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Abstract Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Abnormally high expression of Golgi protein 73 (GP73) and pyruvate kinase M2 (PKM2) is intimately associated with HCC progression. However, as secreted proteins, the role of their extracellular secretions in HCC progression remains unclear. Here, we demonstrated that the expression of extracellular GP73 was positively correlated with extracellular PKM2. GP73 interacted with PKM2 to promote SUMO1 modification of PKM2, which in turn enhanced the interaction of GP73 and PKM2. This process continuously promoted the transfer of PKM2 from the cytoplasm to the membrane in HCC cells, and finally secretion. Extracellular PKM2 and GP73 synergistically promoted angiogenesis and polarization of M2-type macrophages, thereby leading to malignant progression and sorafenib resistance in HCC. Sorafenib combined with shikonin, a specific inhibitor of PKM2, has a strong anti-tumor effect. This study reveals the role of GP73 in enhancing PKM2 and GP73 secretion in promoting HCC progression, providing a theoretical basis and drug targets for HCC therapy.

In order to explore the movement and distribution of particles in the tank of jet and agitation co-flotation machine, a geometric model of the tank of jet and agitation co-flotation machine was established. The COMSOL software was used to simulate the flow field distribution and particle movement in the flotation tank under impeller agitation, and a test system of jet and agitation co-flotation device was set up to test the particle dispersion effect. The results showed that some particles pass through the gap between the impeller blades and spiral downward under the action of flow field, the other part of the particles are thrown out by the blade and move helically around and up under the coupling effect of the blade and the flow field. The trajectory curves of all particles were drawn to explore the particle movement and distribution law during the operation of the flotation machine. It was found that the trajectory curves of particles at the bottom of the flotation cell, around the wall and at the corner of the tank have a high coincidence degree, which indicates that the probability of particles moving there is large. The coincidence degree of particle motion trajectories in the upper part of the flotation tank and the area between the wall and the impeller is small, and the probability of particle movement there is low, and only a few particles are distributed there. The uniformity of particle distribution does not increase with the increase of impeller stirring speed, but there is an optimal impeller working parameter. The results of simulation and test showed that the jet and agitation co-flotation machine has better particle dispersion performance under the condition of impeller speed of 6.25 r/s. The particle dispersion is affected by the shape and internal structure of the tank. Adding baffle or using column flotation cell can effectively promote the uniform distribution of particles. The study of the movement and distribution of particles in the tank is beneficial to optimize the structure of the jet and agitation co-flotation machine and improve its flotation efficiency.

Abstract Background Chronic kidney disease (CKD) is a complex condition with diverse etiology and outcomes. Utilizing a data-driven clustering approach holds promise in identifying distinct CKD subgroups associated with specific risk profiles for death. Methods Unsupervised consensus clustering was utilized to classify chronic kidney disease (CKD) into subtypes based on 45 baseline characteristics in a cohort of 6,526 participants from the US National Health and Nutrition Examination Survey (NHANES) spanning the years 1999–2000 to 2017–2018.We examined the associations between CKD subgroups and clinical endpoints related to mortality, including all-cause mortality, cardiovascular disease mortality, cancer mortality, and mortality due to other causes. Results A total of 6,526 individuals with CKD were classified into four clusters at baseline. Cluster 1 (n = 508) comprised patients with relatively favorable levels of cardiac and kidney function markers, lower prevalence of cancer and higher prevalence of obesity, lower medication usage, and younger age. Cluster 4 (n = 2,029) comprised patients with the worst cardiac and kidney function markers. The characteristics of cluster 2 (n = 1,439) and 3 (n = 2,550) fell in between these two clusters. From cluster 1 to cluster 4, we observed a gradual increase in the hazard ratios of all-cause mortality, cardiovascular disease mortality, and mortality due to other causes. Additionally, further sensitivity analysis revealed patient heterogeneity among predefined subgroups with similar baseline kidney function and mortality risks. Conclusions Consensus clustering integrated baseline clinical and laboratory measures, revealing distinct CKD subgroups with markedly different risks of death, suggesting that further examination of patient subgroups could advance precision medicine.

Abstract Transactivation of epidermal growth factor receptors (EGFR) provides intricate control over multiple regulatory cellular processes that merge the diversity of G protein-coupled receptors (GPCRs) with the robust signaling capacities of receptor tyrosine kinases. Contrary to the typical assertions, our findings demonstrate that EGFR transactivation contributes to the desensitization of GPCRs. Repeated agonist stimulation of certain GPCRs enhanced EGFR transactivation, triggering a series of cellular events associated with GPCR desensitization. This effect was observed in receptors undergoing desensitization (D3R, K149C-D2R, β2AR) but not in those resistant to desensitization (D2R, C147K-D3R, D4R, β2AR mutants lacking GRK2 or GRK6 phosphorylation sites). The EGFR inhibitor AG1478 prevented both desensitization and the associated cellular events. Similarly, these cellular events were also observed when cells were treated with EGF, but only in GPCRs that undergo desensitization. These findings suggest that EGFR transactivation diversifies pathways involved in ERK activation through the EGFR signaling system and also mediates GPCR desensitization. Alongside the widely accepted steric hindrance model, these findings offer new insights into understanding the mechanisms of GPCR desensitization, which occurs through complex cellular processes.

