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Abstract Achieving solid superlubricity in high-humidity environments is of great practical importance yet remains challenging nowadays, due to the complex physicochemical roles of water and concomitant oxidation on solid surfaces. Here we report a facile way to access humidity-insensitive solid superlubricity (coefficient of friction 0.0035) without detectable wear and running-in at a humidity range of 2–80%. Inspired by the concept of structural superlubricity, this is achieved between Au-capped microscale graphite flake and graphene nanoflake-covered hydrogen-free amorphous carbon (GNC a-C). Such GNC a-C exhibits reduced pinning effects of water molecules and weak oxidation, which demonstrates stable structural superlubricity even after air exposure of the surfaces for 365 days. The manufacturability of such design enables the macroscopic scale-up of structural superlubricity, achieving the leap from 4 μm × 4 μm contact to 3 mm ball-supported contact with a wide range of materials. Our results suggest a strategy for the macroscale application of structural superlubricity under ambient condition.

Abstract Background Currently, the synthesis of compounds based on microbial cell factories is rapidly advancing, yet it encounters several challenges. During the production process, engineered strains frequently encounter disturbances in the cultivation environment or the impact of their metabolites, such as high temperature, acid-base imbalances, hypertonicity, organic solvents, toxic byproducts, and mechanical damage. These stress factors can constrain the efficiency of microbial fermentation, resulting in slow cell growth, decreased production, significantly increased energy consumption, and other issues that severely limit the application of microbial cell factories. Results This study demonstrated that sterol engineering in Kluyveromyces marxianus, achieved by overexpressing or deleting the coding genes for the last five steps of ergosterol synthase (Erg2-Erg6), altered the composition and ratio of sterols in its cell membrane, and affected its multiple tolerance. The results suggest that the knockout of the Erg5 can enhance the thermotolerance of K. marxianus, while the overexpression of the Erg4 can improve its acid tolerance. Additionally, engineering strain overexpressed Erg6 improved its tolerance to elevated temperature, hypertonic, and acid. YZB453, obtained by overexpressing Erg6 in an engineering strain with high efficiency in synthesizing xylitol, produced 101.22 g/L xylitol at 45oC and 75.11 g/L xylitol at 46oC. Using corncob hydrolysate for simultaneous saccharification and fermentation (SSF) at 46oC that xylose released from corncob hydrolysate by saccharification with hemicellulase, YZB453 can produce 45.98 g/L of xylitol, saving 53.72% of the cost of hemicellulase compared to 42oC. Conclusions This study elucidates the mechanism by which K. marxianus acquires resistance to various antifungal drugs, high temperatures, high osmolarity, acidity, and other stressors, through alterations in the composition and ratio of membrane sterols. By employing sterol engineering, the fermentation temperature of this unconventional thermotolerant K. marxianus was further elevated, ultimately providing an efficient platform for synthesizing high-value-added xylitol from biomass via the SSF process at temperatures exceeding 45 °C.

Abstract Protein-protein interactions (PPIs) stabilization with molecular glues plays a crucial role in drug discovery, albeit with significant challenges. In this study, we propose a dual-site approach, targeting the PPI region and its dynamic surroundings. We conduct molecular dynamics simulations to identify critical sites on the PPI that stabilize the cyclin-dependent kinase 12 - DNA damage-binding protein 1 (CDK12-DDB1) complex, resulting in further cyclin K degradation. This exploration leads to the creation of LL-K12-18, a dual-site molecular glue, which enhances the glue properties to augment degradation kinetics and efficiency. Notably, LL-K12-18 demonstrates strong inhibition of gene transcription and anti-proliferative effects in tumor cells, showing significant potency improvements in MDA-MB-231 (88-fold) and MDA-MB-468 cells (307-fold) when compared to its precursor compound SR-4835. These findings underscore the potential of dual-site approaches in disrupting CDK12 function and offer a structural insight-based framework for the design of cyclin K molecular glues.

BaiYangJie (BYJ) is a terrestrial perennial plant commonly used as a Dai medicine and has therapeutic effects on liver and kidney diseases. Cisplatin (CP), a chemotherapy drug, has good therapeutic effects but causes many side effects, including nephrotoxicity. This article investigated the toxicology of the methanol extract of BYJ (ME-BYJ) and its protective effect on CP-induced acute kidney injury (AKI) through pharmacological experiments. The results showed that the treated mice had no toxicological symptoms and no anatomical, physiological, or histological abnormalities. The BYJ-high-dose group showed significantly attenuated CP-induced AKI. It is concluded that ME-BYJ has the most significant protective effect on AKI at a dose of 8 g/kg and BYJ was not toxic.

Abstract To determine the presence of a consistent osseous corridor from the lateral-posterior aspect of the anterior inferior iliac spine to the sacral wing that could be used for safe trans percutaneous screw fixation for pelvic fragility fractures of the iliac wing and fracture dislocations of the sacroiliac joint (FFP types IIIa and IIIb). Computed tomography (CT) scans were obtained from 100 patients and imported to Mimics software for 3D reconstruction. Then, a cylinder was drawn to imitate the modified LC-II screw and adjusted to a maximum radius and length to obtain the feasible region. Thirteen parameters of the osseous corridor of the modified LC-II screw were measured. Differences between sex groups were compared, and significant statistical correlations were carefully studied to determine potentially important clinical relationships. The records of patients with FFP type IIIa and IIIb fragility fractures of the pelvis were extracted from our hospital. Patients who underwent modified LC-II screw fixation, LC-II screw fixation or reconstruction plate fixation were included. Patients’ operative characteristics and complications were recorded at follow-up. Fracture reduction quality was assessed using the Matta standard. Functional outcomes were evaluated using the Majeed grading system. The mean maximum diameters of the osseous corridors of the modified LC-II screw in males and females were 12.73 and 10.83 mm, respectively. The mean maximum lengths of the osseous corridors of the modified LC-II screw in males and females were 96.37 and 93.37 mm, respectively. In the treatment of patients with FFP IIIa and FFP IIIb fractures, the group of treatment by the modified LC-II screws fixation was shown significantly shorter operative time and fewer intraoperative blood loss in comparison to that by the reconstruction plates. In the present study, all the males and females had a complete osseous corridor of the modified LC-II screw. The clinical results of the patients who were treated with modified LC-II screw fixation suggest that the novel method has a good preliminary outcome.

Background/Aims Metabolic dysfunction-associated steatotic liver disease (MASLD) has become an increasingly important health challenge, with a substantial rise linked to changing lifestyles and global obesity. Ursolic acid, a natural pentacyclic triterpenoid, has been explored for its potential therapeutic effects. Given its multifunctional bioactive properties, this research further revealed the pharmacological mechanisms of ursolic acid on MASLD. Methods Drug target chips and bioinformatics analysis were combined in this study to explore the potential therapeutic effects of ursolic acid on MASLD. Molecular docking simulations, surface plasmon resonance analyses, pull-down experiments, and co-immunoprecipitation assays were used to verify the direct interactions. Gene knockdown mice were generated, and high-fat diets were used to validate drug efficacy. Furthermore, initial CD4+ T cells were isolated and stimulated to demonstrate our findings. Results In this study, the multifunctional extracellular matrix phosphorylated glycoprotein secreted phosphoprotein 1 (SPP1) was investigated, highlighting its capability to induce Th17 cell differentiation, amplifying inflammatory cascades, and subsequently promoting the evolution of MASLD. In addition, this study revealed that in addition to the canonical TGF-β/IL-6 cytokine pathway, SPP1 can directly interact with ITGB1 and CD44, orchestrating Th17 cell differentiation via their joint downstream ERK signaling pathway. Remarkably, ursolic acid intervention notably suppressed the protein activity of SPP1, suggesting a promising avenue for ameliorating the immunoinflammatory trajectory in MASLD progression. Conclusions Ursolic acid could improve immune inflammation in MASLD by modulating SPP1-mediated Th17 cell differentiation via the ERK signaling pathway, which is orchestrated jointly by ITGB1 and CD44, emerging as a linchpin in this molecular cascade.

