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Abstract# It is worth mentioning that the Chinese version of this guideline has been published in the Chinese Journal of Multiple Organ Diseases in the Elderly (Chinese version) in the July 28, 2024 Guidelines and Consensus Column, Vol. 23, No. 7, pages 481-490.: With the rapid advancement of digitalization and intelligence in the medical field, a plethora of cutting-edge technologies are gradually being applied to revolutionize healthcare. In the medical data security privacy protection and artificial intelligence encryption computing, blockchain stands out due to its inherent characteristics of traceability, tamper-proofing, and high credibility. Although blockchain technology has been applied in various industries, its application in the medical field needs more driving force, and its development needs to be standardized. This clinical practice guideline is developed following the World Health Organization's recommended process, adopting Grading of Recommendations Assessment, Development and Evaluation in assessing evidence quality. Considering the integration of blockchain and medical scenarios, we focus on the value and implementability of practical medical applications and provide the guidance on the construction and application of medical blockchain. This practice guideline includesd 10 potential medical application scenarios and usage frameworks. It is worth highlighting that electronic medical record sharing, drug and device anti-counterfeiting, medical digital intellectual property protection, and public health management are considered to be the most easily implemented and effective medical scenarios. The recommendations in this guideline were formulated based on the consideration of stakeholder values and preferences, resource utilization, feasibility, and acceptability, may have a profound impact on the construction of medical blockchain-related scenarios in China and internationally.Registration: Practice Guidance Registration for Transparency (PREPARE) website (http://www.guidelines-registry.cn) Registration No. PREPARE-2023CN637.

Background and aim: Cordyceps militaris (CM) and Armillaria mellea (AM) are medicinal mushrooms with potential applications in the treatment of mood disorders, including depression and anxiety. While research suggests that both CM and AM possess anti-inflammatory properties and hold potential for treating depression when administered separately, there is limited knowledge about their efficacy when combined in a formula, as well as the underlying mechanism involving the modulation of microglia. Experimental procedure: Rats received oral administrations of the low-dose formulation, medium-dose formulation, and high-dose formulation over 28 consecutive days as part of the UCMS protocols. The concentrations of serotonin, dopamine, and the corresponding metabolites in the rat prefrontal cortex and hippocampus were assessed. Blood samples were collected to examine corticosterone levels, and the brains were dissected for evaluating activated microglia morphologies and associated pro- and anti-inflammatory signaling pathways. Results and conclusion: The CM-AM formula effectively averted abnormal behaviors triggered by UCMS, such as anhedonia and hypoactivity, and decreased the turnover rate of monoamines in both the prefrontal cortex and hippocampus. The formula mitigated the increase in serum corticosterone levels induced by chronic stress. Furthermore, the formula alleviated stress-induced microglia activation in the hippocampus, achieving this by down-regulating hyperactivated pro-inflammatory proteins and up-regulating hypoactivated anti-inflammatory proteins in the hippocampus. The antidepressant-like effects potentially stemming from the regulation of neurotransmitters and immunomodulation, likely by restoring the balance of M1 and M2 microglia fractions in the hippocampus. Consequently, the CM-AM formula could be explored as a prospective complementary and alternative therapy for depression.

Magnesium and its alloys show strong mechanical anisotropy due to their hexagonal close-packed structure. This paper processed ambient extrusion and subsequent annealing on AZ31 magnesium alloy bars to investigate the effect of working hardening and texture weakening on yield anisotropy of magnesium alloy. After ambient extrusion, yield strength on different loading direction are improved due to working hardening. ED-yield strength has the highest increment because work hardening has a higher effect on prismatic slip. Then, yield anisotropy becomes stronger with the increase of extrusion train. During annealing, static recrystallization occurs firstly in {101‾1} twinning zones and producing recrystallized grains with random orientation. With the growth of recrystallized grains, basal fiber texture is weakened gradually. Such weak basal texture can promote the activation of basal slip when loading along ED, so ED-yield strength shows a high decrement. On this way, the yield anisotropy in AZ31 magnesium alloy bars is weakened through ambient extrusion and subsequent annealing.

Abstract The tomato hind (Cephalopholis sonnerati) is an emerging economically important grouper in recent years. With the increasing maturity of sequencing technologies and assembly methodologies, a higher quality reference genome has become both accessible and necessary. In this study, we present two telomere-to-telomere (T2T) gap-free haplotype assemblies of the tomato hind with lengths of 1039.53 Mb (YSFRI_Csonn_HA_1.0, N50 43.83 Mb) and 1039.91 Mb (YSFRI_Csonn_HB_1.0, N50 44.09 Mb). Reads from next-generation sequencing, ONT ultra-long sequencing, and PacBio HiFi sequencing exhibited mapping rates exceeding 99.8% when aligned to these two assemblies. Evaluation using Merqury indicated high accuracy for both assemblies, with average quality values of 51.80 and 51.83, respectively. Percentages of 97.9% and 97.8% of complete BUSCOs were achieved, and a total of 23,270 and 23,184 protein-code genes were inferred in each assembly. Moreover, telomere identification, centromere prediction, and repetitive sequence annotation were also successfully performed. These two assemblies provide robust foundation for the genetic analysis and development of molecular genetic breeding technologies in C. sonnerati.

The occurrence of intrusive rocks within the Xinlin area, northeastern China, provides insights into the Neoproterozoic–Mesozoic geodynamic setting of the Erguna block. In this study, we present petrographic, geochemical, and geochronological data on intrusive rocks from the Xinlin area. Zircon U–Pb and muscovite 40Ar/39Ar geochronology reveal that magmatism occurred during the Neoproterozoic (ca. 864.98 Ma), Early Ordovician (ca. 470.0 Ma), Late Carboniferous (ca. 306.9 Ma), Early Permian (ca. 296.9 Ma), and Early Cretaceous (ca. 117.8 Ma) periods. The Neoproterozoic and Early Ordovician intermediate–mafic intrusive rocks have low Rb/Sr contents, high Mg#, and weakly negative Eu anomalies. These results suggest that the magma sources of these rocks varied: intermediate–acidic magmas were derived from the lower crust, and intermediate–mafic magmas originated from the mantle and were subsequently contaminated by crustal material. In contrast, the Late Carboniferous, Early Permian, Late Triassic–Early Jurassic, and Early Cretaceous intermediate–acidic intrusive rocks display high Rb/Sr contents, low Mg#, and strongly negative Eu anomalies, indicating derivation from the partial melting of the lower crust. Our findings, along with previous studies, suggest that Neoproterozoic intrusive rocks were formed during the breakup of the Rodinia supercontinent. The Paleozoic intrusive rocks are associated with the collision and amalgamation of the Erguna and Xing’an blocks, as well as the Songnen and Xing’an blocks. Early Mesozoic intrusive rocks were developed during the subduction of the Mongol-Okhotsk oceanic intracontinental system. Finally, the late Mesozoic intrusive rocks were formed in a non-orogenic extensional setting, potentially linked to the final closure of the Mongol-Okhotsk Ocean or the rollback of the Paleo-Pacific Plate.

Bevacizumab is widely used in various clinical indications, but investigations into its optimal dosage for treating CNS metastases remain limited. The BEEP regimen, comprising bevacizumab, etoposide, and cisplatin, has recently demonstrated promising clinical outcomes for patients with breast cancer brain metastasis (BCBM) or leptomeningeal metastasis (LM). This study aimed to evaluate the exposure-response relationship of bevacizumab in BCBM patients and to explore the improved CNS penetration of chemotherapy by bevacizumab with LM patients. Twenty-two BCBM patients and six LM patients receiving the BEEP regimen were enrolled. For BCBM patients, blood samples were drawn at trough level of cycles 1 and 6 to investigate the association between bevacizumab concentrations and clinical outcomes. For LM patients, plasma and cerebrospinal fluid (CSF) concentrations of bevacizumab and etoposide were measured to investigate the enhancement of etoposide penetration provided by bevacizumab. Concentration evaluation revealed that bevacizumab plasma concentrations substantially varied between individuals. Additionally, concentrations increased after 6 cycles, indicating bevacizumab accumulation during treatment. Although bevacizumab concentrations did not associate with therapeutic response and progression-free survival, patients with higher bevacizumab concentrations exhibited longer overall survival (adjusted HR 0.78; p = 0.039). Furthermore, a positive correlation was observed between time-weighted average concentration of plasma bevacizumab and CSF penetration of etoposide on day 2 (post-bevacizumab) relative to day 1 (pre-bevacizumab) (r = 0.83; p = 0.042). These findings offer valuable insights into the application of therapeutic drug monitoring of bevacizumab to improve survival outcomes in BCBM patients. Further studies are warranted to determine the optimal bevacizumab concentration.