Abstract Background A cost-effective Escherichia coli expression system has gained popularity for producing virus-like particle (VLP) vaccines. However, the challenge lies in balancing the endotoxin residue and removal costs, as residual endotoxins can cause inflammatory reactions in the body. Results In this study, porcine parvovirus virus-like particles (PPV-VLPs) were successfully assembled from Decreased Endotoxic BL21 (BL21-DeE), and the effect of structural changes in the lipid A of BL21 on endotoxin activity, immunogenicity, and safety was investigated. The lipopolysaccharide purified from BL21-DeE produced lower IL-6 and TNF-α than that from wild-type BL21 (BL21-W) in both RAW264.7 cells and BALB/c mice. Additionally, mice immunized with PPV-VLP derived form BL21-DeE (BL21-DeE-VLP) showed significantly lower production of inflammatory factors and a smaller increase in body temperature within 3 h than those immunized with VLP from BL21-W (BL21-W-VLP) and endotoxin-removed VLP (ReE-VLP). Moreover, mice in the BL21-DeE-VLP immunized group had similar levels of serum antibodies as those in the BL21-W-VLP group but significantly higher levels than those in the ReE-VLP group. Furthermore, the liver, lungs, and kidneys showed no pathological damage compared with the BL21-W-VLP group. Conclusion Overall, this study proposes a method for producing VLP with high immunogenicity and minimal endotoxin activity without chemical or physical endotoxin removal methods. This method could address the issue of endotoxin residues in the VLP and provide production benefits.

Abstract Stress granules (SGs) are considered to be the nonmembrane discrete assemblies present in the cytoplasm to cope with various environmental stress. SGs can promote the progression and drug resistance of hepatocellular carcinoma (HCC). Therefore, it is important to explore the mechanism of SG formation to reduce drug resistance in HCC. In this study, we demonstrate that p110α is required for SGs assembly. Mechanistically, the Arg-Gly (RG) motif of p110α is required for SG competence and regulates the recruitment of SG components. The methylation of p110α mediated by protein arginine methyltransferase 1 (PRMT1) interferes with the recruitment of p110α to SG components, thereby inhibiting the promotion of p110α to SGs. On this basis, we generated metal-polyphenol-network-coated R612F nanoparticles (MPN-R612F), which can efficiently enter HCC cells and maintain the hypermethylation state of p110α, thereby inhibiting the assembly of SGs and ultimately reducing the resistance of HCC cells to sorafenib. The combination of MPN-R612F nanoparticles and sorafenib can kill HCC cells more effectively and play a stronger anti-tumor effect. This study provides a new perspective for targeting SGs in the treatment of HCC.

Abstract Introduction Haemophilia A (HA) is an X-linked recessive bleeding disorder caused by lack or deficiency of coagulation factor VIII. Aim The aim of this study is to determine the incidence and treatment-related risk factors of inhibitor development after intensive FVIII replacement for major orthopaedic surgery in previous treated persons with HA. Methods A total of 151 HA who underwent 221 major orthopaedic surgical procedures after intensive FVIII treatment were reviewed. The results of inhibitor tests were collected. Potential clinical risk factors for inhibitor development were analyzed. Results 111 people were diagnosed with severe HA. Thirty-seven persons (24.5%) had history of previous intensive FVIII treatment for surgical procedure. They received a mean perioperative cumulative FVIII of 498 iu/kg within first week after surgery. Seven cases (4.6%) developed an inhibitor post-operatively in our study. Surgical procedure for pseudotumor and the group of persons who experienced postoperative complications had the higher incidence of inhibitor development (9.5%, 13.3% respectively). Only previous history for intensive FVIII exposure was considered as a significant predictor for postoperative inhibitor development after multivariate logistic regression analysis (OR: 29.5, P = 0.002). Conclusion The incidence of inhibitor development in previously treated persons with HA undergoing major orthopaedic surgery was 4.6% and the history of previous intensive FVIII treatment for surgery was associated with higher risk of inhibitor development.

Virus-like particles (VLPs) are used as nanocontainers for targeted drug, protein, and vaccine delivery. The phage P22 VLP is an ideal macromolecule delivery vehicle, as it has a large exterior surface area, which facilitates multivalent genetic and chemical modifications for cell recognition and penetration. Arginine-rich cell-penetrating peptides (CPPs) can increase cargo transport efficiency in vivo. However, studies on the tissue distribution and retention of P22 VLPs mediated by TAT and 8R are lacking. This study aimed to analyze the TAT and 8R effects on the P22 VLPs transport efficiency and tissue distribution both in vitro and in vivo. We used a prokaryotic system to prepare P22 VLP self-assembled particles and expressed TAT-or 8R-conjugated mCherry on the VLP capsid protein as model cargoes and revealed that the level of P22 VLP-mCherry penetrating the cell membrane was low. However, both TAT and 8R significantly promoted the cellular uptake efficiency of P22 VLPs in vitro, as well as enhanced the tissue accumulation and retention of P22 VLPs in vivo. At 24 h postinjection, TAT enhanced the tissue distribution and retention in the lung, whereas 8R could be better accumulation in brain. Thus, TAT was superior in terms of cellular uptake and tissue accumulation in the P22 VLPs delivery system. Understanding CPP biocompatibility and tissue retention will expand their potential applications in macromolecular cargo delivery.

Abstract Photoelectrochemical seawater splitting is a promising route for direct utilization of solar energy and abundant seawater resources for H2 production. However, the complex salinity composition in seawater results in intractable challenges for photoelectrodes. This paper describes the fabrication of a bilayer stack consisting of stainless steel and TiO2 as a cocatalyst and protective layer for Si photoanode. The chromium-incorporated NiFe (oxy)hydroxide converted from stainless steel film serves as a protective cocatalyst for efficient oxygen evolution and retarding the adsorption of corrosive ions from seawater, while the TiO2 is capable of avoiding the plasma damage of the surface layer of Si photoanode during the sputtering of stainless steel catalysts. By implementing this approach, the TiO2 layer effectively shields the vulnerable semiconductor photoelectrode from the harsh plasma sputtering conditions in stainless steel coating, preventing surface damages. Finally, the Si photoanode with the bilayer stack inhibits the adsorption of chloride and realizes 167 h stability in chloride-containing alkaline electrolytes. Furthermore, this photoanode also demonstrates stable performance under alkaline natural seawater for over 50 h with an applied bias photon-to-current efficiency of 2.62%.

