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Abstract Oxford Nanopore Technologies (ONT) offers ultrahigh-throughput multi-sample sequencing but only provides barcode kits that enable up to 96-sample multiplexing. We present TDFPS-Designer, a new toolkit for nanopore sequencing barcode design, which creates significantly more barcodes: 137 with a length of 20 base pairs, 410 at 24 bp, and 1779 at 30 bp, far surpassing ONT’s offerings. It includes GPU-based acceleration for ultra-fast demultiplexing and designs robust barcodes suitable for high-error ONT data. TDFPS-Designer outperforms current methods, improving the demultiplexing recall rate by 20% relative to Guppy, without a reduction in precision.

The autophagy–lysosome axis is an evolutionarily conserved intracellular degradation pathway which constitutes an important component of host innate immunity against microbial infections. Here, we show that African swine fever virus (ASFV), one of most devastating pathogens to the worldwide swine industry, can reshape the autophagy–lysosome axis by recruiting the critical lysosome membrane proteins (LAMP1 and LAMP2) to viral factories while inhibiting autophagic induction in macrophages. The screening of viral membrane proteins led to the identification of several ASFV membrane proteins, exemplified by viral protein pEP153R, that could significantly alter the subcellular localization of LAMP1/2 when expressed alone in transfected cells. Further analysis showed that pEP153R was also a component of viral factories and could induce endoplasmic reticulum (ER) retention of LAMP1/2, leading to the inhibition of the fusion of autophagosomes with lysosomes. Interestingly, the ASFV mutant lacking EP153R could still actively recruit LAMP into viral factories (VFs) and inhibit autophagic flux, indicating the existence of a functional redundancy of other viral proteins in the absence of pEP153R and highlighting the complexity of ASFV replication biology. Taken together, our results reveal novel information about the interplay of ASFV with the autophagy–lysosome axis and a previously unrecognized function of ASFV protein pEP153R in regulating the cellular autophagic process.

Abstract Osteopetrosis is an inherited metabolic disease, characterized by increased bone density and narrow marrow cavity. Patients with severe osteopetrosis exhibit abnormal bone brittleness, anemia, and infection complications, which commonly cause death within the first decade of life. Pathologically, osteopetrosis impairs not only the skeletal system, but also the hemopoietic and immune systems during development, while the underlying osteoimmunological mechanisms remain unclear. Osteoclastic mutations are regarded as the major causes of osteopetrosis, while osteoclast non-autonomous theories have been proposed in recent years with unclear underlying mechanisms. Retinoic acid (RA), the metabolite of Vitamin A, is an essential requirement for skeletal and hematopoietic development, through the activation of retinoic acid signaling. RA can relieve osteopetrosis symptoms in some animal models, while its effect on bone health is still controversial and the underlying mechanisms remain unclear. In this study, we constructed an osteoblast-specific inhibitory retinoic acid signaling mouse model and surprisingly found it mimicked the symptoms of osteopetrosis found in clinical cases: dwarfism, increased imperfectly-formed trabecular bone deposition with a reduced marrow cavity, thin cortical bone with a brittle skeleton, and hematopoietic and immune dysfunction. Micro-CT, the three-point bending test, and histological analysis drew a landscape of poor bone quality. Single-cell RNA sequencing (scRNA-seq) of the femur and RNA-seq of osteoblasts uncovered an atlas of pathological skeletal metabolism dysfunction in the mutant mice showing that osteogenesis was impaired in a cell-autonomous manner and osteoclastogenesis was impaired via osteoblast-osteoclast crosstalk. Moreover, scRNA-seq of bone marrow and flow cytometry of peripheral blood, spleen, and bone marrow uncovered pathology in the hematopoietic and immune systems in the mutant mice, mimicking human osteopetrosis. Results showed that hematopoietic progenitors and B lymphocyte differentiation were affected and the osteoblast-dominated cell crosstalk was impaired, which may result from transcriptional impairment of the ligands Pdgfd and Sema4d. In summary, we uncovered previously unreported pathogenesis of osteopetrosis-like disorder in mice with skeletal, hematopoietic, and immune system dysfunction, which was induced by the inhibition of retinoic acid signaling in osteoblasts, and sheds new insights into a potential treatment for osteopetrosis.

5-Aminolevulinic acid (ALA), as a novel plant growth regulator, is a critical precursor for the biosynthesis of porphyrin compounds in all organisms. Many studies have reported that exogenous ALA treatment could improve fruit sweetness. However, the mechanism by which ALA promotes the increase in sugar content in fruit remains unclear. In this study, we found that ALA significantly promoted sucrose accumulation and SPS (sucrose phosphate synthase) activity in peach fruit. At 14, 28, 42, 50 and 60 days after ALA treatment, sucrose content of fruit was increased by 23%, 43%, 37%, 40% and 16%, respectively, compared with control treatment, and SPS enzyme activity was increased by 21%, 28%, 47%, 37% and 29%, respectively. Correlation analysis showed that the sucrose content of peach fruit under ALA treatment was significantly positively correlated with SPS activity. Subsequently, bioinformatics was used to identify SPS gene family members in peach fruit, and it was found that there were four members of the PpSPS gene family, distributed on chromosomes 1, 7 and 8, named PpSPS1, PpSPS2, PpSPS3 and PpSPS4, respectively. The results of qRT-PCR showed that PpSPS2 and PpSPS3 were highly expressed in response to ALA during fruit development, and the expression of PpSPS2 was positively correlated with SPS activity and sucrose accumulation in peach fruit. The results of tobacco subcellular localization showed that PpSPS2 was mainly distributed in the cytoplasm and nucleus, while PpSPS3 was mainly distributed in the nucleus. The results of this study will lay the foundation for further study on the functions of PpSPS and the regulation of sugar metabolism during the development and ripening of peach fruit by ALA.

Abstract During early embryonic development, the transition from totipotency to pluripotency is a fundamental and critical process for proper development. However, the regulatory mechanisms governing this transition remain elusive. Here, we conducted a comprehensive genome-wide CRISPR/Cas9 screen to investigate the 2-cell-like cells (2CLCs) phenotype in mouse embryonic stem cells (mESCs). This effort led to the identification of ten regulators that play a pivotal role in determining cell fate during this transition. Notably, our study revealed Mdm2 as a significant negative regulator of 2CLCs, as perturbation of Mdm2 resulted in a higher proportion of 2CLCs. Mdm2 appears to influence cell fate through its impact on cell cycle progression and H3K27me3 epigenetic modifications. In summary, the results of our CRISPR/Cas9 screen have uncovered several genes with distinct functions in regulating totipotency and pluripotency at various levels, offering a valuable resource for potential targets in future molecular studies.

