. Once the range is exceeded, the internal force of the tunnel support structure is not sensitive to the surcharge load. In engineering, the surface surcharge can be controlled within the safety displacement limit by referring to the displacement calculation results.

Abstract Despite the pivotal role of stannum doping in achieving ultrahigh piezoelectric performance in barium titanate-based ceramics, the fundamental mechanisms underlying this enhancement remain elusive. Here, we introduce a single variable nonstoichiometric stannum strategy in lead-free barium titanate-based ceramics with giant piezoelectricity, revealing that stannum doping contributes intrinsically and extrinsically to enhance piezoelectricity. Density functional theory calculations elucidate the intrinsic enhancement of polarization arising from lattice distortion and increased space for titanium-oxygen bonds induced by optimal stannum doping, which is corroborated by Rayleigh analysis. A phase transition from ferroelectric multiphase coexistence to paraelectric phase is observed, alongside a rapid miniaturized and eventually disappeared domains with increasing stannum doping. This evolution in phase structure and domain configuration induces a nearly vanishing polarization anisotropy and low domain wall energy, facilitating easy polarization rotation and domain wall motion, thereby significantly contributing to the extrinsic piezoelectric response. Consequently, the origins of ultrahigh performance can be attributed to the synergistic effect of stannum-induced intrinsic and extrinsic contributions in barium titanate-based ceramics. This study provides fundamental insights into the role of doping elements and offers guidance for the design of high-performance piezoelectrics.

Objective: Periodontitis is a complex and multifactorial disease and it is challenging to decipher its underlying causes and mechanisms. This study attempted to explore potential circulating proteins in connection to periodontitis through proteome-wide Mendelian randomisation (MR). Methods: We analysed 1722 circulating proteins to identify prospective drug targets for tackling periodontitis, using the genomic dataset from the FinnGen study. Two-sample MR was conducted to evaluate the bidirectional relationship between circulating proteins and periodontitis risk. A dataset from the UK Biobank was used to validate the findings. Single-cell analysis was performed to assess the cellular expression of the identified proteins within gingival tissues. Results: MR analyses found that genetically predicted circulating levels of von Willebrand factor A domain-containing 1 (von Willebrand factor A domain containing 1 [VWA1], odds ratios: 0.94, 95% CI 0.92-0.97, P = 1.28 × 10−5) were inversely associated with periodontitis. In contrast, the level of growth differentiation factor 15 (growth differentiation factor 15 [GDF15], odds ratios: 1.05, 95% CI 1.02-1.07, P = 2.12 × 10−5) might be associated with an increased risk of periodontitis. Single-cell analysis indicated that VWA1 was primarily expressed in endothelial cells of healthy gingival tissues, while the main source of GDF15 was not derived from periodontal cells. Conclusions: The present study suggests that certain plasma proteins like VWA1 and GDF15 may be potentially indicative of the risk and susceptibility to periodontitis. These proteins could possibly be the potential therapeutic targets for treating periodontitis, and further investigation is highly warranted.

Objectives: Femtosecond laser technology has become the primary method for micropore processing due to its high precision and low energy consumption. However, during the process, it is easy to cause microcracks and burrs in the micropores. Additionally, due to the small size, low structural stability and weak wear resistance of the micropores, conventional methods are ineffective in polishing them. To address the challenge of polishing femtosecond laser-processed micropores, the abrasive water jet polishing method is employed. This method leverages the stable removal function and strong adaptability of the abrasive water jet to improve the quality of femtosecond laser-processed micropores. Methods: Computational fluid dynamics (CFD) simulations of the abrasive water jet micropore polishing process under different process parameters were carried out by using Fluent software. A finite element model of abrasive water jet polishing for femtosecond laser-processed micropores was established under various working conditions. The flow field distribution, the erosion rate and the wall shear force under different parameters were analyzed. Corresponding experiments were conducted for each variable discussed in the Fluent simulation, and the variation patterns of micropore inner wall roughness were summarized. Subsequently, optimization experiments were conducted on the three factors, namely jet target distance, jet pressure and abrasive particle size, using the response surface method. The mean square error of shear force on the inner wall of the hole was taken as the response value Y, and the response surface equation was established. The optimal polishing parameter combination was obtained through the response surface equation and experimentally verified. Results: A jet impact angle of 90° is suitable for polishing the inner wall of the micropore, as wall erosion is uniform and the shear force distribution is concentrated at this angle. At a target distance of 4.2 to 6.0 mm, the jet on the end face enters the deceleration stage, and the jet velocity decreases as the target distance increases. The shear force increases with increasing jet pressure. When the jet pressure is 0.80 MPa, the shear force is the smallest, concentrated in the range of 1 500 to 3 500 Pa. At a jet pressure of 1.50 MPa, the shear force is the largest, concentrated in the range of 3 500 to 5 500 Pa. When jet pressure increases from 0.80 to 1.50 MPa, the shear force on the inner wall of the hole increases more than twice. The effects of abrasive particle size and jet pressure on wall shear force are similar. When the abrasive particle size is 1.0 μm, the shear force is the smallest, concentrated in the range of 1 000 to 2 500 Pa. At an abrasive particle size of 30.0 μm, the shear force reaches its maximum, concentrated between 3 000 and 5 500 Pa. Corresponding tests are carried out for each variable discussed in the simulation, and the minimum roughness Ra of the inner wall of the micropore was 0.386 μm. The optimal process parameter combination obtained through response surface analysis is as follows: jet impact angle of 90°, jet target distance of 3.5 mm, jet pressure of 1.10 MPa, and abrasive particle size of 15.0 μm. Under the optimal parameter combination, with an abrasive mass fraction of 5% and a polishing time of 5.0 minutes, the surface roughness Ra of the polished micropore inner wall surface was reduced to 0.354 µm, which is better than the minimum roughness of 0.386 µm observed in the simulation. Polishing efficiency is improved by about 3%, and the quality of the micropore inner wall surface is further enhanced. Conclusions: When the impact angle is constant, the shear force on the inner wall of the hole increases with increasing jet pressure and abrasive particle size. It increases first and then decreases with the increase in jet target distance, with jet pressure having the greatest influence on the wall shear force. Different structural segments of the jet can be applied to different working conditions due to different properties. Additionally, the simulation and experimental results are in good agreement, and the improvement in roughness is significant. This indicates that abrasive water jet polishing significantly enhances the quality of micropore walls, and the data model for response surface prediction has high accuracy.

AgNbO3 (AN) and modified AgNbO3 have been extensively investigated as promising lead-free antiferroelectric (AFE) energy storage materials. Previous studies have focused mainly on the use of an ion dopant at the A/B site to obtain a stabilized AFE phase; however, simultaneous improvements in the recoverable energy storage density (Wrec) and efficiency (η) are still difficult to realize. Herein, we innovatively constructed a AgNbO3–NaNbO3–(Sr0.7Bi0.2)TiO3 (AN–NN–SBT) ternary solid solution to achieve a relaxor AFE in AgNbO3-based materials. The coexistence of antiferroelectric (M3) and paraelectric (O) phases in 0.8(0.7AgNbO3–0.3NaNbO3)–0.2(Sr0.7Bi0.2)TiO3 confirms the successful realization of a relaxor AFE, attributed to multiple ion occupation at the A/B sites. Consequently, a high Wrec of 7.53 J·cm−3 and η of 74.0% are acquired, together with superior stability against various temperatures, frequencies, and cycling numbers. Furthermore, a high power density (298.7 MW·cm−3) and fast discharge speed (41.4 ns) are also demonstrated for the AgNbO3-based relaxor AFE. This work presents a promising energy storage AgNbO3-based ternary solid solution and proposes a novel strategy for AgNbO3-based energy storage via the design of relaxor AFE materials.