Abstract Linear ubiquitination catalyzed by HOIL-1-interacting protein (HOIP), the key component of the linear ubiquitination assembly complex, plays fundamental roles in tissue homeostasis by executing domain-specific regulatory functions. However, a proteome-wide analysis of the domain-specific interactome of HOIP across tissues is lacking. Here, we present a comprehensive mass spectrometry-based interactome profiling of four HOIP domains in nine mouse tissues. The interaction dataset provides a high-quality HOIP interactome resource with an average of approximately 90 interactors for each bait per tissue. HOIP tissue interactome presents a systematic understanding of linear ubiquitination functions in each tissue and also shows associations of tissue functions to genetic diseases. HOIP domain interactome characterizes a set of previously undefined linear ubiquitinated substrates and elucidates the cross-talk among HOIP domains in physiological and pathological processes. Moreover, we show that linear ubiquitination of Integrin-linked protein kinase (ILK) decreases focal adhesion formation and promotes the detachment of Shigella flexneri-infected cells. Meanwhile, Hoip deficiency decreases the linear ubiquitination of Smad ubiquitination regulatory factor 1 (SMURF1) and enhances its E3 activity, finally causing a reduced bone mass phenotype in mice. Overall, our work expands the knowledge of HOIP-interacting proteins and provides a platform for further discovery of linear ubiquitination functions in tissue homeostasis.

Abstract Background Pancreatic cancer stem cells are crucial for tumorigenesis and cancer metastasis. Presently, long non-coding RNAs were found to be associated with Pancreatic Ductal Adenocarcinoma stemness characteristics but the underlying mechanism is largely known. Here, we aim to explore the function of LINC00909 in regulating pancreatic cancer stemness and cancer metastasis. Methods The expression level and clinical characteristics of LINC00909 were verified in 80-paired normal pancreas and Pancreatic Ductal Adenocarcinoma tissues from Guangdong Provincial People’s Hospital cohort by in situ hybridization. RNA sequencing of PANC-1 cells with empty vector or vector encoding LINC00909 was experimented for subsequent bioinformatics analysis. The effect of LINC00909 in cancer stemness and metastasis was examined by in vitro and in vivo experiments. The interaction between LINC00909 with SMAD4 and the pluripotency factors were studied. Results LINC00909 was generally upregulated in pancreatic cancer tissues and was associated with inferior clinicopathologic features and outcome. Over-expression of LINC00909 enhanced the expression of pluripotency factors and cancer stem cells phenotype, while knock-down of LINC00909 decreased the expression of pluripotency factors and cancer stem cells phenotype. Moreover, LINC00909 inversely regulated SMAD4 expression, knock-down of SMAD4 rescued the effect of LINC00909-deletion inhibition on pluripotency factors and cancer stem cells phenotype. These indicated the effect of LINC00909 on pluripotency factors and CSC phenotype was dependent on SMAD4 and MAPK/JNK signaling pathway, another downstream pathway of SMAD4 was also activated by LINC00909. Specifically, LINC00909 was localized in the cytoplasm in pancreatic cancer cells and decreased the stability the SMAD4 mRNA. Finally, we found over-expression of LINC00909 not only accelerated tumor growth in subcutaneous mice models, but also facilitated tumorigenicity and spleen metastasis in orthotopic mice models. Conclusion We demonstrate LINC00909 inhibits SMAD4 expression at the post-transcriptional level, which up-regulates the expression of pluripotency factors and activates the MAPK/JNK signaling pathway, leading to enrichment of cancer stem cells and cancer metastasis in pancreatic cancer.

The COVID-19 pandemic provided an additional spotlight on the longstanding socioeconomic/health impacts of redlining and has added to the myriad of environmental justice issues, which has caused significant loss of life, health, and productive work. The Centers for Disease Control and Prevention (CDC) reports that a person with any selected underlying health conditions is more likely to experience severe COVID-19 symptoms, with more than 81% of COVID-19-related deaths among people aged 65 years and older. The effects of COVID-19 are not homogeneous across populations, varying by socioeconomic status, PM2.5 exposure, and geographic location. This variability is supported by analysis of existing data as a function of the number of cases and deaths per capita/1,00,000 persons. We investigate the degree of correlation between these parameters, excluding health conditions and age. We found that socioeconomic variables alone contribute to ~40% of COVID-19 variability, while socioeconomic parameters, combined with political affiliation, geographic location, and PM2.5 exposure levels, can explain ~60% of COVID-19 variability per capita when using an OLS regression model; socioeconomic factors contribute ~28% to COVID-19-related deaths. Using spatial coordinates in a Random Forest (RF) regressor model significantly improves prediction accuracy by ~120%. Data visualization products reinforce the fact that the number of COVID-19 deaths represents 1% of COVID-19 cases in the US and globally. A larger number of democratic voters, larger per-capita income, and age >65 years is negatively correlated (associated with a decrease) with the number of COVID cases per capita. Several distinct regions of negative and positive correlations are apparent, which are dominated by two major regions of anticorrelation: (1) the West Coast, which exhibits high PM2.5 concentrations and fewer COVID-19 cases; and (2) the middle portion of the US, showing mostly high number of COVID-19 cases and low PM2.5 concentrations. This paper underscores the importance of exercising caution and prudence when making definitive causal statements about the contribution of air quality constituents (such as PM2.5) and socioeconomic factors to COVID-19 mortality rates. It also highlights the importance of implementing better health/lifestyle practices and examines the impact of COVID-19 on vulnerable populations, particularly regarding preexisting health conditions and age. Although PM2.5 contributes comparable deaths (~7M) per year, globally as smoking cigarettes (~8.5M), quantifying any causal contribution toward COVID-19 is non-trivial, given the primary causes of COVID-19 death and confounding factors. This becomes more complicated as air pollution was reduced significantly during the lockdowns, especially during 2020. This statistical analysis provides a modular framework, that can be further expanded with the context of multilevel analysis (MLA). This study highlights the need to address socioeconomic and environmental disparities to better prepare for future pandemics. By understanding how factors such as socioeconomic status, political affiliation, geographic location, and PM2.5 exposure contribute to the variability in COVID-19 outcomes, policymakers and public health officials can develop targeted strategies to protect vulnerable populations. Implementing improved health and lifestyle practices and mitigating environmental hazards will be essential in reducing the impact of future public health crises on marginalized communities. These insights can guide the development of more resilient and equitable health systems capable of responding effectively to similar future scenarios.