Background: Parkinson's disease (PD) is a common central neurodegenerative disease in middle-aged and elderly people. The progressive degeneration and death of dopaminergic neurons leads to insufficient dopamine (DA) neurotransmitters. Acupuncture and moxibustion can alleviate the aging of neurons. Therefore, studying the neuroprotective effects of electroacupuncture (EA) in PD mice is particularly important. Methods: Intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg) was used to establish a PD mouse model, and lipopolysaccharide (LPS) was used to induce microglia polarization. Western blotting, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), Nissl staining and immunohistochemistry were used to detect neuronal apoptosis and injury, α-syn expression and microglial accumulation in PD mice. In addition, the levels of inflammatory factors were determined using enzyme-linked immunosorbent assay (ELISA). Flow cytometry was used to detect the Ca2+ content. The fluorescein isothiocyanate (FITC) labeling method was used to assess glucose uptake. A reagent kit was used to detect glucose and lactate levels. Results: MPTP induced the selective loss of DA neurons in the SN of mice, altered Ca2+ homeostasis, and induced an inflammatory response. In addition, maintaining Ca2+ homeostasis depends on the activity of transient receptor potential channel 1 (TRPC1). EA therapy promotes TRPC1 expression, which has a negative regulatory effect on sodium–glucose cotransporter 1 (SGLT1). Under the action of EA, TRPC1 protein expression increased, Ca2+ concentrations increased, and the effect of SGLT1 was inhibited, thereby facilitating glucose metabolism, blocking the activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, restraining M1 polarization of microglia, and alleviating the PD process. Conclusion: EA promotes TRPC1/Ca2+ pathway activation, inhibits SGLT1-mediated regulation of glucose metabolism and PI3K/AKT pathway activation, inhibits microglial M1 polarization, and alleviates PD.

Many different factors, such as species traits, socio-economic factors, geographical and environmental factors, can lead to specimen collection preference. This study aims to determine whether grassland specimen collection in China is preferred by species traits (i.e., plant height, flowering and fruiting period), environmental range (i.e., the temperature and precipitation range) and geographical range (i.e., distribution range and altitudinal range). Ordinary least squares models and phylogenetic generalized linear mixed models were used to analyze the relationships between specimen number and the explanatory variables. Random Forest models were then used to find the most parsimonious multivariate model. The results showed that interannual variation in specimen number between 1900 and 2020 was considerable. Specimen number of these species in southeast China was notably lower than that in northwest China. Environmental range and geographical range of species had significant positive correlations with specimen number. In addition, there were relatively weak but significant associations between specimen number and species trait (i.e., plant height and flowering and fruiting period). Random Forest models indicated that distribution range was the most important variable, followed by flowering and fruiting period, and altitudinal range. These findings suggest that future floristic surveys should pay more attention to species with small geographical range, narrow environmental range, short plant height, and short flowering and fruiting period. The correction of specimen collection preference will also make the results of species distribution model, species evolution and other works based on specimen data more accurate.

The production of reactive oxygen species (ROS) is susceptible to external excitation or insufficient supply of related participants (e.g., hydrogen peroxide (H2O2) and sensitizer), liming ROS-driven tumor treatment. Additionally, the lysosomal retention effect severely hinders the utilization of ROS-based nanosystems and severely restricted the therapeutic effect of tumors. Therefore, first reported herein an intelligent nanocatalyst, TCPP-Cu@MnOx ((MnII)1(MnIII)2.1(MnIV)2.6O9.35), and proposed a programmed ROS amplification strategy to treat tumors. Initially, the acidity-unlocked nanocatalyst was voluntarily triggered to generate abundant singlet oxygen (1O2) to mediate acid lysosomal ablation to assist nanocatalyst escape and partially induce lysosomal death, a stage known as lysosome-driven therapy. More unexpectedly, the high-yielding production of 1O2 in acid condition (pH 5.0) was showed compared to neutral media (pH 7.4), with a difference of about 204 times between the two. Subsequently, the escaping nanocatalyst further activated H2O2-mediated 1O2 and hydroxyl radical (•OH) generation and glutathione (GSH) consumption for further accentuation tumor therapy efficiency, which is based on the Fenton-like reaction and Russell reaction mechanisms. Therefore, in this system, a program-activatable TCPP-Cu@MnOx nanocatalyst, was proposed to efficiently destruct organelle-lysosome via 1O2 inducing, and stimulated H2O2 conversion into highly toxic 1O2 and •OH in cytoplasm, constituting an attractive method to overcome limitations of current ROS treatment.

Triple negative breast cancer (TNBC) as the most aggressive molecular subtype of breast cancer is characterized by high cancer cell proliferation and poor patient prognosis. Abnormal lipid metabolism contributes to the malignant process of cancers. Study observed significantly enhanced cholesterol biosynthesis in TNBC. However, the mechanisms underlying the abnormal increase of cholesterol biosynthesis in TNBC are still unclear. Hence, we identified a member of the serine/threonine protein kinase family PKMYT1 as a key driver of cholesterol synthesis in TNBC cells. Aberrantly high-expressed PKMYT1 in TNBC was indicative of unfavorable prognostic outcomes. In addition, PKMYT1 promoted sterol regulatory element-binding protein 2 (SREBP2)-mediated expression of enzymes related to cholesterol biosynthesis through activating the TNF/ TNF receptor-associated factor 1 (TRAF1)/AKT pathway. Notably, downregulation of PKMYT1 significantly inhibited the feedback upregulation of statin-mediated cholesterol biosynthesis, whereas knockdown of PKMYT1 promoted the drug sensitivity of atorvastatin in TNBC cells. Overall, our study revealed a novel function of PKMYT1 in TNBC cholesterol biosynthesis, providing a new target for targeting tumor metabolic reprogramming in the cancer.

E-skin is a bionic device with flexible and intelligent sensing ability that can mimic the touch, temperature, pressure, and other sensing functions of human skin. Because of its flexibility, breathability, biocompatibility, and other characteristics, it is widely used in health management, personalized medicine, disease prevention, and other pan-health fields. With the proposal of new sensing principles, the development of advanced functional materials, the development of microfabrication technology, and the integration of artificial intelligence and algorithms, e-skin has developed rapidly. This paper focuses on the characteristics, fundamentals, new principles, key technologies, and their specific applications in health management, exercise monitoring, emotion and heart monitoring, etc. that advanced e-skin needs to have in the healthcare field. In addition, its significance in infant and child care, elderly care, and assistive devices for the disabled is analyzed. Finally, the current challenges and future directions of the field are discussed. It is expected that this review will generate great interest and inspiration for the development and improvement of novel e-skins and advanced health monitoring systems.

A narrow genetic basis limits further the improvement of modern Gossypium hirsutum cultivar. The abundant genetic diversity of wild species provides available resources to solve this dilemma. In the present study, a chromosome segment substitution line (CSSL) population including 553 individuals was established using G. darwinii accession 5-7 as the donor parent and G. hirsutum cultivar CCRI35 as the recipient parent. After constructing a high-density genetic map with the BC1 population, the genotype and phenotype of the CSSL population were investigated. A total of 235 QTLs, including 104 QTLs for fiber-related traits and 132 QTLs for seed-related traits, were identified from four environments. Among these QTLs, twenty-seven QTLs were identified in two or more environments, and twenty-five QTL clusters consisted of 114 QTLs. Moreover, we identified three candidate genes for three stable QTLs, including GH_A01G1096 (ARF5) and GH_A10G0141 (PDF2) for lint percentage, and GH_D01G0047 (KCS4) for seed index or oil content. These results pave way for understanding the molecular regulatory mechanism of fiber and seed development and would provide valuable information for marker-assisted genetic improvement in cotton.