Abstract Background Adverse atherogenic lipid profile is associated with an increased risk of major adverse cardiac events in patients after acute coronary syndrome (ACS). Knowledge regarding the impact of statins on lipid profile remains limited. Methods We retrospectively analysed multicenter, real-world data from the Chinese Cardiovascular Association Database-iHeart Project. Patients with a primary diagnosis of ACS from 2014 to 2021 during index hospitalisation and having at least one lipid panel record after discharge within 12 months were enrolled. We analysed target achievement of atherogenic lipid profile, including apolipoprotein B (

Abstract Drought is a major abiotic stress affecting crop yields. Mapping quantitative trait loci (QTLs) and mining genes for drought tolerance in rice are important for identifying gene functions and targets for molecular breeding. Here, we performed linkage analysis of drought tolerance using a recombinant inbred line population derived from Jileng 1 (drought sensitive) and Milyang 23 (drought tolerant). An ultra-high-density genetic map, previously constructed by our research team using genotype data from whole-genome sequencing, was used in combination with phenotypic data for rice grown under drought stress conditions in the field in 2017–2019. Thirty-nine QTLs related to leaf rolling index and leaf withering degree were identified, and QTLs were found on all chromosomes except chromosomes 6, 10, and 11. qLWD4-1 was detected after 32 days and 46 days of drought stress in 2017 and explained 7.07–8.19% of the phenotypic variation. Two loci, qLRI2-2 and qLWD4-2, were identified after 29, 42, and 57 days of drought stress in 2018. These loci explained 10.59–17.04% and 5.14–5.71% of the phenotypic variation, respectively. There were 281 genes within the QTL interval. Through gene functional annotation and expression analysis, two candidate genes, Os04g0574600 and OsCHR731, were found. Quantitative reverse transcription PCR analysis showed that the expression levels of these genes were significantly higher under drought stress than under normal conditions, indicating positive regulation. Notably, Os04g0574600 was a newly discovered drought tolerance gene. Haplotype analysis showed that the RIL population carried two haplotypes (Hap1 and Hap2) of both genes. Lines carrying Hap2 exhibited significantly or extremely stronger drought tolerance than those carrying Hap1, indicating that Hap2 is an excellent haplotype. Among rice germplasm resources, there were two and three haplotypes of Os04g0574600 and OsCHR731, respectively. A high proportion of local rice resources in Sichuan, Yunnan, Anhui, Guangdong and Fujian provinces had Hap of both genes. In wild rice, 50% of accessions contained Hap1 of Os04g0574600 and 50% carried Hap4; 13.51%, 59.46% and 27.03% of wild rice accessions contained Hap1, Hap2, and Hap3, respectively. Hap2 of Os04g0574600 was found in more indica rice resources than in japonica rice. Therefore, Hap2 has more potential for utilization in future drought tolerance breeding of japonica rice.

Abstract Background Medication-related osteonecrosis of the Jaw (MRONJ) is a rare but severe side effect in patients treated with medications such as Bisphosphonates (BPs). Its pathophysiological mechanism needs to be more precise. Establishing preventive measures and treatment standards is necessary. This study aimed to develop a composite hydrogel scaffold constituted by methacrylated gelatin (GelMA), methacrylated heparin (HepMA) and PRF, and investigate its potential application value in the prevention of MRONJ. Methods GelMA, HepMA, and PRF were prepared using specific ratios for hydrogel scaffolds. Through mechanical properties and biocompatibility analysis, the release rate of growth factors and the ability to promote bone differentiation in vitro were evaluated. To explore the healing-enhancing effects of hydrogels in vivo, the composite hydrogel scaffold was implanted to the MRONJ rat model. Micro-computed tomography (Micro-CT) and histological examination were conducted to evaluate the bone morphology and tissue regeneration. Results The Hep/GelMA-PRF hydrogel improved the degradation rate and swelling rate. It was also used to control the release rate of growth factors effectively. In vitro, the Hep/GelMA-PRF hydrogel was biocompatible and capable of reversing the inhibitory effect of zoledronic acid (ZOL) on the osteogenic differentiation of MC3T3-E1s. In vivo, the micro-CT analysis and histological evaluation demonstrated that the Hep/GelMA-PRF group exhibited the best tissue reconstruction. Moreover, compared to the ZOL group, the expression of osteogenesis proteins, including osteocalcin (OCN), type collagen I (Col I), and bone morphogenetic protein-2 (BMP-2) in the Hep/GelMA-PRF group were all significantly upregulated (P

Abstract The time-dependent effects in steel-concrete composite beam bridges can intensify track irregularities, subsequently leading to amplified train-bridge coupling vibrations. This phenomenon may increase the stress amplitudes in the bridge steel, thereby impacting the fatigue performance of the composite structures. This paper employs multiple rigid body dynamics to construct a high-speed train model and utilizes the finite element method to develop a steel-concrete composite beam element model that accounts for time-dependent effects, interfacial slip, and shear hysteresis. This approach enables the computational analysis of the train-bridge coupling system, facilitating an investigation into the influence of concrete’s time-dependent effects on the fatigue performance of railway steel-concrete composite bridges. Focusing on a 40-m simply supported composite bridge, the train-bridge coupling dynamic responses were computed for each operational year within a decade of the completion of construction. Applying the P-M linear fatigue damage accumulation theory, statistical analysis of stress history data across various operational periods was conducted to quantify the fatigue damage induced by a single eight-car high-speed train on the lower flange of the mid-span steel beam and the beam-end studs. The findings reveal that the beam-end studs sustain greater damage than the mid-span steel beam. Moreover, the detrimental impact of time-dependent effects diminishes with the increase of operational years. Notably, compared to the initial year, the fatigue damage to the lower flange of the mid-span steel beam by an eight-car train in the tenth year has surged by 39.3%. Conversely, the damage to the beam-end studs has decreased by 47.5%.

Abstract Background The determining effect of facial hard tissues on soft tissue morphology in orthodontic patients has yet to be explained. The aim of this study was to clarify the hard-soft tissue relationships of the lower 1/3 of the face in skeletal Class II-hyperdivergent patients compared with those in Class I-normodivergent patients using network analysis. Methods Fifty-two adult patients (42 females, 10 males; age, 26.58 ± 5.80 years) were divided into two groups: Group 1, 25 subjects, skeletal Class I normodivergent pattern with straight profile; Group 2, 27 subjects, skeletal Class II hyperdivergent pattern with convex profile. Pretreatment cone-beam computed tomography and three-dimensional facial scans were taken and superimposed, on which landmarks were identified manually, and their coordinate values were used for network analysis. Results (1) In sagittal direction, Group 2 correlations were generally weaker than Group 1. In both the vertical and sagittal directions of Group 1, the most influential hard tissue landmarks to soft tissues were located between the level of cemento-enamel junction of upper teeth and root apex of lower teeth. In Group 2, the hard tissue landmarks with the greatest influence in vertical direction were distributed more forward and downward than in Group 1. (2) In Group 1, all the correlations for vertical-hard tissue to sagittal-soft tissue position and sagittal-hard tissue to vertical-soft tissue position were positive. However, Group 2 correlations between vertical-hard tissue and sagittal-soft tissue positions were mostly negative. Between sagittal-hard tissue and vertical-soft tissue positions, Group 2 correlations were negative for mandible, and were positive for maxilla and teeth. Conclusion Compared with Class I normodivergent patients with straight profile, Class II hyperdivergent patients with convex profile had more variations in soft tissue morphology in sagittal direction. In vertical direction, the most relevant hard tissue landmarks on which soft tissue predictions should be based were distributed more forward and downward in Class II hyperdivergent patients with convex profile. Class II hyperdivergent pattern with convex profile was an imbalanced phenotype concerning sagittal and vertical positions of maxillofacial hard and soft tissues.

