TM7SF3 controls TEAD1 splicing to prevent MASH-induced liver fibrosis.

The mechanisms of hepatic stellate cell (HSC) activation and the development of liver fibrosis are not fully understood. Here, we show that deletion of a nuclear seven transmembrane protein, TM7SF3, accelerates HSC activation in liver organoids, primary human HSCs, and in vivo in metabolic-dysfunction-associated steatohepatitis (MASH) mice, leading to activation of the fibrogenic program and HSC proliferation. Thus, TM7SF3 knockdown promotes alternative splicing of the Hippo pathway transcription factor, TEAD1, by inhibiting the splicing factor heterogeneous nuclear ribonucleoprotein U (hnRNPU). This results in the exclusion of the inhibitory exon 5, generating a more active form of TEAD1 and triggering HSC activation. Furthermore, inhibiting TEAD1 alternative splicing with a specific antisense oligomer (ASO) deactivates HSCs in vitro and reduces MASH diet-induced liver fibrosis. In conclusion, by inhibiting TEAD1 alternative splicing, TM7SF3 plays a pivotal role in mitigating HSC activation and the progression of MASH-related fibrosis.

Genomic Characterization of a Carbapenem-Resistant Raoultella planticola Strain Co-Harboring blaIMP-4 and blaSHV-12 Genes.

Raoultella planticola is an emerging bacterial pathogen responsible for causing infections in both humans and animals. Unfortunately, sporadic reports of carbapenem-resistant R. planticola (CRRP) have been documented worldwide. Here we first reported the complete genome sequence of a CRRP isolate RP_3045 co-carrying blaIMP-4 and blaSHV-12, recovered from a patient in China, and its genetic relatedness to 82 R. planticola strains deposited in the NCBI GenBank database, sourced from humans, animals, and the environment. Whole-genome sequencing was performed using the Illumina NovaSeq 6000 and Oxford Nanopore MinION platforms. Phylogenetic analysis was also performed and visualized using a single nucleotide polymorphism (SNP)-based strategy. The complete genome of R. planticola strain RP_3045 was determined to be 6,312,961 bp in length, comprising five contigs that included one chromosome and four plasmids. RP_3045 was found to be multidrug-resistant and harbored several antimicrobial resistance genes, including both blaIMP-4 and blaSHV-12 genes located on a single plasmid. The most closely related strain was hkcpe63, recovered from humans in Hong Kong, China, in 2014, with 506 SNP differences. R. planticola strains were distributed globally and exhibited strong associations among isolates obtained from different sectors. This study provides evidence for the potential of R. planticola to disseminate carbapenem resistance across different sectors, highlighting the critical need for active and continuous surveillance of CRRP.

Surface Modification Progress for PLGA-Based Cell Scaffolds.

Poly(lactic-glycolic acid) (PLGA) is a biocompatible bio-scaffold material, but its own hydrophobic and electrically neutral surface limits its application as a cell scaffold. Polymer materials, mimics ECM materials, and organic material have often been used as coating materials for PLGA cell scaffolds to improve the poor cell adhesion of PLGA and enhance tissue adaptation. These coating materials can be modified on the PLGA surface via simple physical or chemical methods, and coating multiple materials can simultaneously confer different functions to the PLGA scaffold; not only does this ensure stronger cell adhesion but it also modulates cell behavior and function. This approach to coating could facilitate the production of more PLGA-based cell scaffolds. This review focuses on the PLGA surface-modified materials, methods, and applications, and will provide guidance for PLGA surface modification.

Monitoring the long-term spatiotemporal transmission dynamics and ecological surveillance of multidrug-resistant Salmonella enterica serovar Goldcoast: A multicenter genomic epidemiology study.