Background: There is a strong causal relationship between intimate partner violence and major depressive disorder, which partly endangers women's safety across the life course and potentially affects the development of future generations. The international community has placed a high priority on addressing the intimate partner violence and the resulting burden of mental illness. Data collection needs to be captured across the temporal trend and spatial distribution for major depressive disorder attributed to intimate partner violence, to reflect the priorities and expectations of survivors.Method: This research obtained raw disability-adjusted life years (DALYs) information for major depressive disorder attributed to intimate partner violence from the Global Burden of Disease 2019. Using estimated annual percentage change and two-way fixed effects models, a secondary spatio-temporal analysis of the age-standardized DALYs rate from 1990 to 2019 was performed.Results: In 2019, DALYs lost among women experiencing major depressive disorder (3.16 million) accounted for 37.18% of the DALYs lost worldwide due to intimate partner violence. The age-standardized DALYs rate of major depressive disorder attributed to intimate partner violence was 108.57 per 100,000. The highest was concentrated in the menopausal transition (45-55), with 133.61 per 100,000, and particularly distributed in Uganda (429.31 per 100,000). The early reproductive period (15–19) showed the increasing age-standardized DALYs rate from 1990 to 2019, which was mainly driven by Malaysia (3.73% per year). Furthermore, countries with higher initial levels of the age-standardized DALYs rate were growing faster than those with lower levels.Conclusions: The burden of major depressive disorder attributed to intimate partner violence showed biological and spatial inequality, prioritized intervention should be targeted at vulnerable stage women in their early reproductive period and menopausal transition. Combined political, socio-cultural as well as medical measures to prevent violence and treat major depressive disorder should be implemented and developed.

The gut microbiota plays an important role in the development and treatment of hepatocellular carcinoma (HCC). However, the implication of specific gut microbiota in targeted sorafenib therapy for advanced HCC and the microbiota mode of action, remain to be elucidated. Here, we confirmed that four bacterial genera, Lachnoclostridium, Lachnospira, Enterobacter and Enterococcus, are associated with the therapeutic efficacy of Sorafenib, and that Enterobacter faecium (Efm) plays a crucial role in modulating the sorafenib activity. The effective colonization by Emf induced the IL-12 and IFN-γ production and an increased proportion of IFN-γ+CD8+ T cells in the tumor microenvironment. Finally, exopolysaccharides (EPS) from Efm were the primary inducer to prompt IFN-γ+CD8+ T cells to secrete IFN-γ, which together with sorafenib instigated ferroptosis in HCC cells. Collectively, these results indicate that Efm is a promising probiotics that enhances the efficacy of sorafenib treatment in advanced HCC.

BackgroundPeripheral artery disease (PAD) affects millions globally, causing significant morbidity. Traditional treatments like plain old balloon angioplasty (POBA) have limited success due to high restenosis rates. Drug-coated balloon angioplasty (DCBA) has emerged as a promising alternative, locally delivering antiproliferative drugs like paclitaxel to reduce restenosis. However, the clinical outcomes of DCBA compared to POBA remain inconsistent across various studies.ObjectiveThis umbrella meta-analysis aimed to compare the clinical outcomes of DCBA and POBA in PAD patients, synthesizing data from multiple meta-analyses to provide a more robust evidence base.MethodsWe conducted an umbrella meta-analysis following PRISMA guidelines, systematically reviewing Cochrane Library, Embase, PubMed, and Web of Science. Studies were included if they compared DCBA and POBA in PAD patients, focusing on primary outcomes such as target lesion revascularization (TLR), primary patency (PP), all-cause mortality (ACM), and amputation. Secondary outcomes included restenosis, late lumen loss (LLL), and major adverse events (MAE).ResultsSixteen meta-analyses were included. DCBA significantly reduced the risk of TLR (OR: 0.41, 95% CI: 0.34–0.49), PP was significantly higher in DCBA (OR: 2.05, 95% CI: 1.53–2.75), and restenosis was lower (OR: 0.46, 95% CI: 0.41–0.51). No significant differences were found in ACM or amputation risk between the two groups. Heterogeneity was moderate to high across most outcomes.ConclusionDCBA provides significant advantages over POBA in reducing TLR and restenosis while maintaining vessel patency. However, the effects on ACM and amputation remain inconclusive. Future research should focus on long-term safety and identifying which patient subgroups benefit most from DCBA.Systematic Review Registrationhttps://www.crd.york.ac.uk/, PROSPERO [CRD42024591967].

In the present work, the modification effect of Te and the corresponding growth process of Mg2Si were clarified. With 0.5 wt% Te addition, the dendritic primary Mg2Si transformed to polygons, accompanied by a reduction in size from over ∼165 μm–∼18 μm. However, 2.0 wt% Te addition resulted in degradation of modification effect, and the morphology of Mg2Si changed to dendrite. Three-dimensional morphology of primary Mg2Si indicated that Te altered the morphology of primary Mg2Si from dendrites to polyhedrons surrounded by {111} and {100}. The modification mechanism of Te can be attributed to the heterogeneous nucleation and the doping of Te during the growth process of primary Mg2Si, which greatly contributed to dimension decrease and morphology evolution of primary Mg2Si respectively. With Te corporation, the relative surface energy between the {100} and {111} (r) drops, contributing to the exposure of {100}. Our work shows that the solute concentration under non-equilibrium solidification plays an important role in determining the final morphology of Mg2Si. The local segregation of Mg and Si solutes results in the degradation of dendrite arms along certain directions during the initial stage of crystal growth. Combined with the modifying effect of Te, which alters the surface energy of the crystal, the final crystal morphology deviates from its equilibrium state. Our study demonstrates that ultimate morphology and dimensions of primary Mg2Si can be determined simultaneously with the addition of certain modifiers, which can be achieved by regulating the growth and nucleation of Mg2Si at the same time.

Objective To compare the clinical efficacy of anterior column reconstruction using single or double titanium mesh cage (TMC) after total en bloc spondylectomy (TES) of thoracic and lumbar spinal tumors. Methods A retrospective cohort study was performed involving 39 patients with thoracic or lumbar spinal tumors. All patients underwent TES, followed by anterior reconstruction and screw-rod instrumentation via a posterior-only procedure. Twenty-two patients in group A were treated with a single TMC to reconstruct the anterior column, whereas 17 patients in group B were reconstructed with double TMCs. Results The overall follow-up is 20.5 ± 4.6 months. There is no significant difference between the 2 groups regarding age, sex, body mass index, tumor location, operative time, and intraoperative blood loss. The time for TMC placement was significantly shortened in the double TMCs group (5.2 ± 1.3 minutes vs. 15.6 ± 3.3 minutes, p = 0.004). Additionally, postoperative neural complications were significantly reduced with double TMCs (5/22 vs. 0/17, p = 0.046). The kyphotic Cobb angle and mean intervertebral height were significantly corrected in both groups (p ≤ 0.001), without obvious loss of correction at the last follow-up in either group. The bone fusion rates for single TMC and double TMCs were 77.3% and 76.5%, respectively. Conclusion Using 2 smaller TMCs instead of a single large one eases the placement of TMC by shortening the time and avoiding nerve impingement. Anterior column reconstruction with double TMC is a clinically feasible, and safe alternative following TES for thoracic and lumbar tumors.

Abstract Although the chloroplast genome (cpDNA) of higher plants is known to exist as a large protein-DNA complex called ‘plastid nucleoid’, researches on its DNA state and regulatory elements are limited. In this study, we performed the assay for transposase-accessible chromatin sequencing (ATAC-seq) on five common tissues across five grasses, and found that the accessibility of different regions in cpDNA varied widely, with the transcribed regions being highly accessible and accessibility patterns around gene start and end sites varying depending on the level of gene expression. Further analysis identified a total of 3970 putative protein binding footprints on cpDNAs of five grasses. These footprints were enriched in intergenic regions and co-localized with known functional elements. Footprints and their flanking accessibility varied dynamically among tissues. Cross-species analysis showed that footprints in coding regions tended to overlap non-degenerate sites and contain a high proportion of highly conserved sites, indicating that they are subject to evolutionary constraints. Taken together, our results suggest that the accessibility of cpDNA has biological implications and provide new insights into the transcriptional regulation of chloroplasts.