Abstract Histone lysine methyltransferase 2D (KMT2D) is the most frequently mutated epigenetic modifier in head and neck squamous cell carcinoma (HNSCC). However, the role of KMT2D in HNSCC tumorigenesis and whether its mutations confer any therapeutic vulnerabilities remain unknown. Here we show that KMT2D deficiency promotes HNSCC growth through increasing glycolysis. Additionally, KMT2D loss decreases the expression of Fanconi Anemia (FA)/BRCA pathway genes under glycolytic inhibition. Mechanistically, glycolytic inhibition facilitates the occupancy of KMT2D to the promoter/enhancer regions of FA genes. KMT2D loss reprograms the epigenomic landscapes of FA genes by transiting their promoter/enhancer states from active to inactive under glycolytic inhibition. Therefore, combining the glycolysis inhibitor 2-DG with DNA crosslinking agents or poly (ADP-ribose) polymerase (PARP) inhibitors preferentially inhibits tumor growth of KMT2D-deficient mouse HNSCC and patient-derived xenografts (PDXs) harboring KMT2D-inactivating mutations. These findings provide an epigenomic basis for developing targeted therapies for HNSCC patients with KMT2D-inactivating mutations.

Abstract Background This study quantitatively analyzed the anatomic structure of the alveolar bone in the maxillary molar region at three potential locations for Temporary Anchorage Device (TAD) placement. Additionally, the study compared the variability in this region across different age groups, sagittal skeletal patterns, vertical facial types, and sexes. Methods In this retrospective cone-beam computed tomography study, the buccal alveolar bone was analyzed in the posterior molar area of 200 patients, the measurement items include buccal alveolar bone height, alveolar bone thickness, interradicular distance, and maxillary retromolar space. Results Buccal alveolar height was greatest in the U56 region. The interradicular space was largest in the U56 region and increased from the alveolar crest to the sinus floor. Buccal alveolar bone thickness was highest in the U67 region and generally increased from the alveolar crest to the sinus floor. The maxillary retromolar space gradually increased from the alveolar crest to the root apex. Conclusions TADs are safest when placed in the buccal area between the maxillary second premolar and the first molar, particularly at the 9 mm plane. The U67 region is the optimal safe zone for TAD placement for maxillary dentition distalization. TADs placement in adolescents can be challenging. Maxillary third molar extraction can be considered for maxillary dentition distalization.

Abstract Background The potentially fatal attacks experienced by porphyria carriers are triggered by various porphyrinogenic drugs. However, determining the safety of particular drugs is challenging. Methods We retrospectively used the U.S. Food and Drug Administration’s Adverse Event Reporting System (FAERS) to identify drugs associated with porphyria as an adverse event (AE) extracted from data from January 2004 to March 2022. The associated search terms included “Porphyria,” “Porphyria screen,” “Porphyria non-acute,” “Porphyria acute,” “Acquired porphyria,” and “Pseudoporphyria.” Signal mining analysis was performed to identify the association between drugs and AEs by four algorithms, namely the reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker. Results FAERS reported 1470 cases of porphyria-related AEs, and 406 drugs were screened after combining trade and generic names. All four algorithms identified 52 drugs with signals. The characteristics of all the reports and signaling drugs were analyzed. Conclusions This is the first report of drug-associated porphyria that provides critical information on drug porphyrogenicity, facilitating rational and evidence-based drug prescription and improving the accuracy of porphyrogenicity prediction based on model algorithms. Moreover, this study serves a reference for clinicians to ensure that porphyrinogenic drugs are not prescribed to carriers of porphyria genetic mutations.

Abstract Compared with teenage patients, adult patients generally show a slower rate of tooth movement and more pronounced alveolar bone loss during orthodontic treatment, indicating the maladaptation of alveolar bone homeostasis under orthodontic force. However, this phenomenon is not well-elucidated to date, leading to increased treatment difficulties and unsatisfactory treatment outcomes in adult orthodontics. Aiming to provide a comprehensive knowledge and further inspire insightful understanding towards this issue, this review summarizes the current evidence and underlying mechanisms. The age-related abatements in mechanosensing and mechanotransduction in adult cells and periodontal tissue may contribute to retarded and unbalanced bone metabolism, thus hindering alveolar bone reconstruction during orthodontic treatment. To this end, periodontal surgery, physical and chemical cues are being developed to reactivate or rejuvenate the aging periodontium and restore the dynamic equilibrium of orthodontic-mediated alveolar bone metabolism. We anticipate that this review will present a general overview of the role that aging plays in orthodontic alveolar bone metabolism and shed new light on the prospective ways out of the impasse.

Abstract In the digital era, digital platforms are gradually changing the ways of life and social production and are becoming the centre of digital services in various industries. Additionally, they break the established institutional framework of social recognition and promote technological change and innovation. Thus, examining the quality of innovation facilitated by digital platforms has become an important area of research. This paper utilises China’s 2011–2021 provincial panel data and examines digital platforms, resource mismatches and innovation quality within the same research framework. The direct, indirect and nonlinear effects of digital platforms on innovation quality are explored using the fixed effects model, intermediary effect model and dynamic threshold regression model. The findings indicate that digital platforms have a significant positive direct effect on innovative quality, and resource mismatches play intermediary and threshold roles in the process. These findings offer policy guidance for constructing robust digital platform ecosystems and enhancing innovation quality.

Abstract Background Rash is one of common adverse drug reaction and which have been reported in typical and atypical antipsychotics. Reports of lurasidone induced skin reactions are sparse. In this study, we report a case of rash caused by lurasidone. Case presentation A 63-year-old man with bipolar disorder (BD) who is treated by lurasidone. However, the patient presents a rash all over after lurasidone dose increasing from 40 mg/day to 60 mg/day. With the diagnosis of drug induced rash, lurasidone was discontinued, and the rash complete disappears within 2 weeks. In addition, all case reports about antipsychotics associated rash were reviewed by searching English and Chinese database including Pubmed, Embase, Cochrane Library, CNKI and Wanfang database. A total of 139 articles contained 172 patients were included in our study. The literature review and our case suggest that the cutaneous adverse events caused by antipsychotic drugs should not be ignored, particularly for the patient who was first use or at dose increasing of antipsychotic. Conclusions In conclusion, we report a case of lurasidone related rash and review rash caused by antipsychotics. Psychiatrists should be alert to the possibility of the rash caused by antipsychotics, especially the patient was first use of antipsychotics or the antipsychotic dose was increasing.

Abstract Background Exercise has been identified as a promising non-pharmacological therapy for the management of depression, but there is still controversy over which type is most effective. We aimed to compare and rank the types of exercise that improve depression in postmenopausal women by quantifying information from randomized controlled trials (RCTs). Methods The PubMed, Web of Science, SPORTDiscus, CNKI, The Cochrane Library, PsycINFO, EMBASE, and CINAHL Plus databases were searched to identify articles published from inception to 1 March 2024 reporting RCTs that examined the effectiveness of exercise on depression in postmenopausal women. The risk of bias was assessed using the revised Cochrane risk-of-bias tool for RCTs. The quality of the evidence for each comparison was graded using the online confidence in network meta-analysis tool (CINeMA). Standardized mean differences (SMDs) were calculated using the mean and standard deviation of pre-to-post intervention changes and then pooled using a random effects model in a pairwise meta-analysis using Review Manager 5.4. Then, a frequentist network meta-analysis was conducted using a random effects model was conducted to evaluate the efficacy of different exercise types using the network package of Stata 15. Results This study included 26 studies involving 2,170 participants. The pairwise meta-analysis revealed that exercise had a significant positive effect on depression in postmenopausal women (SMD = -0.71, 95% confidence interval [CI] = -0.94 to -0.48; I 2 = 78%). The network meta-analysis revealed that mind-body exercise (SMD = -0.97, 95% CI = -1.28 to -0.67), aerobic exercise (SMD = -0.58, 95% CI = -0.88 to -0.27) and multicomponent exercise (SMD = -0.57, 95% CI = -1.15 to -0.002) significantly reduced depression compared to the control intervention. Mind-body exercise had the highest probability of being the most effective intervention. Exercise interventions also showed positive effects on anxiety. Most studies were judged to have some concerns regarding their risk of bias, and the confidence in evidence was often very low according to CINeMA. Conclusion For postmenopausal women, there is very low to moderate quality evidence that exercise interventions are an effective antidepressant therapy, with mind-body exercise most likely being the optimal type. Trial registration This meta-analysis was prospectively registered with PROSPERO (registration number: CRD42024505425).