Abstract Background Tumor mutational burden (TMB) is one of the most significant predictive biomarkers of immunotherapy efficacy in non-small cell lung cancer (NSCLC). Radiomics allows high-throughput extraction and analysis of advanced and quantitative medical imaging features. This study develops and validates a radiomic model for predicting TMB level and the response to immunotherapy based on CT features in NSCLC. Method Pre-operative chest CT images of 127 patients with NSCLC were retrospectively studied. The 3D-Slicer software was used to outline the region of interest and extract features from the CT images. Radiomics prediction model was constructed by LASSO and multiple logistic regression in a training dataset. The model was validated by receiver operating characteristic (ROC) curves and calibration curves using external datasets. Decision curve analysis was used to assess the value of the model for clinical application. Results A total of 1037 radiomic features were extracted from the CT images of NSCLC patients from TCGA. LASSO regression selected three radiomics features (Flatness, Autocorrelation and Minimum), which were associated with TMB level in NSCLC. A TMB prediction model consisting of 3 radiomic features was constructed by multiple logistic regression. The area under the curve (AUC) value in the TCGA training dataset was 0.816 (95% CI: 0.7109–0.9203) for predicting TMB level in NSCLC. The AUC value in external validation dataset I was 0.775 (95% CI: 0.5528–0.9972) for predicting TMB level in NSCLC, and the AUC value in external validation dataset II was 0.762 (95% CI: 0.5669–0.9569) for predicting the efficacy of immunotherapy in NSCLC. Conclusion The model based on CT radiomic features helps to achieve cost effective improvement in TMB classification and precise immunotherapy treatment of NSCLC patients.

Abstract Rare earth elements have excellent catalytic effects on improving hydrogen storage properties of the Mg2Ni-based alloys. This study used a small amount of Y to substitute Mg partially in Mg2Ni0.9Co0.1 and characterized and discussed the effects of Y on the solidification and de-/hydrogenation behaviors. The Mg2−xYxNi0.9Co0.1 (x = 0, 0.2, 0.3, and 0.4) hydrogen storage alloys were prepared using a metallurgy method. The phase composition of the alloys was studied using X-ray diffraction (XRD). Additionally, their microstructure and chemical composition were studied using scanning electron microscopy and energy-dispersive X-ray spectroscopy, respectively. The hydrogen absorption and desorption properties of the alloys were studied using pressure-composition isotherms and differential scanning calorimetric (DSC) measurements. The structure of the as-cast Mg2Ni0.9Co0.1 alloy was composed of the peritectic Mg2Ni, eutectic Mg–Mg2Ni, and a small amount of pre-precipitated Mg–Ni–Co ternary phases, and was converted into the Mg2NiH4, Mg2Ni0.9Co0.1H4, and MgH2 phases after hydrogen absorption. Furthermore, the XRD patterns of the alloys showed the MgYNi4 phase and a trace amount of the Y2O3 phase along with the Mg and Mg2Ni phases after the addition of Y. After hydrogen absorption, the phase of the alloys was composed of the Mg2NiH4, MgH2, MgYNi4, YH3, Y2O3, and Mg2NiH0.3 phases. With the increase of Y addition, the area ratios of the peritectic Mg2Ni matrix phase in the Mg2−xYxNi0.9Co0.1 (x = 0, 0.2, 0.3, and 0.4) alloys gradually decreased until they disappeared. However, the eutectic structure gradually increased, and the microstructures of the alloys were obviously refined. The addition of Y improves the activation performance of the alloys. The alloy only needed one cycle of de-/hydrogenation to complete the activation for x = 0.4. The DSC curves showed that the initial dehydrogenation temperatures of Mg2Ni0.9Co0.1 and Mg1.8Y0.2Ni0.9Co0.1 were 200 and 156 °C, respectively. The desorption activation energies of the hydrides of the Mg2Ni0.9Co0.1 and Mg1.8Y0.2Ni0.9Co0.1 alloys calculated using the Kissinger method were 94.7 and 56.5 kJ/mol, respectively. Moreover, the addition of Y reduced the initial desorption temperature of the alloys and improved their kinetic properties.

Single-nucleotide polymorphisms (SNPs) that are located near CpG sites have the potential to influence DNA methylation levels, leading to distinct patterns of DNA methylation. These methylation quantitative trait loci (meQTLs) can influence methylation levels across the entire genome, thereby impacting phenotypic traits. In this study, we utilised reduced representation bisulphite sequencing (RRBS) to analyse DNA methylation in muscle tissue samples collected from 140 Yorkshire pigs. Additionally, we assessed SNPs using the Porcine 50K chip, examined 17 fatty acid traits, and conducted epigenome-wide association studies (EWAS) and genome-wide association studies (GWAS). Our investigation revealed numerous associations between DNA methylation and fatty acid traits, including C16:0, C18:0, C20:3n-3, and C22:6n-3. Notably, a substantial portion of these associations was specifically identified by EWAS and not GWAS. Subsequently, we performed GWAS to identify meQTLs using methylation levels of significant CpGs from the EWAS as traits. The results revealed the predominance of trans-meQTLs; however, we also discovered a cis-meQTL on SSC12. Finally, we reported a crucial CpG site (SSC12:3735523) and its cis-meQTL on SSC12, which are located in close proximity to the FASN gene. Our findings contribute to the identification of CpG sites and their cis-meQTLs associated with fatty acid traits, utilising comprehensive genome and methylome data. Moreover, our study provides novel insights into the molecular mechanisms underlying fatty acid traits in pigs.