The space hurricane is a newly discovered large-scale three-dimensional magnetic vortex structure that spans the polar ionosphere and magnetosphere. It has been suggested to open a fast energy transport channel for the solar wind to invade Earth’s magnetosphere under northward interplanetary magnetic field (IMF) conditions. It is, therefore, an important phenomenon to understand the solar wind–magnetosphere–ionosphere coupling process under northward IMF conditions. In this study, we report the three-dimensional ionospheric plasma properties of a space hurricane event in the Northern Hemisphere observed by multiple instruments. Based on the convection velocity observations from ground-based radars and polar satellites, we confirm that the major modulation to the polar cap convection called a space hurricane rotates clockwise at the altitude of the ionosphere. Ground-based incoherent scatter radar and polar satellite observations reveal four features associated with the space hurricane: 1) strong plasma flow shears and being embedded in a clockwise lobe convection cell; 2) a major addition to the total energy deposition in the ionosphere–thermosphere system by Joule heating; 3) downward ionospheric electron transport; and 4) multiple ion-temperature enhancements in the sunward velocity region, likely from the spiral arms of the space hurricane. These results present, first, the impact of space hurricane on the low-altitude ionosphere and provide additional insights on the magnetospheric impact on structuring in the polar ionosphere.

Abstract The organophosphate (OP)‐hydrolyzing enzyme phosphotriesterase (PTE, variant L7ep‐3a) immobilized within a partially oxidized mesoporous silicon nanoparticle cage is synthesized and the catalytic performance of the enzyme@nanoparticle construct for hydrolysis of a simulant, dimethyl p‐nitrophenyl phosphate (DMNP), and the live nerve agent VX is benchmarked against the free enzyme. In a neutral aqueous buffer, the optimized construct shows a ≈2‐fold increase in the rate of DMNP turnover relative to the free enzyme. Enzyme@nanoparticles with more hydrophobic surface chemistry in the interior of the pores show lower catalytic activity, suggesting the importance of hydration of the pore interior on performance. The enzyme@nanoparticle construct is readily separated from the neutralized agent; the nanoparticle is found to retain DMNP hydrolysis activity through seven decontamination/recovery cycles. The nanoparticle cage stabilizes the enzyme against thermal denaturing and enzymatic (trypsin) degradation conditions relative to free enzyme. When incorporated into a topical gel formulation, the PTE‐loaded nanoparticles show high activity toward the nerve agent VX in an ex vivo rabbit skin model. In vitro acetylcholinesterase (AChE) assays in human blood show that the enzyme@nanoparticle construct decontaminates VX, preserving the biological function of AChE when exposed to an otherwise incapacitating dose.

PurposePropofol, a widely utilized anesthetic, is employed to alleviate pain and anxiety in outpatient oocyte retrieval procedures. However, its potential impact and safety profile in the context of in vitro fertilization and embryo transfer (IVF-ET) remain unclear.MethodsThis retrospective study enrolled 1187 patients undergoing IVF-ET, and divided into two groups depending on whether they received propofol (propofol group, n=140) or not (control group, n=1047) for anesthesia during oocyte retrieval.ResultsThe baseline characteristics were comparable between the groups. Compared with control group, the number of oocytes retrieved in propofol group was more (p=0.012), while both the estradiol (E2) level on the trigger day and the pre-ovulatory follicle count were higher in propofol group ((p20) to eliminate the influence of inconsistency in the estimation of the pre-ovulatory follicle count between the two groups. Analysis revealed that the use of propofol during oocyte retrieval was particularly advantageous in the subgroup with a pre-ovulatory follicle count of 11–20, yielding a higher oocyte retrieval rate (p

Objective To investigate the changes in liver and kidney function, red blood cell (RBC) count and hemoglobin (HGB) levels in patients undergoing ultrasound-guided percutaneous microwave ablation (UPMWA) for uterine fibroids on postoperative day 1.Methods The changes in liver and kidney function, RBC count and HGB levels in 181 patients who underwent selective UPMWA in the Second Affiliated Hospital of Shantou University Medical College, China, between August 2017 and January 2023 were retrospectively analyzed.Results All patients underwent UPMWA for uterine fibroids; 179 patients had multiple uterine fibroids and 2 patients had single uterine fibroids. The maximum fibroid diameter ranged from 18 to 140 mm, with an average of 68.3 mm. Ultrasound imaging was used to confirm that the blood flow signal within the mass had disappeared in all patients, indicating that the ablation was effective. Within 24 h, compared with before UPMWA, levels of total bilirubin, direct bilirubin, indirect bilirubin and aspartate aminotransferase had significantly increased (p

PurposeThis study aimed to compare the distribution of plantar pressure and anterior-posterior (AP) or medial-lateral (ML) shear forces in healthy younger (HY) people, healthy older (HO) people, and diabetic patients, both in static standing and during gait.Materials and methodsA total of 20 HY adults, 16 HO adults and 15 diabetic patients were included. The static mechanical distribution measurements included: static horizontal, AP slope plane, and left/right slope standing. Data collected during the gait cycle encompassed the plantar pressure-time integral (PTI), peak pressure (PP), AP/ML shear force-time integral (AP-STI/ML-STI), and AP/ML peak shear force (AP-PS/ML-PS). The plantar surface was segmented into regions including hallux (HL), 2nd~5th toes (T2-5), 1st metatarsal head (M1), 2nd~3rd metatarsal heads (M2-3), 4th~5th metatarsal heads (M4-5), lateral foot arch (LA), and heel regions.ResultsThe HO group exhibited increased static pressure in M2-3 and heel regions and AP shear force in the entire plantar and M1 regions, in comparison to the HY group. The diabetes group showed increased static pressure in entire plantar, M1, M2-3 and heel regions and AP shear force in the entire plantar, T2-5, M1, M2-3 and heel regions. During gait, the HO group exhibited increased PTI in the whole plantar, T2-5, M2-3, and M4-5 regions, while the diabetes group showed increased PTI in the whole plantar, M1 and M2-3 regions. The HO group showed increased PP in the whole plantar, M1 and heel regions, while decreased in the M2-3 region. The diabetes group showed increased PP in the whole plantar, T2-5, M2-3, M4-5 and heel regions. The HO group showed increased AP-STI in the T2-5, M1, and M2-3 regions, while the diabetes group showed increased AP-STI in the whole plantar, M2-3 and heel regions.ConclusionsOur findings indicate that both static and dynamic plantar pressures and shear forces are significantly greater in diabetic patients and HO individuals compared to HY adults. The most substantial increases was occurred under the M2-3 and heel regions.

Aeromonas dhakensis is an increasingly recognized human pathogen in recent years and was first isolated and reported in a sample of childhood diarrhea in Bangladesh. More and more cases of Aeromonas dhakensis infection have been reported in recent years. Here we report a case of severe pneumonia caused by Aeromonas dhakensis with severe atrial septal defect. The patient, a 56-year-old male, was admitted to the hospital with severe hypoxemia and severe septic shock. Detection of the patient’s bronchoalveolar lavage fluid (BALF) and peripheral blood by the metagenomic next generation sequencing (mNGS) indicated Aeromonas dhakensis infection.

Citrus melanose, caused by Diaporthe citri, is one of the most prevalent and important fungal diseases of citrus crops globally. However, the overuse of chemical fungicides for disease control has an adverse impact on citrus production. In contrast, biological control agents (BCAs) are environmentally friendly and have become essential tools for plant disease control. In the present study, Bacillus subtilis M23, a strain isolated from healthy citrus leaves, significantly suppressed the mycelial growth of D. citri, the causal agent of citrus melanose, in vitro. The fermentation broth of B. subtilis M23 also exhibited good antifungal activity against D. citri on citrus plants in greenhouse and field experiments. Lipopeptides (LPs) produced by M23 exhibited excellent antifungal activity against D. citri, with a 50 % effective concentration (EC50) of approximately 1.00 and 0.28 μg/mL for inhibition of mycelial growth and conidial germination, respectively. LP biosynthesis genes were identified in the M23 genome using a PCR assay. Notably, LP extracts significantly reduced the formation of pycnidia and ATP biosynthesis in D. citri. Comparative transcriptome analysis revealed significant differences in the expression of genes associated with fungal vacuole, oxidoreductase activity and endopeptidase activity in D. citri treated with B. subtilis M23. Both RNA-seq and RT-qPCR analysis provided similar results on the expression of selected genes. Collectively, our data provided convincing data supporting the biocontrol potential of B. subtilis M23 for the management of citrus melanose.

Abstract Background Systemic therapy is the primary treatment for advanced thymic malignancies. However, there is an urgent need to improve clinical outcome. Personalized treatment based on predictive biomarkers is a potential approach to address this requirement. In this study, we aimed to show the correlation between drug sensitivity tests on CTCs‐derived organoids and clinical response in patients with thymic malignancies. This approach carries the potential to create personalized cancer avatars and improve treatment outcome for patients. Methods We previously reported potential treatment outcome prediction with patient‐derived organoids (cancer avatars) in patients with pancreatic ductal adenocarcinoma. To further investigate the feasibility of this approach in advanced thymic malignancies, we conducted a study in which 12 patients were enrolled and 21 liquid biopsies were performed. Results Cancer avatars were successfully derived in 16 out of 21 samples (success rate 76.2%). We found a sensitivity of 1.0 and specificity of 0.6 for drug sensitivity tests on the cancer avatars, and a two‐tailed Fisher's exact test revealed a significant correlation between drug sensitivity tests and clinical responses (p = 0.0275). Conclusion This study supports the potential of circulating tumor cell‐derived organoids to inform personalized treatment for advanced thymic malignancies. Further validation of this proof of concept finding is ongoing.