Contrast-induced acute kidney injury (CI-AKI) is the third leading cause of hospital-acquired acute kidney injury. Cellular senescence is associated with CI-AKI. P16INK4a (p16) is a cell cycle regulator and link to aging and senescence. We found that the expression of p16 was elevated in CI-AKI renal tissues, however its role in CI-AKI remains insufficiently understood. In this study, we used p16 knockout (p16KO) mice and wild-type (WT) littermates to establish CI-AKI mice model to elucidate the impact of p16 on CI-AKI. The results showed that serum creatinine (SCr), blood urea nitrogen (BUN), and serum neutrophil gelatinase-associated lipocalin (NGAL) levels were markedly reduced in p16KO CI-AKI mice. Both immunohistochemistry and western blot analyses confirmed that p16 knockout alleviated renal cell apoptosis. Furthermore, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) were attenuated by downregulating NLRP3 and NF-κB inflammasomes. Additionally, ROS levels were diminished via activating Nrf2/Keap-1 pathway in p16KO CI-AKI mice. Collectively, our findings suggest that p16 deletion exerts protective effects against apoptosis, inflammation, and oxidative stress in CI-AKI mice model, p16 deletion might be a potential therapeutic strategy for ameliorating CI-AKI.

Antibody leads must fulfill multiple desirable properties to be clinical candidates. Primarily due to the low throughput in the experimental procedure, the need for such multi-property optimization causes the bottleneck in preclinical antibody discovery and development, because addressing one issue usually causes another. We developed a reinforcement learning (RL) method, named AB-Gen, for antibody library design using a generative pre-trained transformer (GPT) as the policy network of the RL agent. We showed that this model can learn the antibody space of heavy chain complementarity determining region 3 (CDRH3) and generate sequences with similar property distributions. Besides, when using human epidermal growth factor receptor-2 (HER2) as the target, the agent model of AB-Gen was able to generate novel CDRH3 sequences that fulfill multi-property constraints. Totally, 509 generated sequences were able to pass all property filters, and three highly conserved residues were identified. The importance of these residues was further demonstrated by molecular dynamics simulations, consolidating that the agent model was capable of grasping important information in this complex optimization task. Overall, the AB-Gen method is able to design novel antibody sequences with an improved success rate than the traditional propose-then-filter approach. It has the potential to be used in practical antibody design, thus empowering the antibody discovery and development process. The source code of AB-Gen is freely available at Zenodo (https://doi.org/10.5281/zenodo.7657016) and BioCode (https://ngdc.cncb.ac.cn/biocode/tools/BT007341).

Abstract DNA barcodes enable Oxford Nanopore sequencing to sequence multiple barcoded DNA samples on a single flow cell. DNA sequences with the same barcode need to be grouped together through demultiplexing. As the number of samples increases, accurate demultiplexing becomes difficult. We introduce HycDemux, which incorporates a GPU-parallelized hybrid clustering algorithm that uses nanopore signals and DNA sequences for accurate data clustering, alongside a voting-based module to finalize the demultiplexing results. Comprehensive experiments demonstrate that our approach outperforms unsupervised tools in short sequence fragment clustering and performs more robustly than current state-of-the-art demultiplexing tools for complex multi-sample sequencing data.

Abstract Repetitive DNA sequences playing critical roles in driving evolution, inducing variation, and regulating gene expression. In this review, we summarized the definition, arrangement, and structural characteristics of repeats. Besides, we introduced diverse biological functions of repeats and reviewed existing methods for automatic repeat detection, classification, and masking. Finally, we analyzed the type, structure, and regulation of repeats in the human genome and their role in the induction of complex diseases. We believe that this review will facilitate a comprehensive understanding of repeats and provide guidance for repeat annotation and in-depth exploration of its association with human diseases.

Abstract Background Single-cell RNA sequencing (scRNA-seq) has revolutionized the transcriptomics field by advancing analyses from tissue-level to cell-level resolution. Despite the great advances in the development of computational methods for various steps of scRNA-seq analyses, one major bottleneck of the existing technologies remains in identifying the molecular relationship between disease phenotype and cell subpopulations, where “disease phenotype” refers to the clinical characteristics of each patient sample, and subpopulation refer to groups of single cells, which often do not correspond to clusters identified by standard single-cell clustering analysis. Here, we present PACSI, a method aimed at distinguishing cell subpopulations associated with disease phenotypes at the single-cell level. Results PACSI takes advantage of the topological properties of biological networks to introduce a proximity-based measure that quantifies the correlation between each cell and the disease phenotype of interest. Applied to simulated data and four case studies, PACSI accurately identified cells associated with disease phenotypes such as diagnosis, prognosis, and response to immunotherapy. In addition, we demonstrated that PACSI can also be applied to spatial transcriptomics data and successfully label spots that are associated with poor survival of breast carcinoma. Conclusions PACSI is an efficient method to identify cell subpopulations associated with disease phenotypes. Our research shows that it has a broad range of applications in revealing mechanistic and clinical insights of diseases.

Summary: The homeostatic regulation of serine palmitoyltransferase (SPT) activity in yeast involves N-terminal phosphorylation of Orm proteins, while higher eukaryotes lack these phosphorylation sites. Although recent studies have indicated a conserved ceramide-mediated feedback inhibition of the SPT-ORM/ORMDL complex in higher eukaryotes, its conservation and relationship with phosphorylation regulation in yeast remain unclear. Here, we determine the structure of the yeast SPT-Orm2 complex in a dephosphomimetic state and identify an evolutionarily conserved ceramide-sensing site. Ceramide stabilizes the dephosphomimetic Orm2 in an inhibitory conformation, facilitated by an intramolecular β-sheet between the N- and C-terminal segments of Orm2. Moreover, we find that a phosphomimetic mutant of Orm2, positioned adjacent to its intramolecular β-sheet, destabilizes the inhibitory conformation of Orm2. Taken together, our findings suggest that both Orm dephosphorylation and ceramide binding are crucial for suppressing SPT activity in yeast. This highlights a distinctive regulatory mechanism in yeast involving the collaborative actions of phosphorylation and ceramide.

Summary: Macrophages are phenotypically and functionally diverse in the tumor microenvironment (TME). However, how to remodel macrophages with a protumor phenotype and how to manipulate them for therapeutic purposes remain to be explored. Here, we show that in the TME, RARγ is downregulated in macrophages, and its expression correlates with poor prognosis in patients with colorectal cancer (CRC). In macrophages, RARγ interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), which prevents TRAF6 oligomerization and autoubiquitination, leading to inhibition of nuclear factor κB signaling. However, tumor-derived lactate fuels H3K18 lactylation to prohibit RARγ gene transcription in macrophages, consequently enhancing interleukin-6 (IL-6) levels in the TME and endowing macrophages with tumor-promoting functions via activation of signal transducer and activator of transcription 3 (STAT3) signaling in CRC cells. We identified that nordihydroguaiaretic acid (NDGA) exerts effective antitumor action by directly binding to RARγ to inhibit TRAF6-IL-6-STAT3 signaling. This study unravels lactate-driven macrophage function remodeling by inhibition of RARγ expression and highlights NDGA as a candidate compound for treating CRC.