Abstract. Background:. The ability to generate functional hepatocytes without relying on donor liver organs holds significant therapeutic promise in the fields of regenerative medicine and potential liver disease treatments. Clustered regularly interspaced short palindromic repeats (CRISPR) activator (CRISPRa) is a powerful tool that can conveniently and efficiently activate the expression of multiple endogenous genes simultaneously, providing a new strategy for cell fate determination. The main purpose of this study is to explore the feasibility of applying CRISPRa for hepatocyte reprogramming and its application in the treatment of mouse liver fibrosis. Method:. The differentiation of mouse embryonic fibroblasts (MEFs) into functional induced hepatocyte-like cells (iHeps) was achieved by utilizing the CRISPRa synergistic activation mediator (SAM) system, which drove the combined expression of three endogenous transcription factors—Gata4, Foxa3, and Hnf1a—or alternatively, the expression of two transcription factors, Gata4 and Foxa3. In vivo, we injected adeno-associated virus serotype 6 (AAV6) carrying the CRISPRa SAM system into liver fibrotic Col1a1-CreER; Cas9fl/fl mice, effectively activating the expression of endogenous Gata4 and Foxa3 in fibroblasts. The endogenous transcriptional activation of genes was confirmed using real-time quantitative polymerase chain reaction (RT-qPCR) and RNA-seq, and the morphology and characteristics of the induced hepatocytes were observed through microscopy. The level of hepatocyte reprogramming in vivo is detected by immunofluorescence staining, while the improvement of liver fibrosis is evaluated through Sirius red staining, alpha-smooth muscle actin (α-SMA) immunofluorescence staining, and blood alanine aminotransferase (ALT) examination. Results:. Activation of only two factors, Gata4 and Foxa3, via CRISPRa was sufficient to successfully induce the transformation of MEFs into iHeps. These iHeps could be expanded in vitro and displayed functional characteristics similar to those of mature hepatocytes, such as drug metabolism and glycogen storage. Additionally, AAV6-based delivery of the CRISPRa SAM system effectively induced the hepatic reprogramming from fibroblasts in mice with live fibrosis. After 8 weeks of induction, the reprogrammed hepatocytes comprised 0.87% of the total hepatocyte population in the mice, significantly reducing liver fibrosis. Conclusion:. CRISPRa-induced hepatocyte reprogramming may be a promising strategy for generating functional hepatocytes and treating liver fibrosis caused by hepatic diseases.

Abstract Scar tissue is the inevitable result of repairing human skin after it has been subjected to external destructive stimuli. It leads to localized damage to the appearance of the skin, accompanied by symptoms such as itching and pain, which reduces the quality of life of the patient and causes serious medical burdens. With the continuous development of economy and society, there is an increasing demand for beauty. People are looking forward to a safer and more effective method to eliminate pathological scarring. In recent years, adipose-derived stem cells (ADSCs) have received increasing attention from researchers. It can effectively improve pathological scarring by mediating inflammation, regulating fibroblast proliferation and activation, and vascular reconstruction. This review focuses on the pathophysiological mechanisms of hypertrophic scarring, summarizing the therapeutic effects of in vitro, in vivo, and clinical studies on the therapeutic effects of ADSCs in the field of hypertrophic scarring prevention and treatment, the latest application techniques, such as cell-free therapies utilizing ADSCs, and discussing the advantages and limitations of ADSCs. Through this review, we hope to further understand the characterization of ADSC and clarify the effectiveness of its application in hypertrophic scarring treatment, so as to provide clinical guidance.

Enhanced oil recovery (EOR) remains paramount for tapping into residual oil post primary and secondary recovery stages. While conventional methods hold their ground, the rise of chemical EOR, especially utilizing nanofluids, stands out due to its economic viability, enhanced recovery efficiency, and adaptability. The allure of nanofluid-enhanced oil recovery (N-EOR) has grown amongst researchers, albeit with underlying mechanisms that still harbor inconsistencies and ambiguities. This review meticulously examines the micro-mechanics of nanofluid interactions with heavy oil molecules, particles, and surfaces, the methodologies underpinning nanofluid-assisted EOR, multiphase displacement within pores and cores, and the fluid–solid coupling during such flows. Key findings show that nanofluids alter mineral wettability, adjust oil/water interfacial tension, shift structural disjoining pressure, and curtail viscosity. The prowess of N-EOR largely hinges on nanoparticle adsorption. Their affinity for mineral surfaces induces a shift towards water-wet states, while their interplay at oil/water boundaries can tweak interfacial tensions, fostering emulsification. One standout revelation is the adsorption of asphaltenes on nanoparticles, which mitigates asphaltene concentrations in heavy oil, thereby diminishing viscosity and amplifying oil extraction. Contrary to previous studies that merely spotlighted outcomes, our review delves deep into the complexities of nanoparticle adsorption, spotlighting the harmonious interplay between nanoparticle adsorption features and N-EOR operations. We unravel the intricacies of nanofluid behaviors during multiphase core displacement and provide a detailed overview of pertinent simulations. To encapsulate, this study demystifies potential N-EOR techniques and charts fresh research trajectories. Our revelations aim to enrich the comprehension of N-EOR phenomena, accentuating the pivotal role of nanofluids in multiphase core transitions and computational simulations. Furthermore, we highlight lingering challenges, directing the scientific community towards continued nanoparticle innovations and exploration. The novelty of this study is as follows: Nanofluids are mainly used in the third oil recovery process, and are not used in the first and second oil recovery processes. In addition, during the third oil recovery, some nanofluids may remain in the mine due to the sedimentation characteristics of nanomaterials. Currently, we are also committed to developing new processes to reduce the deposition of nanomaterials in the mine. At present, it is not clear how nanofluids enhance the oil recovery mechanism, and the oil recovery mechanism is relatively chaotic. In this article, we analyzed these mechanisms.

Metal halide perovskite has generated significant attention due to its high optical absorption coefficient, the tunability of bandgap, and its solution processing properties, all of which have led to a range of applications including solar cells, photodetectors, light-emitting diodes and lasers. However, the material's application as an optical modulator for high-energy ultrafast lasers is still limited by its slow nonlinear optical response, low damage threshold and the inferior stability. Herein, we developed a saturable absorber (SA) with the thermally stable Cs0.15FA0.85PbI2.85Br0.15 perovskite thin films as an optical modulator towards the near-infrared nanosecond passively Q-switched Nd:YAG laser generation for the first time. The Cs0.15FA0.85PbI2.85Br0.15 perovskite SA optical modulator produced an exceptional nonlinear optical response with a notable modulation depth of 15.1%, an ultrashort recovery time of 52.46 ps, and a high optical damage threshold exceeding 275.9 mJ/cm2. Of further significance, it displayed an excellent operational stability, and when incorporated into the oscillator of the Nd:YAG laser, allowed for a stable operation of 166 ns pulse laser with a center wavelength of 1.06 μm. The findings provide a pathway for the employment of the Cs0.15FA0.85PbI2.85Br0.15 perovskite SA optical modulator in near-infrared ultrafast laser applications.

Abstract Radiated tumor cell‐derived extracellular vesicles (RT‐EVs) encapsulate abundant DNA fragments from irradiated tumor cells, in addition to acting as integrators of multiple tumor antigens. Accumulating evidence indicates these DNA fragments from damaged cells are involved in downstream immune responses, but most of them are degraded in cells before incorporation into derived RT‐EVs, thus the low abundance of DNA fragments limits immune responses of RT‐EVs. Here, this study found that different radiations affected fates of DNA fragments in RT‐EVs. Boron neutron capture therapy (BNCT) induced DNA accumulation in RT‐EVs (BEVs) by causing more DNA breaks and DNA oxidation resisting nuclease degradation. This is attributed to the high‐linear energy transfer (LET) properties of alpha particles from the neutron capture reaction of 10B. When being internalized by dendritic cells (DCs), BEVs activated the DNA sensing pathway, resulting in functional enhancements including antigen presentation, migration capacity, and cytokine secretion. After vaccination of the BEVs‐educated DCs (BEV@BMDCs), the effector T cells significantly expanded and infiltrated into tumors, suggesting robust anti‐tumor immune activation. BEV@BMDCs not only effectively inhibited the primary tumor growth and metastasis formation but also elicited long‐term immune memory. In conclusion, a successful DC vaccine is provided as a promising candidate for tumor vaccine.

BackgroundMitochondrial dysfunction has been shown to play a critical role in cancer biology. However, its involvement in intrahepatic cholangiocarcinoma (iCCA) remains significantly understudied.MethodsRNA sequencing data of 30 pairs of iCCA and paracancerous tissues were collected from the First Affiliated Hospital of Wenzhou Medical University (WMU). The WMU cohort (n = 30) was integrated with public TCGA (n = 30) and GSE107943 (n = 30) datasets to establish a multi-center iCCA cohort. We merged the TCGA and GSE107943 cohorts into an exploration cohort to develop a mitochondria signature for prognosis assessment, and utilized the WMU cohort for external validation. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Hallmarker analyses were used for functional interpretation of iCCA associated mitochondria-related genes (MRGs). In addition, unsupervised clustering was performed to identify mitochondria-based iCCA subtypes with the data of three institutions. Further investigations were conducted to examine the impact of mitochondrial dysfunction on drug responses, alteration of the tumor immune microenvironment, and immune responses.ResultsTwo hundred and sixty-three iCCA-related MRGs were identified to be related to fatty acid metabolism, oxidative phosphorylation, and apoptosis. Through univariate and multivariate Cox, and LASSO analyses, a mitochondria signature with five optimal MRGs was established to evaluate the prognosis of iCCA patients with the AUC values ranged from 0.785 to 0.928 in the exploration cohort. The signature also exhibited satisfactory performance in the WMU cohort with AUC values of 0.817–0.871, and was identified as an independent risk predictor in both cohorts. Additionally, we found that patients with higher mitochondria score with poor prognosis presented lower infiltration levels of CD4+ T-cell, NK cells, and monocytes, and demonstrated higher sensitivity to targeted therapies, including sorafenib. Furthermore, two distant mitochondria-based subtypes were determined, and subtype 2 was associated with shorter survival time and immunosuppressive tumor microenvironment. Finally, the differential protein expression of five key MRGs was verified by Immunohistochemistry.ConclusionWe found mitochondrial dysfunction modulates aberrant metabolism, oxidative stress, immune responses, apoptosis, and drug sensitivity in iCCA. A mitochondria signature and two mitochondria-based iCCA subtypes were identified for clinical risk stratification and immunophenotyping.