Abstract Pyopneumothorax with bronchopleural fistula is a rare complication of lung infection. We herein report a case of pyopneumothorax with bronchopleural fistula caused by Porphyromonas gingivalis infection, a common pathogenic pathogen of periodontitis, in a 49‐year‐old man with periodontitis. The patient was admitted with respiratory failure. Pleural puncture yielded a lot of gas continually and foul‐smelling light brown pus, which was found to be caused due to infection with P. gingivalis by the metagenomic next generation sequencing (mNGS) and anaerobic culture.

The accurate and rapid estimation of canopy nitrogen content (CNC) in crops is the key to optimizing in-season nitrogen fertilizer application in precision agriculture. However, the determination of CNC from field sampling data for leaf area index (LAI), canopy photosynthetic pigments (CPP; including chlorophyll a, chlorophyll b and carotenoids) and leaf nitrogen concentration (LNC) can be time-consuming and costly. Here we evaluated the use of high-precision unmanned aerial vehicle (UAV) multispectral imagery for estimating the LAI, CPP and CNC of winter wheat over the whole growth period. A total of 23 spectral features (SFs; five original spectrum bands, 17 vegetation indices and the gray scale of the RGB image) and eight texture features (TFs; contrast, entropy, variance, mean, homogeneity, dissimilarity, second moment, and correlation) were selected as inputs for the models. Six machine learning methods, i.e., multiple stepwise regression (MSR), support vector regression (SVR), gradient boosting decision tree (GBDT), Gaussian process regression (GPR), back propagation neural network (BPNN) and radial basis function neural network (RBFNN), were compared for the retrieval of winter wheat LAI, CPP and CNC values, and a double-layer model was proposed for estimating CNC based on LAI and CPP. The results showed that the inversion of winter wheat LAI, CPP and CNC by the combination of SFs+TFs greatly improved the estimation accuracy compared with that by using only the SFs. The RBFNN and BPNN models outperformed the other machine learning models in estimating winter wheat LAI, CPP and CNC. The proposed double-layer models (R2=0.67–0.89, RMSE=13.63–23.71 mg g–1, MAE=10.75–17.59 mg g–1) performed better than the direct inversion models (R2=0.61–0.80, RMSE=18.01–25.12 mg g–1, MAE=12.96–18.88 mg g–1) in estimating winter wheat CNC. The best winter wheat CNC accuracy was obtained by the double-layer RBFNN model with SFs+TFs as inputs (R2=0.89, RMSE=13.63 mg g–1, MAE=10.75 mg g–1). The results of this study can provide guidance for the accurate and rapid determination of winter wheat canopy nitrogen content in the field.

The rapid spread of the coronavirus disease (COVID-19) pandemic in over 200 countries poses a substantial threat to human health. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, can be discharged with feces into the drainage system. However, a comprehensive understanding of the occurrence, presence, and potential transmission of SARS-CoV-2 in sewers, especially in community sewers, is still lacking. This study investigated the virus occurrence by viral nucleic acid testing in vent stacks, septic tanks, and the main sewer outlets of community where confirmed patients had lived during the early days of the epidemic in Wuhan, China. The results indicated that the risk of long-term emission of SARS-CoV-2 to the environment via vent stacks of buildings was low after confirmed patients were hospitalized. SARS-CoV-2 were mainly detected in the liquid phase, as opposed to being detected in aerosols, and its RNA in the sewage of septic tanks could be detected for only four days after confirmed patients were hospitalized. The surveillance of SARS-CoV-2 in sewage could be a sensitive indicator for the possible presence of asymptomatic patients in the community, though the viral concentration could be diluted more than ten times, depending on the sampling site, as indicated by the Escherichia coli test. The comprehensive investigation of the community sewage drainage system is helpful to understand the occurrence characteristics of SARS-CoV-2 in sewage after excretion with feces and the feasibility of sewage surveillance for COVID-19 pandemic monitoring.

Edwardsiella tarda is a major causative pathogen of bacterial ascites in Japanese flounder, leading to massive economic losses, and the discovery of molecular markers linked to disease resistance is an effective strategy in resistance breeding programs. The Rho GTPase family comprises small proteins with a molecular weight of 20~30 kDa. Rho GTPase family members are involved in diverse cellular processes, such as cytoskeleton, cell adhesion, vesicle transport, and proliferation. In addition, they play pivotal roles in infection by different pathogens. Rho-related GTP-binding protein Rho6 (Rnd1), a member of the Rho-GTPase family, participates in various biological functions, including neural junction formation, axonal extension, tumorigenesis, neuronal function, and apoptosis. Some members of the Rho family, such as Rac1 and Rac2, regulate immune response in grass carp, large yellow croaker, zebrafish, and half-smooth tongue sole. However, the function of Rnd1 in fish is poorly understood. Japanese flounder (Paralichthys olivaceus) is greatly affected by E. tarda infections during the breeding process. In previous studies, whole-genome sequencing and assembly of Japanese flounder were performed, and subsequently, various disease resistance genes were screened to support the improvement of Japanese flounder germplasm resources. To study the role of Pornd1 in resistance against E. tarda infection in Japanese flounder, Pornd1 was cloned and identified using PCR. The full-length Pornd1 cDNA was 699 bp, containing an open reading frame encoding a 232-amino acid protein. The predicted molecular weight of PoRnd1 was 26 kDa. Sequence and homology analyses showed that the Rnd1 protein harbors a Rho-GTP superfamily structural domain, which is highly conserved in various species. PoRnd1 shares the highest homology with Rnd1 from Hippoglossus hippoglossus (98.28%). On phylogenetic tree, PoRnd1 was clustered with Rnd1 from other fish species. The single-nucleotide polymorphism (SNP) locus associated with E. tarda resistance is located at 4 575 720 bp on chromosome 14 of Japanese flounder. The frequency of the T allele in disease-resistant families (freqT=0.92) was significantly higher than that in susceptible families (freqT=0.20). The SNP was located at the 2nd intron of Pornd1. Real-time quantitative PCR was employed to characterize the expression profiles of Pornd1 in the tissues of healthy and E. tarda-infected fish. Pornd1 expression was the highest in the heart, followed by the liver, kidney, head kidney, and spleen, but its expression was low in the skin, blood, gills, and muscle. In E. tarda-infected fish, the expression of Pornd1 mRNA decreased after 6 h, then gradually increased, and subsequently reached the highest level after 48 h in the liver, kidney, and spleen. Pornd1 expression in the kidney and spleen in the 48 h group was significantly higher than that in the 6 and 12 h groups. Furthermore, Pornd1 expression in the liver of resistant families was significantly higher than that in susceptible families. Based on its His tag, the PoRnd1 recombinant protein was purified using an Ni column and subjected to SDS-PAGE. The target band of PoRnd1 at 32 kDa was observed in the gel after Coomassie Blue staining. The PoRnd1 recombinant protein (0.5 mg/mL) was used to study antibacterial activity through the Oxford cup assay. PoRnd1 significantly inhibited the growth of Staphylococcus aureus, Escherichia coli, E. tarda, and Vibrio harveyi. In summary, Pornd1 may be closely linked to disease resistance in Japanese flounder and can thus serve as an effective gene marker for disease resistance breeding. Our findings provide a theoretical basis for further elucidating the molecular mechanisms of immunity in Japanese flounder.

Background Dubin-Johnson syndrome (DJS), a rare autosomal recessive liver condition, is caused by biallelic loss-of-function mutations of the ABCC2 gene. This study aimed to investigate genetic variations in the drug efflux transporter ABCC2 (MRP2) gene in patients with DJS and to characterise the expression and mechanism of the ABCC2 gene variant.Methods Trio whole exome sequencing was performed in the family to identify the genetic causes. Bioinformatics analysis was performed to assess pathogenicity. In in vitro experiments, site-directed mutagenesis was used to introduce ABCC2 variants in constructs then expressed in HEK293T, HuH-7 and HepG2 cell lines. The expression of total and cell membrane MRP2 was quantified in cells expressing the wild-type or variant forms. Chloroquine and MG132 were used to evaluate the effects of p.R393W on lysosomal and/or proteasomal degradation.Results The twin probands carry DJS-associated variants c.1177C>T (rs777902199) in the ABCC2 gene inherited from the father and the c.3632T>C mutation in the other allele inherited from the mother. The ABCC2 variant, c.1177C>T, results in a p.R393W substitution in MRP2 that is highly conserved among vertebrates, drastically decreasing the expression of mutant protein by promoting proteasomal degradation. Another variant c.3632T>C results in a p.L1211P substitution in MRP2, decreasing the expression of membrane MRP2 but not changing the expression of total protein.Conclusion These results strongly suggest that the p.R393W variant affects the stability of the MRP2 protein and decreases its expression by ubiquitin-mediated proteasomal degradation, and the p.L1211P decreases the expression of membrane MRP2, indicating that these two variants, respectively, cause a loss-of-function of the MRP2 protein and membrane MRP2 ultimately leading to DJS development.