Abstract Background Mediterranean diet rich in polyphenolic compounds holds great promise to prevent and alleviate multiple sclerosis (MS), a central nervous system autoimmune disease associated with gut microbiome dysbiosis. Health-promoting effects of natural polyphenols with low bioavailability could be attributed to gut microbiota reconstruction. However, its underlying mechanism of action remains elusive, resulting in rare therapies have proposed for polyphenol-targeted modulation of gut microbiota for the treatment of MS. Results We found that oral ellagic acid (EA), a natural polyphenol rich in the Mediterranean diet, effectively halted the progression of experimental autoimmune encephalomyelitis (EAE), the animal model of MS, via regulating a microbiota-metabolites-immunity axis. EA remodeled the gut microbiome composition and particularly increased the relative abundances of short-chain fatty acids -producing bacteria like Alloprevotella. Propionate (C3) was most significantly up-regulated by EA, and integrative modeling revealed a strong negative correlation between Alloprevotella or C3 and the pathological symptoms of EAE. Gut microbiota depletion negated the alleviating effects of EA on EAE, whereas oral administration of Alloprevotella rava mimicked the beneficial effects of EA on EAE. Moreover, EA directly promoted Alloprevotella rava (DSM 22548) growth and C3 production in vitro. The cell-free supernatants of Alloprevotella rava co-culture with EA suppressed Th17 differentiation by modulating acetylation in cell models. C3 can alleviate EAE development, and the mechanism may be through inhibiting HDAC activity and up-regulating acetylation thereby reducing inflammatory cytokines secreted by pathogenic Th17 cells. Conclusions Our study identifies EA as a novel and potentially effective prebiotic for improving MS and other autoimmune diseases via the microbiota-metabolites-immunity axis. Video Abstract

While the impact of the house purchase restriction (HPR) policy on the housing market in China has been deeply examined, there is still little known about how the housing market varies when such policy is abandoned. To fill this gap, we first theoretically propose two hypotheses concerning the relationship between abandoning HPR policy and housing price and transaction based on the housing literature. We then examine the hypotheses by taking Jinan, China as empirical case that offer an excellent policy setting of some districts having discarded the policy while the other remains. The results derived from Synthetic Control Method (SCM) showed that the cancellation of the HPR policy plays a vital role in increasing the transaction volume, but it fails to promote house prices. The findings remain reliable after a series of placebo and robustness tests. This article adds new insight to the debate on efficacy of government intervention via more granular quantitative data, and further contributes to policy implications regarding housing market development.

Abstract The design and preparation of efficient catalysts for ammonia production under mild conditions is a desirable but highly challenging target. Here, we report a series of single-atom catalysts [M-SACs, M = Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II), Mo(II)] derived from UiO-66 containing structural defects and their application to electrochemical reduction of nitrate (NO3 -) to ammonia (NH3). Cu-SAC and Fe-SAC exhibit remarkable yield rates for NH3 production of 30.0 and 29.0 mg h−1 cm−2, respectively, with a high Faradaic efficiency (FENH3) of over 96% at −1.0 V versus the reversible hydrogen electrode. Importantly, their catalytic performance can be retained in various simulated wastewaters. Complementary experiments confirmed the nature of single-atom sites within these catalysts and the binding domains of NO3 - in UiO-66-Cu. In situ spectroscopic techniques, coupled with density functional theory calculations confirm the strong binding of NO3 - and the formation of reaction intermediates, thus facilitating the catalytic conversion to NH3.

Abstract Background Cervical cancer is one of the most common gynecological malignancies. Previous studies have shown that the ethanol extract of Sophora moorcroftiana seeds (EESMS) possesses an antiproliferative effect on several tumors in vitro. Therefore, in this study, we assessed the impact of EESMS on human cervical carcinoma (HeLa) cell proliferation. Methods The proliferation and apoptotic effects of HeLa cells treated with EESMS were evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay, dual acridine orange/ethidium bromide double staining, flow cytometry, and western blotting. Single-cell level atomic force microscopy (AFM) was conducted to detect the mechanical properties of HeLa cells, and proteomics and bioinformatics methods were used to elucidate the molecular mechanisms of EESMS. Results EESMS treatment inhibited HeLa cell proliferation by blocking the G0/G1 phase, increasing the expression of Caspase-3 and affecting its mechanical properties, and the EESMS indicated no significant inhibitory effect on mouse fibroblasts L929 cell line. In total, 218 differentially expressed proteins were identified using two-dimensional electrophoresis, and eight differentially expressed proteins were successfully identified using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. The differentially expressed proteins were involved in various cellular and biological processes. Conclusion This study provides a perspective on how cells change through biomechanics and a further theoretical foundation for the future application of Sophora moorcroftiana as a novel low-toxicity chemotherapy medication for treating human cervical cancer.

Abstract Background Palliative care and the integration of health and social care have gradually become the key direction of development to address the aging of the population and the growing burden of multimorbidity at the end of life in the elderly. Aims To explore the benefits/effectiveness of the availability and stability of palliative care for family members of terminally ill patients in an integrated institution for health and social care. Methods This prospective observational study was conducted at an integrated institution for health and social care. 230 patients with terminal illness who received palliative care and their family members were included. Questionnaires and scales were administered to the family members of patients during the palliative care process, including quality-of-life (SF-8), family burden (FBSD, CBI), anxiety (HAMA), and distress (DT). We used paired t-tests and correlation analyses to analyze the data pertaining to our research questions. Results In the integrated institution for health and social care, palliative care can effectively improve quality of life, reduce the family’s burden and relieve psychological impact for family members of terminally ill patients. Palliative care was an independent influencing factor on the quality of life, family burden, and psychosocial status. Independently of patient-related and family-related factors, the results are stable and widely applicable. Conclusion The findings underline the availability and stability of palliative care and the popularization of an integrated service model of health and social care for elder adults.

ObjectiveThis study aimed to use visual mapping and bibliometric analysis to summarize valuable information on the tumor microenvironment (TME)-related research on hepatocellular carcinoma (HCC) in the past 20 years and to identify the research hotspots and trends in this field.MethodsWe screened all of the relevant literature on the TME of HCC in the Web of Science database from 2003 to 2023 and analysed the research hotspots and trends in this field via VOSviewer and CiteSpace.ResultsA total of 2,157 English studies were collected. According to the prediction, the number of papers that were published in the past three years will be approximately 1,394, accounting for 64.63%. China published the most papers (n=1,525) and had the highest total number of citations (n=32,253). Frontiers In Immunology published the most articles on the TME of HCC (n=75), whereas, Hepatology was the journal with the highest total number of citations (n=4,104) and average number of citations (n=91). The four clusters containing keywords such as “cancer-associated fibroblasts”, “hepatic stellate cells”, “immune cells”, “immunotherapy”, “combination therapy”, “landscape”, “immune infiltration”, and “heterogeneity” are currently hot research topics in this field. The keywords “cell death”, “ferroptosis”, “biomarkers”, and “prognostic features” have emerged relatively recently, and these research directions are becoming increasingly popular.ConclusionsWe identified four key areas of focus in the study of the TME in HCC: the main components and roles in the TME, immunotherapy, combination therapy, and the microenvironmental landscape. Moreover, the result of our study indicate that effect of ferroptosis on the TME in HCC may become a future research trend.

