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Phylogenetic framework for the closely related Ancylodiscoidinae and Ancyrocephalinae subfamilies remains contentious. As this issue was never studied using a large molecular marker, we sequenced the first two Ancylodiscoidinae mitogenomes: Thaparocleidus asoti and Thaparocleidus varicus. Both mitogenomes had two non-coding regions (NCRs) that contained a number of repetitive hairpin-forming elements (RHE). Due to these, the mitogenome of T. asoti (16,074 bp) is the longest among the Monogenea; especially large is its major NCR, with 3500 bp, approximately 1500 bp of which could not be sequenced (thus, the total mitogenome size is ≈ 17,600 bp). Although RHEs have been identified in other monopisthocotyleans, they appear to be independently derived in different taxa. The presence of RHEs may have contributed to the high gene order rearrangement rate observed in the two mitogenomes, including the first report of a transposition of rRNA genes within the Neodermata. Phylogenetic analyses using mitogenomic dataset produced Dactylogyrinae embedded within the Ancyrocephalinae (paraphyly), whereas Ancylodiscoidinae formed a sister-group with them. This was also supported by the gene order analysis. 28S rDNA dataset produced polyphyletic Dactylogyridae and Ancyrocephalinae. The phylogeny of the two subfamilies shall have to be further evaluated with more data.

Induced pluripotent stem cells (iPSCs) can be personalized and differentiated into neural stem cells (NSCs), thereby effectively providing a source of transplanted cells for spinal cord injury (SCI). To further improve the repair efficiency of SCI, we designed a functional neural network tissue based on TrkC-modified iPSC-derived NSCs and a CBD-NT3-modified linear-ordered collagen scaffold (LOCS). We confirmed that transplantation of this tissue regenerated neurons and synapses, improved the microenvironment of the injured area, enhanced remodeling of the extracellular matrix, and promoted functional recovery of the hind limbs in a rat SCI model with complete transection. RNA sequencing and metabolomic analyses also confirmed the repair effect of this tissue from multiple perspectives and revealed its potential mechanism for treating SCI. Together, we constructed a functional neural network tissue using human iPSCs-derived NSCs as seed cells based on the interaction of receptors and ligands for the first time. This tissue can effectively improve the therapeutic effect of SCI, thus confirming the feasibility of human iPSCs-derived NSCs and LOCS for SCI repair and providing a valuable direction for SCI research.

Since its initial release in 2001, the human reference genome has undergone continuous improvement in quality, and the recently released telomere-to-telomere (T2T) version — T2T-CHM13 — reaches its highest level of continuity and accuracy after 20 years of effort by working on a simplified, nearly homozygous genome of a hydatidiform mole cell line. Here, to provide an authentic complete diploid human genome reference for the Han Chinese, the largest population in the world, we assembled the genome of a male Han Chinese individual, T2T-YAO, which includes T2T assemblies of all the 22 + X + M and 22 + Y chromosomes in both haploids. The quality of T2T-YAO is much better than those of all currently available diploid assemblies, and its haploid version, T2T-YAO-hp, generated by selecting the better assembly for each autosome, reaches the top quality of fewer than one error per 29.5 Mb, even higher than that of T2T-CHM13. Derived from an individual living in the aboriginal region of the Han population, T2T-YAO shows clear ancestry and potential genetic continuity from the ancient ancestors. Each haplotype of T2T-YAO possesses ∼ 330-Mb exclusive sequences, ∼ 3100 unique genes, and tens of thousands of nucleotide and structural variations as compared with CHM13, highlighting the necessity of a population-stratified reference genome. The construction of T2T-YAO, an accurate and authentic representative of the Chinese population, would enable precise delineation of genomic variations and advance our understandings in the hereditability of diseases and phenotypes, especially within the context of the unique variations of the Chinese population.

