Search

Abstract Liver fibrosis is a common progressive liver disease that can cause liver dysfunction and lead to serious complications. Zi Qi decoction (ZQ) is a traditional formulation that exerts pharmacological effects on the treatment of liver fibrosis. However, precise intervention mechanisms remain unclear. The aim of this study was to synergistically harness proteomics and metabolomics techniques to elucidate the specific target of ZQ and its potential mechanism of action. A carbon tetrachloride (CCl4)-induced liver fibrosis mouse model was established. Subsequently, the protective effect of ZQ on liver fibrosis mice was evaluated according to histopathological examination and biochemical indicators. Quantitative proteomics based on data independent acquisition (DIA) and non-targeted metabolomic analyses revealed the pharmacodynamic mechanism of ZQ. In addition, various cellular and molecular assays were used to detect changes in glycolysis levels in LSECs and mouse liver fibrosis models. The study results showed that ZQ significantly alleviated CCl4-induced liver injury and fibrosis in mice. DIA-based quantitative proteomics and non-targeted metabolomics analyses indicated that ZQ treatment downregulated glycolysis-related proteins such as PKM2, PFKP, and HK2, while regulating glycolysis-related metabolites and pathways. In addition, ZQ down-regulated glycolytic activity in mice with liver fibrosis and in LSECs, and inhibited CXCL1 secretion and neutrophil recruitment. ZQ inhibited LSEC glycolysis and mitigated neutrophil infiltration, thereby playing a therapeutic role in liver fibrosis.

To study the new method of aflatoxin removal by Lactobacillus plantarum materials, and provide a new idea for the efficient biological removal of aflatoxin B1, this study used the polydopamine-based atom transfer radical polymerization (p-ATRP) and cell-catalyzed copper-free atom transfer radical polymerization (c-ATRP) to modify the surface modification of living cells of Lactobacillus plantarum, and guided the self-assembly polymerization reaction within the ATRP system to form polymer materials, characterized the modified Lactobacillus plantarum and compared its adsorption and desorption capabilities towards aflatoxin B1 before and after modification. Results showed that, the unmodified Lactobacillus plantarum had a smooth cell surface, while the Lactobacillus plantarum modified by p-ATRP had a very rough cell surface, and the Lactobacillus plantarum modified by c-ATRP had wrinkles on the cell surface. The Zeta point of unmodified Lactobacillus plantarum was -8.43 mV, while the points of Lactobacillus plantarum after PD and PNIPAAm modification were 1.791 and 13.767 mV, respectively. The adsorption rate of Lactobacillus plantarum for aflatoxin B1 at concentrations ranging from 0.1~100 μg/mL was 75.3%. Furthermore, the adsorption capacity of p-ATRP and c-ATRP modified Lactobacillus plantarum exhibited an increase of 7.8% and 6.4%, respectively, compared with unmodified Lactobacillus plantarum. Additionally, at the same concentration of aflatoxin B1, the desorption rate of Lactobacillus plantarum was 6.1%, while the desorption capabilities of p-ATRP and c-ATRP modified Lactobacillus plantarum were enhanced by 14.4% and 42%, respectively. Overall, the modified Lactobacillus plantarum demonstrated a significant enhancement in both adsorption and desorption abilities towards aflatoxin.

Abstract Background Studies have reported that ciprofol has the advantage of reducing injection pain compared to propofol during gastroscopy, colonoscopy, and fiberoptic bronchoscopy. The effect of ciprofol on the injection pain in painless hysteroscopy needs to further explore. Methods A double-blind randomized controlled trial (RCT) was designed, and patients were recruited from the First Central Hospital of Baoding from March 2024 to June 2024. The eligible participants were allocated into ciprofol group (ciprofol combined with alfentanil) and propofol group (propofol combined with alfentanil) at 1:1 ratio. The primary outcome was injection pain. The secondary outcomes included sedation success rate, anesthesia success rate, adverse events, patient satisfaction, and comparison of vital signs before and after administration. Results A total of 217 participants were included for analysis, with 109 participants in the ciprofol group and 108 participants in the propofol group. The injection pain rate of ciprofol group (18.35%) was significantly lower than the propofol group (40.74%). Both the ciprofol group and propofol group had 100% of the sedation success rate. The anesthesia success rate between the two groups was comparable (P > 0.05). The rate of adverse events was lower (27.52% vs. 45.37%) and patient satisfaction was higher (9.84 ± 0.45 vs. 9.65 ± 0.85) in the ciprofol group than the propofol group. In addition, values of systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) in propofol group were significantly lower than those in ciprofol group at the time of cervical dilation and consciousness recovery. Conclusions Ciprofol exhibits comparable efficacy to that of propofol, and is associated with less injection pain rate, fewer adverse events, higher patient satisfaction, and more stable hemodynamics when used for general anesthesia during the painless hysteroscopy. Clinical trial number NCT06413862.

Abstract Background Asthma poses a significant global health challenge, characterized by high rates of morbidity and mortality. Despite available treatments, many severe asthma patients remain poorly managed, highlighting the need for novel therapeutic strategies. This study aims to identify potential drug targets for asthma by examining the influence of circulating plasma proteins on asthma risk. Methods This study employs summary-data-based Mendelian randomization (MR) and two-sample MR methods to investigate the association between 2940 plasma proteins from the UK Biobank study and asthma. The analysis includes discovery (FinnGen cohort) and replication (GERA cohort) phases, with Bayesian colocalization used to validate the relationships between proteins and asthma. Furthermore, protein–protein interaction and druggability assessments were conducted on high-evidence strength protein biomarkers, and candidate drug prediction and molecular docking were performed for proteins without targeted drugs. Given the complexity of asthma pathogenesis, the study also explores the relationships between plasma proteins and asthma-related endpoints (e.g., obesity-related asthma, infection-related asthma, childhood asthma) to identify potential therapeutic targets for different subtypes. Results In the discovery cohort, 75 plasma proteins were associated with asthma, including IL1RAP, IL1RL1, IL6, CXCL5, and CXCL8. Additionally, 6 proteins (IL4R, LTB, CASP8, MAX, PCDH12, and SCLY) were validated through co-localization analysis and validation cohort. The assessment of drug targetability revealed potential drug targets for IL4R, CASP8, and SCLY, while candidate drugs were predicted for LTB and MAX proteins. MAX exhibited strong binding affinity with multiple small molecules indicating a highly stable interaction and significant druggability potential. Analysis of the 75 proteins with 9 asthma-related endpoints highlighted promising targets such as DOK2, ITGAM, CA1, BTN2A1, and GZMB. Conclusion These findings elucidate the link between asthma, its related endpoints, and plasma proteins, advancing our understanding of molecular pathogenesis and treatment strategies. The discovery of potential therapeutic targets offers new insights into asthma drug target research.