The emergence of multidrug-resistant Salmonella enterica serovar Goldcoast poses a significant threat to the effective treatment and control of salmonellosis within the ecological environment. Here, we conducted a genomic epidemiological study delineate the global dissemination scenarios of the multidrug-resistant S. Goldcoast originated from 11 countries for over 20 years. The population structure and evolutionary history of multidrug-resistant S. Goldcoast was investigated through phylogenomic and long-term spatiotemporal transmission dynamic analysis. ST358 and ST2529 are the predominant lineages of S. Goldcoast. Multidrug-resistant S. Goldcoast strains have mainly been identified in the ST358 lineage from human and the ST2529 lineage from livestock. ST358 S. Goldcoast was estimated to have emerged in the United Kingdom in 1969, and then spread to China, with both countries serve as centers for the global dissemination of the ST358 lineage. After its emergence and subsequent spread in Chinese clinical and environmental samples, occasional instances of this lineage have been reported in Canada, the United Kingdom, and Ireland. Clonal transmission of ST358 and ST2529 S. Goldcoast have occurred not only on an international and intercontinental scale but also among clinical, environmental and livestock samples. These data indicated that international circulation and local transmission of S. Goldcoast have occurred for over a decade. Continued surveillance of multidrug-resistant S. Goldcoast from a global "One Health" perspective is urgently needed to facilitate monitoring the spread of the antimicrobial resistant high-risk clones.

MGA-seq: robust identification of extrachromosomal DNA and genetic variants using multiple genetic abnormality sequencing.

Genomic abnormalities are strongly associated with cancer and infertility. In this study, we develop a simple and efficient method - multiple genetic abnormality sequencing (MGA-Seq) - to simultaneously detect structural variation, copy number variation, single-nucleotide polymorphism, homogeneously staining regions, and extrachromosomal DNA (ecDNA) from a single tube. MGA-Seq directly sequences proximity-ligated genomic fragments, yielding a dataset with concurrent genome three-dimensional and whole-genome sequencing information, enabling approximate localization of genomic structural variations and facilitating breakpoint identification. Additionally, by utilizing MGA-Seq, we map focal amplification and oncogene coamplification, thus facilitating the exploration of ecDNA's transcriptional regulatory function.

Self-Boosting Vaccination Based on Pulsatile Antigen Release from Core-Shell Microparticles.

Vaccination is among the most effective ways to prevent infectious diseases. Subunit vaccines are safe but usually require multiple booster shots, which may lead to immunity loss and economic consume. In this study, a self-boosting vaccine is developed based on the pulsatile release of antigen from the core-shell microparticle after single-injection immunization. Self-healing technology applied to form an "antigen core" can avoid organic solvents from destroying the spatial structure of the antigen. The "antigen shell" is built-up by self-assemble of the antigen with the opposite charged polypeptide. Primary immunization occurs with the self-assembled film disintegration, and the booster comes with the microparticle degradation. The changing of antigen-specific antibodies after immunization with the core-shell microparticle vaccine is consistent with that caused by the two shots of immunization. The immune effect and safety evaluation results support the translational potential of this self-boosting core-shell microparticle vaccine.

[Development law of soil cracks in karst peak-cluster depressions under dry and wet alternations]. / 干湿交替条件下喀斯特峰丛洼地土壤裂隙发育规律.

In an experiment with alternating dry and wet conditions of soil in cultivated land, orchards and forest lands with limestone and dolomite in karst peak depression, combined with digital image processing technology, we investigated the development law of soil surface cracks under alternating dry and wet condition. The results showed that with the alternation of wet and dry, the average width of cracks decreased at a fast-slow-slower rate, with an order of limestone > dolomite under the same land use, and orchard > cultivated land > forest soil under the same soil-forming parent rock. In the first four dry and wet alternations, the degrees of soil fragmentation and connectivity were higher in dolomite development than in limestone, with significant differences in fracture development rose diagrams. In the subsequent cycles, soil fragmentation of most samples increased, the difference dominated by parent rock gradually decreased, the crack development rose diagram converged, and the connectivity showed the pattern of forest land > orchard > cultivated land. After the fourth cycle, the alternations of dry and wet seriously damaged soil structure. The physical and chemical properties of capillary porosity and non-capillary tube porosity were dominant in the development of cracks before that, but it was more dependent on the organic matter content and the sand composition after that.

TWAS Atlas: a curated knowledgebase of transcriptome-wide association studies.