To address the issue of insufficient durability of traditional modified emulsified asphalt in the application of cold mix and cold paving anti-skid wear layers, this study utilizes cationic waterborne polyurethane (PU+) for composite modification to enhance adhesion and performance across a range of temperatures. Initially, composite-modified emulsified asphalt samples were prepared with varying dosages of PU+ according to a gradient method. Routine performance tests were conducted on the evaporated residues for analysis. Advanced rheological tests, including temperature sweep (TS), frequency sweep (FS), linear amplitude sweep (LAS), and multi-stress creep recovery (MSCR) tests, were performed using a dynamic shear rheometer (DSR). Surface free energy (SFE) tests were conducted with a fully automated surface tension meter (STM). A comprehensive evaluation of the high-temperature rheological properties, fatigue properties, adhesion properties, and water damage resistance of the modified emulsified asphalt residues was carried out. Chemical changes before and after modification were characterized using Fourier transform infrared spectroscopy (FTIR), and the distribution of polymers in the evaporated residue was observed using fluorescence microscopy (FM). The results demonstrated that cationic waterborne polyurethane significantly enhanced the fatigue and adhesion properties of SBS-modified emulsified asphalt, but it also weakened the water damage resistance of asphalt. MSCR tests revealed that the addition of cationic waterborne polyurethane might reduce the elastic recovery performance of modified asphalt, thereby weakening its resistance to rutting. Among the samples, the modified asphalt with a PU+ content of 6% exhibited good high-temperature shear resistance and elastic recovery performance, demonstrating the best anti-rutting performance.

Oil palm is a versatile oil crop with numerous applications. Significant progress has been made in applying histological techniques in oil palm research in recent years. Whole genome sequencing of oil palm has been carried out to explain the function and structure of the order genome, facilitating the development of molecular markers and the construction of genetic maps, which are crucial for studying important traits and genetic resources in oil palm. Transcriptomics provides a powerful tool for studying various aspects of plant biology, including abiotic and biotic stresses, fatty acid composition and accumulation, and sexual reproduction, while proteomics and metabolomics provide opportunities to study lipid synthesis and stress responses, regulate fatty acid composition based on different gene and metabolite levels, elucidate the physiological mechanisms in response to abiotic stresses, and explain intriguing biological processes in oil palm. This paper summarizes the current status of oil palm research from a multi-omics perspective and hopes to provide a reference for further in-depth research on oil palm.

A foundation pit is constructed in the floodplain of Yangtze River, and a deep and thick layer of large-particle pebble gravel exists below the base slab, thus forming a connected supply channel with the adjacent Yangtze River. The large water volume, high water pressure, and strong permeability of this layer bring great risks to the foundation pit construction. In view of the fact that conventional waterproof curtain construction technologies such as the deep mixing column and high-pressure jet grouting column cannot meet the engineering requirements under these kinds of geological and environmental conditions, a new waterproof curtain construction technology that combines the trenching technology of the diaphragm wall with the TRD (Trench cutting Remixing Deep wall) technology is proposed, i.e., the trenching-and-replacing-style TRD technology, as well as the construction process of this technology, is presented. After the waterproof curtain is built using the proposed technology, the strength, integrity, uniformity, and service performance of the waterproof curtain wall are tested and evaluated by the comprehensive methods of coring, borehole television imaging, resistivity CT, and a group well pumping test. The results show that the proposed technology overcomes the adverse effects of underlying large-particle pebble gravel layer, and the waterproof curtain built by it effectively cuts off the hydraulic connection inside and outside the pit. The technical proposal can provide useful references for similar projects.

Visualizing synaptic connectivity has traditionally relied on time-consuming electron microscopy-based imaging approaches. To scale the analysis of synaptic connectivity, fluorescent protein-based techniques have been established, ranging from the labeling of specific pre- or post-synaptic components of chemical or electrical synapses to transsynaptic proximity labeling technology such as GRASP and iBLINC. In this paper, we describe WormPsyQi, a generalizable image analysis pipeline that automatically quantifies synaptically localized fluorescent signals in a high-throughput and robust manner, with reduced human bias. We also present a resource of 30 transgenic strains that label chemical or electrical synapses throughout the nervous system of the nematode Caenorhabditis elegans, using CLA-1, RAB-3, GRASP (chemical synapses), or innexin (electrical synapse) reporters. We show that WormPsyQi captures synaptic structures in spite of substantial heterogeneity in neurite morphology, fluorescence signal, and imaging parameters. We use these toolkits to quantify multiple obvious and subtle features of synapses – such as number, size, intensity, and spatial distribution of synapses – in datasets spanning various regions of the nervous system, developmental stages, and sexes. Although the pipeline is described in the context of synapses, it may be utilized for other ‘punctate’ signals, such as fluorescently tagged neurotransmitter receptors and cell adhesion molecules, as well as proteins in other subcellular contexts. By overcoming constraints on time, sample size, cell morphology, and phenotypic space, this work represents a powerful resource for further analysis of synapse biology in C. elegans.