Abstract Coal and gas outbursts, along with rock bursts, are common dynamic disasters in coal mining, threatening the safety and green production of coal mines. The distribution of coal seam stress is an external factor contributing to coal mine power disasters. The drainage of confined water in coal seam roof is the primary factor of coal seam stress changes. Using theoretical analysis and numerical simulations, the influence of roof confined water on coal seam stress by looking at the law of stress and stress conservation transfer in the drainage layer is investigated. Our results show that: (1) after drainage, there is an increase in the local stress within the coal seam, with a stress concentration factor of 1.35. The influence range of theoretically calculated stress is consistent with the measured results. (2) the maximum value of drainage boundary stress correlated positively with the angle of the water-rich abnormal area, with a linear fitting of R2 = 0.98. These findings hold significant theoretical and practical implications for preventing and controlling dynamic disasters during the mining of water-rich coal seams.

Abstract Background Lipid metabolism dysregulation is a key characteristic of hepatocellular carcinoma (HCC) onset and progression. Elevated expression of immunoglobulin (Ig), especially the Igκ free light chain with a unique Vκ4-1/Jκ3 rearrangement in cancer cells, is linked to increased malignancy and has been implicated in colon cancer tumorigenesis. However, the role of Igκ in HCC carcinogenesis remains unclear. The aim of this study was to elucidate the pivotal roles of hepatocyte-derived Igκ in HCC development. Methods The rearrangement sequence and expression level of hepatocyte-derived Igκ in HCC cells were determined via RT-PCR, Sanger sequencing, immunohistochemistry, and western blot analysis. The function of Igκ in HCC tumorigenesis was assessed by silencing Igκ using siRNA or gRNA in various HCC cell lines. To assess the role of Igκ in HCC pathogenesis in vivo, a mouse model with hepatocyte-specific Igκ knockout and diethylnitrosamine (DEN) and carbon tetrachloride (CCL4)-induced HCC was utilized. The molecular mechanism by which Igκ affects HCC tumorigenesis was investigated through multiomics analyses, quantitative real-time PCR, immunoprecipitation, mass spectrometry, immunofluorescence, and metabolite detection. Results We confirmed that Igκ, especially Vκ4-1/Jκ3-Igκ, is highly expressed in human HCC cells. Igκ depletion inhibited HCC cell proliferation and migration in vitro, and hepatocyte-specific Igκ deficiency ameliorated HCC progression in mice with DEN and CCL4-induced HCC in vivo. Mechanistically, Vκ4-1/Jκ3-Igκ interacts with electron transfer flavoprotein subunit α (ETFA), delaying its protein degradation. Loss of Igκ led to a decrease in the expression of mitochondrial respiratory chain complexes III and IV, resulting in aberrant fatty acid β-oxidation (FAO) and lipid accumulation, which in turn inhibited HCC cell proliferation and migration. Conclusion Our findings indicate that the Igκ/ETFA axis deregulates fatty acid β-oxidation, contributing to HCC progression, which suggests that targeting fatty acid metabolism may be an effective HCC treatment strategy. The results of this study suggest that hepatocyte-derived Vκ4-1/Jκ3-Igκ may serve as a promising therapeutic target for HCC.

Abstract Bladder cancer is the fourth most common malignancy in men with poor prognosis. Programmed cell death (PCD) exerts crucial functions in many biological processes and immunotherapy responses of cancers. Cell death signature (CDS) is novel gene signature comprehensively considering the characteristics of 15 patterns of programmed cell death, which could affect the prognosis and immunotherapy benefits of cancer patients. Integrative machine learning procedure including 10 algorithms was conducted to construct a prognostic CDS using TCGA, GSE13507, GSE31684, GSE32984 and GSE48276 datasets. Immunophenoscore, intratumor heterogeneity (ITH), tumor immune dysfunction and exclusion (TIDE) score and five immunotherapy cohorts were used to evaluate the predictive value of CDS in immunotherapy response. The prognostic CDS constructed by StepCox[backward] + Ridge algorithms was regarded as the optimal prognostic model. The CDS had a stable and powerful performance in predicting overall survival of bladder cancer patients with the AUCs at 3-year, 5-year, and 7-year ROC of 0.740, 0.763 and 0.820 in TCGA cohort. Moreover, CDS score acted as an independent risk factor for overall survival rate of bladder cancer patients. Low CDS score had a higher abundance of immuno-activated cells, higher PD1&CTLA4 immunophenoscore, higher TMB score, lower TIDE score, lower immune escape score, lower ITH score, lower cancer-related hallmarks score in bladder cancer. The CDS score was higher in non-responders in pan-cancer patients receiving immunotherapy. Our study constructed a novel prognostic CDS, which could serve as an indicator for predicting the prognosis in postoperative bladder cancer cases and immunotherapy benefits in pan-cancer. Low CDS score indicated a better prognosis and immunotherapy benefits.