Background: Chronic stress can induce the cognitive impairment, and even promote the occurrence and development of Alzheimer's disease (AD). Evidence has suggested that chronic stress impacts on glucose metabolism, and both of these have been implicated in AD. Here we focused on the effect of insulin resistance in glucose metabolism, and further evaluated the changes in cognition and pathology. Methods: Male 9-month-old wild-type and APP/PS1 mice were randomly divided into 4 groups. Mice in the chronic unpredictable mild stress (CUMS) groups were exposed for 4 weeks. Homeostatic Model Assessment (HOMA) was utilized to evaluate insulin sensitivity. A total of eighty-four genes related to the insulin signaling pathway were examined for rapid screening. Additionally, the phosphorylated protein expressions of insulin receptors (IR), IR substrate 1 (IRS1), c-Jun N-terminal kinase (JNK), and amyloid were detected in the hippocampus. Cognitive function was assessed through ethological methods. Cognitive function was assessed using both the Morris water maze (MWM) and the Passive avoidance test (PAT). Results: Four weeks of CUMS exposure significantly increased the HOMA value, indicating reduced insulin sensitivity. The gene expressions of Insr and Lipe were downregulated. Additionally, the analysis revealed a significant interaction between the genotype (wild-type vs. APP/PS1) and CUMS treatment on the phosphorylated protein expressions of insulin receptor substrate 1 (IRS1). Specifically, CUMS exposure increased the inhibitory phosphorylation site (IRS1-pSer636) and decreased the excitatory phosphorylation site (IRS1-pTyr465) in the post-insulin receptor signaling pathway within the hippocampus of both wild-type and APP/PS1 mice. Moreover, CUMS exposure induced and exacerbated cognitive impairments in both wild-type and APP/PS1 mice, as assessed by the Morris water maze (MWM) and Passive avoidance test (PAT). However, there was no significant effect of CUMS on senile plaque deposition or levels of Aβ42 and Aβ40 in wild-type mice. Conclusions: Chronic stress significantly affects hippocampal cognitive function through insulin resistance and exacerbates AD pathology. This study reveals the complex relationship between chronic stress, insulin resistance, and AD, providing new insights for developing interventions targeting chronic stress and insulin resistance.

Amid the escalating conflicts between urban demography, resource availability, and environmental constraints, there is an accelerating demand for emergency medical services prompted by a spectrum of factors including diseases, natural calamities, and unforeseen events. This growth is further accentuated by an imbalance in the allocation of emergency facilities, amplifying public anxiety and underscoring the urgent necessity for scientifically informed optimization of pre-hospital emergency facilities. To this end, the present study articulates specific optimization goals for facility deployment and introduces a nuanced set coverage optimization model that integrates spatiotemporal determinants of emergency service requirements. The model is fortified with a constellation of constraints, including spatial constraint, temporal constraint, and coverage constraint. For spatial constraints, we use the Monte Carlo simulation to predict the spatial distribution of emergency demands. Temporal constraints involve determining the actual travel time matrix from predicted demand points to candidate sites. Coverage constraints specify the effective demand coverage rate. This study uses Nanjing as a case example, utilizing multisource big data, including ambulance GPS logs from June 2016 to May 2017, Amap traffic congestion indicators, and survey data on existing emergency facilities in Nanjing City. By preprocessing and analyzing the existing data, this study thoroughly investigates the spatiotemporal distribution of emergency demands and the impact of traffic congestion on emergency service effectiveness. Consequently, the model incorporates constraints that ensure, under the specified planning and actual traffic conditions, 95 % of the simulated emergency demands can be met within an 8-minute on-route time. Locations for pre-hospital emergency stations are optimized using a genetic algorithm, achieving the best solution at the 120th iteration. Verification confirms 134 optimal sites; after excluding 52 existing sites, 82 potential sites are identified. The new layout plan has reduced Nanjing’s average emergency response time from 18.6 min to 12 min. Additionally, under peak and average traffic conditions, emergency demand coverage rates improved from 76.92 % and 83.18 % at 15 min to 95.61 % and 98.10 % at 12 min, respectively. These results demonstrate that the new layout significantly enhances practical application effectiveness. The approach presented in this paper addresses the previously overlooked randomness of emergency incidents and traffic conditions, offering innovative strategies for improving the efficiency and effectiveness of emergency station planning and site selection models.

Vitamin D binding protein (VDBP) serves as a key transporter protein responsible for binding and delivering vitamin D and its metabolites to target organs. VDBP plays a crucial part in the inflammatory reaction following tissue damage and is engaged in actin degradation. Recent research has shed light on its potential role in various diseases, leading to a growing interest in understanding the implications of VDBP in psychiatric and neurological disorders. The purpose of this review was to provide a summary of the existing understanding regarding the involvement of VDBP in neurological and psychiatric disorders. By examining the intricate interplay between VDBP and these disorders, this review contributes to a deeper understanding of underlying mechanisms and potential therapeutic avenues. Insights gained from the study of VDBP could pave the way for novel strategies in the diagnosis, prognosis, and treatment of psychiatric and neurological disorders.

Abstract Background Pharmacist clinics offer professional pharmaceutical services that can improve public health outcomes. However, primary healthcare staff in China face various barriers and challenges in implementing such clinics. To identify existing problems and provide recommendations for the implementation of pharmacist clinics, this study aims to assess the knowledge, attitudes, and practices of pharmacist clinics among primary healthcare providers. Methods A cross-sectional survey based on the Knowledge-Attitude-Practice (KAP) model, was conducted in community health centers (CHCs) and private hospitals in Shanghai, China in May, 2023. Descriptive analytics and the Pareto principle were used to multiple-answer questions. Chi-square test, Fisher’s exact test, and binary logistic regression models were employed to identify factors associated with the knowledge, attitudes, and practices of pharmacist clinics. Results A total of 223 primary practitioners participated in the survey. Our study revealed that most of them had limited knowledge (60.1%, n = 134) but a positive attitude (82.9%, n = 185) towards pharmacist clinics, with only 17.0% (n = 38) having implemented them. The primary goal of pharmacist clinics was to provide comprehensive medication guidance (31.5%, n = 200), with medication education (26.3%, n = 202) being the primary service, and special populations (24.5%, n = 153) identified as key recipients. Logistic regression analysis revealed that education, age, occupation, position, work seniority, and institution significantly influenced their perceptions. Practitioners with bachelor’s degrees, for instance, were more likely than those with less education to recognize the importance of pharmacist clinics in medication guidance (aOR: 7.130, 95%CI: 1.809–28.099, p-value = 0.005) and prescription reviews (aOR: 4.675, 95% CI: 1.548–14.112, p-value = 0.006). Additionally, practitioners expressed positive attitudes but low confidence, with only 33.3% (n = 74) feeling confident in implementation. The confidence levels of male practitioners surpassed those of female practitioners (p-value = 0.037), and practitioners from community health centers (CHCs) exhibited higher confidence compared to their counterparts in private hospitals (p-value = 0.008). Joint physician-pharmacist clinics (36.8%, n = 82) through collaboration with medical institutions (52.0%, n = 116) emerged as the favored modality. Daily sessions were preferred (38.5%, n = 86), and both registration and pharmacy service fees were considered appropriate for payment (42.2%, n = 94). The primary challenge identified was high outpatient workload (30.9%, n = 69). Conclusions Although primary healthcare practitioners held positive attitudes towards pharmacist clinics, limited knowledge, low confidence, and high workload contributed to the scarcity of their implementation. Practitioners with diverse sociodemographic characteristics, such as education, age, and institution, showed varying perceptions and practices regarding pharmacist clinics.