Given the deformation issues in machining segmented equal-base bevel gears, this paper investigates the variations of additional stress during the machining process, considering the gear blank material, residual internal stress, and gear blank design. A model for calculating internal additional stress and torque during gear machining has been developed. The calculation formula for the bending deformation of the gear blank has been derived using the torque–area method. By analyzing the time-varying stiffness of the blank, a calculation model for the bending deformation of the gear blank has been constructed, and the projection analysis of gear stock deformation has been completed. Based on the cumulative superposition effect of its deformation projection, a calculation model for the overall deformation of the segmented gear blank has been formulated. The deformation calculation model has been validated through finite element simulation, deformation calculation, actual machining, and measurement verification.

Bacterial diversity and its distribution characteristics in sediments are critical to understanding and revealing biogeochemical cycles in sediments. However, little is known about the relationship between biogeochemistry processes and vertical spatial distribution of bacterial communities in sandy sediments. In this study, we used fluorescence quantitative PCR, high-throughput sequencing technology and statistical analysis to explore the vertical distribution pattern of bacterial community diversity and its influencing factors in sandy sediments of the Yangtze River Basin. The aim is to enrich the understanding of the ecological characteristics and functions of bacteria in river ecosystems. The results showed that both sediment bacterial abundance and diversity showed a gradual decrease from surface to bottom in the vertical distribution. The main environmental factors that influenced the bacterial distribution pattern were pore water dissolved oxygen (DO), total nitrogen (TN) concentration and sediment nitrogen (N) content. The dominant bacterial species, Massilia and Flavobacterium, are suitable for growth and reproduction in high oxygen and nutrient-richer environments, while Limnobacter prefers low oxygen or anaerobic conditions. The vertical distribution pattern of bacteria and its influencing factors in river sandy sediment found in this study differ from the results in mud sediment, which may be related to the larger granular gap between sandy sediment and the lower content of organic matter. The findings of this study further our understanding of the distribution patterns and ecological preferences of microbial communities in river sediments, providing insights into how these communities may adapt to varying environmental conditions.

Posterior capsule opacification (PCO) is the most common long-term postoperative complication of cataract surgery, leading to secondary vision loss. Optimized intraocular lens (IOL) structure and appropriate pharmacological intervention, which provides physical barriers and biological inhibition, respectively, can block the migration, proliferation, and epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) for PCO prophylaxis. Herein, a novel indomethacin-eluting IOL (INDOM-IOL) with an optimized sharper edge and a sustained drug release behavior was developed for PCO prevention. Indomethacin (INDOM), an ophthalmic non-steroidal anti-inflammatory drug (NSAID) used for postoperative ocular inflammation, was demonstrated to not only be able to suppress cell migration and down-regulate the expression of cyclooxygenase-2 (COX-2) and EMT markers, including alpha-smooth muscle actin (α-SMA) and cyclin D1, but also promote the autophagy activation in LECs. Additionally, autophagy was also verified to be a potential therapeutic target for the down-regulation of EMT in LECs. The novel IOL, serving as a drug delivery platform, could carry an adjustable dose of hydrophobic indomethacin with sustained drug release ability for more than 28 days. In the rabbit PCO model, the indomethacin-eluting IOL showed excellent anti-inflammatory and anti-PCO effects. In summary, indomethacin is an effective pharmacological intervention in PCO prophylaxis, and the novel IOL we developed prevented PCO in vivo under its sustained indomethacin release property, which provided a promising approach for PCO prophylaxis in clinical application.