Transcriptome-wide association studies (TWASs), as a practical and prevalent approach for detecting the associations between genetically regulated genes and traits, are now leading to a better understanding of the complex mechanisms of genetic variants in regulating various diseases and traits. Despite the ever-increasing TWAS outputs, there is still a lack of databases curating massive public TWAS information and knowledge. To fill this gap, here we present TWAS Atlas (https://ngdc.cncb.ac.cn/twas/), an integrated knowledgebase of TWAS findings manually curated from extensive literature. In the current implementation, TWAS Atlas collects 401,266 high-quality human gene-trait associations from 200 publications, covering 22,247 genes and 257 traits across 135 tissue types. In particular, an interactive knowledge graph of the collected gene-trait associations is constructed together with single nucleotide polymorphism (SNP)-gene associations to build up comprehensive regulatory networks at multi-omics levels. In addition, TWAS Atlas, as a user-friendly web interface, efficiently enables users to browse, search and download all association information, relevant research metadata and annotation information of interest. Taken together, TWAS Atlas is of great value for promoting the utility and availability of TWAS results in explaining the complex genetic basis as well as providing new insights for human health and disease research.

Decoding the spatial chromatin organization and dynamic epigenetic landscapes of macrophage cells during differentiation and immune activation.

Immunocytes dynamically reprogram their gene expression profiles during differentiation and immunoresponse. However, the underlying mechanism remains elusive. Here, we develop a single-cell Hi-C method and systematically delineate the 3D genome and dynamic epigenetic atlas of macrophages during these processes. We propose "degree of disorder" to measure genome organizational patterns inside topologically-associated domains, which is correlated with the chromatin epigenetic states, gene expression, and chromatin structure variability in individual cells. Furthermore, we identify that NF-κB initiates systematic chromatin conformation reorganization upon Mycobacterium tuberculosis infection. The integrated Hi-C, eQTL, and GWAS analysis depicts the atlas of the long-range target genes of mycobacterial disease susceptible loci. Among these, the SNP rs1873613 is located in the anchor of a dynamic chromatin loop with LRRK2, whose inhibitor AdoCbl could be an anti-tuberculosis drug candidate. Our study provides comprehensive resources for the 3D genome structure of immunocytes and sheds insights into the order of genome organization and the coordinated gene transcription during immunoresponse.

Strong Coupling Superconductivity in Ca-Intercalated Bilayer Graphene on SiC.

The metal-intercalated bilayer graphene has a flat band with a high density of states near the Fermi energy and thus is anticipated to exhibit an enhanced strong correlation effect and associated fascinating phenomena, including superconductivity. By using a self-developed multifunctional scanning tunneling microscope, we succeeded in observing the superconducting energy gap and diamagnetic response of a Ca-intercalated bilayer graphene below a critical temperature of 8.83 K. The revealed high value of gap ratio, 2Δ/kBTc ≈ 5.0, indicates a strong coupling superconductivity, while the variation of penetration depth with temperature and magnetic field indicates an isotropic s-wave superconductor. These results provide crucial experimental clues for understanding the origin and mechanism of superconductivity in carrier-doped graphene.

Precision Killing of Sinoporphyrin Sodium-Mediated Photodynamic Therapy against Malignant Tumor Cells.

Photodynamic therapy (PDT) has significant advantages in the treatment of malignant tumors, such as high efficiency, minimal invasion and less side effects, and it can preserve the integrity and quality of the organs. The power density, irradiation time and photosensitizer (PS) concentration are three main parameters that play important roles in killing tumor cells. However, until now, the underlying relationships among them for PDT outcomes have been unclear. In this study, human malignant glioblastoma U-118MG and melanoma A375 cells were selected, and the product of the power density, irradiation time and PS concentration was defined as the total photodynamic parameter (TPP), in order to investigate the mechanisms of PS sinoporphyrin sodium (DVDMS)-mediated PDT (DVDMS-PDT). The results showed that the survival rates of the U-118MG and A375 cells were negatively correlated with the TPP value in the curve, and the correlation exactly filed an e-exponential function. Moreover, according to the formula, we realized controllable killing effects of the tumor cells by randomly adjusting the three parameters, and we finally verified the accuracy and repeatability of the formula. In conclusion, the establishment and implementation of a newly functional relationship among the PDT parameters are essential for predicting PDT outcomes and providing personalized precise treatment, and they are contributive to the development of PDT dosimetry.