This study retrospectively analyzes the immune and inflammatory indices of patients with lacrimal-gland benign lymphoepithelial lesion (LGBLEL) in order to screen out reference indices with higher diagnostic efficacy. The medical histories of patients whose diagnoses of LGBLEL and primary lacrimal prolapse were confirmed by pathology between August 2010 and August 2019 were collected. In the LGBLEL group, the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, rheumatoid factor (RF), and immunoglobulins G, G1, G2, and G4 (IgG, IgG1, IgG2, IgG4) were higher (p < 0.05) and the expression level of C3 was lower (p < 0.05) compared to the lacrimal-gland prolapse group. Multivariate logistic regression analysis showed that IgG4, IgG, and C3 were independent risk factors for predicting LGBLEL occurrence (p < 0.05). The area under the receiver operating characteristic (ROC) curve of the prediction model (IgG4+IgG+C3) was 0.926, which was significantly better than that of any single factor. Therefore, serum levels of IgG4, IgG, and C3 were independent risk factors for predicting the occurrence of LGBLEL, and the combined diagnostic efficacy of IgG4+IgG+C3 was the highest.

The periosteum plays a critical role in bone repair and is significantly influenced by the surrounding immune microenvironment. In this study, we employed 10× single-cell RNA sequencing to create a detailed cellular atlas of the swine cranial periosteum, highlighting the cellular dynamics and interactions essential for cranial bone injury repair. We noted that such injuries lead to an increase in M2 macrophages, which are key in modulating the periosteum’s immune response and driving the bone regeneration process. These macrophages actively recruit periosteal stromal cells (PSCs) by secreting Neuregulin 1 (NRG1), a crucial factor in initiating bone regeneration. This recruitment process emphasizes the critical role of PSCs in effective bone repair, positioning them as primary targets for therapeutic interventions. Our results indicate that enhancing the interaction between M2 macrophages and PSCs could significantly improve the outcomes of treatments aimed at cranial bone repair and regeneration.

Timely and accurately detecting personal protective equipment (PPE) usage among workers is essential for substation safety management. However, traditional algorithms encounter difficulties in substations due to issues such as varying target scales, intricate backgrounds, and many model parameters. Therefore, this paper proposes MEAG-YOLO, an enhanced PPE detection model for substations built upon YOLOv8n. First, the model incorporates the Multi-Scale Channel Attention (MSCA) module to improve feature extraction. Second, it newly designs the EC2f structure with one-dimensional convolution to enhance feature fusion efficiency. Additionally, the study optimizes the Path Aggregation Network (PANet) structure to improve feature learning and the fusion of multi-scale targets. Finally, the GhostConv module is integrated to optimize convolution operations and reduce computational complexity. The experimental results show that MEAG-YOLO achieves a 2.4% increase in precision compared to YOLOv8n, with a 7.3% reduction in FLOPs. These findings suggest that MEAG-YOLO is effective in identifying PPE in complex substation scenarios, contributing to the development of smart grid systems.

A novel nanotechnology-based drug delivery system (DDS) targeted at pancreatic cancer cells was developed, characterized, and tested. The system consisted of liposomes as carriers, an anticancer drug (paclitaxel) as a chemotherapeutic agent, and a modified synthetic somatostatin analog, 5-pentacarbonyl-octreotide, a ligand for somatostatin receptor 2 (SSTR2), as a targeting moiety for pancreatic cancer. The cellular internalization, cytotoxicity, and antitumor activity of the DDS were tested in vitro using human pancreatic ductal adenocarcinoma (PDAC) cells with different expressions of the targeted SSTR2 receptors, and in vivo on immunodeficient mice bearing human PDAC xenografts. The targeted drug delivery system containing paclitaxel exhibited significantly enhanced cytotoxicity compared to non-targeted DDS, and this efficacy was directly related to the levels of SSTR2 expression. It was found that octreotide-targeted DDS proved exceptionally effective in suppressing the growth of PDAC tumors. This study underscores the potential of octreotide-targeted liposomal delivery systems to enhance the therapeutic outcomes for PDAC compared with non-targeted liposomal DDS and Paclitaxel-Cremophor® EL, suggesting a promising avenue for future cancer therapy innovations.

In cyanobacteria and chloroplasts (in algae and plants), ATP synthase plays a pivotal role as a photosynthetic membrane complex responsible for producing ATP from adenosine diphosphate and inorganic phosphate, utilizing a proton motive force gradient induced by photosynthesis. These two ATP synthases exhibit similarities in gene organization, amino acid sequences of subunits, structure, and functional mechanisms, suggesting that cyanobacterial ATP synthase is probably the evolutionary precursor to chloroplast ATP synthase. In this review, we explore the precise synthesis and assembly of ATP synthase subunits to address the uneven stoichiometry within the complex during transcription, translation, and assembly processes. We also compare the regulatory strategies governing ATP synthase activity to meet varying energy demands in cyanobacteria and chloroplasts amid fluctuating natural environments. Furthermore, we delve into the role of ATP synthase in stress tolerance and photosynthetic carbon fixation efficiency in oxygenic photosynthetic organisms (OPsOs), along with the current researches on modifying ATP synthase to enhance carbon fixation efficiency under stress conditions. This review aims to offer theoretical insights and serve as a reference for understanding the functional mechanisms of ATP synthase, sparking innovative ideas for enhancing photosynthetic carbon fixation efficiency by utilizing ATP synthase as an effective module in OPsOs.

Favipiravir (FP) and ebselen (EB) belong to a diverse class of antiviral drugs known for their significant efficacy in treating various viral infections. Utilizing molecular dynamics (MD) simulations, machine learning, and van der Waals density functional theory, we accurately elucidate the binding properties of these antiviral drugs on a phosphorene single-layer. To further investigate these characteristics, this study employs four distinct machine learning models—Random Forest, Gradient Boosting, XGBoost, and CatBoost. The Hamiltonian of antiviral molecules within a monolayer of phosphorene is appropriately trained. The key aspect of utilizing machine learning (ML) in drug design revolves around training models that are efficient and precise in approximating density functional theory (DFT). Furthermore, the study employs SHAP (SHapley Additive exPlanations) to elucidate model predictions, providing insights into the contribution of each feature. To explore the interaction characteristics and thermodynamic properties of the hybrid drug, we employ molecular dynamics and DFT calculations in a vacuum interface. Our findings suggest that this functionalized 2D complex exhibits robust thermostability, indicating its potential as an effective and enabled entity. The observed variations in free energy at different surface charges and temperatures suggest the adsorption potential of FP and EB molecules from the surrounding environment.