Platelet extracellular vesicles (PEVs) are an emerging delivery vehi for anticancer drugs due to their ability to target and remain in the tumor microenvironment. However, there is still a lack of understanding regarding yields, safety, drug loading efficiencies, and efficacy of PEVs. In this study, various methods were compared to generate PEVs from clinical-grade platelets, and their properties were examined as vehicles for doxorubicin (DOX). Sonication and extrusion produced the most PEVs, with means of 496 and 493 PEVs per platelet (PLT), respectively, compared to 145 and 33 by freeze/thaw and incubation, respectively. The PEVs were loaded with DOX through incubation and purified by chromatography. The size and concentration of the PEVs and PEV-DOX were analyzed using dynamic light scattering and nanoparticle tracking analysis. The results showed that the population sizes and concentrations of PEVs and PEV-DOX were in the ranges of 120–150 nm and 1.2–6.2 × 1011 particles/mL for all preparations. The loading of DOX determined using fluorospectrometry was found to be 2.1 × 106, 1.7 × 106, and 0.9 × 106 molecules/EV using freeze/thaw, extrusion, and sonication, respectively. The internalization of PEVs was determined to occur through clathrin-mediated endocytosis. PEV-DOX were more efficiently taken up by MDA-MB-231 breast cancer cells compared to MCF7/ADR breast cancer cells and NIH/3T3 cells. DOX-PEVs showed higher anticancer activity against MDA-MB-231 cells than against MCF7/ADR or NIH/3T3 cells and better than acommercial liposomal DOX formulation. In conclusion, this study demonstrates that PEVs generated by PLTs using extrusion, freeze/thaw, or sonication can efficiently load DOX and kill breast cancer cells, providing a promising strategy for further evaluation in preclinical animal models. The study findings suggest that sonication and extrusion are the most efficient methods to generate PEVs and that PEVs loaded with DOX exhibit significant anticancer activity against MDA-MB-231 breast cancer cells.

The microstructure and the mechanical properties of α-phase Cu–5Sn alloy, Cu–10Sn alloy, and Cu–15Sn alloy (wt.%) prepared by selective laser melting have been studied in this work. Under the same process condition, the laser absorption of the alloys increases continuously with the increase in Sn content. The optimal process parameters of the three alloys were obtained by Response Surface Method. The Sn content was found to have a significant effect on the relative density of the Cu–Sn alloys, as well as the laser power. The effect of laser power on the relative density of the alloys is weakened by the increase in laser absorption as the Sn content increases. Comparing the melt pool of the three alloys, they all show mainly columnar grains. As the Sn content increases, the size of the columnar grains becomes larger, and when the Sn content reaches 15 wt%, the columnar grains can penetrate through several melt pools. With the increase of Sn content from 5 wt% to 15 wt%, the tensile strength of the alloy increased from 382 MPa to 738 MPa, but the plasticity decreased significantly and the elongation decreased from 26% to 9%. As the Sn content increases from 5 to 15 wt%, the amount of solid-soluble Sn in the α-phase alloy increases, creating a lattice distortion stress field that effectively prevents dislocation movement. Thus, the stress field effectively increasing the yield and tensile strength of the alloy. Meanwhile, the increase in Sn content leads to the appearance of many brittle, hard and rich phases on the micron scale and precipitation from grain boundaries within the lattice, resulting in an increase in strength and a decrease in plasticity of the alloy. In conclusion, Cu–10Sn alloy has more excellent tensile properties and higher yield and tensile strengths with good ductility compared to Cu–5Sn and Cu–15Sn alloys.

Objective Adolescent idiopathic scoliosis (AIS) is a three‐dimensional structural deformity of the spine caused by the disruption of the biomechanical balance of the spine. However, the current biomechanical modeling and analysis methods of scoliosis cannot really describe the real state of the spine. This study aims to propose a high‐precision biomechanical modeling and analysis method that can reflect the spinal state under gravity and provide a theoretical basis for therapeutics. Methods Combining CT and X‐ray images of AIS patients, this study constructed an adjusted three‐dimensional model and FE model of the spine corresponding to the patient's gravity position, including vertebral bodies, intervertebral discs, ribs, costal cartilage, ligaments, and facet cartilage. Then, the displacement and stress of the spine under gravity were analyzed. Results A model of the T1‐Sacrum with 1.7 million meshes was constructed. After adding the gravity condition, the maximum displacement point was at T1 of thoracic vertebra (20.4 mm). The analysis indicates that the stress on the lower surface of the vertebral body in thoracolumbar scoliosis tended to be locally concentrated, especially on the concave side of the primary curvature's vertebral body (the maximum stress on the lower surface of T9 is 32.33 MPa) and the convex side of the compensatory curvature's vertebral body (the maximum stress on the lower surface of L5 is 41.97 MPa). Conclusion This study provides a high‐precision modeling and analysis method for scoliosis with full consideration of gravity. The reliability of the method was verified based on patient data. This model can be used to analyze the biomechanical characteristics of patients in the treatment plan design stage.

Until now the genus Amana (Liliaceae), known as ‘East Asian tulips’, has contained just seven species. In this study, a phylogenomic and integrative taxonomic approach was used to reveal two new species, Amana nanyueensis from Central China and A. tianmuensis from East China. A. nanyueensis resembles Amana edulis in possessing a densely villous-woolly bulb tunic and two opposite bracts, but differs in its leaves and anthers. Amana tianmuensis resembles Amana erythronioides in possessing three verticillate bracts and yellow anthers, but differs in aspects of its leaves and bulbs. These four species are clearly separated from each other in principal components analysis based on morphology. Phylogenomic analyses based on plastid CDS further support the species delimitation of A. nanyueensis and A. tianmuensis and suggests they are closely related to A. edulis. Cytological analysis shows that A. nanyueensis and A. tianmuensis are both diploid (2n = 2x = 24), different from A. edulis, which is either diploid (northern populations) or tetraploid (southern populations, 2n = 4x = 48). The pollen morphology of A. nanyueensis is similar to other Amana species (single-groove germination aperture), but A. tianmuensis is quite different because of the presence of a sulcus membrane, which creates the illusion of double grooves. Ecological niche modelling also revealed a niche differentiation between A. edulis, A. nanyueensis and A. tianmuensis.

Abstract Repeated cocaine exposure causes compensatory neuroadaptations in neurons in the nucleus accumbens (NAc), a region that mediates reinforcing effects of drugs. Previous studies suggested a role for adenosine monophosphate-activated protein kinase (AMPK), a cellular energy sensor, in modulating neuronal morphology and membrane excitability. However, the potential involvement of AMPK in cocaine use disorder is still unclear. The present study employed a cocaine self-administration model in rats to investigate the effect of AMPK and its target cyclic adenosine monophosphate response element binding protein-regulated transcriptional co-activator 1 (CRTC1) on cocaine reinforcement and the motivation for cocaine. We found that intravenous cocaine self-administration significantly decreased AMPK activity in the NAc shell (NAcsh), which persisted for at least 7 days of withdrawal. Cocaine reinforcement, reflected by self-administration behavior, was significantly prevented or enhanced by augmenting or suppressing AMPK activity pharmacologically and genetically, respectively. No difference in sucrose self-administration behavior was found after the same manipulations. The inhibition of AMPK activity in the NAcsh also increased the motivation for cocaine in progressive-ratio schedules of reinforcement, whereas the activation of AMPK had no effect. The knockdown of CRTC1 in the NAcsh significantly impaired cocaine reinforcement, which was rescued by pharmacologically increasing AMPK activity. Altogether, these results indicate that AMPK in the NAcsh is critical for cocaine reinforcement, possibly via the regulation of CRTC1 signaling. These findings may help reveal potential therapeutic targets and have important implications for the treatment of cocaine use disorder and relapse.