Selfish genetic elements can promote their transmission at the expense of individual survival, creating conflict between the element and the rest of the genome. Recently, a large number of toxin-antidote (TA) post-segregation distorters have been identified in non-obligate outcrossing nematodes. Their origin and the evolutionary forces that keep them at intermediate population frequencies are poorly understood. Here, we study a TA element in Caenorhabditis elegans called zeel-1;peel-1. Two major haplotypes of this locus, with and without the selfish element, segregate in C. elegans. We evaluate the fitness consequences of the zeel-1;peel-1 element outside of its role in gene drive in non-outcrossing animals and demonstrate that loss of the toxin peel-1 decreased fitness of hermaphrodites and resulted in reductions in fecundity and body size. These findings suggest a biological role for peel-1 beyond toxin lethality. This work demonstrates that a TA element can provide a fitness benefit to its hosts either during their initial evolution or by being co-opted by the animals following their selfish spread. These findings guide our understanding on how TA elements can remain in a population where gene drive is minimized, helping resolve the mystery of prevalent TA elements in selfing animals.

Summary: As a prominent feature of gout, monosodium urate (MSU) crystal deposition induces gout flares, but its impact on immune inflammation in gout remission remains unclear. Using single-cell RNA sequencing (scRNA-seq), we characterize the transcription profiling of peripheral blood mononuclear cells (PBMCs) among intercritical remission gout, advanced remission gout, and normal controls. We find systemic inflammation in gout remission with MSU crystal deposition at the intercritical and advanced stages, evidenced by activated inflammatory pathways, strengthened inflammatory cell-cell interactions, and elevated arachidonic acid metabolic activity. We also find increased HLA-DQA1high classic monocytes and PTGS2high monocytes in advanced gout and overactivated CD8+ T cell subtypes in intercritical and advanced gout. Additionally, the osteoclast differentiation pathway is significantly enriched in monocytes, T cells, and B cells from advanced gout. Overall, we demonstrate systemic inflammation and distinctive immune responses in gout remission with MSU crystal deposition, allowing further exploration of the underlying mechanism and clinical significance in conversion from intercritical to advanced stage.

The deployment of megaconstellations in low Earth orbit (LEO) poses significant collision risks with space debris. This paper focuses on analyzing the short-term and long-term collision probabilities of megaconstellations to assess their collision risk. Firstly, a short-term collision risk evolution model is developed to accurately address rendezvous collisions. Secondly, a long-term collision risk evolution model is established by considering space object density, space debris attenuation, space target disintegration, and the distribution of disintegration targets. Through simulations conducted on the Starlink Phase I constellation, the results demonstrate a 30–40% increase in short-term collision probability within the constellation shell, a 70.2% probability of at least one collision during the constellation’s lifetime, and a 25.3% increase in secondary collisions following a collision event. This study provides a reference and application for analyzing the orbital safety of LEO megaconstellations and for promoting the sustainable development and utilization of space resources.

Surface cracks and joint deteriorations are typical premature failures of urban cement concrete pavement. However, traffic loads on the urban pavement are much lower than those on highways. Limited research has been conducted to investigate the causes of accelerated damage in urban cement concrete roads. To investigate the foundation issues that may cause the accelerated damage of urban cement concrete pavements, in this study, field evaluations were conducted to assess pavement foundation support and drainage conditions. Field visual inspections, Ground Penetrating Radar (GPR) survey, Dynamic Cone Penetrometer (DCP) test, and the Core-Hole Permeameter (CHP) test were performed. In urban residential areas with inadequate subgrade bearing capacity, cement concrete pavements are prone to early damage. Foundations with a higher content of coarse particles exhibit a higher CBR value, which can extend the service life of the pavement. The compaction of foundation materials near sewer pipelines and manholes is insufficient, leading to non-uniform support conditions. Moreover, the permeability of the foundation material can influence the service life of pavement surface structures. Foundation materials with fewer fine particles enhance drainage performance, contributing to a longer service life for PCC pavements. In areas with inadequate drainage, water accumulation reduces the bearing capacity of the foundation, thereby accelerating pavement deterioration. The poor bearing capacity and drainage conditions of the foundation lead to cavities between the surface layer and foundation material thus yielding stress concentrations on the pavement surface, which cause the formation of pavement surface cracks.