Abstract The characterization of protein complex is vital for unraveling biological mechanisms in various life processes. Despite advancements in biophysical tools, the capture of non-covalent complexes and deciphering of their biochemical composition continue to present challenges for low-input samples. Here we introduce SNAP-MS, a Stationary-phase-dissolvable Native Affinity Purification and Mass Spectrometric characterization strategy. It allows for highly efficient purification and characterization from inputs at the pico-mole level. SNAP-MS replaces traditional elution with matrix dissolving during the recovery of captured targets, enabling the use of high-affinity bait-target pairs and eliminates interstitial voids. The purified intact protein complexes are compatible with native MS, which provides structural information including stoichiometry, topology, and distribution of proteoforms, size variants and interaction states. An algorithm utilizes the bait as a charge remover and mass corrector significantly enhances the accuracy of analyzing heterogeneously glycosylated complexes. With a sample-to-data time as brief as 2 hours, SNAP-MS demonstrates considerable versatility in characterizing native complexes from biological samples, including blood samples.

Abstract Linear frequency modulation (LFM) signal is a common radar signal in modern electronic warfare, and smeared spectrum (SMSP) can generate multiple false targets, causing jamming to radar detection. The authors propose a chirplet‐based masking algorithm that can solve the problem of SMSP jamming suppression and address a more complex problem: the separation of jamming signal and multiple LFM signals from intercepted mixed signal. First, the authors obtain matched chirp rates of the source signals through the changing tendency of the Rényi entropy. Then, the ridge of each source signal is extracted from the high‐resolution chirplet transform result using an image processing‐based algorithm. Finally, the jamming and LFM signals are accurately reconstructed through the time‐frequency mask to achieve separation. Even in the extreme case where multiple source signals with close chirp rates are overlapped, the proposed slope‐matching ridge extraction method and iterative update reconstruction method can still achieve commendable signal separation effects. Extensive experimental results demonstrate that the proposed algorithm performs well under extreme conditions of low signal‐to‐noise ratio, high jamming‐to‐signal ratio, and high sea state.

Abstract Recent observations have revealed upregulation of H3K27cr in colorectal cancer (CRC) tissues; however, the underlying cause remains elusive. This study aimed to investigate the mechanism of H3K27cr upregulation and its roles in CRC metastasis. Clinically, our findings showed that H3K27cr served as a highly accurate diagnostic marker to distinguish CRC tissues from healthy controls. Elevated levels of LINC00887 and H3K27cr were associated with a poorer prognosis in CRC patients. Functionally, LINC00887 and H3K27cr facilitated the migration and invasion of CRC cells. Mechanistically, LINC00887 interacted with SIRT3 protein. Overexpressed of LINC00887 obstructed the enrichment of SIRT3 within GCN5 promoter, thereby elevating H3K27ac but not H3K27cr level within this region, subsequently activating GCN5 expression. This activation increased the global level of H3K27cr, promoting the enrichment of GCN5, H3K27cr, and YEATS2 within ETS1 promoter, activating ETS1 transcription and ultimately promoting the metastasis of CRC. The in vivo study demonstrated that inhibition of LINC00887 suppressed CRC metastasis, but this inhibitory effect was nullified when mice were treated with NaCr. In conclusion, our results confirmed the diagnostic biomarker potential of H3K27cr in individuals with CRC, and proposed a functional model to elucidate the involvement of LINC00887 in promoting CRC metastasis by elevating H3K27cr level.

Abstract We study the operator algebra of extended conformal defects in more than two spacetime dimensions. Such algebra structure encodes the combined effect of multiple impurities on physical observables at long distances as well as the interactions among the impurities. These features are formalized by a fusion product which we define for a pair of defects, after isolating divergences that capture the effective potential between the defects, which generalizes the usual Casimir energy. We discuss general properties of the corresponding fusion algebra and contrast with the more familiar cases that involve topological defects. We also describe the relation to a different defect setup in the shape of a wedge. We provide explicit examples to illustrate these properties using line defects and interfaces in the Wilson-Fisher CFT and the Gross-Neveu(-Yukawa) CFT and determine the defect fusion data thereof.

Abstract Background Intrahepatic cholangiocarcinoma (iCCA) is one of the most lethal malignancies and highly heterogeneous. We thus aimed to identify and characterize iCCA cell subpopulations with severe malignant features. Methods Transcriptomic datasets from three independent iCCA cohorts (iCCA cohorts 1–3, n = 382) and formalin-fixed and paraffin-embedded tissues from iCCA cohort 4 (n = 31) were used. An unbiased global screening strategy was established, including the transcriptome analysis with the activated malignancy/stemness (MS) signature in iCCA cohorts 1–3 and the mass spectrometry analysis of the sorted stemness reporter-positive iCCA cells. A group of cellular assays and subcutaneous tumor xenograft assay were performed to investigate functional roles of the candidate. Immunohistochemistry was performed in iCCA cohort 4 to examine the expression and localization of the candidate. Molecular and biochemical assays were used to evaluate the membrane localization and functional protein domains of the candidate. Cell sorting was performed and the corresponding cellular molecular assays were utilized to examine cancer stem cell features of the sorted cells. Results The unbiased global screening identified RRM2 as the top candidate, with a significantly higher level in iCCA patients with the MS signature activation and in iCCA cells positive for the stemness reporter. Consistently, silencing RRM2 significantly suppressed iCCA malignancy phenotypes both in vitro and in vivo. Moreover, immunohistochemistry in tumor tissues of iCCA patients revealed an unreported cell membrane localization of RRM2, in contrast to its usual cytoplasmic localization. RRM2 cell membrane localization was then confirmed in iCCA cells via immunofluorescence with or without cell membrane permeabilization, cell fractionation assay and cell surface biotinylation assay. Meanwhile, an unclassical signal peptide and a transmembrane domain of RRM2 were revealed experimentally. They were essential for RRM2 trafficking to cell membrane via the conventional endoplasmic reticulum (ER)–Golgi secretory pathway. Furthermore, the membrane RRM2-positive iCCA cells were successfully sorted. These cells possessed significant cancer stem cell malignant features including cell differentiation ability, self-renewal ability, tumor initiation ability, and stemness/malignancy gene signatures. Patients with membrane RRM2-positive iCCA cells had poor prognosis. Conclusions RRM2 had an alternative cell membrane localization. The membrane RRM2-positive iCCA cells represented a malignant subpopulation with cancer stem cell features.