This review critically evaluates advancements in multifunctional hydrogels, particularly focusing on their applications in osteoarthritis (OA) therapy. As research evolves from traditional natural materials, there is a significant shift towards synthetic and composite hydrogels, known for their superior mechanical properties and enhanced biodegradability. This review spotlights novel applications such as injectable hydrogels, microneedle technology, and responsive hydrogels, which have revolutionized OA treatment through targeted and efficient therapeutic delivery. Moreover, it discusses innovative hydrogel materials, including protein-based and superlubricating hydrogels, for their potential to reduce joint friction and inflammation. The integration of bioactive compounds within hydrogels to augment therapeutic efficacy is also examined. Furthermore, the review anticipates continued technological advancements and a deeper understanding of hydrogel-based OA therapies. It emphasizes the potential of hydrogels to provide tailored, minimally invasive treatments, thus highlighting their critical role in advancing the dynamic field of biomaterial science for OA management.

Histone post-translational modification is one of the main mechanisms of epigenetic regulation, which plays a crucial role in the control of gene expression and various biological processes. However, whether or not it affects fungal virulence in Sclerotinia sclerotiorum is not clear. In this study, we identified and cloned the histone methyltransferase Defective in methylation 5 (Dim5) in S. sclerotiorum, which encodes a protein containing a typical SET domain. SsDim5 was found to be dynamically expressed during infection. Knockout experiment demonstrated that deletion of SsDim5 reduced the virulence in Ssdim5-1/Ssdim5-2 mutant strains, accompanied by a significant decrease in H3K9 trimethylation levels. Transcriptomic analysis further revealed the downregulation of genes associated with mycotoxins biosynthesis in SsDim5 deletion mutants. Additionally, the absence of SsDim5 affected the fungus’s response to oxidative and osmotic, as well as cellular integrity. Together, our results indicate that the H3K9 methyltransferase SsDim5 is essential for H3K9 trimethylation, regulating fungal virulence throug mycotoxins biosynthesis, and the response to environmental stresses in S. sclerotiorum.

In recent years, the Sanjiang Plain has experienced drastic human activities, which have dramatically changed its ecological environment. Soil microorganisms can sensitively respond to changes in soil quality as well as ecosystem function. In this study, we investigated the changes in soil microbial community diversity and composition of three typical land use types (forest, wetland and cropland) in the Sanjiang Plain using phospholipid fatty acid analysis (PLFA) technology, and 114 different PLFA compounds were identified. The results showed that the soil physicochemical properties changed significantly (p < 0.05) among the different land use types; the microbial diversity and abundance in cropland soil were lower than those of the other two land use types. Soil pH, soil water content, total organic carbon and available nitrogen were the main soil physico-chemical properties driving the composition of the soil microbial community. Our results indicate that the soil microbial community response to the three different habitats is complex, and provide ideas for the mechanism by which land use changes in the Sanjiang Plain affect the structure of soil microbial communities, as well as a theoretical basis for the future management and sustainable use of the Sanjiang plain, in the northeast of China.

The high-speed freight electric multiple unit (EMU) is one of the important development directions for railway freight transportation. To investigate the bridge radiation noise induced by the freight EMU, a noise prediction model consisting of the containers–vehicle–track–bridge dynamic model, finite element model, and boundary element model are established and validated. Through simulation, the bridge radiation noise under different train loading conditions is compared, and the noise radiation mechanism is revealed. Moreover, the noise reduction effect of the noise wall is studied, and the influences of noise wall heights and sound absorption materials are investigated. Results indicate that the bridge sound power and the sound pressure levels (SPLs) of near-field points increase slightly with train loads in the frequency range below 20 Hz and above 125 Hz, with a maximum increase of about 6.8 dB. The structure resonance, intense local vibration, and high acoustic radiation efficiency cause strong bridge radiation noise. The noise wall can realize a good overall noise reduction effect in the sound shadow zone; nevertheless, SPLs increased in areas between the bridge and the noise wall. The ground reflection affects the superposition of transmitted, reflected, and diffracted sound waves, which causes nonlinear relationships of noise reduction effects with the noise wall height. From the perspective of human hearing sensitivity, the loudness levels of typical field points increase with the frequency in the range of 20~80 Hz, and SPLs below 25 Hz are less than the threshold of hearing. Setting the noise wall can effectively reduce the loudness levels, and the reduction effect increases with the noise wall height.

To uncover the internal mechanisms of various drought stress intensities affecting the soluble sugar content in organs and its regulation by endogenous abscisic acid (ABA), we selected the saplings of Platycladus orientalis, a typical tree species in the Beijing area, as our research subject. We investigated the correlation between tree soluble sugars and endogenous ABA in the organs (comprised of leaf, branch, stem, coarse root, and fine root) under two water treatments. One water treatment was defined as T1, which stopped watering until the potted soil volumetric water content (SWC) reached the wilting coefficient and then rewatered the sapling. The other water treatment, named T2, replenished 95% of the total water loss of one potted sapling every day and irrigated the above-mentioned sapling after its SWC reached the wilt coefficients. The results revealed that (1) the photosynthetic physiological parameters of P. orientalis were significantly reduced (p < 0.05) under fast and slow drought processes. The photosynthetic physiological parameters of P. orientalis in the fast drought–rehydration treatment group recovered faster relative to the slow drought–rehydration treatment group. (2) The fast and slow drought treatments significantly (p < 0.05) increased the ABA and soluble sugar contents in all organs. The roots of the P. orientalis exhibited higher sensitivity in ABA and soluble sugar content to changes in soil moisture dynamics compared to other organs. (3) ABA and soluble sugar content of P. orientalis showed a significant positive correlation (p < 0.05) under fast and slow drought conditions. During the rehydration stage, the two were significantly correlated in the T2 treatment (p < 0.05). In summary, soil drought rhythms significantly affected the photosynthetic parameters, organ ABA, and soluble sugar content of P. orientalis. This study elucidates the adaptive mechanisms of P. orientalis plants to drought and rehydration under the above-mentioned two water drought treatments, offering theoretical insights for selecting and cultivating drought-tolerant tree species.

Summary: EGFRT790M mutation causes resistance to the first-generation tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). However, the therapeutic options for sensitizing first TKIs and delaying the emergence of EGFRT790M mutant are limited. In this study, we show that quercetin directly binds with glucose-6-phosphate dehydrogenase (G6PD) and inhibits its enzymatic activity through competitively abrogating NADP+ binding in the catalytic domain. This inhibition subsequently reduces intracellular NADPH levels, resulting in insufficient substrate for methionine reductase A (MsrA) to reduce M790 oxidization of EGFRT790M and inducing the degradation of EGFRT790M. Quercetin synergistically enhances the therapeutic effect of gefitinib on EGFRT790M-harboring NSCLCs and delays the acquisition of the EGFRT790M mutation. Notably, high levels of G6PD expression are correlated with poor prognosis and the emerging time of EGFRT790M mutation in patients with NSCLC. These findings highlight the potential implication of quercetin in overcoming EGFRT790M-driven TKI resistance by directly targeting G6PD.