Analgesic and Anxiolytic Effects of Gastrodin and Its Influences on Ferroptosis and Jejunal Microbiota in Complete Freund's Adjuvant-Injected Mice.

This study investigated the effects of gastrodin (GAS) on analgesic, anxiolytic, ferroptosis, and jejunal microbiota in chronic inflammatory pain mice. The chronic inflammatory pain model of C57BL/6J mice was established by hindpaw injection of complete Freund's adjuvant (CFA). After GAS treatment, thermal hyperalgesia test, mechanical allodynia test, elevated plus-maze (EPMT), and open-field test (OFT) were performed to assess the behavioral changes of pain and anxiety. mRNAs of FTHI, GPX4, HO-1, and PTGS2 and jejunal microbiota were measured by qPCR. In CFA-injected C57BL/6 mice, we found that the mechanical and thermal pain threshold were increased with treatment of GAS. In EPMT, the number of entries in open arms and retention times of open arms were increased by GAS. In the OFT, the time spent in the central area was also increased. Furthermore, GAS enhanced mRNA expressions of FTHI, GPX4, and HO-1 but decreased the expression of PTGS2 in a dose-dependent manner. GAS is effective in the treatment of mice chronic inflammatory pain and anxiety-like behaviors. It may be exhibits potential neuroprotective effects through inhibition of ferroptosis independently of the intestinal microbiota.

Solid lipid nanoparticles as an effective sodium aescinate delivery system: formulation and anti-inflammatory activity.

Sodium aescinate-loaded solid lipid nanoparticles were fabricated using a melt-emulsification and ultrasonication method. Based on mean particle size, polydispersity index, and encapsulation efficiency, orthogonal and Box-Behnken designs were applied to optimize solid lipid nanoparticles with single emulsification and double emulsification methods. The characterization of solid lipid nanoparticles was investigated by X-ray diffractometry, differential scanning calorimetry, and scanning electron microscopy. After optimization of sodium aescinate-loaded solid lipid nanoparticles with single emulsification, the particle size was 90.7 nm and encapsulation efficiency was 76.5%. The sodium aescinate-loaded solid lipid nanoparticles with double emulsification were negatively charged spherical particles with the size of 109.4 nm and encapsulation efficiency up to 86.6%. Both solid lipid nanoparticles with single emulsification and double emulsification exhibited sustained release for 12 h without an initial burst release. The results indicated that sodium aescinate-loaded solid lipid nanoparticles by double emulsification showed more drug loading and stability after reconstitution. The sodium aescinate-solid lipid nanoparticles with double emulsification demonstrated stronger anti-inflammatory activity, including paw edema and ear swelling in mice than that of free sodium aescinate. Therefore, solid lipid nanoparticles have great potential as an effective sodium aescinate delivery system for application in medicine.

PAM-free loop-mediated isothermal amplification coupled with CRISPR/Cas12a cleavage (Cas-PfLAMP) for rapid detection of rice pathogens.

Pathogenic disease is an important factor affecting rice growth, yield and quality, and the development and application of rapid diagnostic methods will contribute to the prevention and control of rice disease. Herein, we developed a novel protospacer adjacent motif (PAM)-free loop-mediated isothermal amplification (LAMP) assisted CRISPR/Cas12a cleavage (Cas-PfLAMP) assay for detection of three rice pathogens; Xanthomonas oryzae pv. Oryzae (XOO), rice stripe virus (RSV), and rice black-streaked dwarf virus (RBSDV). The Cas-PfLAMP assay showed high specificity due to doubly specific recognition of LAMP primer sets and FnCas12a/sgRNA, and high sensitivity down to 9 or 3 copies due to LAMP amplification and CRISPR/Cas12a trans cleavage activity. Furthermore, a visual on-spot Cas-PfLAMP platform was established for detection of rice pathogens by combining solid-phase nucleic acid extraction and a lateral flow strip (LFS) test. Analysis of rice leaf field samples confirmed the impressive performance of the Cas-PfLAMP platform, demonstrating its suitability for rapid (∼50 min) on-spot detection of rice diseases. The assay could also be extended to detection of other plant diseases, and other nucleic acid field tests.