The Road of Tang Poetry in Eastern Zhejiang is a cultural route where nature and culture harmoniously intertwine. Mountain-type scenic areas play a vital role in providing core cultural ecosystem services (CES). To investigate the significance and distribution of landscape resources along the Poetry Road, a preliminary study was conducted in the densely concentrated areas of Shaoxing, Taizhou, and Ningbo. From these regions, six representative mountain-type scenic areas were selected for the research: Kuaiji Mountain, Qinwang Mountain, Wanwei Mountain, Tianmu Mountain, Tiantai Mountain, and Xuedou Mountain. Based on their designation status, these areas were categorized into national and non-national scenic areas. The research employed a combination of online and offline questionnaires, as well as semi-structured interviews. An importance-performance analysis (IPA) was introduced, and SPSS software was utilized to conduct U-tests on the statistical results. This analysis aimed to compare the differences in importance and performance of CES among the various mountain-type scenic areas. Furthermore, an overall evaluation of CES for the mountain-type scenic area was carried out using an optimization demand zoning approach, involving categories such as “Keeping up the good job”, “Concentrate here”, “Possible overkill”, and “Low priority”. Additionally, a comparative analysis was conducted between the two types of mountain-type scenic areas, considering aspects like aesthetic value, leisure tourism, cultural diversity, and nature education. The findings indicate that the overall importance of the core CES provided by mountain-type scenic areas significantly exceeds the performance score, implying that public expectations for these sites surpass the actual experience. Notably, the distinction between the two types of mountain-type scenic areas, national and non-national, lies primarily in their performance. Among the evaluation subcomponents, respondents’ perceptions are notably influenced by natural resource advantages, architectural style, recreation offerings, site iconicity, and historical heritage and preservation. The abundance of cultural activities emerges as a crucial factor contributing to the substantial performance disparity between the two types of scenic areas, underscoring the significant impact of cultural heritage on the development imbalance in mountain-type region. Furthermore, cultural heritage plays a pivotal role in promoting the establishment and enhancing the competitiveness and identity of mountain-type scenic areas. Consequently, prioritizing the protection and utilization of non-national mountain-type scenic areas cultural heritage can effectively elevate the level of CES supply and meet the demand in mountain-type scenic areas. The IPA has promoted the CES performance of mountain-type scenic areas to be closer to its importance, thereby fostering a more balanced CES of the Road of Tang Poetry in Eastern Zhejiang.

The study focused on the utilization of heat-pressed and stuffy slag, processed into an ultrafine vertical grinding mill. This pressed-heat and stuffy slag powder replaced traditional anticorrosion fillers, such as epoxy resin, xylene, butanol, and polyamide, therefore forming a composite anticorrosion coating. Tests were conducted to assess the hardness, adhesion, abrasion resistance, and flexibility of these coatings according to various standards: GB/T 1730—2007 (paints and varnishes–pendulum damping test), GB/T 1720—2020 (circle-drawing test of coating films), GB/T 1768—2006 (paints and varnishes–determination of resistance to abrasion-rotating abrasive rubber wheel method), and GB/T 1731—2020 (determination of flexibility of coating and putty films), respectively. Additionally, the salt mist resistance was tested in conformance with GB/T 1771—2007 (paints and varnishes–determination of resistance to neutral salt spray) and water absorption was evaluated consistent with HG/T 3344—2012 (determination of water absorption of paint film) for coatings. The contact angle, impedance modulus, and corrosion potential of the coatings were also determined using a contact angle measuring instrument, a precision impedance tester, and an electrochemical workstation. Moreover, the micromorphology, chemical composition, mineral composition, and particle size distribution were evaluated using electron microscopy, X-ray spectroscopy, X-ray diffraction, and laser particle size analysis, respectively. The research analyzed the impact of pressed-heat and stuffy slag powder on the mechanical properties and anticorrosive properties of the epoxy composite anticorrosion coatings. It found that the pressed-heat and stuffy slag consisted of C3S, C2S, Ca(OH)2, C2F, RO phase, and f-CaO possessed properties similar to silicate, thereby improving durability. The processing method using an ultrafine vertical grinding mill facilitated the mineralization of f-CaO, reducing particle size and increasing specific surface area. The study concluded that the optimal performance of heat-pressed and stuffy slag powder/epoxy composite anticorrosion coatings was achieved when the particle size uniformity was 2.240 and the addition rate was 5%. At this rate, the performance of the composite anticorrosion coating is the best, the average swing rod hardness test result is 115.75 s, adhesion reached level 3, wear was minimized, flexibility measured 4 mm, impedance modulus was 106.1 Ω·cm−2, and corrosion potential (E) was 0.143 V. In summary, heat-pressed and stuffy slag, a type of rigid particle, can improve the hardness, friction resistance, and mechanical properties of the epoxy coating system. A uniform particle size can enhance the denseness and anticorrosive properties of these coatings. This opens up new possibilities for the high-value utilization of pressed-heat and stuffy slag outside of building materials and fulfilling the dual purpose of “increasing efficiency with waste” in the steel industry and “reducing cost with waste” in the paint industry.