Ridge and furrow plastic film mulching (RFM) has improved net primary productivity (NPP) to a high level in semi-arid rainfed agricultural regions. Yet, it is unclear whether there is still a room for further improvement on NPP while stabilizing soil organic carbon through returning previous maize stover pieces. To address this issue, maize stubbles were smashed into pieces and in situ ploughed into 30 cm topsoil at a semi-arid site in northwest China from 2016 to 2017. This was done using the Pioneer 335 maize variety with three treatments (CK, ridge and furrow without mulching; RFM, ridge and furrow with plastic mulching; RFML, 3.49 t ha−1 of maize stover returning in RFM; RFMH, 5.24 t ha−1 of returning in RFM). The results indicated that maize stover returning exhibited similar trend as RFM at early cool seedling stage, raising the topsoil temperature. However, in warm and dry silking stage (2017), both stover returning rates reduced soil temperatures by 1.33 and 0.8 ◦C relative to RFM and CK (P

Osteoporosis (OP), a common systemic bone metabolism disease with a high incidence rate, is a serious health risk factor. Osteogenic differentiation balance is regulated by bone marrow mesenchymal stem cells (BMSCs) and plays a key role in OP occurrence and progression. Although, LIM homeobox 8 (Lhx8) has been identified to affect BMSCs osteogenic differentiation, its roles in OP and the associated mechanism remains unclear. Here, we aimed to elucidate the role and mechanism of Lhx8 in the osteogenic differentiation of BMSCs. BMSCs isolated from wild type and OP Sprague–Dawley rats were cultured and confirmed via flow cytometry and microscopy. Based on dual-luciferase reporter assay, BMSCs were transfected with miR-142-5p mimics and miR-NC (negative control). Real-time quantitative reverse transcription polymerase chain reaction and Western blot analyses were performed to determine the role of Lhx8 in BMSCs osteogenic differentiation. Lhx8 expression was significantly reduced in OP, whereas that of miR-142-5p, a possible Lhx8 regulator, was significantly upregulated. Dual-luciferase reporter assay demonstrated that miR-142-5p exerted a direct targeted regulatory effect on Lhx8. Moreover, miR-142-5p mimics significantly inhibited BMSCs osteogenic differentiation as well as Lhx8 expression in vitro, indicating that miR-142-5p may be involved in BMSCs osteogenic differentiation via Lhx8 expression regulation and may serve as a potential diagnostic target for OP. Overall, these findings indicated that miR-142-5p inhibits BMSCs osteogenic differentiation by suppressing Lhx8. These may serve as a foundation for further studies on OP treatment based on miR-142-5p targeting.

Background Brain natriuretic peptide (BNP) and troponin have a close relationship with cardiogenic cerebral embolism (CCE), but their relationship with noncardiogenic patients with anterior circulation ischemia (ACI) and posterior circulation ischemia (PCI) is not clear. Objective To explore the predictive value of serum initial BNP and troponin on the functional prognosis of patients with noncardiogenic ACI and PCI. Methods Consecutive patients with first-episode cerebral infarction within 12 hours of symptom onset were enrolled in the present 1-year prospective cohort study. Serum levels of BNP and troponin were collected within 12 hours of onset. Infarction location was classified as ACI and PCI by magnetic resonance imaging (MRI). According to the modified Rankin Scale (mRS) score at 90 days after onset, ACI and PCI cases were respectively divided into a good prognosis group (mRS score between 0 and 2) and a poor prognosis group (mRS score between 3 and 6). The general state of health and results of laboratory examinations and other auxiliary examinations of all patients were recorded. Single-factor analysis and multivariate logistic regression analysis were used to assess the relationship between serum levels of BNP, troponin, and functional outcome. Results The multivariate logistic regression found that higher levels of initial BNP (odds ratio [OR] = 1.024; 95% confidence interval [CI]: 1.006–1.041; p = 0.007) and C-reactive protein (CRP) (OR = 1.184; 95%CI: 1.024–1.369; p = 0.022) were independent predictors of poor functional prognosis of noncardiogenic PCI at 90 days after onset after adjusting for age, gender, ethnicity, history of hypertension and of diabetes. Conclusions The levels of initial BNP and CRP were related to poor functional outcomes in noncardiogenic PCI patients at 3 months, independent of troponin.

Summary: Background: ALKBH5 belongs to the ALKB family consists of a Fe (II) and a-ketoglutarate-dependent dioxygenase. ALKBH5 directly catalyzes the oxidative demethylation of m6A-methylated adenosine. ALKBH5 involves in tumorigenesis and tumor progression, and is often dysregulated in a wide range of cancers, including colorectal cancer. Emerging evidence indicates that the expression of ALKBH5 is associated with the abundance of infiltrating immune cells in the microenvironment. However, how ALKBH5 affects immune cell infiltration in the microenvironment in colorectal cancer (CRC) has not been reported. The aim of this study was to identify how the expression of ALKBH5 affects the biological behaviors of CRC cell lines and regulates the effects on infiltrating CD8+ T cells in CRC microenvironment with its specific mechanism. Methods: Firstly, the transcriptional expression profiles of CRC were downloaded from TCGA database and integrated via R software (4.1.2). Between CRC and normal colorectal tissues, ALKBH5 mRNA expressions were compared (Wilcoxon rank-sum). We further identified the expression levels of ALKBH5 in CRC tissues and cell lines through quantitative PCR, western blot, and immunohistochemistry. Then, how ALKBH5 affects the biological behaviors of CRC cells were confirmed by gain- and loss-of-function analysis. Furthermore, the relationship between ALKBH5 level and 22 tumor-infiltrating immune cells was examined through CIBERSORT in R software. Furthermore, we explored the correlation between ALKBH5 expression and tumor-infiltrated CD8+, CD4+ and regulatory T cells by utilizing the TIMER database. Finally, the association between chemokines and CD8+ T cells infiltration in CRC was analyzed using GEPIA online database. qRT-PCR, WB and IHC were used to further determine the effect of ALKBH5 on NF-κB-CCL5 signaling axis and CD8+ T cells infiltration. Results: Clinically, ALKBH5 expression was downregulated in CRC and low levels of ALKBH5 expression were correlated with poor overall survival (OS). Functionally, overexpression of ALKBH5 reduced the proliferation, migration and invasion of CRC cells, and vice versa. Overexpression of ALKBH5 suppresses NF-κB pathway, thus reduces CCL5 expression and promotes CD8+ T cells infiltration in CRC microenvironment. Conclusions: ALKBH5 is poorly expressed in CRC, and overexpression of ALKBH5 attenuates CRC malignant progression by inhibiting CRC cell proliferation, migration, invasion and promoting CD8+ T cells infiltration in the tumor microenvironment through NF-κB-CCL5 axis.

IntroductionIt was first reported that germ cell tumor patients suffer from hematologic malignancies 37 years ago. Since then, the number of relevant reports has increased each year, with most cases being mediastinal germ cell tumor. Theories have been proposed to explain this phenomenon, including a shared origin of progenitor cells, the effects of treatment, and independent development. However, up to now, no widely accepted explanation exists. The case with acute megakaryoblastic leukemia and intracranial germ cell tumor has never been reported before and the association is far less known.MethodsWe used whole exome sequencing and gene mutation analysis to study the relationship between intracranial germ cell tumor and acute megakaryoblastic leukemia of our patient.ResultsWe report a patient who developed acute megakaryoblastic leukemia after treatment for an intracranial germ cell tumor. Through whole exome sequencing and gene mutation analysis, we identified that both tumors shared the same mutation genes and mutation sites, suggesting they originated from the same progenitor cells and differentiated in the later stage.DiscussionOur findings provide the first evidence supporting the theory that acute megakaryoblastic leukemia and intracranial germ cell tumor has the same progenitor cells.

BackgroundOwing to the lack of valid biomarkers, the diagnosis of autism spectrum disorder (ASD) diagnosis relies solely on the behavioral phenotypes of children. Several researchers have suggested an association between ASD and inflammation; however, the complex relationship between the two is unelucidated to date. Therefore, the current study aims to comprehensively identify novel circulating ASD inflammatory biomarkers.MethodsOlink proteomics was applied to compare the plasma inflammation-related protein changes in a group of the healthy children (HC, n = 33) and another with ASD (n = 31). The areas under the receiver operating characteristic curves (AUCs) of the differentially expressed proteins (DEPs) were calculated. The functional analysis of the DEPs was performed using Gene Ontology and Kyoto Encyclopedia Genes and Genomes. Pearson correlation tests were used employed to analyze the correlation between the DEPs and clinical features.ResultsA total of 13 DEPs were significantly up-regulated in the ASD group compared with the HC group. The four proteins, namely, STAMBP, ST1A1, SIRT2, and MMP-10 demonstrated good diagnostic accuracy with the corresponding AUCs (95% confidence interval, CI) of 0.7218 (0.5946–0.8489), 0.7107 (0.5827–0.8387), 0.7016 (0.5713–0.8319), and 0.7006 (0.568–0.8332). Each panel of STAMBP and any other differential protein demonstrated a better classification performance [AUC values from 0.7147 (0.5858–0.8436, STAMBP/AXIN1) to 0.7681 (0.6496–0.8867, STAMBP/MMP-10)]. These DEP profiles were enriched in immune and inflammatory response pathways, including TNF and NOD-like receptor signaling pathways. The interaction between STAMBP and SIRT2 (R = 0.97, p = 8.52 × 10−39) was found to be the most significant. In addition, several DEPs related to clinical features in patients with ASD, particularly AXIN1 (R = 0.36, p = 0.006), SIRT2 (R = 0.34, p = 0.010) and STAMBP (R = 0.34, p = 0.010), were positively correlated with age and parity, indicating that older age and higher parity may be the inflammation-related clinical factors in ASD.ConclusionInflammation plays a crucial role in ASD, and the up-regulated inflammatory proteins may serve as potential early diagnostic biomarkers for ASD.