Vibrio harveyi is a major pathogen in yellow drum (Nibea albiflora) aquaculture, causing significant mortality and economic losses. In this study, using the latest assembled reference genome of yellow drum by our laboratory, we conducted genome-wide association study (GWAS) analysis on 345 individuals (197 susceptible and 148 resistant). The analysis revealed 24 significant single nucleotide polymorphisms (SNPs) on chromosome 24 within a 217 Kb region. The estimated heritability for all genome-wide SNPs was 0.3578, while the heritability for the 24 significant SNPs was 0.0710. Four candidate genes were identified within this region: Suppressor of Cytokine Signaling 1 (SOCS1), C-type Lectin Domain Family 16A (CLEC16A), Major Histocompatibility Complex Class II Transactivator (CIITA), and Protein Kinase Cβ (PRKCB). Subsequently, expression quantitative trait loci (eQTL) analysis was performed on transcriptome sequencing data from spleen tissues of 78 individuals from the resistant group. On average, each chromosome harbored 49,396 eQTL loci, with an average of one SNP regulate 1.3 genes. Notably, 22.79% of SNPs showed significant associations with the expression of one or more genes. By integrating GWAS and eQTL data, seven SNPs were identified to have significant associations with regulated genes in the eQTL results. All seven SNPs were found to target the same gene, namely Zinc Finger Protein yd23210 in yellow drum. This study provides genetic markers and candidate genes for molecular breeding of yellow drum against V. harveyi infection, offering insights into the molecular immune mechanisms and potential pathways for genetic improvement of disease resistance traits in this species.

The aim of this paper is to study the flexural behavior of reinforced concrete (RC) beams reinforced by engineered cementitious composite (ECC). The reinforcement effect of ECC on RC beam is studied by experiments, numerical simulation and theoretical analysis, considering the secondary load. Five beams were tested under static load, including two beams with ECC layers at the top and bottom (TBEB), two beams with ECC layers at the bottom (BEB) and one unreinforced beam. Different parameters in the test include reinforcement ratio, whether the top is equipped with ECC layer, and the thickness of the top ECC layer. The test data were used to validate the finite element model developed to simulate the bending response of the ECC layer reinforced beam. Then, a series of parameter studies were carried out to evaluate the effects of ECC layer thickness, reinforcement ratio and ECC elastic modulus on the reinforced beam. The experimental and numerical simulation results show that compared with other reinforced beams, TBEB equipped with 50 mm ECC layer at the top and bottom has better performance. Compared with the control beams, the ultimate bearing capacity is increased by 82.6 %, ductility and deformation capacity are increased by 2.38 times and 2.11 times, respectively. Finally, a calculation model for predicting the flexural capacity of TBEB is presented. The predicted flexural capacity is in good agreement with the experimental results.

Abstract Background Recent advances in gene editing technology have opened up new avenues for in vivo gene therapy, which holds great promise as a potential treatment method for dilated cardiomyopathy (DCM). The CRISPR-Cas13 system has been shown to be an effective tool for knocking down RNA expression in mammalian cells. PspCas13b, a type VI-B effector that can be packed into adeno-associated viruses and improve RNA knockdown efficiency, is a potential treatment for diseases characterized by abnormal gene expression. Results Using PspCas13b, we were able to efficiently and specifically knockdown the mutant transcripts in the AC16 cell line carrying the heterozygous human TNNT2 R141W (hTNNT2 R141W ) mutation. We used adeno-associated virus vector serotype 9 to deliver PspCas13b with specific single guide RNA into the hTNNT2 R141W transgenic DCM mouse model, effectively knocking down hTNNT2 R141W transcript expression. PspCas13b-mediated knockdown significantly increased myofilament sensitivity to Ca2+, improved cardiac function, and reduced myocardial fibrosis in hTNNT2 R141W DCM mice. Conclusions These findings suggest that targeting genes through Cas13b is a promising approach for in vivo gene therapy for genetic diseases caused by aberrant gene expression. Our study provides further evidence of Cas13b’s application in genetic disease therapy and paves the way for future applicability of genetic therapies for cardiomyopathy.

In this paper, we present a hybrid heuristic method based on the harmonic search algorithm to solve the vehicle routing problem with time windows. The importance of efficient path planning in logistics and supply chain management is emphasized herein, particularly under complex constraints like time window and vehicle capacity limits. The hybrid heuristic harmony search algorithm combines the global search capability of the harmony search algorithm with the accuracy of the local search heuristic to efficiently explore and harness the solution space. Through rigorous testing on the Solomon dataset, the hybrid heuristic harmony search algorithm performed remarkably in the generation of competitive solutions while maintaining the computational efficiency of the solutions. The results showed that the algorithm achieved competitive solutions even under strict time window constraints. The convergence of the algorithm was examined, and its strong performance in handling complex instances was revealed. This study enhances the operational efficiency of an organization and provides perspectives and solutions for optimization strategies in the domains of logistics and supply chain management.

Abstract Aims Neutrophil extracellular traps (NETs) have been implicated in thrombotic diseases. There is no definitive explanation for how NETs form during acute ischemic strokes (AIS). The purpose of our study was to investigate the potential mechanism and role of NETs formation in the AIS process. Methods As well as 45 healthy subjects, 45 patients with AIS had ELISA tests performed to detect NET markers. Expression of high-mobility group box 1 (HMGB1) on platelet microvesicles (PMVs) was analyzed by flow cytometry in healthy subjects and AIS patients’ blood samples. We established middle cerebral artery occlusion (MCAO) mice model to elucidate the interaction between PMPs and NETs. Results A significant elevation in NET markers was found in patient plasma in AIS patients, and neutrophils generated more NETs from patients’ neutrophils. HMGB1 expression was upregulated on PMVs from AIS patients and induced NET formation. NETs enhanced Procoagulant activity (PCA) through tissue factor and via platelet activation. Targeting lactadherin in genetical and in pharmacology could regulate the formation of NETs in MCAO model. Conclusions NETs mediated by PMVs derived HMGB1 exacerbate thrombosis and brain injury in AIS. Video Abstract

In order to reduce the influence of coupling capacitance variations on cable voltage measurement, this paper proposes a self-compensating non-intrusive ring-type AC voltage sensor based on capacitive coupling. A theoretical model of the sensor was established, and the influence of parasitic capacitance changes on sensor output was analyzed. Furthermore, a theoretical analysis shows that the parasitic capacitance between the external cable and the sensing probe, as well as between the ground and the sensing probe, will significantly affect the sensitivity of the sensor and increases the measurement error. A ring-type inductive probe and a signal processing circuit were designed, incorporating a reference signal to compensate for the influence of coupling capacitance variations. Additionally, to minimize the impact of parasitic capacitance on sensor output, the length of the outer ring electrode was extended, and a PTFE housing was designed for protection. A prototype of the sensor was developed and tested. This prototype has a good linear response to AC voltage in the measurement range of 0–1000 V with a linearity of 0.86%. The effects of changes in cable diameter and cable position on the measurement were tested separately. The worst-case error of the sensor output is less than 6.44%, representing a reduction of 21.4% compared to the uncompensated case. Under external cable interference, the sensor exhibited an output error of less than 1.85%. The results show that the designed sensor can accurately measure cable voltage despite changes in cable diameter or installation position, and also demonstrates effective shielding against external interference.

Wound healing is a complex and precisely regulated process that encompasses multiple stages, including inflammation, anti-inflammation, and tissue repair. It involves various cells and signaling molecules, with macrophages demonstrating a significant degree of plasticity and playing a crucial regulatory role at different stages. In recent years, the use of biomaterials, which include both natural and synthetic polymers or macromolecules, has proliferated for the purpose of enhancing wound healing. This review summarizes how these diverse biomaterials promote wound healing by modulating macrophage behavior and examines the broader implications of these modulations. Additionally, we discuss the limitations associated with the clinical application of immunomodulatory biomaterials and propose potential solutions. Finally, we look towards future developments in the design of immunomodulatory biomaterials intended to enhance wound healing.