Abstract Background The operation accuracy and efficiency of dynamic navigated endodontic surgery were evaluated through in vitro experiments. This study provides a reference for future clinical application of dynamic navigation systems in endodontic surgery. Materials and methods 3D-printed maxillary anterior teeth were used in the preparation of models for endodontic surgery. Endodontic surgery was performed with and without dynamic navigation by an operator who was proficient in dynamic navigation technology but had no experience in endodontic surgery. Optical scanning data were applied to evaluate the length and angle deviations of root-end resection. And the operation time was recorded. T tests were used to analyze the effect of dynamic navigation technology on the accuracy and duration of endodontic surgery. Results With dynamic navigation, the root-end resection length deviation was 0.46 ± 0.06 mm, the angle deviation was 2.45 ± 0.96°, and the operation time was 187 ± 22.97 s. Without dynamic navigation, the root-end resection length deviation was 1.20 ± 0.92 mm, the angle deviation was 16.20 ± 9.59°, and the operation time was 247 ± 61.47 s. Less deviation was achieved and less operation time was spent with than without dynamic navigation (P

Carbon emissions from China’s forest products industry were considered based on the data of 2001-2020. Then a carbon emissions Kuznets curve was constructed to judge the relationship between the economic development level and carbon emissions. The logarithmic mean Divisia index (LMDI) was used to analyze the influencing factors of carbon emissions. The carbon emissions from China’s forest products industry showed a trend of rapid growth in the early stage and slow decline in the later stage, increasing from 19.46 million tonnes in 2001 to 54.18 million tonnes in 2020. Consumption of raw coal was the main reason for the increase in carbon emissions. There was an inverted-U relationship between the economic development level and carbon emissions, and the industry output value of CNY 3306.56 billion was the theoretical inflection point. The current economic development level of the industry was in the left-half part of the inverted “U” shape, indicating that carbon emissions from this industry will continue to increase with the increase of industrial output. Economic development was the key factor driving the increase of carbon emissions in the forest products industry, while the energy intensity was the key factor inhibiting the growth of carbon emissions.

Abstract The mechanisms of bifurcation, a key step in thyroid development, are largely unknown. Here we find three zebrafish lines from a forward genetic screening with similar thyroid dysgenesis phenotypes and identify a stop-gain mutation in hgfa and two missense mutations in met by positional cloning from these zebrafish lines. The elongation of the thyroid primordium along the pharyngeal midline was dramatically disrupted in these zebrafish lines carrying a mutation in hgfa or met. Further studies show that MAPK inhibitor U0126 could mimic thyroid dysgenesis in zebrafish, and the phenotypes are rescued by overexpression of constitutively active MEK or Snail, downstream molecules of the HGF/Met pathway, in thyrocytes. Moreover, HGF promotes thyrocyte migration, which is probably mediated by downregulation of E-cadherin expression. The delayed bifurcation of the thyroid primordium is also observed in thyroid-specific Met knockout mice. Together, our findings reveal that HGF/Met is indispensable for the bifurcation of the thyroid primordium during thyroid development mediated by downregulation of E-cadherin in thyrocytes via MAPK-snail pathway.

The N6-methyladenosine (m6A) modification is the most prevalent modification of eukaryotic mRNAs and plays a crucial role in various physiological processes by regulating the stability or function of target mRNAs. Accumulating evidence has suggested that m6A methylation may be involved in the pathological process of major depressive disorder (MDD), a common neuropsychiatric disorder with an unclear aetiology. Here, we found that the levels of the circular RNA HECW2 (circHECW2) were significantly increased in the plasma of both MDD patients and the chronic unpredictable stress (CUS) mouse model. Notably, the downregulation of circHECW2 attenuated astrocyte dysfunction and depression-like behaviors induced by CUS. Furthermore, we demonstrated that the downregulation of circHECW2 increased the expression of the methylase WTAP, leading to an increase in Gng4 expression via m6A modifications. Our findings provide functional insight into the correlation between circHECW2 and m6A methylation, suggesting that circHECW2 may represent a potential target for MDD treatment.

Condyloma acuminatum (CA) is a sexually transmitted disease characterized by proliferative lesions in the anogenital region, and its pathogenesis is mainly related to HPV infection and disturbed immune responses. Studies have shown that the incidence of CA is higher in women than in men, and the incidence of CA during pregnancy is higher than that during non-pregnancy. Sex hormones may be related to the occurrence and development of CA. This article reviews the association of estrogen and progesterone with CA, and discusses the possible link of estrogen and CA to the balance of Th1/Th2 and Th17/Treg in cellular immunity during HPV infection, in addition to exploration of the role of estrogen and progesterone in the pathogenesis and recurrence of CA, in order to provide new ideas for the clinical diagnosis and treatment of CA.

Abstract Despite the dominance of lead-based piezoelectric materials with ultrahigh electric-field-induced strain in actuating applications, seeking eco-friendly substitutes with an equivalent performance remains an urgent demand. Here, a strategy of regulating the irreversible non-180° domain via phase engineering is introduced to optimize the available strain (the difference between the maximum strain and the remnant strain in a unipolar strain curve) in the lead-free potassium–sodium niobate-based piezoelectric ceramics. In situ synchrotron X-ray diffraction and Rayleigh analysis reveal the contribution of the non-180° domain to available strain in the tetragonal–orthorhombic–rhombohedral phase boundary. The reducing orthorhombic phase and increasing rhombohedral/tetragonal phase accompanied by the reduced irreversible non-180° domain are obtained with increasing doping of Sb5+, resulting in an enlarged available strain due to the significantly lowered remnant strain. This optimization is mainly attributed to the reduced irreversible non-180° domain wall motion and the increased lattice distortion, which are beneficial to decrease extrinsic contribution and enhance intrinsic contribution. The mesoscopic structure of miniaturized nanosized domain with facilitated domain switching also contributes to the enhancement of available strain due to the improved random field and decreased energy barrier. The study will shed light on the design of lead-free high-performance piezoelectric ceramics for actuator applications.

Background: Information on the association between physical activity (PA) and the risk of chronic kidney disease (CKD) is limited. We aimed to explore the associations of total, domain-specific, and intensity-specific PA with CKD and its subtypes in China. Methods: The study included 475,376 adults from the China Kadoorie Biobank aged 30–79 years during 2004–2008 at baseline. An interviewer-administered questionnaire was used to collect the information about PA, which was quantified as metabolic equivalent of task hours per day (MET-h/day) and categorized into 4 groups based on quartiles. Cox regression was used to analyze the association between PA and CKD risk. Results: During a median follow-up of 12.1 years, 5415 incident CKD cases were documented, including 1159 incident diabetic kidney disease (DKD) cases and 362 incident hypertensive nephropathy (HTN) cases. Total PA was inversely associated with CKD risk, with an adjusted hazard ratio (HR, 95% confidence interval (95%CI)) of 0.83 (0.75–0.92) for incident CKD in the highest quartile of total PA as compared with participants in the lowest quartile. Similar results were observed for risk of DKD and HTN, and the corresponding HRs (95%CIs) were 0.75 (0.58–0.97) for DKD risk and 0.56 (0.37–0.85) for HTN risk. Increased nonoccupational PA, low-intensity PA, and moderate-to-vigorous-intensity PA were significantly associated with a decreased risk of CKD, with HRs (95%CIs) of 0.80 (0.73–0.88), 0.85 (0.77–0.94), and 0.85 (0.76–0.95) in the highest quartile, respectively. Conclusion: PA, including nonoccupational PA, low-intensity PA, and moderate-to-vigorous-intensity PA, was inversely associated with the risk of CKD, including DKD, HTN, and other CKD, and such associations were dose dependent.