Dental mesenchymal stem cells (DMSCs) are multipotent progenitor cells that can differentiate into multiple lineages including odontoblasts, osteoblasts, chondrocytes, neural cells, myocytes, cardiomyocytes, adipocytes, endothelial cells, melanocytes, and hepatocytes. Odontoblastic differentiation of DMSCs is pivotal in dentinogenesis, a delicate and dynamic process regulated at the molecular level by signaling pathways, transcription factors, and posttranscriptional and epigenetic regulation. Mutations or dysregulation of related genes may contribute to genetic diseases with dentin defects caused by impaired odontoblastic differentiation, including tricho-dento-osseous (TDO) syndrome, X-linked hypophosphatemic rickets (XLH), Raine syndrome (RS), hypophosphatasia (HPP), Schimke immuno-osseous dysplasia (SIOD), and Elsahy-Waters syndrome (EWS). Herein, recent progress in the molecular regulation of the odontoblastic differentiation of DMSCs is summarized. In addition, genetic syndromes associated with disorders of odontoblastic differentiation of DMSCs are discussed. An improved understanding of the molecular regulation and related genetic syndromes may help clinicians better understand the etiology and pathogenesis of dentin lesions in systematic diseases and identify novel treatment targets.

Background Fusarium head blight (FHB) is a disease affecting wheat spikes caused by some Fusarium species and leads to cases of severe yield reduction and seed contamination. Identifying resistance genes/QTLs from wheat germplasm may help to improve FHB resistance in wheat production. Methods Our study evaluated 205 elite winter wheat cultivars for FHB resistance. A high-density 90K SNP array was used for genotyping the panel. A genome-wide association study (GWAS) from cultivars from three different environments was performed using a mixed linear model (MLM). Results Sixty-six significant marker-trait associations (MTAs) were identified (P

The accurate annotation of transcription start sites (TSSs) and their usage are critical for the mechanistic understanding of gene regulation in different biological contexts. To fulfill this, specific high-throughput experimental technologies have been developed to capture TSSs in a genome-wide manner, and various computational tools have also been developed for in silico prediction of TSSs solely based on genomic sequences. Most of these computational tools cast the problem as a binary classification task on a balanced dataset, thus resulting in drastic false positive predictions when applied on the genome scale. Here, we present DeeReCT-TSS, a deep learning-based method that is capable of identifying TSSs across the whole genome based on both DNA sequence and conventional RNA sequencing data. We show that by effectively incorporating these two sources of information, DeeReCT-TSS significantly outperforms other solely sequence-based methods on the precise annotation of TSSs used in different cell types. Furthermore, we develop a meta-learning-based extension for simultaneous TSS annotations on 10 cell types, which enables the identification of cell type-specific TSSs. Finally, we demonstrate the high precision of DeeReCT-TSS on two independent datasets by correlating our predicted TSSs with experimentally defined TSS chromatin states. The source code for DeeReCT-TSS is available at https://github.com/JoshuaChou2018/DeeReCT-TSS_release and https://ngdc.cncb.ac.cn/biocode/tools/BT007316.

Abstract Background Interspecific postzygotic reproduction isolation results from large genetic divergence between the subgenomes of established hybrids. Polyploidization immediately after hybridization may reset patterns of homologous chromosome pairing and ameliorate deleterious genomic incompatibility between the subgenomes of distinct parental species in plants and animals. However, the observation that polyploidy is less common in vertebrates raises the question of which factors restrict its emergence. Here, we perform analyses of the genome, epigenome, and gene expression in the nascent allotetraploid lineage (2.95 Gb) derived from the intergeneric hybridization of female goldfish (Carassius auratus, 1.49 Gb) and male common carp (Cyprinus carpio, 1.42 Gb), to shed light on the changes leading to the stabilization of hybrids. Results We firstly identify the two subgenomes derived from the parental lineages of goldfish and common carp. We find variable unequal homoeologous recombination in somatic and germ cells of the intergeneric F1 and allotetraploid (F22 and F24) populations, reflecting high plasticity between the subgenomes, and rapidly varying copy numbers between the homoeolog genes. We also find dynamic changes in transposable elements accompanied by genome merger and duplication in the allotetraploid lineage. Finally, we observe the gradual decreases in cis-regulatory effects and increases in trans-regulatory effects along with the allotetraploidization, which contribute to increases in the symmetrical homoeologous expression in different tissues and developmental stages, especially in early embryogenesis. Conclusions Our results reveal a series of changes in transposable elements, unequal homoeologous recombination, cis- and trans-regulations (e.g. DNA methylation), and homoeologous expression, suggesting their potential roles in mediating adaptive stabilization of regulatory systems of the nascent allotetraploid lineage. The symmetrical subgenomes and homoeologous expression provide a novel way of balancing genetic incompatibilities, providing a new insight into the early stages of allopolyploidization in vertebrate evolution.

Abstract Pickering emulsions have been widely used for biphasic catalysis in the past decade. However, it remains a great challenge to achieve simple product collection and enzyme recovery. Poly(N‐isopropylacrylamide) (PNIPAM)‐based microgels can endow Pickering emulsions with stimuli‐responsiveness, while most microgel‐stabilized emulsions are oil‐in‐water (O/W) type and not ideal for interfacial catalysis. Besides, altering temperature or pH value for demulsification is time‐ and energy‐consuming and may cause irreversible deactivation of enzymes. In this work, inverse water‐in‐oil (W/O) Pickering emulsions were formed using hexanoic acid‐swollen microgels as the sole emulsifiers. When lipase was added in the water phase, stable oil‐in‐water‐in‐oil (O/W/O) Pickering double emulsions could be formed through one‐step emulsification, owing to the synergistic effect of the hydrophobic microgels and hydrophilic lipase at the interface. Compared with other biphasic systems, such double emulsion systems represent a desirable platform for highly efficient biodiesel production because of the ultra‐high interfacial areas and fast mass transport between two phases. More importantly, the switchable transition between hydrophobicity/hydrophilicity of microgels is controlled by the catalytic reaction. Therefore, double emulsions demulsify spontaneously when substrates are used up without the need for energy input or loss of enzymatic activity, enabling the facile collection of products and demonstrating the excellent recyclability of the biphasic catalysis system.

Several TMED protein family members are overexpressed in malignant tumors and associated with tumor progression. TMED1 belongs to the TMED protein family and is involved in protein vesicular trafficking. However, the expression level and biological role of TMED1 in colorectal cancer (CRC) have yet to be fully elucidated. In this study, the integration of patient survival and multi-omics data (immunohistochemical staining, transcriptomics, and proteomics) revealed that the highly expressed TMED1 was related to the poor prognosis in CRC. Crystal violet staining indicated the cell growth was reduced after knocking down TMED1. Moreover, the flow cytometry results showed that TMED1 knockdown could increase cell apoptosis. The expression of TMED1 was positively correlated with other TMED family members (TMED2, TMED4, TMED9, and TMED10) in CRC, and the protein–protein interaction network suggested its potential impact on immune regulation. Furthermore, TMED1 expression was positively associated with the infiltration levels of regulatory T cells (Tregs), cancer-associated fibroblasts (CAFs), and endothelial cells and negatively correlated with the infiltration levels of CD4+ T cells, CD8+ T cells, and B cells. At last, the CTRP and GDSC datasets on the GSCA platform were used to analyze the relationship between TMED1 expression and drug sensitivity (IC50). The result found that the elevation of TMED1 was positively correlated with IC50 and implied it could increase the drug resistance of cancer cells. This research revealed that TMED1 is a novel prognostic biomarker in CRC and provided a valuable strategy for analyzing potential therapeutic targets of malignant tumors.