Abstract We investigate finite-temperature observables in three-dimensional large N critical vector models taking into account the effects suppressed by 1 N $$ \frac{1}{N} $$ . Such subleading contributions are captured by the fluctuations of the Hubbard-Stratonovich auxiliary field which need to be handled with care due to a subtle divergence structure which we clarify. The examples we consider include the scalar O(N) model, the Gross-Neveu model, the Nambu-Jona-Lasinio model and the massless Chern-Simons Quantum Electrodynamics. We present explicit results for the free energy density to the subleading order in 1 N $$ \frac{1}{N} $$ , which captures the thermal one-point function of the stress-energy tensor to this order. We also include the dependence on a chemical potential. We determine the Wilson coefficient in the thermal effective action that is sensitive to global symmetry for the first time directly in interacting CFTs, which produces a symmetry-resolved asymptotic density of states. We further provide a formula from diagrammatics for the one-point functions of general single-trace higher-spin currents. We observe that in most cases considered, these subleading effects lift the apparent degeneracies between observables in different models at infinite N, while in special cases the discrepancies only start to appear at the next-to-subleading order.

Abstract This study deeply analyzes the ecocultural heritage of the Tiantai Mountain area in Eastern China, assesses its current status and explores effective mechanisms for its conservation and construction. Employing remote sensing technology, kernel density analysis and Minimum Cumulative Resistance Model, the study comprehensively evaluated the environmental characteristics of the region and its role in historical and modern conservation efforts. The results demonstrate the unique distribution patterns of ecocultural heritage in various conservation zones, such as restoration, controlled construction and core conservation zone. Furthermore, the study highlights the importance of religious beliefs and clan systems in the preservation of traditional knowledge and practices, with significant impacts of local community participation on conservation strategies. This research provides new theoretical and practical support for the implemention of ecocultural heritage conservation and development within religiously significant areas, highlights the need for conservation measures and synergistic strategies between ecological and cultural practices.

Freshwater crabs play essential roles in the well-functioning of the inland aquatic ecosystems. However, due to the lack of sufficient molecular resources, the study of freshwater crabs has been greatly hindered. In this study, the mitochondrial genome of Huananpotamon koatenense, a freshwater crab endemic to China, was sequenced for the first time. This mitogenome sequence is 15,528 bp long, and contains 13 protein-coding genes, 2 rRNA genes and 22 tRNA genes. Phylogenetic analyses based on 25 mitogenomes showed that H. koatenense was clustered with the known congeneric species of H. lichuanense.

Abstract PARP inhibitor (PARPi) therapy has transformed outcomes for patients with homologous recombination DNA repair (HRR) deficient ovarian cancers, for example those with BRCA1 or BRCA2 gene defects. Unfortunately, PARPi resistance is common. Multiple resistance mechanisms have been described, including secondary mutations that restore the HR gene reading frame. BRCA1 splice isoforms △11 and △11q can contribute to PARPi resistance by splicing out the mutation-containing exon, producing truncated, partially functional proteins. However, the clinical impacts and underlying drivers of BRCA1 exon skipping are not fully understood. We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre- and post-chemotherapy/PARPi. BRCA1 exon 11 skipping was elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary BRCA1 splice site mutations (SSMs) that drive exon skipping, confirmed using qRT-PCR, RNA sequencing, immunoblotting and minigene modelling. CRISPR/Cas9-mediated disruption of splicing functionally validated exon skipping as a mechanism of PARPi resistance. SSMs were also enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials. Few PARPi resistance mechanisms have been confirmed in the clinical setting. While secondary/reversion mutations typically restore a gene’s reading frame, we have identified secondary mutations in patient cohorts that hijack splice sites to enhance mutation-containing exon skipping, resulting in the overexpression of BRCA1 hypomorphs, which in turn promote PARPi resistance. Thus, BRCA1 SSMs can and should be clinically monitored, along with frame-restoring secondary mutations.

Metal–organic frameworks (MOFs) are highly promising porous materials known for their exceptional porosity, extensive surface area, and customizable pore structures, making them an ideal solution for hydrogen storage. However, most MOFs research remains confined to the laboratory, lacking practical applications. To address this, the author proposes a shift towards practical applications, the creation of a comprehensive MOFs database, alignment of synthesis with practical considerations, and diversification of MOFs applications. These steps are crucial for harnessing the full potential of MOFs in real-world energy challenges.

In recent years, significant progress has been made in video-based person re-identification (Re-ID). The key challenge in video person Re-ID lies in effectively constructing discriminative and robust person feature representations. Methods based on local regions utilize spatial and temporal attention to extract representative local features. However, prior approaches often overlook the correlations between local regions. To leverage relationships among different local regions, we have proposed a novel video person Re-ID representation learning approach based on a graph transformer, which facilitates contextual interactions between relevant region features. Specifically, we construct a local relation graph to model intrinsic relationships between nodes representing local regions. This graph employs the architecture of a transformer for feature propagation, iteratively refining region features and considering information from adjacent nodes to obtain partial feature representations. To learn compact and discriminative representations, we have further proposed a global feature learning branch based on a vision transformer to capture the relationships between different frames in a sequence. Additionally, we designed a dual-branch interaction network based on multi-head fusion attention to integrate frame-level features extracted by both local and global branches. Finally, the concatenated global and local features, after interaction, are used for testing. We evaluated the proposed method on three datasets, namely iLIDS-VID, MARS, and DukeMTMC-VideoReID. Experimental results demonstrate competitive performance, validating the effectiveness of our proposed approach.