The diversity of nematode-trapping fungi (NTF) holds significant theoretical and practical implications in the study of adaptive evolution and the bio-control of harmful nematodes. However, compared to terrestrial ecosystems, research on aquatic NTF is still in its early stages. During a survey of NTF in six watersheds in Yunnan Province, China, we isolated 10 taxa from freshwater sediment. Subsequent identification based on morphological and multigene (ITS, TEF1-α, and RPB2) phylogenetic analyses inferred they belong to five new species within Arthrobotrys. This paper provides a detailed description of these five novel species (Arthrobotrys cibiensis, A. heihuiensis, A. jinshaensis, A. yangbiensis, and A. yangjiangensis), contributing novel insights for further research into the diversity of NTF and providing new material for the biological control of aquatic harmful nematodes. Additionally, future research directions concerning aquatic NTF are also discussed.

Nematode-trapping fungi are a highly specialised group in fungi and are essential regulators of natural nematode populations. At present, more than 130 species have been discovered in Zygomycota (Zoopagaceae), Basidiomycota (Nematoctonus), and Ascomycota (Orbiliaceae). Amongst them, nematode-trapping fungi in Orbiliaceae have become the research focus of carnivorous fungi due to their abundant species. During the investigation of carnivorous fungi in Yunnan, China, four fungal strains isolated from burned forest soil were identified as two new nematode-trapping species in Drechslerella (Orbiliaceae), based on multigene phylogenetic analysis and morphological characters.Drechslerella daliensis sp. nov. is characterised by its ellipsoid, 1–2-septate macroconidia, clavate or bottle-shaped, 0–1-septate microconidia and unbranched, simple conidiophores. D. xiaguanensis sp. nov. is characterised by fusiform or spindle-shaped, 2–4-septate conidia and unbranched, simple conidiophores. Both of them produce constricting rings to capture nematodes. The phylogenetic analysis, based on combined ITS, TEF1-α and RPB2 sequences, determined their placement in Drechslerella. D. daliensis forms a basal lineage closely nested with D. hainanensis (YMF1.03993). D. xiaguanensis forms a sister lineage with D. bembicodes (1.01429), D. aphrobrocha (YMF1.00119) and D. coelobrocha (FWY03-25-1).

Abstract Background Bladder cancer (BCa) is a fatal form of cancer worldwide associated with a poor prognosis. Identifying novel drivers of growth and metastasis hold therapeutic potential for the disease. Transport homeostasis between the endoplasmic reticulum and Golgi and the secretion of matrix metalloproteinases (MMPs) mediated by Golgi have been reported to be closely associated with tumor progression. However, to date, mechanistic studies remain limited. Results Here, we identified KDELR2 as a potential risk factor with prognostic value in patients with BCa, especially those harbouring the KDELR2 amplification. In addition, we found that KDELR2 is a regulator of BCa cell proliferation and tumorigenicity based on bioinformatic analysis with functional studies. Mechanistically, we revealed that KDELR2 could regulate the expression of KIF20A, thus stimulating the expression of MMP2, MMP9 and MKI67. Functionally, the overexpression of KDELR2 and KIF20A markedly promoted proliferation, migration, and invasion in vitro and enhanced tumor growth in vivo, while knockdown of KDELR2 and KIF20A exerted the opposite effects. And the overexpression of KDELR2 also enhanced lymph node metastasis in vivo. Conclusions Collectively, our findings clarified a hitherto unexplored mechanism of KDELR2-KIF20A axis in increasing Golgi-mediated secretion of MMPs to drive tumor progression in BCa.