Abstract Background Acute ischemic stroke is a common neurological disease with a significant financial burden but lacks effective drugs. Hypoxia-inducible factor (HIF) and prolyl hydroxylases (PHDs) participate in the pathophysiological process of ischemia. However, whether FG4592, the first clinically approved PHDs inhibitor, can alleviate ischemic brain injury remains unclear. Methods The infarct volumes and behaviour tests were first analyzed in mice after ischemic stroke with systemic administration of FG4592. The knockdown of HIF-1α and pretreatments of HIF-1/2α inhibitors were then used to verify whether the neuroprotection of FG4592 is HIF-dependent. The targets predicting and molecular docking methods were applied to find other targets of FG4592. Molecular, cell biological and gene knockdown methods were finally conducted to explore the potential neuroprotective mechanisms of FG4592. Results We found that the systemic administration of FG4592 decreased infarct volume and improved neurological defects of mice after transient or permanent ischemia. Meanwhile, FG4592 also activated autophagy and inhibited apoptosis in peri-infarct tissue of mice brains. However, in vitro and in vivo results suggested that the neuroprotection of FG4592 was not classical HIF-dependent. 2-oxoglutarate and iron-dependent oxygenase domain-containing protein 1 (OGFOD1) was found to be a novel target of FG4592 and regulated the Pro-62 hydroxylation in the small ribosomal protein s23 (Rps23) with the help of target predicting and molecular docking methods. Subsequently, the knockdown of OGFOD1 protected the cell against ischemia/reperfusion injury and activated unfolded protein response (UPR) and autophagy. Moreover, FG4592 was also found to activate UPR and autophagic flux in HIF-1α independent manner. Blocking UPR attenuated the neuroprotection, pro-autophagy effect and anti-apoptosis ability of FG4592. Conclusion This study demonstrated that FG4592 could be a candidate drug for treating ischemic stroke. The neuroprotection of FG4592 might be mediated by inhibiting alternative target OGFOD1, which activated the UPR and autophagy and inhibited apoptosis after ischemic injury. The inhibition of OGFOD1 is a novel therapy for ischemic stroke.

Abstract Background This study assessed the effect of standardized efficacy markers on prognosis in patients with newly diagnosed multiple myeloma (MM) during the induction phase of treatment with bortezomib, cyclophosphamide, and dexamethasone (BCD). Methods We retrospectively analyzed clinical data in 197 newly diagnosed MM patients treated with BCD as front‐line regimen at Peking Union Medical College Hospital from January 1, 2013 to December 31, 2018. Results There were 107 patients with International Staging System (ISS) III and 51 with paraprotein of light chain. Of these, 77 completed nine cycles of the BCD regimen. As the number of treatment cycles increased, the proportions of serum and urine immunofixation electrophoresis (IFE) tests elevated from 40.39% to 62.22% and 16.75% to 37.78%, respectively. More than 90% of intact immunoglobulin chain MM patients were evaluated for blood M protein per cycle, but that of urinary M protein was less than 60%. The detection rate of urinary M protein in light chain MM was more than 70% per cycle. Patients with a very good partial response (VGPR) had longer progression‐free survival (PFS) than those with uncertain VGPR (32 vs. 26 months, p = 0.0336). Of the 141 patients who completed at least four cycles without undergoing autologous hematopoietic stem cell transplantation, those who were regularly assessed at every other cycle showed more favorable PFS than those who visited irregularly (27 vs. 22 months, p = 0.059). Conclusion Urinary M protein detection rate is significantly lower than that in serum, leading to an overestimation of efficacy, premature reduction of treatment intensity, and shortened PFS. Precise response assessments are critical to treatment decisions and clinical diagnoses.

Abstract Abnormal lipid metabolism promotes hepatocellular carcinoma (HCC) progression, which engenders therapeutic difficulties owing to unclear mechanisms of the phenomenon. We precisely described a special steatotic HCC subtype with HBV-related cirrhosis and probed its drivers. Hematoxylin-eosin (HE) staining of 245 HCC samples revealed a special HCC subtype (41 cases) characterized by HBV-related cirrhosis and intratumoral steatosis without fatty liver background, defined as steatotic HCC with HBV-related cirrhosis (SBC-HCC). SBC-HCC exhibits a larger tumor volume and worse prognosis than non-SBC-HCC. Screening for driver genes promoting fatty acid (FA) biosynthesis in the Gao’s HBV-related cirrhosis HCC cases and GSE121248’ HBV-related HCC cases revealed that high expression of SOCS5 predicts increased FA synthesis and that SOCS5 is upregulated in SBC-HCC. Through proteomics, metabolomics, and both in vivo and in vitro experiments, we demonstrated that SOCS5 induces lipid accumulation to promote HCC metastasis. Mechanistically, through co-IP and GST-pulldown experiments, we found that the SOCS5-SH2 domain, especially the amino acids Y413 and D443, act as critical binding sites for the RBMX-RRM domain. SOCS5-RBMX costimulates the promoter of SREBP1, inducing de novo lipogenesis, while mutations in the SH2 domain, Y413, and D443 reverse this effect. These findings precisely identified SBC-HCC as a special steatotic HCC subtype and highlighted a new mechanism by which SOCS5 promotes SBC-HCC metastasis.

Ischemic stroke is a high-mortality disease that urgently requires new therapeutic strategies. Insufficient cerebral blood supply can induce poly (ADP-ribose) polymerase (PARP) activation and mitochondrial dysfunction, leading to tissue damage and motor dysfunction. We demonstrate that the expression of TCDD inducible PARP (TIPARP) is elevated in ischemic stroke patients and mice. Knockdown of Tiparp reduces brain infarction and promotes recovery of motor function in ischemic stroke mice. A rationally designed TIPARP inhibitor, XG-04-B1, promotes repair of brain injury and recovery of motor function in ischemic stroke mice. Mechanistically, XG-04-B1 increases neuronal plasticity and inhibits astrocyte activation in ischemic stroke mice. In addition, eukaryotic translation initiation factor 3 subunit B (EIF3B) is a direct target of TIPARP. TIPARP interacts with EIF3B through nucleoplasmic redistribution, leading to mitochondrial dysfunction. Knockdown of Tiparp and inhibition of TIPARP via XG-04-B1 restore mitochondrial homeostasis in ischemic stroke mice. Taken together, TIPARP activation contributes to mitochondrial dysfunction and subsequent brain injury, and is therefore a promising therapeutic target for stroke.

Background Elderly patients with transfusion-dependent non-severe aplastic anemia (TD-NSAA) face limited treatment options owing to transplantation incompatibility and safety concerns.Methods Data from older patients (≥60 years) newly diagnosed with TD-NSAA and had been treated with either avatrombopag (AVA) + cyclosporine (CsA) or CsA monotherapy at our center were retrospectively collected.Results In total, 52 patients were enrolled, with 26 receiving AVA + CsA and 26 receiving CsA monotherapy. The overall response (OR) rate was higher in the AVA + CsA group than in the CsA group at the 1st, 2nd, 3rd, 6th months, and at the end of the follow-up (all p < 0.05). The complete response (CR) rate was higher in the AVA + CsA group than in the CsA group at the 6th month and at the end of follow-up (p = 0.017 and 0.039). Patients receiving AVA + CsA had a shorter time to achieve the first response (p = 0.008) and CR (p = 0.010) than those receiving CsA monotherapy. Furthermore, patients receiving AVA + CsA exhibited a higher rate of platelet transfusion independence at the 3rd (p = 0.041), 6th (p = 0.008) months, and likewise at the end of the follow-up (p = 0.097).Conclusions The addition of AVA to CsA can significantly improve the OR or CR rate and platelet levels with acceptable side effects in elderly patients, which implies that the combination is a viable alternative for elderly patients with TD-NSAA.

As an exogenous pollutant, the microplastics accumulated in soil could alter microbial activity. The use of plastic mulch in greenhouse vegetable planting not only enhances vegetable yield and quality, but also leads to the formation and accumulation of microplastics in the soil over time. It is essential to determine the characteristics of microplastics and microorganisms in soils with varying years of planting is crucial for ensuring vegetable quality and quantity. Therefore, this study investigated the abundance and particle size of microplastics, the concentration of phthalates (PAEs), and the dynamics of soil microbial activity in greenhouse soils with different planting years (5, 10, 15, 20, 25, and 30 years). Results showed that microplastics increased in abundance, particle size, and PAEs concentration as planting years progressed. Specifically, the abundance of microplastics rose from 70.0 ± 8.7 to 224.0 ± 10.4 items/kg, with the proportion of microplastics sized 0–2 mm increasing from 14.02 to 69.11 %, and the total PAEs concentration in the soil escalating from 0.31 to 1.89 mg/kg. Additionally, Bacteroidetes and Actinobacteria levels increased, correlating with organic matter degradation. Metabolic pathway linked to degradation were enriched according to KEGG analysis. Correlation analysis revealed that microplastics notably decreased soil pH, creating an acidic environment that boosted urease activity and the relative abundance of Nitrospirae. This study sheds light on the accumulation characteristics of microplastics and their impact on soil microbial activity following prolonged planting.