Long pressure short extraction ventilation and dust removal method is one of the effective methods for removing high mass concentration dust in the excavation area of coal mine comprehensive heading face. Especially, the local flow field generated by the combination of pressure and suction is conducive to the removal and reduction of respiratory dust. However, the dynamic changes in the location of dust production sources have an unclear impact on the dust removal performance of this method. By considering the movement paths and reciprocating times of the dust source location in both horizontal and vertical directions, four dust source movement paths were designed based on the long pressure short extraction test platform. Combined with the regulation of the parameters of the long pressure short extraction ventilation system, the impact of the dust source on the spatial dust mass concentration, particle size mass concentration, and particle size distribution under different movement conditions was tested and analyzed. The results show that under the same ventilation parameters, the dust mass concentration caused by the horizontal path on the respiratory belt positions of drivers and pedestrians is lower than that caused by the vertical path. In the horizontal path, when the pressure air duct is located on the side near the exhaust duct and the pressure air outlet is located in an area about 1 m in front of the driver, the particle size mass concentrations of PM1, PM2.5 and PM10 at the breathing zone between the driver and pedestrian are the lowest, and the ventilation and dust removal effect is the best. The diffusion of spatial dust is manifested as: particles with a particle size less than 2.5 µm are easily collected and removed by the exhaust flow field at the exhaust port, while the particles with a particle size greater than 10 µm will escape from the dust generation source and exhaust area to the driver and the area behind them, and mainly settle naturally. Based on the optimal dust source movement path and ventilation parameters obtained from preliminary experiments, on-site experiments were conducted on the 2304 fully mechanized heading face of a coal mine in northern Shaanxi. The results show that the total dust mass concentration at the driver's position and pedestrian breathing zone position under the lateral path decreased to 85.6 mg/m3 and 21.9 mg/m3, respectively, with the highest dust reduction rate reaching 76.9%. The mass concentration of respirable dust decreased to 15.3 mg/m3 and 10.5 mg/m3 respectively, with a maximum dust reduction rate of 85.2% and the dust removal performance was significantly improved.

The ecological quality of a region is significantly influenced by its geographical conditions, which can yield different effects on ecosystems. Nevertheless, the lack of adequate technology has impeded quantitative investigations into these differences. Consequently, there is an increasing demand for effective techniques to quantitatively measure differences in ecological quality resulting from variations in geographical conditions. This study applied the novel Remote Sensing-based Ecological Index (RSEI) concurrently to two distinct provincial-level regions in China, Fujian and Ningxia, to quantitatively detect their ecological differences. These two regions possess contrasting geographical conditions, with Fujian having high forest coverage and abundant rainfall, while Ningxia features low forest coverage and extensive loess plateau and desert terrain. By linking geographical factors with their corresponding ecological responses, we conducted a comprehensive analysis to determine whether the contrasting geographical conditions between the two regions had caused significant disparities in their ecological status. The results indicate that the contrasting geographical conditions have indeed led to marked ecological differences, with Fujian exhibiting excellent ecological status, while Ningxia lags behind due to unfavorable geographical conditions. In terms of RSEI scores, Fujian consistently achieved higher RSEI values (>0.8) in the study years, reaching an excellent ecological level, whereas Ningxia recorded scores lower than 0.45 during the comparable years, corresponding to a poor to moderate ecological level. Regarding the impact of geographical factors on ecological conditions, the positive contributions of greenness and wetness indicators to the ecology in Fujian were significantly greater than those in Ningxia (58% vs. 39%), whereas the contributions of negative indicators, dryness and hotness, were notably higher in Ningxia compared to Fujian (|–61|% vs. |–42|%). The successful concurrent application of RSEI to these two geographically distant regions also demonstrates the robustness of the RSEI technique.

Abstract Identifying spatially variable genes (SVGs) is crucial for understanding the spatiotemporal characteristics of diseases and tissue structures, posing a distinctive challenge in spatial transcriptomics research. We propose HEARTSVG, a distribution-free, test-based method for fast and accurately identifying spatially variable genes in large-scale spatial transcriptomic data. Extensive simulations demonstrate that HEARTSVG outperforms state-of-the-art methods with higher $${F}_{1}$$ F 1 scores (average $${F}_{1}$$ F 1 Score=0.948), improved computational efficiency, scalability, and reduced false positives (FPs). Through analysis of twelve real datasets from various spatial transcriptomic technologies, HEARTSVG identifies a greater number of biologically significant SVGs (average AUC = 0.792) than other comparative methods without prespecifying spatial patterns. Furthermore, by clustering SVGs, we uncover two distinct tumor spatial domains characterized by unique spatial expression patterns, spatial-temporal locations, and biological functions in human colorectal cancer data, unraveling the complexity of tumors.

Abstract Recapitulating the natural extracellular physical microenvironment has emerged as a promising method for tissue regeneration, as multiple physical interventions, including ultrasound, thermal and electrical therapy, have shown great potential. However, simultaneous coupling of multiple physical cues to highly bio-mimick natural characteristics for improved tissue regeneration still remains formidable. Coupling of intrinsic electrical and mechanical cues has been regarded as an effective way to modulate tissue repair. Nevertheless, precise and convenient manipulation on coupling of mechano-electrical signals within extracellular environment to facilitate tissue regeneration remains challengeable. Herein, a photothermal-sensitive piezoelectric membrane was designed for simultaneous integration of electrical and mechanical signals in response to NIR irradiation. The high-performance mechano-electrical coupling under NIR exposure synergistically triggered the promotion of osteogenic differentiation of stem cells and enhances bone defect regeneration by increasing cellular mechanical sensing, attachment, spreading and cytoskeleton remodeling. This study highlights the coupling of mechanical signals and electrical cues for modulation of osteogenesis, and sheds light on alternative bone tissue engineering therapies with multiple integrated physical cues for tissue repair. Graphical Abstract

Abstract We study generalized symmetries of quantum field theories in 1+1D generated by topological defect lines with no inverse. This paper follows our companion paper on gapped phases and anomalies associated with these symmetries. In the present work we focus on identifying fusion category symmetries, using both specialized 1+1D methods such as the modular bootstrap and (rational) conformal field theory (CFT), as well as general methods based on gauging finite symmetries, that extend to all dimensions. We apply these methods to c = 1 CFTs and uncover a rich structure. We find that even those c = 1 CFTs with only finite group-like symmetries can have continuous fusion category symmetries, and prove a Noether theorem that relates such symmetries in general to non-local conserved currents. We also use these symmetries to derive new constraints on RG flows between 1+1D CFTs.