Streptococcus suis is an important bacterial pathogen that affects the global pig industry. The immunosuppressive nature of S. suis infection is recognized, and our previous research has confirmed thymus atrophy with a large number of necrotic cells. In this current work, we aimed to uncover the role of pyroptosis in cellular necrosis in thymic cells of S. suis-infected mice. Confocal microscopy revealed that S. suis activated the M1 phenotype and primed pyroptosis in the macrophages of atrophied thymus. Live cell imaging further confirmed that S. suis could induce porcine alveolar macrophage (PAM) pyroptosis in vitro, displaying cell swelling and forming large bubbles on the plasma membrane. Meanwhile, the levels of p-p38, p-extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) were increased, which indicated the mitogen-activated protein kinase (MAPK) and AKT pathways were also involved in the inflammation of S. suis-infected PAMs. Furthermore, RT-PCR revealed significant mRNA expression of pro-inflammatory mediators, including interleukin (IL)-1β, IL-6, IL-18, tumor necrosis factor (TNF)-α and chemokine CXCL8. The data indicated that the inflammation induced by S. suis was in parallel with pro-inflammatory activities of M1 macrophages, pyroptosis and MAPK and AKT pathways. Pyroptosis contributes to necrotic cells and thymocyte reduction in the atrophied thymus of mice.

Abstract Angelica sinensis roots (Angelica roots) are rich in many bioactive compounds, including phthalides, coumarins, lignans, and terpenoids. However, the molecular bases for their biosynthesis are still poorly understood. Here, an improved chromosome-scale genome for A. sinensis var. Qinggui1 is reported, with a size of 2.16 Gb, contig N50 of 4.96 Mb and scaffold N50 of 198.27 Mb, covering 99.8% of the estimated genome. Additionally, by integrating genome sequencing, metabolomic profiling, and transcriptome analysis of normally growing and early-flowering Angelica roots that exhibit dramatically different metabolite profiles, the pathways and critical metabolic genes for the biosynthesis of these major bioactive components in Angelica roots have been deciphered. Multiomic analyses have also revealed the evolution and regulation of key metabolic genes for the biosynthesis of pharmaceutically bioactive components; in particular, TPSs for terpenoid volatiles, ACCs for malonyl CoA, PKSs for phthalide, and PTs for coumarin biosynthesis were expanded in the A. sinensis genome. These findings provide new insights into the biosynthesis of pharmaceutically important compounds in Angelica roots for exploration of synthetic biology and genetic improvement of herbal quality.

The genetic trait of residual feed intake (RFI) holds considerable importance in the swine industry. Recent research indicates that the gut microbiota of pigs plays a pivotal role in the manifestation of the RFI trait. Nevertheless, the metabolic pathways involved in the functioning of these microorganisms remain elusive. Thus, based on the ranking of the RFI trait in Duroc pigs, the present study selected the top 10 and bottom 10 pigs as the experimental subjects. The distribution and metabolite differences of cecal microbiota were analyzed using 16S rRNA gene sequencing and liquid chromatography–tandem mass spectrometry (LC–MS/MS) techniques. The low RFI cecal group was named LRC, and the high RFI cecal group was named HRC. The results indicate that the LRC group had lower RFI, feed conversion ratio (FCR), average daily feed intake (ADFI) (p

Taxanes are natural compounds for the treatment of lung cancer, but the molecular mechanism behind the effects is unclear. In the present study, through network pharmacology and molecular docking, the mechanism of the target and pathway of taxanes in the treatment of lung cancer was studied. The taxanes targets were determined by PubChem database, and an effective compounds-targets network was constructed. The GeneCards database was used to determine the disease targets of lung cancer, and the intersection of compound targets and disease targets was obtained. The Protein–Protein Interaction (PPI) network of the intersection targets was analyzed, and the PPI network was constructed by Cytoscape 3.6.0 software. The hub targets were screened according to the degree value, and the binding activity between taxanes and hub targets was verified by molecular docking. The results showed that eight taxane-active compounds and 444 corresponding targets were screened out, and 131 intersection targets were obtained after mapping with lung cancer disease targets. The hub targets obtained by PPI analysis were TP53, EGFR, and AKT1. Gene Ontology (GO) biological function enrichment analysis obtained 1795 biological process (BP) terms, 101 cellular component (CC) terms, and 164 molecular function (MF) terms. There were 179 signaling pathways obtained by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Twenty signaling pathways were screened out, mainly pathways in cancer, proteoglycans in cancer pathway, microRNAs in cancer pathway, and so on. Molecular docking shows that the binding energies of eight taxanes with TP53, EGFR, and AKT1 targets were less than −8.8 kcal/mol, taxanes acts on TP53, EGFR, and AKT1 targets through pathways in cancer, proteoglycans in cancer pathway and microRNAs in cancer pathway, and plays a role in treating lung cancer in biological functions such as protein binding, enzyme binding, and identical protein binding.

Abstract Super-enhancers (SEs) consist of multiple typical enhancers enriched at high density with transcription factors, histone-modifying enzymes and cofactors. Oncogenic SEs promote tumorigenesis and malignancy by altering protein-coding gene expression and noncoding regulatory element function. Therefore, they play central roles in the treatment of cancer. Here, we review the structural characteristics, organization, identification, and functions of SEs and the underlying molecular mechanism by which SEs drive oncogenic transcription in tumor cells. We then summarize abnormal SE complexes, SE-driven coding genes, and noncoding RNAs involved in tumor development. In summary, we believe that SEs show great potential as biomarkers and therapeutic targets.

Mesenchymal stem cells (MSCs) possess significant differentiation potential, making them highly promising in medicine and immunotherapy due to their regenerative capabilities and exosome secretion. However, challenges such as limited cell divisions and complex testing hinder large-scale MSC production. In this study, we successfully established an immortalized MSC line by transfecting the human telomerase reverse transcriptase (TERT) gene into MSCs isolated from pregnant sheep umbilical cords. This approach effectively inhibits cell senescence and promotes cell proliferation, enabling the generation of umbilical cord mesenchymal stem cells (UCMSCs) on a larger scale. Our findings demonstrate that these transfected TERT-UCMSCs exhibit enhanced proliferative capacity and a reduced aging rate compared to regular UCMSCs while maintaining their stemness without tumorigenicity concerns. Consequently, they hold great potential for medical applications requiring large quantities of functional MSCs.