The Study of the Transport Mechanism of Isorhynchophylline in Liver.

To investigate the transport mechanism of isorhynchophylline (IRN) by using the specific inhibitors of organic cation transporters (OCTs) and organic anion transporting polypeptides (OATPs) and attempt illustrate the metabolic mechanism of IRN in the liver. All animals were randomly divided into three groups: control group (only inject IRN), RIF group (inject IRN and rifampicin), and ADR group (inject IRN and adrenalone). The control group was injected with IRN via the caudal vein. The RIF group was injected with rifampicin (RIF) by gavage, and after 1 h, IRN was injected into the caudal vein. Similarly, the ADR group received adrenalone by the caudal vein, and after 0.5 h, IRN was injected into the caudal vein. Thereafter, blood samples were obtained by the heart punctures at 90 min, 180 min, and 300 min following drug administration. Rats were sacrificed at 300 min after drug administration; then, the liver tissue was harvested. The level of IRN was measured by using high-performance liquid chromatography (HPLC), and the Kp values were calculated. After RIF administration (OATPs inhibitors), the Kp value of IRN was slightly decreased when compared with that of the control group. Meanwhile, the Kp value of IRN was dramatically reduced compared to that of the control group following ADR administration (OCTs inhibitors). The results suggested that OCTs have mainly participated in the hepatic uptake process of IRN.

iPro-GAN: A novel model based on generative adversarial learning for identifying promoters and their strength.

BACKGROUND AND OBJECTIVE: Promoter is a component of the gene, which can specifically bind with RNA polymerase and determine where transcription starts, and also determine the transcription efficiency of the gene. Promoters can be divided into strong promoters and weak promoters because their structures and the interaction time interval are quite different. The functional variation of the promoter can lead to a variety of diseases. Therefore, identifying promoters and their strength is necessary and has important biological significance. A novel and promising model based on deep learning is proposed to achieve it. METHODS: In this work, we build a power model named iPro-GAN for identification of promoters and their strength. First, we collect benchmark datasets and independent datasets for training and testing. Then, Moran-based spatial auto-cross correlation method is used as feature extraction method. Finally, deep convolution generative adversarial network with 10-fold cross validation is applied for classifying. The first layer of the model is used to identify the promoter and the second layer is used to determine its type. RESULTS: On the benchmark data set, the accuracy of the first layer predictor is 93.15%, and the accuracy of the second layer predictor is 92.30%. On the independent data set, the accuracy of the first layer predictor is 86.77%, and the accuracy of the second layer predictor is 91.66%. In particular, breakthrough progress has been made in the identification of promoters' strength. CONCLUSIONS: These results are far higher than the existing best predictor, which indicate that our model is serviceable and practicable to identify promoters and their strength. Furthermore, the datasets and source codes are available from this link: https://github.com/Bovbene/iPro-GAN.

M6A-GSMS: Computational identification of N6-methyladenosine sites with GBDT and stacking learning in multiple species.

N6-methyladenosine (m6A) is one of the most abundant forms of RNA methylation modifications currently known. It involves a wide range of biological processes, including degradation, stability, alternative splicing, etc. Therefore, the development of convenient and efficient m6A prediction technologies are urgent. In this work, a novel predictor based on GBDT and stacking learning is developed to identify m6A sites, which is called M6A-GSMS. To achieve accurate prediction, we explore RNA sequence information from four aspects: correlation, structure, physicochemical properties and pseudo ribonucleic acid composition. After using the GBDT algorithm for feature selection, a stacking model is constructed by combining seven basic classifiers. Compared with other state-of-the-art methods, the results show that M6A-GSMS can obtain excellent performance for identifying the m6A sites. The prediction accuracy of A.thaliana, D.melanogaster, M.musculus, S.cerevisiae and Human reaches 88.4%, 60.8%, 80.5%, 92.4% and 61.8%, respectively. This method provides an effective prediction for the investigation of m6A sites. In addition, all the datasets and codes are currently available at https://github.com/Wang-Jinyue/M6A-GSMS.Communicated by Ramaswamy H. Sarma.