In geotechnical engineering, side friction resistance (SFR) is difficult to be measured directly. To further understand distribution law of the SFR, this paper developed a monitoring device that can directly measure the SFR. Further, a theoretical conversion formula for the elastic deformation and the SFR that considers the end effect of sensor sealing was proposed to guide the selection of sensor size and sealing material. Moreover, the monitoring device for the SFR was then calibrated using a large-scale direct shear apparatus and analyzed the stability of the sensor. The calibration results revealed that under cyclic loading and unloading conditions, the linear correlation coefficient of the sensor was greater than 0.996, and the sensitivity after sealing could reach 4.836 με/kPa, which met requirements of the engineering application. The developed monitoring device characterized by simple testing principle, low cost, and high precision were successfully applied to an open caisson project in Harbin City, which contributes to address the difficult problem of efficiently collecting the SFR in highways, bridges, water conservancy, and other projects.

BackgroundLaminotomy and laminar replantation have emerged as novel treatment modalities for intraspinal tumors, aiming to minimize postoperative complications and retain spinal mobility. However, existing research predominantly emphasizes their application in the thoracolumbar spine. The unique anatomy of the atlantoaxial segments necessitates surgical techniques that differ from those used in other spinal regions, and the clinical effect of such procedure remains unknown.Case presentationA 61-year-old male patient with intradural schwannoma at the atlantoaxial level was operated on. The patient underwent posterior laminectomy, as well as a combined replantation of the posterior arch of the atlas and bilateral axial laminae. Postoperatively, the patient experienced significant neurological improvement, with no deformities or instability on the radiological assessments during the follow-up.ConclusionLaminotomy with combined replantation of the posterior arch of the atlas and bilateral axial lamina emerges as an effective approach for managing intraspinal tumors at the atlantoaxial level. This technique not only offers ample operating space but also restores the stability of the spinal canal. Moreover, it preserves the mobility of the atlantoaxial segment, minimizes impact on adjacent segments, and mitigates the formation of postoperative fibrosis.

Background: Constipation is one of the chronic gastrointestinal functional diseases that affects the quality of life. While Qi Lang Formula (QLF) has demonstrated effectiveness in alleviating constipation symptoms, its precise mechanism remains elusive. Methods: QLF was analyzed using UPLC-MS/MS. Targets for QLF were collected from SwissADME, Herb, ITCM databases, and constipation-related targets from scRNA-seq and Genecards databases. Overlapping targets suggested potential QLF therapy targets for constipation. Enrichment analysis used the KOBAS database. A ''drug-ingredient-target'' network was constructed with Cytoscape, and AutoDock verified active ingredient binding. H&E staining assessed colonic mucosa changes, TEM examined ICC structural changes. ELISA measured neurotransmitter levels, and Western blot verified QLF's effect on target proteins. ICC proliferation was observed through immunofluorescence. Results: We identified 89 targets of QLF associated with ICC-related constipation, with c-Kit emerging as the pivotal target. Molecular docking studies revealed that Atractylenolide Ⅲ, Apigenin, Formononetin, Isorhamnetin, Naringenin, and Ononin exhibited strong binding affinities for the c-Kit structural domain. QLF significantly enhanced first stool passage time, fecal frequency, fecal moisture content, and intestinal propulsion rate. Further analysis unveiled that QLF not only restored neurotransmitter levels but also mitigated colon muscular fiber ruptures. ICC ultrastructure exhibited partial recovery, while Western blot confirmed upregulated c-Kit expression and downstream targets. Immunofluorescence results indicated ICC proliferation post QLF treatment in rat colon. Conclusion: Our findings suggest that QLF may promote ICC proliferation by targeting SCF/c-Kit and its downstream signaling pathway, thereby regulating intestinal motility.

The environmental agenda is decisive in the formation of the world economy at the present stage. The need for a green transition is rarely questioned by scientists. However, there remains a wide range of opinions about which instruments are the most effective in achieving the set goals of reducing the carbon footprint. The most popular mechanisms today are the carbon market and carbon tax mechanisms. Aim of the research was using modeling, literature analysis, and deduction methods to compare the similarities and differences between the basic principles of applying a carbon tax and a carbon market mechanism, the authors of the article identify the advantages and disadvantages of both approaches. The results of the research showed that the carbon market mechanism has obvious advantages such as flexibility, cross-industry and crossterritory coverage, and relative benefits for companies compared to a carbon tax mechanism. At the same time, the carbon tax mechanism has the obvious advantage of low management costs and wide coverage, but, on the other hand, these advantages are offset by potential inefficiencies and high “cost” for companies. The analysis of the policies of large countries with large carbon emissions over the past 2-3 years shows that they are more likely to introduce elements of the carbon market to reduce emissions. Based on the theoretical analysis of the main characteristics of the carbon market and carbon tax, as well as their advantages and disadvantages, the authors urge not to be limited to one of the options, but to use both mechanisms simultaneously. In particular, the carbon market should be the main mechanism when the goal is to create more incentives to actively reduce carbon emissions, while carbon tax policies can be an additional measure to incentivize or “punish” those enterprises that exceed emission standards, also, the carbon tax will help to involve those industries that, for various reasons, cannot be represented on the carbon market.

Abstract Background Brain metastases (BMs) are the most frequent intracranial tumours associated with poor clinical outcomes. Radiotherapy is essential in the treatment of these tumours, although the optimal radiation strategy remains controversial. The present study aimed to assess whether whole brain radiation therapy with a simultaneous integrated boost (WBRT + SIB) provides any therapeutic benefit over WBRT alone. Methods We included and retrospectively analysed 82 patients who received WBRT + SIB and 83 who received WBRT alone between January 2012 and June 2021. Intracranial progression-free survival (PFS), local tumour control (LTC), overall survival (OS), and toxicity were compared between the groups. Results Compared to WBRT alone, WBRT + SIB improved intracranial LTC and PFS, especially in the lung cancer subgroup. Patients with high graded prognostic assessment score or well-controlled extracranial disease receiving WBRT + SIB had improved intracranial PFS and LTC. Moreover, WBRT + SIB also improved the long-term intracranial tumour control of small cell lung cancer patients. When evaluating toxicity, we found that WBRT + SIB might slightly increase the risk of radiation-induced brain injury, and that the risk increased with increasing dosage. However, low-dose WBRT + SIB had a tolerable radiation-induced brain injury risk, which was lower than that in the high-dose group, while it was comparable to that in the WBRT group. Conclusions WBRT + SIB can be an efficient therapeutic option for patients with BMs, and is associated with improved intracranial LTC and PFS. Furthermore, low-dose WBRT + SIB (biologically effective dose [BED] ≤ 56 Gy) was recommended, based on the acceptable risk of radiation-induced brain injury and satisfactory tumour control. Trial registration Retrospectively registered.

Hand-foot syndrome (HFS) is a widely recognized dose-limiting cutaneous toxicity effect of fluoropyrimidine chemotherapy agents that impairs clinical benefits and treatment outcomes. Even though the cause and pathophysiology of HFS are relatively widely reported, how the toxicity of fluoropyrimidine translates into persistent inflammation has not been studied. Additionally, prevention and treatment strategies for HFS based on its mechanistic occurrence and development are scarce. In our study, we demonstrated that cGAS-STING signaling pathway-mediated cellular senescence played a critical role in the inflammatory reaction and provided a therapeutic solution for HFS. Mechanistically, DNA damage, as the primary cytotoxic cause, in keratinocytes induces cell cycle arrest, activates the cGAS-STING signaling pathway, and subsequently mediates cellular senescence, ultimately fueling a robust secondary inflammatory response that results in HFS. More importantly, the thymidine prodrug thymidine diacetate was proven to be effective in preventing HFS by compensating for thymidylate deficiency to facilitate the replication and repair of DNA and thus causing the escape from cellular senescence. These data highlight the importance of DNA damage-mediated cellular senescence in the etiology of HFS and provide a potential therapeutic anchor point for fluoropyrimidine-induced HFS.