Objective Pigs, an ideal biomedical model for human diseases, suffer from about 50% early embryonic and fetal death, a major cause of fertility loss worldwide. However, identifying the causal variant remains a huge challenge. This study aimed to detect single nucleotide polymorphisms (SNPs) and candidate genes for the number of mummified (NM) piglets using the imputed whole-genome sequence (WGS) and validate the potential candidate genes. Methods The imputed WGS was introduced from genotyping-by-sequencing (GBS) using a multi-breed reference population. We performed genome-wide association studies (GWAS) for NM piglets at birth from a Landrace pig populatiGWAS peak located on SSC11: 0.10 to 7.11 Mbp (Top SNP, SSC11:1,889,658 bp; p = 9.98E-13) was identified in cyclin dependent kinase on. A total of 300 Landrace pigs were genotyped by GBS. The whole-genome variants were imputed, and 4,252,858 SNPs were obtained. Various molecular experiments were conducted to determine how the genes affected NM in pigs. Results A strong GWAS peak located on SSC11: 0.10 to 7.11 Mbp (Top SNP, SSC11:1,889,658 bp; p = 9.98E-13) was identified in cyclin dependent kinase 8 (CDK8) gene, which plays a crucial role in embryonic retardation and lethality. Based on the molecular experiments, we found that Y-box binding protein 1 (YBX1) was a crucial transcription factor for CDK8, which mediated the effect of CDK8 in the proliferation of porcine ovarian granulosa cells via transforming growth factor beta/small mother against decapentaplegic signaling pathway, and, as a consequence, affected embryo quality, indicating that this pathway may be contributing to mummified fetal in pigs. Conclusion A powerful imputation-based association study was performed to identify genes associated with NM in pigs. CDK8 was suggested as a functional gene for the proliferation of porcine ovarian granulosa cells, but further studies are required to determine causative mutations and the effect of loci on NM in pigs.

Abstract Background Desensitization of G protein–coupled receptors (GPCRs) refers to a rapid attenuation of responsiveness that occurs with repeated or continuous exposure to agonists. GRK-mediated phosphorylation and subsequent binding with arrestins in the activated receptor cytoplasmic cavity in competition with G proteins has been suggested as the conventional mechanism of desensitization. Along with widely accepted conventional mechanism of desensitization, studies of various GPCRs including dopamine D2-like receptors (D2R, D3R, D4R) have suggested the existence of another desensitization mechanism. In this study, loss-of-function approaches and D2-like receptor mutants that display different desensitization properties were used to elucidate the molecular mechanisms responsible for desensitization. Results Desensitization development entailed the signaling cascade composed of Src, PDK1, and Akt, the latter of which in turn interacted with USP33, an arrestin deubiquitinase, to promote arrestin deubiquitination. The deubiquitinated arrestin subsequently formed a complex with Gβγ and translocated to the nucleus via an importin complex, wherein it sequestered Gβγ from the receptor and Gα, thereby attenuating receptor signaling. As in D2-like receptors, both USP33 and importin β1 were involved in the desensitization of the β2 adrenoceptor. Conclusions In addition to the conventional mechanism of desensitization, which occurs on the plasma membrane and in the cytosol, this study provides a new insight that another desensitization pathway in which nuclear trafficking plays a critical role is operating. It is plausible that multiple, complementary desensitization measures are in place to properly induce desensitization depending on receptor characteristics or the surrounding environment. Video Abstract

Background: Co-diabetes pancreatic adenocarcinoma has a poorer prognosis than pancreatic adenocarcinoma without diabetes. This study aimed to develop a reliable prognostic model for patients with co-diabetes pancreatic adenocarcinoma. Method: Overall, 169 patients with co-diabetes pancreatic adenocarcinoma were included in our study. First, the independent risk factors affecting the prognosis of patients with co-diabetes pancreatic adenocarcinoma were determined by univariate and multivariate Cox regression analyses. Based on these identified risk factors, we developed a nomogram and evaluated its predictive ability using the concordance index, receiver operating characteristic curve, calibration plot, decision curve, and net reclassification index. Results: In this study, prealbumin, transferrin, carcinoembryonic antigen, distant metastasis, tumor differentiation neutrophil count, lymphocyte count and fasting blood glucose were confirmed as significant prognostic factors. Based on these predictors, a new nomogram was developed. Compared with the American Joint Committee on Cancer 8 staging system and other models, the nomogram achieved a higher concordance index in the training (0.795) and validation (0.729) queues. The area under the nomogram's curve for predicting patient survival at 0.5, 1, and 1.5 years in the training queue was >0.8. Patients were risk-stratified using the nomogram, and Kaplan–Meier survival curves of subgroups were plotted. The Kaplan–Meier curve also showed better separation than the American Joint Committee on Cancer 8 staging system, indicating that our model has a better risk hierarchical ability. Conclusions: Compared to the American Joint Committee on Cancer 8 staging system and other predictive models, our model showed better predictive ability for patients with co-diabetes pancreatic adenocarcinoma. Our model will help in patients’ risk stratification and improves their prognosis.

Summary: Long interspersed element 1 (LINE-1) is the only currently known active autonomous transposon in humans, and its retrotransposition may cause deleterious effects on the structure and function of host cell genomes and result in sporadic genetic diseases. Host cells therefore developed defense strategies to restrict LINE-1 mobilization. In this study, we demonstrated that IFN-inducible Schlafen5 (SLFN5) inhibits LINE-1 retrotransposition. Mechanistic studies revealed that SLFN5 interrupts LINE-1 ribonucleoprotein particle (RNP) formation, thus diminishing nuclear entry of the LINE-1 RNA template and subsequent LINE-1 cDNA production. The ability of SLFN5 to bind to LINE-1 RNA and the involvement of the helicase domain of SLFN5 in its inhibitory activity suggest a mechanism that SLFN5 binds to LINE-1 RNA followed by dissociation of ORF1p through its helicase activity, resulting in impaired RNP formation. These data highlight a new mechanism of host cells to restrict LINE-1 mobilization.