Abstract Background In this study, we tried to access the efficacy and safety of oxaliplatin plus S-1 with intraperitoneal paclitaxel (PTX) for the treatment of Chinese advanced gastric cancer with peritoneal metastases. Patients and methods Thirty patients diagnosed with advanced gastric cancer underwent laparoscopic exploration and were enrolled when macroscopic disseminated metastases (P1) were confirmed. PTX was diluted in 1 l of normal saline and IP administered through peritoneal port at an initial dose of 40 mg/m2 over 1 h on day1,8, respectively. Oxaliplatin was administered intravenously at an initial dose of 100 mg/m2 on day1, and S-1 was administered orally at an initial dose of 80 mg/m2 for 14 days followed by 7 days rest, repeated by every 3 weeks. Results Of all these 30 patients, the median number of cycles was 6 (range 2–16) due to the limitation of hematotoxicity and peripheral neuropathy by oxaliplatin. There were 11 (36.7%) patients received conversion surgery. The median progression free survival (PFS) was 6.6 months (95% CI = 4.7–8.5 months) and the median overall survival (OS) was 15.1 months (95% CI = 12.4–17.8 months). The grade 3–4 hematological toxicities were leucopenia (23.3%), neutropenia (23.3%), anemia (16.7%), and thrombocytopenia (20%), respectively. The grade 3–4 non-hematological toxicities were tolerated, most of which were peripheral sensory neuropathy (40%) due to oxaliplatin, diarrhea (20%), nausea and vomiting (26.7%). Conclusions SOX+ip PTX regimen was effective in advanced gastric cancer with peritoneal metastasis. Survival time was significantly prolonged by conversion surgery. Grade 3–4 toxicities were uncommon. Large scale clinical trial is necessary to get more evidence to identify its efficacy. Trail registration ChiCTR, ChiCTR-IIR-16009802 . Registered 9 November 2016,

BackgroundOsteoporosis has already been a growing health concern worldwide. The influence of living area, lifestyle, socioeconomic, and medical conditions on the occurrence of osteoporosis in the middle-aged and elderly people in China has not been fully addressed.MethodsThe study was a multicenter cross-sectional study on the middle-aged and elderly permanent residents, which gathered information of 22,081 residents from June 2015 to August 2021 in seven representative regions of China. The bone mineral density of lumbar vertebrae and hip were determined using the dual-energy X-ray absorptiometry densitometer instruments. Serum levels of bone metabolism markers were also measured. Information about education, smoking, and chronic diseases were also collected through face-to-face interviews. Age-standardized prevalence and 95% confidence intervals (CIs) of osteopenia and osteoporosis by various criteria were estimated by subgroups and overall based on the data of China 2010 census. The relationships between the osteoporosis or osteopenia and sociodemographic variables or other factors were examined using univariate linear models and multivariable multinomial logit analyses.ResultsAfter screening, 19,848 participants (90%) were enrolled for the final analysis. The age-standardized prevalence of osteoporosis was estimated to be 33.49%(95%CI, 32.80–34.18%) in the middle-aged and elderly Chinese permanent residents, for men and women was 20.73% (95% CI, 19.58–21.87%) and 38.05% (95% CI, 37.22–38.89%), respectively. The serum concentrations of bone metabolic markers, and calcium and phosphorus metabolism were influenced by age, body mass index (BMI), gender, education level, regions, and bone mass status. Women, aged 60 or above, BMI lower than 18.5 kg/m2, low education level including middle school, primary school and no formal education as well as current regular smoking, a history of fracture were all significantly associated with a higher risk of osteoporosis and osteopenia in the middle-aged and elderly people.ConclusionsThis study revealed dramatic regional differences in osteoporosis prevalence in China, and female, aged 60 or older, low BMI, low education level, current regular smoking, and a history of fracture were associated with a high risk of osteoporosis. More prevention and treatment resources should be invested into particular population exposed to these risk factors.

Water pollution due to heavy metals has become a universal environmental problem. Ni(II) is a common heavy metal ion in polluted wastewater, which has high toxicity and carcinogenicity. In this study, the structure of a calcium-iron layered double hydroxide (Ca-Fe-LDHs) was synthesized and characterized by FTIR, XRD, SEM and XPS. Then, Ni(II) ion was effectively removed by Ca-Fe-LDHs and its mechanism for this materials was described. The maximum adsorption capacity of Ni(II) for Ca-Fe-LDHs was 418.9 mg‧g−1 when the initial concentration of Ni(II) was 1 g/L. The adsorption and removal of Ni(II) by Ca-Fe-LDHs was attributed to the action of hydroxyl groups on the hydrotalcite, generating surface capture. Ni(OH)2)0.75(H2O)0.16(NiCO3)0.09, Ni(OH)2, NiO, NiSO4 and other precipitates were generated on its surface. And a small amount of Ni-Fe-LDHs was generated through isomorphic transition before hydrolysis. Therefore, surface capture and isomorphic transition enhanced the removal efficiency of Ni(II) with Ca-Fe-LDHs, making Ca-Fe-LDHs as a potential material for effective removal of Ni(II).

Corneal transplantation constitutes one of the major treatments in severe cases of corneal diseases. The lack of cornea donors as well as other limitations of corneal transplantation necessitate the development of artificial corneal substitutes. Biosynthetic cornea model using 3D printing technique is promising to generate artificial corneal structure that can resemble the structure of the native human cornea and is applicable for regenerative medicine. Research on bioprinting artificial cornea has raised interest into the wide range of materials and cells that can be utilized as bioinks for optimal clarity, biocompatibility, and tectonic strength. With continued advances in biomaterials science and printing technology, it is believed that bioprinted cornea will eventually achieve a level of clinical functionality and practicality as to replace donated corneal tissues, with their associated limitations such as limited or unsteady supply, and possible infectious disease transmission. Here, we review the literature on bioprinting strategies, 3D corneal modelling, material options, and cellularization strategies in relation to keratoprosthesis design. The progress, limitations and expectations of recent cases of 3D bioprinting of artifial cornea are discussed. An outlook on the rise of 3D bioprinting in corneal reconstruction and regeneration is provided.

Background: Total wrist arthroplasty is an effective treatment for end-stage wrist arthritis from all causes. However, wrist prostheses are still prone to complications such as prosthesis loosening and periprosthetic fractures after total wrist arthroplasty. This may be due to the wrist prosthesis imprecise matching with patient’s bone. In this study, we designed and developed a personalized three-dimensional printed microporous titanium artificial wrist prosthesis (3DMT-Wrist) for the treatment of end-stage wrist joint, and investigated its safety and effectiveness.Methods: Total wrist arthroplasty was performed using 3DMT-Wrist in 14 cases of arthritis between February 2019 and December 2021. Preoperative and postoperative visual analog scale scores, QuickDASH scores, wrist range of motion, and wrist grip strength were evaluated. Data were statistically analyzed using the paired samples t-test.Results: After 19.7 ± 10.7 months of follow-up, visual analog scale decreased from 66.3 ± 8.9 to 6.7 ± 4.4, QuickDASH scores decreased from 47.4 ± 7.3 to 28.2 ± 7.6, grip strength increased from 5.6 ± 1.4 to 17.0 ± 3.3 kg. The range of motion improved significantly in palmar flexion (30.1° ± 4.9° to 44.9° ± 6.5°), dorsal extension (15.7° ± 3.9° to 25.8° ± 3.3°), ulnar deviation (12.2° ± 3.9° to 20.2° ± 4.3°) and radial deviation (8.2° ± 2.3° to 16.2 ± 3.1). No dislocation or loosening of the prosthetic wrist joint was observed.Conclusion: Total wrist arthroplasty using 3DMT-Wrist is a safe and effective new treatment for various types of end-stage wrist arthritis; it offers excellent pain relief and maintains the range of motion.

Hyperuricemic nephropathy (HN) is a common clinical complication of hyperuricemia. The pathogenesis of HN is directly related to urea metabolism in the gut microbiota. Febuxostat, a potent xanthine oxidase inhibitor, is the first-line drug used for the treatment of hyperuricemia. However, there have been few studies on the pharmacokinetics of febuxostat in HN animal models or in patients. In this study, a high-purine diet-induced HN rat model was established. The pharmacokinetics of febuxostat in HN rats was evaluated using LC-MS/MS. Astragaloside IV (AST) was used to correct the abnormal pharmacokinetics of febuxostat. Gut microbiota diversity analysis was used to evaluate the effect of AST on gut microbiota. The results showed that the delayed elimination of febuxostat caused drug accumulation after multiple administrations. Oral but not i. p. AST improved the pharmacokinetics of febuxostat in HN rats. The mechanistic study showed that AST could regulate urea metabolism in faeces and attenuate urea-ammonia liver-intestine circulation. Urease-related genera, including Eubacterium, Parabacteroides, Ruminococcus, and Clostridia, decreased after AST prevention. In addition, the decrease in pathogenic genera and increase in short-chain fatty acids (SCFA) producing genera also contribute to renal function recovery. In summary, AST improved the pharmacokinetics of febuxostat in HN rats by comprehensive regulation of the gut microbiota, including urea metabolism, anti-calcification, and short-chain fatty acid generation. These results imply that febuxostat might accumulate in HN patients, and AST could reverse the accumulation through gut microbiota regulation.