Abstract Background Epidemiological studies have indicated a potential link between the gut microbiome and autoimmune liver disease (AILD) such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The relationship between the gut microbiome and autoimmune liver disease is still uncertain due to confounding variables. In our study, we aim to shed light on this relationship by employing a two-sample Mendelian randomization approach. Methods We conducted a two-sample Mendelian randomization (MR) study using the R package "TwoSampleMR". The exposure data consisted of genetic variants associated with 194 bacterial traits obtained from the MiBioGen consortium. Summary statistics for AILD were obtained from the GWAS Catalog website. Furthermore, a series of sensitivity analyses were performed to validate the initial MR results. Results There were two, four and three bacteria traits associated with an increased risk of AIH. PBC, and PSC respectively. In contrast, there were five, two and five bacteria traits associated with a decreased risk for AIH, PBC and PSC. Notably, the genus_Clostridium_innocuum_group showed a negative association with AIH (OR = 0.67, 95% CI: 0.49–0.93), and the genus_Actinomyces was found to be genetically associated with a decreased risk of PSC (OR = 0.62, 95% CI: 0.42–0.90). Conclusions Our study identified the causal impact of specific bacterial features on the risk of AILD subtypes. Particularly, the genus_Clostridium_innocuum_group and the genus_Actinomyces demonstrated significant protective effects against AIH and PSC respectively. These findings provide further support for the potential use of targeted probiotics in the management of AILD.

The transcription factor activating protein 2α (AP2α) is a nuclear transcription factor that specifically binds to DNA and is involved in the regulation of animal embryonic development, cell growth, apoptosis, tumorigenesis, immunity, and other biological processes. In our previous study, the transcription factor AP2α was discovered as a key disease-resistance candidate gene in the yellow drum, Nibea albiflora, in response to a Vibrio harveyi infection through genome-wide association analysis. In the present study, the AP2α gene, which encodes a protein of 424 amino acids, was cloned from a yellow drum. The N-terminal is a trans-activation domain rich in proline and glutamine (P/Q-rich domain), and the middle is a central basic structure (central basic region), which is a highly conserved helix-span-helix motif responsible for DNA binding and protein dimerization. Multiple alignments of amino acid sequences showed that AP2α was highly conserved, with a homology of more than 84.63% among the detected fish, amphibians, birds, and mammals. Quantitative RT-PCR demonstrated that AP2α was widely distributed in the nine tested tissues, with the highest expression in the blood. Moreover, its transcription was significantly activated in the liver, spleen, and head kidney by V. harveyi infection, especially in the liver wherein the transcript level of AP2α reached a peak at 24 h post infection. Subcellular localization by constructing the recombinant eukaryotic expression plasmid pGEFP-AP2α and transfection into HEK293T cells revealed that AP2α was localized in the nucleus. In addition, the soluble GST-AP2α fusion protein was expressed in Escherichia coli BL21. These results demonstrate that AP2α plays an important role in the immune response against V. harveyi in N. albiflora. We provide new insights into the role of AP2α in the innate immunity of teleost fishes and provide a basis for studies on immune mechanisms and disease-resistant breeding in N. albiflora and other marine fish.

This paper reports the design, fabrication, and characterization of a MEMS capacitive accelerometer with an asymmetrical comb finger arrangement. By optimizing the ratio of the gaps of a rotor finger to its two adjacent stator fingers, the sensitivity of the accelerometer is maximized for the same comb finger area. With the fingers’ length, width, and depth at 120 μm, 4 μm, and 45 μm, respectively, the optimized finger gap ratio is 2.5. The area of the proof mass is 750 μm × 560 μm, which leads to a theoretical thermomechanical noise of 9 μg/√Hz. The accelerometer has been fabricated using a modified silicon-on-glass (SOG) process, in which a groove is pre-etched into the glass to hold the metal electrode. This SOG process greatly improves the silicon-to-glass bonding yield. The measurement results show that the resonant frequency of the accelerometer is about 2.05 kHz, the noise floor is 28 μg/√Hz, and the nonlinearity is less than 0.5%.

This study presents a novel obstacle evasion method for unmanned aerial vehicle (UAV) clusters in the presence of static and dynamic obstacles. First, a discrete three-dimensional model of the UAV is provided. Second, the proposed improved artificial potential field (APF) is illustrated. In designing the improved scheme, a pseudo-exponential function is fused into the potential field, thus avoiding local extreme points. Frictional resistance is introduced to optimize vibration and maintain stability after reaching the desired endpoints. Meanwhile, the relevant parameters are optimized, and appropriate state limits are defined, thus enhancing the control stability. Third, Lyapunov stability analysis proves that all signals in the closed-loop cluster system are ultimately bounded. Finally, the simulation results demonstrate that the UAV cluster can efficiently reconstruct, form, and maintain formations while avoiding static and dynamical obstacles along with maintaining a safe distance, solving the problem of the local extreme of traditional artificial potential field methods. The proposed scheme is also tested under large-scale multi-UAV scenarios. In conclusion, this study provides valuable insights for engineers working with UAV clusters navigating through formations.

To fill the gaps in the theoretical research on the internal force and deformation of the DSCG, the development law of the internal force and deformation of DSCG was explored in conjunction with the theory of elastic analysis. In addition, a finite element model was established to validate the calculation results. The results showed that using different pre-stressing increment calculation methods affected the calculation results of the composite interface deformation, with the equivalent section method accounting for 0.74% and the principle of the virtual work method for 0.03%. On the other hand, the development of internal forces and deformations in the DSCG was closely related to the magnitude of the load forms and axle weights. At the same time, material non-linearity had less influence on these factors. Finally, the development patterns of the internal forces and deformations of the DSCG with different spans were similar. The specific values were closely related to the span of the guideway, and the interfacial slip, axial force, and deflection of the DSCG with span L = 25 m were 0.60, 0.41, and 0.23 times those of the DSCG with span L = 35 m, respectively. The conclusions of this paper fill the gaps in the theoretical study of multi-system guideways.

Selenium (Se) is an essential trace element known for its significant role in maintaining human health and mitigating disease progression. Selenium and its compounds exhibit high selective cytotoxicity against tumor cells. However, their anti-cervical cancer (CC) effects and underlying mechanisms have not been fully explored. This study found that sodium selenite (SS) inhibits the viability of HeLa and SiHa cells in a dose- and time-dependent manner. Intraperitoneal injection of 3 and 6 mg/kg SS for 14 days in female nude mice significantly inhibited the growth of HeLa cell xenografts without evident hepatotoxicity or nephrotoxicity. RNA sequencing results indicated that the AMP-activated protein kinase (AMPK), Forkhead box protein O (FOXO), and apoptosis signaling pathways are key regulatory pathways in SS’s anti-CC effects, and SS’s inhibition of HeLa cell proliferation may be related to autophagy and ROS-induced apoptosis. Further research has revealed that SS induces cell autophagy and apoptosis through the AMPK/mTOR/FOXO3a pathway, characterized by the upregulation of p-AMPK/AMPK, FOXO3a, LC3-II, cleaved-caspase3, and cleaved-PARP and the downregulation of p-mTOR/mTOR and p62. Additionally, SS impaired mitochondrial function, including decreased mitochondrial membrane potential, mitochondrial Ca2+ overload, and accumulation of mitochondrial reactive oxygen species (mtROS). Pretreatment with Mitoquinone mesylate (Mito Q) and compound C partially reversed SS-induced apoptosis, autophagy, and proliferation inhibition. Pretreatment with 3-methyladenine (3-MA) enhances SS-induced apoptosis and proliferation inhibition in HeLa cells but reverses these effects in SiHa cells. In summary, SS induces apoptosis, autophagy, and proliferation inhibition in HeLa and SiHa cells through the activation of the AMPK/mTOR/FOXO3a signaling pathway via mtROS. Autophagy activation may be a major risk factor for SS-induced apoptosis in SiHa cells but can protect HeLa cells from SS-induced apoptosis. These findings provide new evidence for understanding the molecular mechanisms underlying SS in potential new drug development for CC.

A large amount of fracturing fluid in hydraulic fracturing is imbibed into the shale fracture/matrix, which leads to significant uncertainty in gas recovery evaluation. The mechanism of imbibition impact on the gas–water flow is not well understood. In this study, systematic comparative experiments are carried out to simulate imbibition in fractured shale samples obtained from the Wufeng-Longmaxi shale reservoirs in China, and the imbibition effect in the fracture–matrix system is qualitatively and quantitatively investigated. Nine cores are collected to measure their porosity and permeability using a helium porosimeter and nitrogen pulse–decay tests. Gas/liquid single-phase flow experiments are then carried out using methane and KCl solution, respectively. Subsequently, dynamic imbibition experiments are carried out on three samples in a visual cell. The gas–water interfacial tension, water imbibition amount, and displacement velocity are recorded. A single-phase gas/liquid flow test shows a high linear correlation between the fluid displacement velocity and pressure gradient in the fractured samples as the fracture is the main flow channel, dominantly determining the flow behavior. Moreover, the capillary force was introduced in the cross-flow term of the triple-medium model to characterize the imbibition effect, and a two-phase flow simulation model considering the fracturing fluid imbibition retention was developed, and the two-phase flow behavior by considering the imbibition effect of the fracturing fluid retention in the shale gas reservoir was analyzed. Valuable experiment data in this work are provided, which can be used to validate analytical equations for gas/water flow in the shale fracture–matrix system.