Cancer-associated muscle wasting is a widespread syndrome in people with cancer and is characterized by weight loss and muscle atrophy, leading to increased morbidity and mortality. However, the tumor-derived factors that affect the development of muscle wasting and the mechanism by which they act remain unknown. To address this knowledge gap, we aimed to delineate differences in tumor molecular characteristics (especially secretion characteristics) between patients with and without sarcopenia across 10 tumor types from The Cancer Genome Atlas (TCGA). We integrated radiological characteristics from CT scans of TCGA cancer patients, which allowed us to calculate skeletal muscle area (SMA) to confirm sarcopenia. We combined TCGA and GTEx (The Genotype-Tissue Expression) data to analyze upregulated secretory genes in 10 tumor types compared with normal tissues. Upregulated secretory genes in the tumor microenvironment and their relation to SMA were analyzed to identify potential muscle wasting biomarkers (560 samples). Meanwhile, their predictive values for patient survival was validated in 3530 samples in 10 tumor types. A total of 560 participants with transcriptomic data and SMA were included. Among those, 136 participants (24.28%) were defined as having sarcopenia based on SMA. Enrichment analysis for upregulated secretory genes in cancers revealed that pathways associated with muscle wasting were strongly enriched in tumor types with a higher prevalence of sarcopenia. A series of SMA-associated secretory protein-coding genes were identified in cancers, which showed distinct gene expression profiles according to tumor type, and could be used to predict prognosis in cancers (p value ≤ 0.002). Unfortunately, those genes were different and rarely overlapped across tumor types. Tumor secretome characteristics were closely related to sarcopenia. Highly expressed secretory mediators in the tumor microenvironment were associated with SMA and could affect the overall survival of cancer patients, which may provide a valuable starting point for the further understanding of the molecular basis of muscle wasting in cancers. More importantly, tumor-derived pro-sarcopenic factors differ across tumor types and genders, which implies that mechanisms of cancer-associated muscle wasting are complex and diverse across tumors, and may require individualized treatment approaches.

The construction of multilayer rail transit systems is a necessary way to realize “modern metropolitan areas on rail”, improve resource sharing, and increase travel services, where data integration is of utmost importance. To break data silos and realize data flow between different rail systems, a fine-grained access control framework is proposed in this paper. Through categorical and hierarchical schemes, a universal security scale is established for cross-domain data resources. Based on this, a trust and sensitivity attribute-based access control (TSABAC) model is put forward to describe the characteristics of the access control process. Furthermore, the method of policy integration is discussed, as well as the solution to the policy incompatibility problem, due to cross-domain interaction. As shown in practical application and simulation analysis, this framework can meet the requirements of security and granularity. This research is of great significance for promoting the high-quality development of urban agglomerations and metropolitan areas, and improving the quality and efficiency of rail transit.

The number of motor vehicles on the road is constantly increasing, leading to a rise in the number of traffic accidents. Accurately identifying the factors contributing to these accidents is a crucial topic in the field of traffic accident research. Most current research focuses on analyzing the causes of traffic accidents rather than investigating the underlying factors. This study creates a complex network for road traffic accident cause analysis using the topology method for complex networks. The network metrics are analyzed using the network parameters to obtain reduced dimensionality feature factors, and four machine learning techniques are applied to accurately classify the accidents’ severity based on the analysis results. The study divides real traffic accident data into three main categories based on the factors that influences them: time, environment, and traffic management. The results show that traffic management factors have the most significant impact on road accidents. The study also finds that Extreme Gradient Boosting (XGBoost) outperforms Logistic Regression (LR), Random Forest (RF) and Decision Tree (DT) in accurately categorizing the severity of traffic accidents.

YM201636 and PI-103 are potent inhibitors of human two-pore channel 2 that act through a channel pore entrance blockade mechanism.

Abstract Background Neutrophil extracellular traps (NETs) contribute to the creation of a coagulation state in various diseases. Currently, it is not clear whether NETs are present in the thrombi and plasma of patients with cerebral venous sinus thrombosis (CVST). This study aimed to investigate the presence of NETs in thrombi and blood samples from CVST patients and the procoagulant activity (PCA) of NETs during the progression of CVST. Results Thrombi obtained from CVST patients undergoing thrombectomy were examined by immunochemistry using neutrophil elastase (NE), CD66b and citrullinated histone H3(citH3). The presence of NET markers in samples from 37 CVST patients and 32 healthy people was evaluated by ELISA. NET-producing neutrophils and neutrophil-platelet (PLT) aggregates were examined in samples obtained from CVST patients and healthy people by flow cytometry. The TAT complex in plasma sample from each group was detected by ELISA to evaluate the procoagulant activity of NETs in CVST patients. Neutrophils from healthy subjects were treated with PLT-rich plasma in the presence of anti-PF4 antibodies or an autophagy inhibitor and analyzed by flow cytometry and confocal microscopy. After treatment with NETs, the expression of von Willebrand factor (VWF), tissue factor (TF) and CD31 in human brain microvascular endothelial cells (HBMECs) was measured by confocal microscopy and western blotting. Our results showed that NETs were abundant in the plasma and thrombi from CVST patients. Platelet factor 4 (PF4) from CVST PLTs induced NET generation through autophagy. NETs could induce PCA by modulating TF and phosphatidylserine (PS) in CVST. NETs also disrupted the endothelial barrier and transformed ECs into a procoagulant phenotype to exacerbate thrombogenicity. Conclusions NET generation was mediated by PF4 from PLTs through autophagy and contribute to thrombosis in CVST patients.

Alternative polyadenylation (APA) is a crucial step in post-transcriptional regulation. Previous bioinformatic studies have mainly focused on the recognition of polyadenylation sites (PASs) in a given genomic sequence, which is a binary classification problem. Recently, computational methods for predicting the usage level of alternative PASs in the same gene have been proposed. However, all of them cast the problem as a non-quantitative pairwise comparison task and do not take the competition among multiple PASs into account. To address this, here we propose a deep learning architecture, Deep Regulatory Code and Tools for Alternative Polyadenylation (DeeReCT-APA), to quantitatively predict the usage of all alternative PASs of a given gene. To accommodate different genes with potentially different numbers of PASs, DeeReCT-APA treats the problem as a regression task with a variable-length target. Based on a convolutional neural network-long short-term memory (CNN-LSTM) architecture, DeeReCT-APA extracts sequence features with CNN layers, uses bidirectional LSTM to explicitly model the interactions among competing PASs, and outputs percentage scores representing the usage levels of all PASs of a gene. In addition to the fact that only our method can quantitatively predict the usage of all the PASs within a gene, we show that our method consistently outperforms other existing methods on three different tasks for which they are trained: pairwise comparison task, highest usage prediction task, and ranking task. Finally, we demonstrate that our method can be used to predict the effect of genetic variations on APA patterns and sheds light on future mechanistic understanding in APA regulation. Our code and data are available at https://github.com/lzx325/DeeReCT-APA-repo.