Abstract Background Patients with salt-sensitive hypertension are often accompanied with severe renal damage and accelerate to end-stage renal disease, which currently lacks effective treatment. Fibroblast growth factor 21 (FGF21) has been shown to suppress nephropathy in both type 1 and type 2 diabetes mice. Here, we aimed to investigate the therapeutic effect of FGF21 in salt-sensitive hypertension-induced nephropathy. Methods Changes of FGF21 expression in deoxycorticosterone acetate (DOCA)-salt-induced hypertensive mice were detected. The influence of FGF21 knockout in mice on DOCA-salt-induced nephropathy were determined. Recombinant human FGF21 (rhFGF21) was intraperitoneally injected into DOCA-salt-induced nephropathy mice, and then the inflammatory factors, oxidative stress levels and kidney injury-related indicators were observed. In vitro, human renal tubular epithelial cells (HK-2) were challenged by palmitate acid (PA) with or without FGF21, and then changes in inflammation and oxidative stress indicators were tested. Results We observed significant elevation in circulating levels and renal expression of FGF21 in DOCA-salt-induced hypertensive mice. We found that deletion of FGF21 in mice aggravated DOCA-salt-induced nephropathy. Supplementation with rhFGF21 reversed DOCA-salt-induced kidney injury. Mechanically, rhFGF21 induced AMPK activation in DOCA-salt-treated mice and PA-stimulated HK-2 cells, which inhibited NF-κB-regulated inflammation and Nrf2-mediated oxidative stress and thus, is important for rhFGF21 protection against DOCA-salt-induced nephropathy. Conclusion These findings indicated that rhFGF21 could be a promising pharmacological strategy for the treatment of salt-sensitive hypertension-induced nephropathy.

Variable stiffness joints have been gradually applied in rehabilitation robots because of their intrinsic compliance and greater ability to adjust mechanical stiffness. This paper designs a variable stiffness joint for upper limb rehabilitation training. The joint adopts the variable stiffness principle based special curved surface. The trapezoidal lead screw in the variable stiffness module has a self-locking function, and the stiffness can be maintained without the continuous output torque of the motor. In the aspect of control, back propagation (BP) neural network PID control strategy is used to control the torque of variable stiffness joint. Experiments show that this control method can effectively improve the torque control performance of variable stiffness joints in the case of low stiffness, and the isotonic centripetal resistance training can be realized by using the joints and control methods designed in this paper.

The space hurricane is a newly discovered large-scale three-dimensional magnetic vortex structure that spans the polar ionosphere and magnetosphere. At the height of the ionosphere, it has a strong circular horizontal plasma flow with a nearly zero-flow center and a coincident cyclone-shaped aurora caused by strong electron precipitation associated with intense upward magnetic field-aligned currents. By analyzing the long-term optical observation onboard the Defense Meteorological Satellite Program (DMSP) F16 satellite from 2005 to 2016, we found that space hurricanes in the Northern Hemisphere occur in summer and have a maximum occurrence rate in the afternoon sector around solar maximum. In particular, space hurricanes are more likely to occur in the dayside polar cap at magnetic latitudes greater than 80°, and their MLT (magnetic local time) dependence shows a positive relationship with the IMF (interplanetary magnetic field) clock angle. We also found that space hurricanes occur mainly under dominant positive IMF By and Bz and negative Bx conditions. It is suggested that the stable high-latitude lobe reconnection, which occurs under the conditions of a large Earth’s dipole tilt angle and high ionosphere conductivity in summer, should be the formation mechanism of space hurricanes. The result will give a better understanding of the solar wind–magnetosphere–ionosphere coupling process under northward IMF conditions.

Summary: Background: Opioid use disorder (OUD) is a chronic relapsing psychiatric disorder. An unconditioned stimulus (US)-triggers a memory reconsolidation updating procedure (MRUP) that has been developed and demonstrated its effectiveness in decreasing relapse to cocaine and heroin in preclinical models. However, utilizations of abused drugs as the US to initiate MRUP can be problematic. We therefore designed a translational rat study and human study to evaluate the efficacy of a novel methadone-initiated MRUP. Methods: In the rodent study, male rats underwent heroin self-administration training for 10 consecutive days, and were randomly assigned to receive saline or methadone at 10 min, 1 h or 6 h before extinction training after 28-day withdrawal. The primary outcome was operant heroin seeking after reinstatement. In the human experimental study, male OUD patients were randomly assigned to get MRUP at 10 min or 6 h after methadone or methadone alone. The primary outcomes included experimental cue-induced heroin craving change, sustained abstinence and retention in the study at post intervention and the 5 monthly follow-up assessments. The secondary outcomes were changes in physiological responses including experimental cue-induced blood pressure and heart rate. Findings: Methadone exposure but not saline exposure at 10 min or 1 h before extinction decreased heroin-induced reinstatement of heroin seeking after 28-day of withdrawal in rats (F (8,80) = 8.26, p < 0.001). In the human study, when the MRUP was performed 10 min, but not 6 h after methadone dosing, the MRUP promoted sustained abstinence from heroin throughout 5 monthly follow-up assessments compared to giving methadone alone without MRUP (Hazard Ratio [95%CI] of 0.43 [0.22, 0.83], p = 0.01). The MRUP at 10 min, but not at 6 h after dosing also decreased experimental cue-induced heroin craving and blood pressure increases during the 6-month study duration (group × months × cue types, F (12, 63·3) = 2.41, p = 0.01). Interpretation: The approach of MRUP within about 1 to 6 h after a methadone dose potently improved several key outcomes of OUD patients during methadone maintenance treatment, and could be a potentially novel treatment to prevent opioid relapse. Funding: National Natural Science Foundation of China (NO. U1802283, 81761128036, 82001400, 82001404 and 31671143) and Chinese National Programs for Brain Science and Brain-like Intelligence Technology (NO. 2021ZD0200800)

Botulinum neurotoxins (BoNTs) are the most toxic known proteins. Naturally occurring botulism in humans is caused by botulinum serotypes A, B, E, and F. Vaccination is an effective strategy to prevent botulism. In this study, a tetravalent botulinum vaccine (TBV) that can prevent serotypes A, B, E, and F was developed using the C-terminal receptor-binding domain of BoNT (Hc) as an antigen. To develop a suitable vaccine formulation, in vitro binding experiments of antigens and aluminum adjuvant in different buffers, and in vivo experiments of TBV at different antigen concentrations, were conducted. Our results showed that the optimal vaccine formulation buffer was a pH 6.0 phosphate buffer, and the suitable antigen concentration was 40 or 80 µg/ml of each antigen. A pilot-scale TBV was then prepared and evaluated for immunogenicity and stability. The results showed that TBV could elicit strong protective efficacy against each BoNT in mice, and remain effective after two years of storage at 4ºC, indicating that the preparation was stable and highly effective. Adsorption experiments also showed that the antigens could be well adsorbed by the aluminum adjuvant after 2 years of storage. Our results provide valuable experimental data supporting the development of a tetravalent botulinum vaccine, which is a promising candidate for the prevention of botulinum serotypes A, B, E, and F.

Background: Dexmedetomidine is considered an adjunct to local anaesthesia (LA) to prolong peripheral nerve block time. However, the results from a previous meta-analysis were not sufficient to support its use in paravertebral block (PVB). Therefore, we performed an updated meta-analysis to evaluate the efficacy of dexmedetomidine combined with LA in PVB.Methods: We performed an electronic database search from the date of establishment to April 2022. Randomized controlled trials (RCTs) investigating the combination of dexmedetomidine and LA compared with LA alone for PVB in adult patients were included. Postoperative pain scores, analgesic consumption, and adverse reactions were analyzed.Results: We identified 12 trials (701 patients) and found that the application of dexmedetomidine as a PVB adjunct reduced the postoperative pain severity of patients 12 and 24 h after surgery compared to a control group. Expressed as mean difference (MD) (95% CI), the results were −1.03 (−1.18, −0.88) (p < 0.00001, I2 = 79%) for 12 h and −1.08 (−1.24, −0.92) (p < 0.00001, I2 = 72%) for 24 h. Dexmedetomidine prolonged the duration of analgesia by at least 173.27 min (115.61, 230.93) (p < 0.00001, I2 = 81%) and reduced postoperative oral morphine consumption by 18.01 mg (−22.10, 13.92) (p < 0.00001, I2 = 19%). We also found no statistically significant differences in hemodynamic complications between the two groups. According to the GRADE system, we found that the level of evidence for postoperative pain scores at 12 and 24 h was rated as moderate.Conclusion: Our study shows that dexmedetomidine as an adjunct to LA improves the postoperative pain severity of patients after surgery and prolongs the duration of analgesia in PVB without increasing the incidence of adverse effects.