Abstract Although antiangiogenic therapy has been used in gastric cancer, disease progression due to drug resistance remains common. Neutrophils play an important role in the occurrence and progression of cancer via neutrophil extracellular traps (NETs). However, few studies have investigated angiogenic regulation in gastric cancer. We aimed to determine the role of NETs in promoting angiogenesis in gastric cancer. Multiple immunohistochemical staining was used to analyze the spatial distribution of NETs and microvessels in patient tissue samples. A mouse subcutaneous tumor model was established to determine the effect of NETs on tumor growth, and changes in microvessel density were observed via immunohistochemical staining. We screened differentially expressed proteins in HUVECs stimulated by NETs via proteomics. Cell Counting Kit-8, EdU labeling, and tubule formation assays were used to verify the effect of NETs on HUVEC proliferation, migration, and tubule formation. Blocking NETs, which was related to decreased microvessel density, significantly inhibited tumor growth in the murine subcutaneous tumor model. Compared with those of the control group, tumor volume and mass among mice in the inhibition group decreased by 61.3% and 77.9%, respectively. The NET-DNA receptor CCDC25 was expressed in HUVECs, providing a platform for NETs to promote HUVEC proliferation, migration, and tubulation. In an in vitro rat aortic explant model, NETs induced HUVEC proliferation, survival, and chemotaxis, which were not significantly different from those observed in the VEGF stimulation group. Our results confirm that NETs promote angiogenesis in gastric cancer, providing a theoretical basis for identifying new anti-vascular therapeutic targets. Graphical Abstract Video Abstract

Abstract Background and Aims: Glucose phosphate isomerase (GPI) deficiency is an extremely rare autosomal recessive disorder caused by mutations in the GPI gene. In this research, the proband displaying typical manifestations of haemolytic anaemia and his family members were recruited to analyse the pathogenicity of the detected variants. Methods: Peripheral blood samples were collected from the family members and genomic DNA was extracted and targeted for capture and sequencing. The effect of the candidate pathogenic variants on splicing was further investigated using the minigene splicing system. The computer simulation was also used for further analysis of the detected data. Results: The proband carried the compound heterozygous variants c.633 + 3 A > G and c.295G > T in the GPI gene, which have never been reported before. In the genealogy, co-segregation of the mutant genotype with the phenotype was established. The minigene study showed that intronic mutations resulted in abnormal pre-mRNA splicing. Specifically, the two aberrant transcripts: r.546_633del and r.633 + 1_633 + 2insGT were transcribed by the minigene plasmid expressing the c.633 + 3 A > G variant. The missense mutation c.295G > T in exon 3 resulted in altering glycine at codon 87 to cysteine which was predicted to be pathogenic in an in silico analysis. Deeper analyses revealed that the Gly87Cys missense mutation led to steric hindrance. Compared to the wild-type, the mutation G87C led to a significant increase in intermolecular forces. Conclusion: Overall, the novel compound heterozygous variants in the GPI gene contributed to the etiology of the disease. Genetic testing can assist in the diagnosis. The novel gene variants identified in the present study has further expanded the mutational spectrum of GPI deficiency, which can better guide family counselling.

Pyruvate kinase deficiency is a rare hereditary erythrocyte enzyme disease caused by mutations in the pyruvate kinase liver and red blood cell gene. The clinical presentations of pyruvate kinase deficiency are significantly heterogeneous, ranging from just mild anemia to hemolytic crisis or even death. The proband in our study was a 2-year-old girl for severe skin and scleral icterus with progressive aggravation. We collected the family's data for further analysis. Whole exome genome sequencing of the pedigree revealed a novel compound heterozygous mutation, c.1097del (p.P366Lfs*12) and c.1493G > A (p.R498H), in the pyruvate kinase liver and red blood cell gene. Furthermore, molecular dynamics simulations were employed to uncover differences between the wild type and mutant pyruvate kinase liver and red blood cell proteins, focusing on structural stability, protein flexibility, secondary structure, and overall conformation. The combined bioinformatic tools were also utilised to assess the effects of the missense mutation on protein function. Thereafter, wild type and mutant plasmids were constructed and transfected into 293T cells, and Western blot assay was conducted to validate the impact of the mutations on the expression of pyruvate kinase liver and red blood cell protein. The data presented in our study enriches the genotype database and provides evidence for genetic counseling and molecular diagnosis of pyruvate kinase deficiency.

Abstract Background Inflammation-related predisposition to cancer plays an essential role in cancer progression and is associated with poor prognosis. A hypoxic microenvironment and neutrophil infiltration are commonly present in solid tumours, including gastric cancer (GC). Neutrophil extracellular traps (NETs) have also been demonstrated in the tumour immune microenvironment (TIME), but how NETs affect GC progression remains unknown. Here, we investigated the role of NET formation in the TIME and further explored the underlying mechanism of NETs in GC tumour growth. Methods Hypoxia-induced factor-1α (HIF-1α), citrulline histone 3 (citH3) and CD66b expression in tumour and adjacent nontumor tissue samples was evaluated by western blotting, immunofluorescence and immunohistochemical staining. The expression of neutrophil-attracting chemokines in GC cells and their hypoxic-CM was measured by qRT‒PCR and ELISA. Neutrophil migration under hypoxic conditions was evaluated by a Transwell assay. Pathway activation in neutrophils in a hypoxic microenvironment were analysed by western blotting. NET formation was measured in vitro by immunofluorescence staining. The protumour effect of NETs on GC cells was identified by Transwell, wound healing and cell proliferation assays. In vivo, an lipopolysaccharide (LPS)-induced NET model and subcutaneous tumour model were established in BALB/c nude mice to explore the mechanism of NETs in tumour growth. Results GC generates a hypoxic microenvironment that recruits neutrophils and induces NET formation. High mobility group box 1 (HMGB1) was translocated to the cytoplasm from the nucleus of GC cells in the hypoxic microenvironment and mediated the formation of NETs via the toll-like receptor 4 (TLR4)/p38 MAPK signalling pathway in neutrophils. HMGB1/TLR4/p38 MAPK pathway inhibition abrogated hypoxia-induced neutrophil activation and NET formation. NETs directly induced GC cell invasion and migration but not proliferation and accelerated the augmentation of GC growth by increasing angiogenesis. This rapid tumour growth was abolished by treatment with the NET inhibitor deoxyribonuclease I (DNase I) or a p38 MAPK signalling pathway inhibitor. Conclusions Hypoxia triggers an inflammatory response and NET formation in the GC TIME to augment tumour growth. Targeting NETs with DNase I or HMGB1/TLR4/p38 MAPK pathway inhibitors is a potential therapeutic strategy to inhibit GC progression. Video Abstract

Bacteria and archaea are foundational life forms on Earth and play crucial roles in the development of our planet’s biological hierarchy. Their interactions influence various aspects of life, including eukaryotic cell biology, molecular biology, and ecological dynamics. However, the coexistence network patterns of these microorganisms within natural river ecosystems, vital for nutrient cycling and environmental health, are not well understood. To address this knowledge gap, we systematically explored the non-random coexistence patterns of planktonic bacteria and archaea in the 6000-km stretch of the Yangtze River by using high-throughput sequencing technology. By analyzing the O/R ratio, representing the divergence between observed (O%) and random (R%) co-existence incidences, and the module composition, we found a preference of both bacteria and archaea for intradomain associations over interdomain associations. Seasons notably influenced the co-existence of bacteria and archaea, and archaea played a more crucial role in spring as evidenced by their predominant presence of interphyla co-existence and more species as keystone ones. The autumn network was characterized by a higher node or edge number, greater graph density, node degree, degree centralization, and nearest neighbor degree, indicating a more complex and interconnected structure. Landforms markedly affected microbial associations, with more complex networks and more core species found in plain and non-source areas. Distance-decay analysis suggested the importance of geographical distance in shaping bacteria and archaea co-existence patterns (more pronounced in spring). Natural, nutrient, and metal factors, including water temperature, NH4+-N, Fe, Al, and Ni were identified as crucial determinants shaping the co-occurrence patterns. Overall, these findings revealed the dynamics of prokaryotic taxa coexistence patterns in response to varying environmental conditions and further contributed to a broader understanding of microbial ecology in freshwater biogeochemical cycling.