Soil aggregate stability and its response to overland flow in successive Eucalyptus plantations in subtropical China.

Soil aggregates constitute the basic units of the soil structure, and soil aggregate stability is an important indicator of soil erodibility. Successive planting of fast-growing plantations can change the erosion resistance of the soil under rainfall conditions. Pure Eucalyptus plantations in this study (first- to fourth-generations, i.e., I, II, III, and IV, respectively) were investigated. The stability and abrasion characteristics of soil aggregates were analyzed by the wet sieving method, the Le Bissonnais (LB) method and a slope flow scouring experiment. With an increase in successive generations of Eucalyptus, the soil bulk density increased, and the saturated water content, porosity, organic matter and Iron, Aluminum and Manganese (Fe-Al-Mn) oxide contents decreased. Additionally, the wet sieving results showed that the first- and second-generations had higher macroaggregate content than the fourth generation. The mean weight diameter (MWD) values decreased with the number of planting significantly. Based on fast wetting (FW), slow wetting (SW) and mechanical breakdown by shaking after pre-wetting (WS), the aggregate stability was ranked in a decreasing order as MWDSW > MWDWS > MWDFW. The relative dissipation index (RSI) and mechanical crushing index (RMI) increased with increasing number of planting generations. Aggregate stability was significantly negatively correlated with the soil bulk density and was significantly positively correlated with the organic matter and Fe-Mn oxide contents. The extent of aggregate abrasion (Wr/Wi) values and MWD values decreased with increasing scouring distance and slope gradient during the transport process. The α and Wr/Wi values of the scoured aggregates were significantly correlated with aggregate stability. Hence, with successive planting of Eucalyptus, the soil aggregate stability decreased, and the soil was prone to erosion when subjected to slope flow.

Substantially enhanced plasticity of bulk metallic glasses by densifying local atomic packing.

Introducing regions of looser atomic packing in bulk metallic glasses (BMGs) was reported to facilitate plastic deformation, rendering BMGs more ductile at room temperature. Here, we present a different alloy design approach, namely, doping the nonmetallic elements to form densely packed motifs. The enhanced structural fluctuations in Ti-, Zr- and Cu-based BMG systems leads to improved strength and renders these solutes' atomic neighborhoods more prone to plastic deformation at an increased critical stress. As a result, we simultaneously increased the compressive plasticity (from ∼8% to unfractured), strength (from ∼1725 to 1925 MPa) and toughness (from 87 ± 10 to 165 ± 15 MPa√m), as exemplarily demonstrated for the Zr20Cu20Hf20Ti20Ni20 BMG. Our study advances the understanding of the atomic-scale origin of structure-property relationships in amorphous solids and provides a new strategy for ductilizing BMG without sacrificing strength.

Heat Transfer Modeling of Oriented Sorghum Fibers Reinforced High-Density Polyethylene Film Composites during Hot-Pressing.

A one-dimensional heat transfer model was developed to simulate the heat transfer of oriented natural fiber reinforced thermoplastic composites during hot-pressing and provide guidance for determining appropriate hot-pressing parameters. The apparent heat capacity of thermoplastics due to the heat of fusion was included in the model, and the model was experimentally verified by monitoring the internal temperature during the hot-pressing process of oriented sorghum fiber reinforced high-density polyethylene (HDPE) film composites (OFPCs). The results showed that the apparent heat capacity of HDPE accurately described its heat fusion of melting and simplified the governing energy equations. The data predicted by the model were consistent with the experimental data. The thermal conduction efficiency increased with the mat density and HDPE content during hot-pressing, and a higher mat density resulted in a higher mat core temperature. The addition of HDPE delayed heat transfer, and the mat had a lower core temperature at a higher HDPE content after reaching the melting temperature of HDPE. Both the experimental and simulated data suggested that a higher temperature and/or a longer duration during the hot-pressing process should be used to fabricate OFPC as the HDPE content increases.