Abstract Background Succinate‐CoA ligase/synthetase (SCS) deficiency is responsible for encephalomyopathy with mitochondrial DNA depletion and mild methylmalonic aciduria. Variants in SUCLG1, the nuclear gene encoding the alpha subunit of the SCS enzyme playing a pivotal role in maintaining mtDNA integrity and stability, are associated with mitochondrial DNA depletion syndrome 9 (MTDPS9). Methods In this study, we reported an infant with clinical features of MTDPS9 from China. Whole exome sequencing (WES) was used to identify the genetic cause. Bioinformatic analysis and mtDNA level detection were performed to assess pathogenicity. Results The proband manifested with hypotonia, lactic acidosis, mild methylmalonic aciduria, hearing loss and psychomotor retardation. WES identified new compound heterozygous SUCLG1 variants of c.601A>G (p.R201G) in exon 6 and c.871G>C (p.A291P) in exon 8. Computational analysis predicted that these missense variants might alter structure stability and mitochondrial translocation of SUCLG1. qRT‐PCR showed 68% depletion of mtDNA content in proband as compared to controls. Conclusion Novel compound heterozygous variants c.601A>G (p.R201G) and c.871G>C (p.A291P) in SUCLG1 may cause MTDPS9 in this family. Our finding should be helpful for molecular diagnosis, genetic counseling and clinical management of SCS deficiency disorders.

Abstract Background Dimensional measurements have been implemented on a variety of entities in morphological studies of the sub-axial cervical vertebral endplate. Despite great progress, little information between the mid-sagittal plane and bilateral uncinate processes has been acquired due to the lack of a reliable method to determine the para-sagittal planes. Also, few studies of this region are available. We proposed a new approach to defining the para-sagittal planes on a 3D cervical vertebral body model; in this approach, dimensions can be measured in a specific plane. The aim of this study was to assess the inter-observer and intra-observer reliability of the measurements in different sagittal planes on sub-axial cervical vertebral endplates of 3D models. Methods We established mid-sagittal and bilateral quarter para-sagittal planes on the 3D model of a sub-axial cervical vertebral body based on landmarks labeled on the surface. By intersecting the vertebral body with the planes, three curves located at the three para-sagittal planes were generated. Linear dimensions were measured on every curve by two observers separately, and in total, 24 sub-axial cervical spines were included in the study. The first observer (O1) performed the procedure twice with an interval of 2 weeks. The paired t test, Wilcoxon matched-pairs signed-rank test and the interclass correlation coefficient (ICC) were employed to evaluate the inter- and intra-observer reliability of the proposed method. Results There were no significant differences in most intra- and inter-observer comparisons, and higher non-significant proportions were found in the intra-observer comparisons than in comparisons between different observers. The interclass correlation coefficients (ICCs) in the measurements were excellent (> 0.75) in most circumstances, and the values in intra-observer comparisons were higher than those in inter-observer comparisons. Conclusions In this study, we proposed an approach to determine the bilateral quarter para-sagittal planes in a 3D cervical vertebral body model; the results demonstrated that the method is reproducible with high intra- and inter-observer agreement.

As an emerging field, telesurgery robotic system is changing the traditional medical mode and can delivery remote surgical treatment anywhere in the world. Advances in telesurgery robotic technology achieve the remote control beyond the current limitation of distance and special medical environment. This review introduces the development history, the current status and the potential in future of the telesurgery robotic system. In addition, it presents the construction of control platform and the application, especially in trauma treatment, as well as the challenge in clinic.

Abstract Background Macrophages and inflammatory cytokines play important roles in bone fracture healing. However, the expression patterns of macrophages and inflammatory cytokines during fracture healing under the condition of postmenopausal osteoporosis have not been fully revealed. Methods Tibia transverse fracture was established 12 weeks after ovariectomy or sham operation in 16-week old female mice. Tibias were harvested before fracture or 1, 3, 5, 7, 14, 21, 28 days after fracture for radiological and histological examinations. M1/M2 inflammatory macrophages, osteal macrophages and gene expressions of tumor necrosis factor-α, interleukin-6, interleukin-1β and macrophage conversion related molecules in the fracture haematoma or callus were also detected. Results The processes of fracture healing, especially the phases of endochondral ossification and callus remodeling, were delayed in ovariectomized mice. The expressions of tumor necrosis factor-α and interleukin-6, but not interleukin-1β, in the fracture haematoma or callus were disturbed. Expressions of tumor necrosis factor-α were decreased at 1, 14 and 21 days post-fracture (DPF), and were increased at 3, 5 and 7 DPF. Interleukin-6 expressions at 1, 3 and 21 DPF were significantly increased. We found the decreases in M1 and M2 macrophages at 1 DPF of the initial inflammatory stage. M2 macrophages at 14 DPF of the middle stage and osteal macrophages at 14, 21 and 28 DPF of the middle and late stages of fracture healing were also reduced in ovariectomized mice. Conclusions The expressions of macrophages and inflammatory cytokines were impaired in ovariectomized mice, which might contribute partially to poor fracture healing.

Abstract Objective To develop and validate a nomogram useful in predicting recurrent lumbar disk herniation (rLDH) within 6 months after percutaneous endoscopic lumbar discectomy (PELD). Methods Information on patients’ lumbar disk herniation (LDH) between January 2018 and May 2019 in addition to 26 other features was collected from the authors’ hospital. The least absolute shrinkage and selection operator (LASSO) method was used to select the most important risk factors. Moreover, a nomogram was used to build a prediction model using the risk factors selected from LASSO regression. The concordance index (C-index), the receiver operating characteristic (ROC) curve, and calibration curve were used to assess the performance of the model. Finally, clinical usefulness of the nomogram was analyzed using the decision curve and bootstrapping used for internal validation. Results Totally, 352 LDH patients were included into this study. Thirty-two patients had recurrence within 6 months while 320 showed no recurrence. Four potential factors, the course of disease, Pfirrmann grade, Modic change, and migration grade, were selected according to the LASSO regression model. Additionally, the C-index of the prediction nomogram was 0.813 (95% CI, 0.726-0.900) and the area under receiver operating characteristic curve (AUC) value was 0.798 while the interval bootstrapping validation C-index was 0.743. Hence, the nomogram might be a good predictive model. Conclusion Each variable, the course of disease, Pfirrmann grade, Modic change, and migration grade in the nomogram had a quantitatively corresponding risk score, which can be used in predicting the overall recurrence rate of rLDH within 6 months.

Single nucleotide polymorphism (SNP) arrays are a powerful genotyping tool used in genetic research and genomic breeding programs. Japanese flounder (Paralichthys olivaceus) is an economically-important aquaculture flatfish in many countries. However, the lack of high-efficient genotyping tools has impeded the genomic breeding programs for Japanese flounder. We developed a 50K Japanese flounder SNP array, “Yuxin No. 1,” and report its utility in genomic selection (GS) for disease resistance to bacterial pathogens. We screened more than 42.2 million SNPs from the whole-genome resequencing data of 1099 individuals and selected 48 697 SNPs that were evenly distributed across the genome to anchor the array with Affymetrix Axiom genotyping technology. Evaluation of the array performance with 168 fish showed that 74.7% of the loci were successfully genotyped with high call rates (> 98%) and that the polymorphic SNPs had good cluster separations. More than 85% of the SNPs were concordant with SNPs obtained from the whole-genome resequencing data. To validate “Yuxin No. 1” for GS, the arrayed genotyping data of 27 individuals from a candidate population and 931 individuals from a reference population were used to calculate the genomic estimated breeding values (GEBVs) for disease resistance to Edwardsiella tarda. There was a 21.2% relative increase in the accuracy of GEBV using the weighted genomic best linear unbiased prediction (wGBLUP), compared to traditional pedigree-based best linear unbiased prediction (ABLUP), suggesting good performance of the “Yuxin No. 1” SNP array for GS. In summary, we developed the “Yuxin No. 1” 50K SNP array, which provides a useful platform for high-quality genotyping that may be beneficial to the genomic selective breeding of Japanese flounder.

Abstract Background To improve the strength of posterior spine fixation in patients with osteoporosis, some scholars have proposed a method of simultaneously inserting traditional pedicle screws and cortical bone trajectory screws into the pedicle. However, due to the difficulty of the operation and few clinical applications, the safety and accuracy of this method are still unclear. The purpose of this study was to investigate the safety and accuracy of double-trajectory lumbar screw placement guided by surgical guide templates. Methods Six wet lumbar specimens were selected for computed tomography (CT) scanning, a three-dimensional (3D) model of the lumbar spine was established using computer software, and surgical guide templates for double-trajectory [traditional pedicle trajectory (TPT) and cortical bone trajectory (CBT)] lumbar screw placement at various segments of the lumbar spine were designed and printed using a 3D printer. Screw placement was guided only by the surgical guide template, with no fluoroscopy. Postoperative CT examination was performed to determine whether the screw penetrated the screw path and the location and depth of penetration of the cortex. The preoperative and postoperative sagittal and axial angles of CBT screws or TPT screws were also measured and compared. Results Four screws were placed in each vertebral body of six lumbar specimens for a total of 120 screws. Screw grades: 99 screws as grade 0, 15 as grade 1, six as grade 2, and zero as grade 3. Thus, grade 0 accounted for 82.5% of the screws. No significant differences in the preoperative and postoperative angles of the screws were found (P > 0.05). Conclusions 3D-printed surgical guide templates for double-trajectory screw placement can reduce the difficulty of surgery and the use of intraoperative fluoroscopy. Using such templates is a safe, feasible, and accurate screw placement method.