A novel pretreatment strategy utilizing a combination of NaOH and 1-Butyl-3-methylimidazolium chloride ([Bmim]Cl) was proposed to enhance the enzymatic hydrolysis of abandoned Medium-density fiberboard (MDF). The synergistic effect of NaOH and [Bmim]Cl pretreatment significantly improved the glucose yield, reaching 445.8 mg/g within 72 h, which was 5.04 times higher than that of the untreated samples. The working mechanism was elucidated according to chemical composition, as well as FTIR, 13C NMR, XRD, and SEM analyses. The combined effects of NaOH and [Bmim]Cl led to lignin degradation, hemicellulose removal, the destruction and erosion of crystalline regions, pores, and an irregular microscopic morphology. In addition, by comparing the enzymatic hydrolysis sugar yield and elemental nitrogen content of untreated MDF samples, eucalyptus, and hot mill fibers (HMF), it was demonstrated that the presence of adhesives and additives in waste MDF significantly influences its hydrolysis process. The sugar yield of untreated MDF samples (88.5 mg/g) was compared with those subjected to hydrothermal pretreatment (183.2 mg/g), Ionic liquid (IL) pretreatment (406.1 mg/g), and microwave-assisted ionic liquid pretreatment (MWI) (281.3 mg/g). A long water bath pretreatment can reduce the effect of adhesives and additives on the enzymatic hydrolysis of waste MDF. The sugar yield produced by the combined pretreatment proposed in this study and the removal ability of adhesives and additives highlight the great potential of our pretreatment technology in the recycling of waste fiberboard.

Conversion of CO2 into value-added products with renewable energy provides a promising route to realize carbon neutrality. Here, authors design and construct a Si photoelectrochemical flow cells for CO2 reduction reaction to achieve a high solar-to-fuel conversion efficiency.

Abstract Recently, Deep Learning based automatic generation of treatment recommendation has been attracting much attention. However, medical datasets are usually small, which may lead to over-fitting and inferior performances of deep learning models. In this paper, we propose multi-objective data enhancement method to indirectly scale up the medical data to avoid over-fitting and generate high quantity treatment recommendations. Specifically, we define a main and several auxiliary tasks on the same dataset and train a specific model for each of these tasks to learn different aspects of knowledge in limited data scale. Meanwhile, a Soft Parameter Sharing method is exploited to share learned knowledge among models. By sharing the knowledge learned by auxiliary tasks to the main task, the proposed method can take different semantic distributions into account during the training process of the main task. We collected an ultrasound dataset of thyroid nodules that contains Findings, Impressions and Treatment Recommendations labeled by professional doctors. We conducted various experiments on the dataset to validate the proposed method and justified its better performance than existing methods.

Malignant proliferation and metastasis are the main causes of breast cancer death. The transcription factor high mobility group (HMG) box-containing protein 1 (HBP1) is an important tumor suppressor whose deletion or mutation is closely related to the appearance of tumors. Here, we investigated the role of HBP1 in breast cancer suppression. HBP1 enhances the activity of the tissue inhibitors of metalloproteinases 3 (TIMP3) promoter, thereby increasing protein and mRNA levels of TIMP3. TIMP3 increases the phosphatase and tensin homolog (PTEN) protein level by inhibiting its degradation and acts as a metalloproteinase inhibitor to inhibit the protein levels of MMP2/9. In this study, we demonstrated that the HBP1/TIMP3 axis plays a crucial role in inhibiting the tumorigenesis of breast cancer. HBP1 deletion interferes with the regulation of the axis and induces the occurrence and malignant progression of breast cancer. In addition, the HBP1/TIMP3 axis promotes the sensitivity of breast cancer to radiation therapy and hormone therapy. Our study opens new perspectives on the treatment and prognosis of breast cancer.

Abstract HBP1 is a sequence-specific transcription factor which generally considered as a crucial growth inhibitor. Posttranslational modification of HBP1 is vital for its function. In this study, we demonstrate that HBP1 is methylated at R378 by PRMT1, which decreases HBP1 protein stability by promoting its ubiquitination and proteasome-mediated degradation. PRMT1-mediated methylation of HBP1 alleviates the repressive effects of HBP1 on tumor metastasis and growth. GSN is identified as a novel target gene of HBP1. Methylation of HBP1 promotes actin cytoskeleton remodeling, glycolysis and tumor progression by downregulating GSN (a vital actin-binding protein) levels. The methylated HBP1-GSN axis is associated with the clinical outcomes of cancer patients. This investigation elucidates the mechanism of how methylated HBP1 facilitates actin cytoskeleton remodeling, thus attenuates its tumor-suppressive function and promotes tumor progression. Targeting methylated HBP1-GSN axis may provide a therapeutic strategy for cancer.

Sail systems and aerodynamic performance are important factors for determining the dynamic performance of unmanned sailboats. First, in order to identify the future trends of the flexible sails of unmanned sailboats, representative unmanned sailboats with flexible sails in the world are reported. The flexible sail system is then summarized in terms of physical characteristics, installation and fixing schemes, and sail trim schemes. The progress of three research methods of numerical simulation, wind tunnel test and sea trial for aerodynamic performance are analyzed respectively, and the basic technical route for research on the aerodynamic performance of flexible sails is summarized. Finally, several future key technologies of unmanned sailboats and flexible sails are predicted.

Preparation of inorganic protective layers for photoelectrodes requires high-quality deposition techniques. Here, the authors report a spin-coated organic protective layer that enables Si photocathodes to realize stable solar water splitting.