Abstract Abnormal trophoblast self-renewal and differentiation during early gestation is the major cause of miscarriage, yet the underlying regulatory mechanisms remain elusive. Here, we show that trophoblast specific deletion of Kat8, a MYST family histone acetyltransferase, leads to extraembryonic ectoderm abnormalities and embryonic lethality. Employing RNA-seq and CUT&Tag analyses on trophoblast stem cells (TSCs), we further discover that KAT8 regulates the transcriptional activation of the trophoblast stemness marker, CDX2, via acetylating H4K16. Remarkably, CDX2 overexpression partially rescues the defects arising from Kat8 knockout. Moreover, increasing H4K16ac via using deacetylase SIRT1 inhibitor, EX527, restores CDX2 levels and promoted placental development. Clinical analysis shows reduced KAT8, CDX2 and H4K16ac expression are associated with recurrent pregnancy loss (RPL). Trophoblast organoids derived from these patients exhibit impaired TSC self-renewal and growth, which are significantly ameliorated with EX527 treatment. These findings suggest the therapeutic potential of targeting the KAT8-H4K16ac-CDX2 axis for mitigating RPL, shedding light on early gestational abnormalities.

Abstract Background Zinc oxide nanoparticle (ZnO NP) is one of the metal nanomaterials with extensive use in many fields such as feed additive and textile, which is an emerging threat to human health due to widely distributed in the environment. Thus, there is an urgent need to understand the toxic effects associated with ZnO NPs. Although previous studies have found accumulation of ZnO NPs in testis, the molecular mechanism of ZnO NPs dominated a decline in male fertility have not been elucidated. Results We reported that ZnO NPs exposure caused testicular dysfunction and identified spermatocytes as the primary damaged site induced by ZnO NPs. ZnO NPs led to the dysfunction of spermatocytes, including impaired cell proliferation and mitochondrial damage. In addition, we found that ZnO NPs induced ferroptosis of spermatocytes through the increase of intracellular chelatable iron content and lipid peroxidation level. Moreover, the transcriptome analysis of testis indicated that ZnO NPs weakened the expression of miR-342-5p, which can target Erc1 to block the NF-κB pathway. Eventually, ferroptosis of spermatocytes was ameliorated by suppressing the expression of Erc1. Conclusions The present study reveals a novel mechanism in that miR-342-5p targeted Erc1 to activate NF-κB signaling pathway is required for ZnO NPs-induced ferroptosis, and provide potential targets for further research on the prevention and treatment of male reproductive disorders related to ZnO NPs. Graphical Abstract

In this study, we aimed to investigate the mechanism by which fluoride exposure causes bone damage and the relationship with the loss of dorsal longitudinal anastomotic vessel (DLAV) formation in zebrafish larvae to further understanding of skeletal fluorosis. We assessed the development of chondrogenesis, osteogenesis, and DLAV angiogenesis, and reactive oxygen species (ROS) in zebrafish larvae subjected to blank control group (Con), low-fluoride group (LF), and high-fluoride group (HF). Abnormal development of the cartilage area, bone mineralization accompanied with abnormal mRNA expression of osteoblast-related OC, ALP, and Runx2b genes and osteoclast-related OPG and RANKL genes, and abnormal DLAV angiogenesis and ROS levels in zebrafish larvae were affected to varying degrees with the increase of fluoride exposure. We concluded that exposure of zebrafish embryos to fluoride can affect bone development process of chondrogenesis and osteogenesis, and that bone damage might be related to the loss of DLAV angiogenesis.

The micro-patterned topography can affect bacterial enrichment and selective distribution by modifying the characteristics of material surface. In this study, we fabricated microcavity patterned silicon surfaces, and quantitatively explored the amount and distribution of Escherichia coli (E. coli) cells attached on a series of defined topographies. The results showed that E. coli cells enrichment was significantly increased on silicon nanowires-based microcavity array when compared to nanowires patterned silicon wafer. Furthermore, the microcavity diameter can control bacterial distribution by changing hydrophilic performance of interface. With the microcavity diameter of 7 µm, the cells colonized into the microcavity almost in its entirety, whilst distributed around the microcavity completely with 10 µm diameter, regardless of centre distances. This phenomenon can be explained by the Cassie-Baxter model equation according to the wettability. The distribution of bacterial enrichment changed with the silicon surfaces turning from non-wetting status to wetting status when treated with oxygen plasma to modify the hydrophobicity. These results demonstrated that microcavity patterned surface could favor bacterial enrichment on silicon and strictly confined bacterial distribution inside/outside the microcavity. Moreover, the nanowires inside microcavity can also increase electron conductivity and reduce the internal resistance, thus providing scientific evidence for the design of wearable microbial fuel cell with rational optimization and integration of different components for electronic skin.

We develop a computational algorithm based on a diffuse interface approach to study the design of bioartificial organ scaffold architectures. These scaffolds, composed of poroelastic hydrogels housing transplanted cells, are linked to the patient's blood circulation via an anastomosis graft. Before entering the scaffold, the blood flow passes through a filter, and the resulting filtered blood plasma transports oxygen and nutrients to sustain the viability of transplanted cells over the long term. A key issue in maintaining cell viability is the design of ultrafiltrate channels within the hydrogel scaffold to facilitate advection-enhanced oxygen supply ensuring oxygen levels remain above a critical threshold to prevent hypoxia. In this manuscript, we develop a computational algorithm to analyze the plasma flow and oxygen concentration within hydrogels featuring various channel geometries. Our objective is to identify the optimal hydrogel channel architecture that sustains oxygen concentration throughout the scaffold above the critical hypoxic threshold. The computational algorithm we introduce here employs a diffuse interface approach to solve a multi-physics problem. The corresponding model couples the time-dependent Stokes equations, governing blood plasma flow through the channel network, with the time-dependent Biot equations, characterizing Darcy velocity, pressure, and displacement within the poroelastic hydrogel containing the transplanted cells. Subsequently, the calculated plasma velocity is utilized to determine oxygen concentration within the scaffold using a diffuse interface advection-reaction-diffusion model. Our investigation yields a scaffold architecture featuring a hexagonal network geometry that meets the desired oxygen concentration criteria. Unlike classical sharp interface approaches, the diffuse interface approach we employ is particularly adept at addressing problems with intricate interface geometries, such as those encountered in bioartificial organ scaffold design. This study is significant because recent developments in hydrogel fabrication make it now possible to control hydrogel rheology and utilize computational results to generate optimized scaffold architectures.