A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.

Kawasaki disease (KD) is a childhood vasculitis disease that is difficult to diagnose, and there is an urgent need for the identification of accurate and specific biomarkers. Here, we aimed to investigate metabolic alterations in patients with KD to determine novel diagnostic and prognostic biomarkers for KD. To this end, we performed untargeted metabolomics and found that several metabolic pathways were significantly enriched, including amino acid, lipid, and tryptophan metabolism, the latter of which we focused on particularly. Tryptophan-targeted metabolomics was conducted to explore the role of tryptophan metabolism in KD. The results showed that Trp and indole acetic acid (IAA) levels markedly decreased, and that l-kynurenine (Kyn) and kynurenic acid (Kyna) levels were considerably higher in patients with KD than in healthy controls. Changes in Trp, IAA, Kyn, and Kyna levels in a KD coronary arteritis mouse model were consistent with those in patients with KD. We further analyzed public single-cell RNA sequencing data of patients with KD and revealed that their peripheral blood mononuclear cells showed Aryl hydrocarbon receptor expression that was remarkably higher than that of healthy children. These results suggest that the Trp metabolic pathway is significantly altered in KD and that metabolic indicators may serve as novel diagnostic and therapeutic biomarkers for KD.

Understanding the reproductive strategy of an organism is important in conservation ecology as it directly affects the population performance under changing environmental conditions. Chinese sturgeon (Acipenser sinensis) are the largest anadromous fish in the Yangtze River, China. Currently, the species has only one spawning ground and has failed to spawn in recent years, leading it to the brink of extinction. To develop effective conservation measures, a further understanding of its reproductive strategy is needed. In our study, we conducted kinship analyses by using mitochondrial and microsatellite DNA data from 216 wild juveniles collected over nine years (2006−2013, 2015) to understand the mating system, breeding interval, effective number of breeding adults, and reproductive success. The results from these analyses suggested polygynandry, with some parents contributing up to eight half-sibling juvenile genotypes. Although the spawning ground was restricted to a limited area, genetic diversity was maintained at a relatively high level (observed heterozygosity from 0.698 to 0.787 and expected heterozygosity from 0.763 to 0.787) and inbreeding coefficients in each year-class ranged from −1% to 9% (low to modest detrimental effects on offspring). A parental inference analysis revealed that Chinese sturgeon have a breeding interval of 2–6 years, indicating that it has the potential to feed, accumulate nutrition in the ocean, and then migrate back to the Yangtze River for iteroparous reproduction. The annual effective number of breeders in the Yangtze River ranged from 14 to 161 during the study period, and it decreased by 62.1% from the 2011−2014 year-classes. This sharp population decline likely contributes to the reproduction failure. However, the ratios of effective to census population size (Ne/Nc) were all larger than 0.20 after the 2010 year-class, indicating relatively even reproductive success. Based on these results, a suggested approach to protect this species is to restock parent fish to increase the reproductive stock size and optimize the discharge of the Three Gorges Dam to reduce the unsuitable hydrological conditions and rehabilitate spawning ground habitats.

Xanthine oxidase (XO), a form of xanthine oxidoreductase, is widely distributed in various human tissues. As a major source for the generation of superoxide radicals, XO is involved in the induction of oxidative stress and inflammation during ischemic and hypoxic tissue injury. Therefore, we designed this study to identify the role of serum XO levels in acute ischemic stroke (AIS) pathogenesis. In this single-center prospective study, 328 consecutive patients with AIS for the first time were included, and 107 age- and sex-matched healthy controls from a community-based stroke screening population were also included. The serum levels of XO and several conventional stroke risk factors were assessed. Multivariate analysis was applied to evaluate the relationship between serum levels of XO and clinical outcomes, and nomogram models were developed to predict the onset, progression and prognosis of AIS. Compared with the healthy control group, the serum level of XO was significantly higher in the AIS group (P

Abstract Premise To genetically discriminate subspecies of the common reed (Phragmites australis), we developed real‐time quantitative (qPCR) assays for identifying P. australis subsp. americanus, P. australis subsp. australis, and P. australis subsp. berlandieri. Methods and Results Utilizing study‐generated chloroplast DNA sequences, we developed three novel qPCR assays. Assays were verified on individuals of each subspecies and against two non‐target species, Arundo donax and Phalaris arundinacea. One assay amplifies only P. australis subsp. americanus, one amplifies P. australis subsp. australis and/or P. australis subsp. berlandieri, and one amplifies P. australis subsp. americanus and/or P. australis subsp. australis. This protocol enhances currently available rapid identification methods by providing genetic discrimination of all three subspecies. Conclusions The newly developed assays were validated using P. australis samples from across the United States. Application of these assays outside of this geographic range should be preceded by additional testing.

Stem cell-derived exosomes (SC-EXO) was an emerging therapeutic agent in regenerative medicine. Intratunical injection of SC-EXO is considered as a prospective approach for erectile dysfunction (ED) treatment. However, high vascularization of cavernous body makes effective retention a major challenge for SC-EXO intratunical injection. In this study, a Polydopamine nanoparticles (PDNPs) incorporated poly (ethylene glycol)-poly(ε-caprolactone-co-lactide) (PDNPs-PELA) thermosensitive hydrogels were fabricated by a facile in situ polymerization for intratunical administration of adipose stem cell-derived exosomes (EXO). The hydrogels exhibited sol-gel transition at body temperature. Moreover, the in-situ polymerization of PDNPs using poly (ethylene glycol)-poly(ε-caprolactone-co-lactide) (PELA) block copolymer as a template was found to be more stable dispersion in the gel system. After being encapsulated into the hydrogel, EXO shows sustained release behavior within two weeks. In vivo animal experiments revealed that exosomes released from hydrogel lead to the healing of endothelial cells and neurons, increase of the cavity's pressure, thereby restoring the erectile function. In particular, since the PDNPs in thermosensitive gels have excellent photoacoustic performance, the hydrogel can be accurately delivered into the tunica albuginea by the guidance of real-time photoacoustic imaging. These results suggest that the as-prepared PDNPs-PELA has a promising future as an injectable exosome carrier for ED treatment.

Prevention of cardiac injury requires a deeper mechanistic understanding of ischemia/reperfusion (I/R) episodes. Here, the authors find that the epigenetic modifier KDM3A plays a crucial role in myocardial I/R injury through its activation of the gene ETS1 and suggest boosting KDM3A expression could be a potential treatment strategy.