ObjectiveThe shape of a sail influences the airflow characteristics around it, and flexible sails are prone to large nonlinear deformation under wind pressure. As such, this paper studies the effects of sail deformation on aerodynamic performance.MethodsA fluid-structure interaction (FSI) study on flexible sail deformation is performed. The initial shape model and material model of a sail are established, an explicit finite element method (FEM) such as AUTODYN is applied to calculate the large nonlinear deformation of the sail, and the shape of the deformed sail is constructed. STAR-CCM+ is applied to predict the performance of the initial and deformed sail.ResultsThe results show that positive pressure on the windward side of the deformed sail increased, and the flow separation generated around the leeside of the sail leech became more severe in upwind conditions with a relative wind angle of 20°. The increase of the lift force due to the rise of the camber was relatively small, resulting in a decrease in overall lift force.ConclusionFSI studies on flexible sail deformation are suitable for the precise evaluation or optimization of sail performance.

Porcine reproductive and respiratory syndrome viruses (PRRSVs) are significant pathogens that affect the global swine industry. Its virions consist of a central core composed of nucleocapsid (N) protein, surrounded by multiple distinct viral envelope proteins. However, the mechanisms underlying the recognition and packaging of N protein by viral envelope proteins remain elusive. In this study, we elucidated the role of nonstructural protein 2 (nsp2) from highly pathogenic PRRSV-2 (HP-PRRSV-2) in viral assembly. Firstly, among all the tested envelope proteins, only glycoprotein 5 (GP5) exhibits limited interaction with N protein. Interestingly, we demonstrated that full-length nsp2 co-immunoprecipitates (Co-IPs) with the N protein and all tested viral envelope proteins. In the presence of full-length nsp2, the N protein interacts with distinct viral envelope proteins. Moreover, upon viral infection, Co-IP experiments using nsp2-specific antibodies or N-specific antibodies revealed the formation of a complex between N and nsp2 with the M protein, GP2a, and GP5. However, neither of the two short forms of nsp2--namely nsp2TF nor nsp2N--participates in this process as they fail to interact with the N protein. Finally, our results demonstrate that this process occurs in the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment (ERGIC). Overall, our findings unveil a novel functional role for full-length nsp2 of HP-PRRSV-2 in facilitating the assembly of the N protein with viral envelope proteins. IMPORTANCE The virus assembly process of arteriviruses remains largely elusive, including the direct interaction between N protein and viral envelope proteins or the potential requirement for additional proteins in facilitating assembly. Moreover, where the N protein assembles with viral envelope proteins during the virus lifecycle remains unclear. This study reveals a novel role for nonstructural protein 2 (nsp2) in highly pathogenic porcine reproductive and respiratory syndrome virus type 2 (HP-PRRSV-2), highlighting its involvement in HP-PRRSV-2 assembly. These findings provide crucial insights into HP-PRRSV-2 assembly and enhance our understanding of their lifecycle. Overall, this study offers an alternative approach to developing a new antiviral strategy targeting PRRSV-2 assembly. [ABSTRACT FROM AUTHOR]

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancer due to its highly aggressive phenotype and lack of effective biomarkers or treatment strategies. ZMAT1 belongs to the C2H2 type zinc finger family, but its biological function is rarely investigated, as well as its role in cancer development. Methods Multiple bioinformatics analyses were used to evaluate ZMAT1 expression and potential role in PDAC. Intro and vivo studies were performed to assess the effects of ZMAT1 on PDAC cells growth. Furthermore, CHIP-seq and luciferase reporter assay was conducted to identify its specific regulatory mechanism in PDAC. Results The current study identified the down-regulation of ZMAT1 and its associations with unfavorable clinicopathological characteristics and poor survival of PDAC. Further, we found overexpression of ZMAT1 inhibited pancreatic cancer cell proliferation by inducing p21, leading to impaired S/G2 cell cycle progression. Besides, over-expression of ZMAT1 led to decreased pancreatic cancer cell apoptosis. Mechanistically, ZMAT1 up-regulated p53 expression and inhibition of p53 abrogated the effect of ZMAT1 over-expression on pancreatic cancer cell, indicating the role of ZMAT1 in PDAC was dependent on p53. By performing CHIP-seq assay, we found ZMAT1 did not bind to P53 but bound to the promoter region of SIRT3, an upstream regulator for p53. Luciferase reporter assay showed transfection of ZMAT1 induced SIRT3 transcription, suggesting ZMAT1 was a transcriptional activator for SIRT3. Conclusion Our findings indicated the role of ZMAT1-SIRT3-p53 signaling pathway during tumor growth, highlighting that ZMAT1 is a tumor suppressor and novel biomarker of PDAC.

The swine pathogens porcine reproductive and respiratory syndrome virus (PRRSV) and Streptococcus suis have both been reported to cause damage to the immune organs. Inguinal lymph node (ILN) injury has been reported in PRRSV-infected pigs with secondary S. suis infection, but not much is known about the mechanism. In this study, secondary S. suis infection after highly pathogenic (HP)-PRRSV infection caused more severe clinical symptoms, mortality, and ILN lesions. Histopathological lesions were seen in ILNs with a marked decrease in lymphocyte numbers. Terminal deoxynucleotidyl transferase (TdT)-mediated de-oxyuridine triphosphate (dUTP)-biotin nick end-labeling (TUNEL) assays revealed that HP-PRRSV strain HuN4 alone induced ILN apoptosis, but dual-infection with S. suis strain BM0806 induced greater levels of apoptosis. Besides, we found that some HP-PRRSV-infected cells underwent apoptosis. Furthermore, anti-caspase-3 antibody staining confirmed that ILN apoptosis was mainly induced by a caspase-dependent pathway. Pyroptosis was also observed in HP-PRRSV-infected cells, and there was more pyroptosis in piglets infected with HP-PRRSV alone compared with those with secondary S. suis infection, and HP-PRRSV-infected cells underwent pyroptosis. Altogether, this is the first report to identify pyroptosis in ILNs and which signaling pathway is related to ILN apoptosis in single or dual-infected piglets. These results contribute to a better understanding of the pathogenic mechanisms during secondary S. suis infection.