ABSTRACTGut microbiota and related metabolites are both crucial factors that significantly influence how individuals with Crohn’s disease respond to immunotherapy. However, little is known about the interplay among gut microbiota, metabolites, Crohn’s disease, and the response to anti-α4β7-integrin in current studies. Our research utilized 2,4,6-trinitrobenzene sulfonic acid to induce colitis based on the humanized immune system mouse model and employed a combination of whole-genome shotgun metagenomics and non-targeted metabolomics to investigate immunotherapy responses. Additionally, clinical cases with Crohn’s disease initiating anti-α4β7-integrin therapy were evaluated comprehensively. Particularly, 16S-rDNA gene high-throughput sequencing and targeted bile acid metabolomics were conducted at weeks 0, 14, and 54. We found that anti-α4β7-integrin therapy has shown significant potential for mitigating disease phenotypes in remission-achieving colitis mice. Microbial profiles demonstrated that not only microbial composition but also microbially encoded metabolic pathways could predict immunotherapy responses. Metabonomic signatures revealed that bile acid metabolism alteration, especially elevated secondary bile acids, was a determinant of immunotherapy responses. Especially, the remission mice significantly enriched the proportion of the beneficial Lactobacillus and Clostridium genera, which were correlated with increased gastrointestinal levels of BAs involving lithocholic acid and deoxycholic acid. Moreover, most of the omics features observed in colitis mice were replicated in clinical cases. Notably, anti-α4β7 integrin provided sustained therapeutic benefits in clinical remitters during follow-up, and long-lasting remission was linked to persistent changes in the microbial-related bile acids. In conclusion, gut microbiota-mediated bile acid metabolism alteration could play a crucial role in regulating immunotherapy responses to anti-α4β7-integrin in Crohn’s disease. Therefore, the identification of prognostic microbial signals facilitates the advancement of targeted probiotics that activate anti-inflammatory bile acid metabolic pathways, thereby improving immunotherapy responses. The integrated multi-omics established in our research provide valuable insights into potential mechanisms that impact treatment responses in complex diseases.

ABSTRACTBackground: Cyclosporine A (CsA) and regular doses of recombinant human thrombopoietin (rhTPO) can accelerate platelet recovery in patients with non-severe aplastic anemia (NSAA). However, it is unclear whether CsA plus rhTPO at a higher dose can further increase the efficacy.Methods: Data from patients with newly diagnosed NSAA, who had been treated with CsA in combination with different doses of rhTPO between February 2021 and August 2021 at Peking Union Medical College Hospital, were reviewed. All the enrolled patients had been treated with CsA at 3–5 mg/(kg/d), and patients were further classified into high-dose (with rhTPO 30000U qd × 14 days for 2 months) group or regular-dose (with rhTPO 15000U qd × 7days for 3 months) group. The treatment response and therapy-related adverse events were compared.Results: 36 patients including 16 (44.4%) in the high-dose and 20 (55.6%) in the regular-dose group were enrolled. The baseline characteristics were compatible between the two groups. The platelet counts were significantly higher at 1/3/6 months in the high-dose group (p = 0.028, 0.0063 and p = 0.040, respectively). The high-dose group had a significantly shorter time to platelet transfusion independence ([1 (0.5–6) months vs 2.5 (1–12) months, p = 0.040]). There was no significant difference in overall response and complete response rate between the two groups at 1/3/6/12 months (p > 0.05). Treatment-related morbidities were similar between the two groups (p > 0.05).Conclusions: Adding a higher dose of rhTPO can further accelerate platelet recovery and platelet transfusion independence in patients with newly diagnosed NSAA.

Abstract Switchable adhesion, a phenomenon characterized by the ability to transition between attachment and detachment states under external stimuli, has recently gained popularity in various advanced devices. The realization of the desired functionalities on such surfaces relies on intricate interfacial designs. A general understanding of the commonalities and distinctions among these designs can foster the development of refined switchable adhesion interfaces (SAIs). To address this, this review first examines adhesion interfaces by focusing on the fundamental interactions at the atomic/molecular level, adhesion models, and their correlation with the diverse forces/bonds that dominate the adhesion behaviors. The latest progress in SAIs based on various forces/bonds, including electrostatic force, van der Waals force, capillary force, chemical bond, and suction force, is then discussed with regard to their specific design strategies, such as structures, components, and triggers. Additionally, an extensive overview of the broad applications of SAIs in fields ranging from space to biomedicine is provided, along with an exploration of the prevailing challenges and potential opportunities. With the rapid progress that has been made in state‐of‐the‐art mechanisms and design strategies, SAIs are expected to undergo booming development in the foreseeable future.

Abstract A comprehensive immune landscape for Brucella infection is crucial for developing new treatments for brucellosis. Here, we utilized single‐cell RNA sequencing (scRNA‐seq) of 290,369 cells from 35 individuals, including 29 brucellosis patients from acute (n = 10), sub‐acute (n = 9), and chronic (n = 10) phases as well as six healthy donors. Enzyme‐linked immunosorbent assays were applied for validation within this cohort. Brucella infection caused a significant change in the composition of peripheral immune cells and inflammation was a key feature of brucellosis. Acute patients are characterized by potential cytokine storms resulting from systemic upregulation of S100A8/A9, primarily due to classical monocytes. Cytokine storm may be mediated by activating S100A8/A9‐TLR4‐MyD88 signaling pathway. Moreover, monocytic myeloid‐derived suppressor cells were the probable contributors to immune paralysis in acute patients. Chronic patients are characterized by a dysregulated Th1 response, marked by reduced expression of IFN‐γ and Th1 signatures as well as a high exhausted state. Additionally, Brucella infection can suppress apoptosis in myeloid cells (e.g., mDCs, classical monocytes), inhibit antigen presentation in professional antigen‐presenting cells (APCs; e.g., mDC) and nonprofessional APCs (e.g., monocytes), and induce exhaustion in CD8+ T/NK cells, potentially resulting in the establishment of chronic infection. Overall, our study systemically deciphered the coordinated immune responses of Brucella at different phases of the infection, which facilitated a full understanding of the immunopathogenesis of brucellosis and may aid the development of new effective therapeutic strategies, especially for those with chronic infection.

Background: The prognosis and therapeutic response of patients with liver hepatocellular carcinoma (LIHC) can be predicted based on programmed cell death (PCD) as PCD plays a crucial role during tumor progression. We developed a PCD-related gene signature to evaluate the therapeutic response and prognosis for patients with LIHC. Methods: Molecular subtypes of LIHC were classified using ConsensusClusterPlus according to the gene biomarkers related to PCD. To predict the prognosis of high- and low-risk LIHC patients, a risk model was established by LASSO regression analysis based on the prognostic genes. Functional enrichment analysis was conducted using clusterProfiler package, and relative abundance of immune cells was quantified applying CIBERSORT package. Finally, to determine drug sensitivity, oncoPredict package was employed. Results: PCD was correlated with the clinicopathologic features of LIHC. Then, we defined four molecular subtypes (C1–C4) of LIHC using PCD-related prognostic genes. Specifically, subtype C1 had the worst prognosis with enriched T cells regulatory (Tregs) and Macrophage_M0 and higher expression of T cell exhaustion markers, meanwhile, C1 also had a relatively higher TIDE score and metastasis potential. A risk model was established using 5 prognostic genes. High-risk patients tended to have higher expression of T cell exhaustion markers and TIDE score and unfavorable outcomes, and they were more sensitive to small molecule drug 5.Fluorouracil. Conclusion: A PCD-related gene signature was developed and verified to be able to accurately predict the prognosis and drug sensitivity of LIHC patients.