Cardiovascular disease has emerged as the leading cause of death worldwide. Since coronary arteries, carotid arteries, and other blood vessels are prone to narrowing, small‐diameter artificial blood channels offer a crucial solution for restoring blood flow. Ideal grafts must emulate the structure of natural blood vessels, possess adequate mechanical strength, ensure long‐term patency, and incorporate functional cells with minimal immunogenicity. Enhanced cell sources and engineering methods are vital for the creation of functional small‐diameter blood vessels (SDBVs). Among potential cell sources, stem cells stand out due to their ability to differentiate into multiple cell types, self‐renew, and exhibit low immunogenicity. Additionally, three‐dimensionally (3D) printed vascular stents have attracted widespread attention for their precision and controllable bioink application. The need for tissue‐engineered blood vessels is currently rising, and innovative design concepts integrating stem cells and 3D printing present promising solutions. Herein, the construction requirements of vascular grafts are reviewed, current status of using stem cells as a cell source and 3D printing as an engineering strategy is described, and prospects and challenges for the development of SDBVs in the medical field are discussed.

Abstract Angiogenesis is crucial for successful bone defect repair. Co‐transplanting Bone Marrow Stromal Cells (BMSCs) and Endothelial Cells (ECs) has shown promise for vascular augmentation, but it face challenges in hostile tissue microenvironments, including poor cell survival and limited efficacy. In this study, the mitochondria of human BMSCs are isolated and transplanted to BMSCs from the same batch and passage number (BMSCsmito). The transplanted mitochondria significantly boosted the ability of BMSCsmito‐ECs to promote angiogenesis, as assessed by in vitro tube formation and spheroid sprouting assays, as well as in vivo transplantation experiments in balb/c mouse and SD rat models. The Dll4‐Notch1 signaling pathway is found to play a key role in BMSCsmito‐induced endothelial tube formation. Co‐transplanting BMSCsmito with ECs in a rat cranial bone defect significantly improves functional vascular network formation, and improve bone repair outcomes. These findings thus highlight that mitochondrial transplantation, by acting through the DLL4‐Notch1 signaling pathway, represents a promising therapeutic strategy for enhancing angiogenesis and improving bone repair. Hence, mitochondrial transplantation to BMSCS as a therapeutic approach for promoting angiogenesis offers valuable insights and holds much promise for innovative regenerative medicine therapies.

Many soils face dual challenges of cadmium (Cd) contamination and salinization. However, the response of crops, especially wheat, to combined Cd and salinity stress is not understood. Here, wheat was grown in a hydroponic model for 14 days under single and combined Cd and NaCl stresses. Growth parameters, tissue Cd2+ and Na+ contents, and leaf chlorophyll (Chl), O2•−, and MDA levels were determined. Comparative transcriptomic and metabolomic analyses of the leaves were performed. The results showed that combined stress had a greater inhibitory effect on Chl contents and generated more O2•− and MDA, resulting in more severe wheat growth retardation than those under Cd or NaCl stress. Stress-induced decrease in Chl levels may be attributed to the inhibition of Chl biosynthesis, activation of Chl degradation, or a decline in glutamate content. Cd addition weakened the promotional effect of NaCl on SOS1 gene expression, thereby increasing the Na+ content. Contrastingly, NaCl supplementation downregulated the Nramp and ZIP gene expressions related to Cd uptake and transport, thereby impeding Cd2+ accumulation. All stresses enhanced tryptophan content via promoting tryptophan biosynthesis. Meanwhile, Cd and NaCl stresses activated phenylpropanoid biosynthesis and purine metabolism, respectively, thereby increasing the levels of caffeic acid, fumaric acid, and uric acid. Activating the TCA cycle was important in the wheat’s response to combined stress. Additionally, NaCl and combined stresses affected starch and sucrose metabolism, resulting in sucrose and trehalose accumulation. Our findings provide a comprehensive understanding of the response of wheat to the combined Cd and salinity stress.

The electrodeposition process confronts significant challenges arising from mass transfer limitation and residual stress. To address these issues, an innovative method, combining megasonic agitation with coaxial jet electrodeposition, is introduced. This approach aims to enhance mass transfer and mitigate residual stress. First, an electrodeposition nozzle device was designed, and the liquid-phase mass transfer during electrodeposition was analyzed through finite element simulation. Simulation results indicate that the mass transfer coefficient increases with rising megasonic power density. Notably, when the megasonic power density reached 20 W/cm2, the mass transfer coefficient increased from 0.45 × 10−7 m/s to 18.63 × 10−7 m/s, compared to electrodeposition without megasonic agitation. Secondly, electrodeposition experiments were conducted both with and without megasonic assistance. X-ray diffraction (XRD) was employed to measure the residual stress values of the electrodeposited layers. The results reveal that samples processed with megasonic assistance exhibit lower residual stress values compared to those without. Specifically, at a megasonic power density of 10 W/cm2, the residual stress was 94.3 MPa, representing a 37.7 % reduction compared to the residual stress of 151.5 MPa observed in samples without megasonic agitation. Overall, the findings demonstrate that coaxial megasonic agitation can effectively enhance the liquid-phase mass transfer capability during electrodeposition and reduce the residual stress of the electroplated layer. This innovative method presents a promising avenue for improving electrodeposition processes and achieving superior material properties.