Full waveform inversion (FWI) is recognized as a leading data-fitting methodology, leveraging the detailed information contained in physical waveform data to construct accurate, high-resolution velocity models essential for crosshole surveys. Despite its effectiveness, FWI is often challenged by its sensitivity to data quality and inherent nonlinearity, which can lead to instability and the inadvertent incorporation of noise and extraneous data into inversion models. To address these challenges, we introduce the scale-aware edge-preserving FWI (SAEP-FWI) technique, which integrates a cutting-edge nonlinear anisotropic hybrid diffusion (NAHD) filter within the gradient computation process. This innovative filter effectively reduces noise while simultaneously enhancing critical small-scale structures and edges, significantly improving the fidelity and convergence of the FWI inversion results. The application of SAEP-FWI across a variety of experimental and authentic crosshole datasets clearly demonstrates its effectiveness in suppressing noise and preserving key scale-aware and edge-delineating features, ultimately leading to clear inversion outcomes. Comparative analyses with other FWI methods highlight the performance of our technique, showcasing its ability to produce images of notably higher quality. This improvement offers a robust solution that enhances the accuracy of subsurface imaging.

Backgrounds and aimsImmunotherapies have formed an entirely new treatment paradigm for hepatocellular carcinoma (HCC). Tertiary lymphoid structure (TLS) has been associated with good response to immunotherapy in most solid tumors. Nonetheless, the role of TLS in human HCC remains controversial, and recent studies suggest that their functional heterogeneity may relate to different locations within the tumor. Exploring factors that influence the formation of TLS in HCC may provide more useful insights. However, factors affecting the presence of TLSs are still unclear. The human gut microbiota can regulate the host immune system and is associated with the efficacy of immunotherapy but, in HCC, whether the gut microbiota is related to the presence of TLS still lacks sufficient evidence.MethodsWe performed pathological examinations of tumor and para-tumor tissue sections. Based on the location of TLS in tissues, all patients were divided into intratumoral TLS (It-TLS) group and desertic TLS (De-TLS) group. According to the grouping results, we statistically analyzed the clinical, biological, and pathological features; preoperative gut microbiota data; and postoperative pathological features of patients.ResultsIn a retrospective study cohort of 60 cases from a single center, differential microbiota analysis showed that compared with the De-TLS group, the abundance of Lachnoclostridium, Hungatella, Blautia, Fusobacterium, and Clostridium was increased in the It-TLS group. Among them, the enrichment of Lachnoclostridium was the most significant and was unrelated to the clinical, biological, and pathological features of the patients. It can be seen that the difference in abundance levels of microbiota is related to the presence of TLS.ConclusionOur findings prove the enrichment of Lachnoclostridium-dominated gut microbiota is associated with the presence of It-TLS in HCC patients.

Acute kidney injury (AKI) presents a daunting challenge with limited therapeutic options. To explore the contribution of N6-methyladenosine (m6A) in AKI development, we have investigated m6A-modified mRNAs within renal tubular cells subjected to injuries induced by diverse stressors. Notably, while the overall level of m6A-modified RNA remains unaltered in renal tubular cells facing stress, a distinct phenomenon emerges—mRNAs bearing m6A methylation exhibit a pronounced tendency to accumulate within stress granules (SGs), structures induced in response to these challenges. Cumulation of m6A-modified mRNA in SGs is orchestrated by YTHDF1, a m6A ‘reader’ closely associated with SGs. Strikingly, AKI patients and various mouse AKI models showcase elevated levels of renal tubular YTHDF1. Depleting YTHDF1 within renal tubular cells leads to a marked reduction in m6A-modified mRNA accumulation within SGs, accompanied by an escalation in cell apoptosis under stress challenges. The significance of YTHDF1's protective role is further underscored by findings in AKI mouse models triggered by cisplatin or renal ischemia-reperfusion treatments. In particular, renal tubular-specific YTHDF1 knockout mice exhibit heightened AKI severity when contrasted with their wild-type counterparts. Mechanistic insights reveal that YTHDF1 fulfills a crucial function by safeguarding m6A-modified mRNAs that favor cell survival—exemplified by SHPK1—within SGs amid stress-challenged renal tubular cells. Our findings collectively shed light on the pivotal role of YTHDF1 in shielding renal tubules against AKI, through its adeptness in recruiting and preserving m6A-modified mRNAs within stress-induced SGs.

Abstract Objectives This study aimed to investigate the symmetry of the Chinese pelvis. Methods Computed tomography scan images of each of 50 Chinese pelvises were converted to 3D models and the left sides of the pelvises were reflected on Mimics software. Then, the reflected left side model was aligned with the right side using the closest point algorithm function of Geomagic software to perform symmetry analysis. The volume and surface area of either side of the pelvises were also calculated. The mean standard deviation (SD), the mean percentage of permissible deviations within the ±2 mm range, the percentage differences in volume and surface area were measured to compare pelvic symmetry. In addition, the distribution of pelvic bilateral symmetry associated with both age and sex were compared. Results The mean SD was 1.15 ± 0.16 mm and the mean percentage of permissible deviations was 90.82% ± 4.67%. The deviation color maps showed that the specific areas of asymmetry were primarily localized to major muscle or ligament attachment sites and the sacroiliac joint surfaces. There was no significant difference between the bilateral sides of the pelvis in either volume or surface area. Additionally, no difference in any indexes was exhibited in relation to sex and age distribution. Conclusion Our results demonstrated that the pelvis has high bilateral symmetry, which confirmed the potential of using contralateral pelvic models to create fully patient‐specific and custom‐made pelvic implants applicable for the treatment of fracture and bony destruction.

Abstract Background and aims Hereditary spherocytosis (HS) is one of the most common hereditary haemolytic disorders. Here, two unrelated families with the probands displaying typical manifestations of HS were enrolled. Our study aimed to characterize the effect of two novel variants in HS patients on gene splicing to help minimize the rate of misdiagnosis of HS and enhance clinicians’ understanding of the disease. Participants and methods A retrospective review was conducted. Peripheral blood samples were collected from all the family members, and genomic DNA was extracted for genetic diagnostics. First, high-throughput sequencing technology was used for the preliminary screening of candidate causative variants. Thereafter, the variants were verified via Sanger sequencing. Furthermore, a pathogenicity analysis of the detected variants was performed including in silico prediction and in vitro experiments. We constructed matched wild-type and mutant-type minigene plasmid of ANK1 based on HEK293T cells to address the effects of variants on mRNA splicing. Results The c.1305 + 2 T > A (family1) and c.1305 + 2del (family2) variants were detected in the ANK1 gene. These two de novo mutations described by us which have not been reported prior to this study. Moreover, the validation results of splicing reporter systems revealed that the intronic mutations resulted in abnormal pre-mRNA splicing. Specifically, the minigene plasmid expressing the c.1305 + 2 T > A variant transcribed the two aberrant transcripts: r.1305_1306ins1305 + 1_1305 + 229 and r.1305_1306ins1305 + 1_1305 + 552. The minigene plasmid expressing c.1305 + 2del transcribed the two aberrant transcripts: r.1305_1306ins1305 + 1_1305 + 228 and r.1305_1306ins1305 + 1_1305 + 551. Conclusion The two de novo variants identified in the ANK1 gene were the genetic etiology of the probands with HS in our study. Our findings further enrich the HS genotype database and provide a basis for genetic counselling and molecular diagnosis.

Abstract Background The tumour microenvironment and cirrhotic liver are excellent sources of cancer-associated fibroblasts (CAFs), which participate in carcinogenesis. Thus, it is important to clarify the crosstalk between CAFs and HCC cells and the related mechanism in regulating carcinogenesis. Methods Human hepatocellular carcinoma (HCC) tissues and matched adjacent normal tissues were obtained from HCC patients. Immunohistochemistry, Western blotting (WB) and RT–qPCR were performed to detect the expression of SCUBE1. The roles of SCUBE1 in inducing stemness features in HCC cells were explored and investigated in vitro and in vivo. Student’s t tests or Mann–Whitney U tests were used to compare continuous variables, while chi-square tests or Fisher’s exact tests were used to compare categorical variables between two groups. Results SCUBE1 was confirmed to be highly expressed in CAFs in HCC and had a strong connection with stemness and a poor prognosis. In addition, CAFs were found to secrete SCUBE1 to enhance the malignancy of HCC cells and increase the proportion of CD133-positive cells. Silencing SCUBE1 expression had the opposite effect. The Shh pathway was activated by SCUBE1 stimulation. Inhibition of cyclopamine partially reversed the stimulating effect of SCUBE1 both in vivo and in vitro. Moreover, based on the RT–qPCR, ELISA and WB results, a high SCUBE1 expression level was found in HCC tissue and serum. Conclusion This study revealed that CAFs-derived SCUBE1 can enhance the malignancy and stemness of HCC cells through the Shh pathway. This study aims to provide new perspectives for future HCC studies and provide new strategies for HCC treatment.