Summary: Single-cell transcriptomic platforms provide an opportunity to map an organism’s response to environmental cues with high resolution. Here, we applied single-nucleus RNA sequencing (snRNA-seq) to establish the tissue and cell type-resolved transcriptome of the adult C. elegans and characterize the inter- and trans-generational transcriptional impact of ethanol. We profiled the transcriptome of 41,749 nuclei resolving into 31 clusters, representing a diverse array of adult cell types including syncytial tissues. Following exposure to human-relevant doses of alcohol, several germline, striated muscle, and neuronal clusters were identified as being the most transcriptionally impacted at the F1 and F3 generations. The effect on germline clusters was confirmed by phenotypic enrichment analysis as well as by functional validation, which revealed a remarkable inter- and trans-generational increase in germline apoptosis, aneuploidy, and embryonic lethality. Together, snRNA-seq represents a valuable approach for the detailed examination of an adult organism’s response to environmental exposures.

Summary: Apatinib has been shown to clinically enhance anti-PD-1 immunotherapy for advanced gastric cancer (GC). However, the complexity of GC immunosuppression remains a challenge for precision immunotherapy. Here, we profile the transcriptomes of 34,182 single cells from GC patient-derived xenografts of humanized mouse models treated with vehicle, nivolumab, or nivolumab plus apatinib. Notably, excessive expression of CXCL5 in the CellCycle malignant epithelium, induced by anti-PD-1 immunotherapy and blocked by combined apatinib treatment, is found to be a key driver of tumor-associated neutrophil (TAN) recruitment in the tumor microenvironment through the CXCL5/CXCR2 axis. We further show that the protumor TAN signature is associated with anti-PD-1 immunotherapy-related progressive disease and poor cancer prognosis. Molecular and functional analyses in cell-derived xenograft models confirm the positive in vivo therapeutic effect of targeting the CXCL5/CXCR2 axis during anti-PD-1 immunotherapy. Altogether, our study elucidates the GC immunosuppressive landscape in anti-PD-1 immunotherapy and highlights potential targets for overcoming checkpoint immunotherapy resistance.

Selecting the appropriate indicators and measuring time point numbers is important for accurately examining the shift in soil gross decomposition channel structure. Through a selected case study on a natural forest vs. rainfed arable system over a two-month-long experiment, the utility of three commonly employed indicators (fungi to bacteria ratio (F:B), fungivore to bacterivore ratio (FF:BF), and glucosamine to muramic acid ratio (GlcN:MurN)) were compared to reflect the shift in soil gross decomposition channel structure. The requirement of measuring the time point numbers for the three indicators was also assessed, and we suggest a potential methodology. Our results revealed that the GlcN:MurN ratio was more reliable for assessing the shifts in gross decomposition channel structure for long-term land use changes, while it was less sensitive to short-term drought compared with the other two indicators. The F:B ratio was more applicable than the FF:BF ratio for reflecting both long- and short-term changes. Furthermore, the reliability of the GlcN:MurN ratio was the least dependent on measuring time point numbers. We suggest the use of multiple indicators and the adoption of multiple measuring time points for the overall methodology.

Due to the rapid development of the mobile Internet and the Internet of Things, the volume of generated data keeps growing. The topic of data quality has gained increasing attention recently. Numerous studies have explored various data quality (DQ) problems across several fields, with corresponding effective data-cleaning strategies being researched. This paper begins with a comprehensive and systematic review of studies related to DQ. On the one hand, we classify these DQ-related studies into six types: redundant data, missing data, noisy data, erroneous data, conflicting data, and sparse data. On the other hand, we discuss the corresponding data-cleaning strategies for each DQ type. Secondly, we examine DQ issues and potential solutions for a public bus transportation system, utilizing a real-world traffic big data platform. Finally, we provide two representative examples, noise filtering and filling missing values, to demonstrate the DQ improvement practice. The experimental results show that: (1) The GPS noise filtering solution we proposed surpasses the baseline and achieves an accuracy of 97%; (2) The multi-source data fusion method can achieve a 100% missing repair rate (MRR) for bus arrival and departure. The average relative error (ARE) of bus arrival and departure times at stations is less than 1%, and the correlation coefficient (R) is also close to 1. Our research can offer guidance and lessons for enhancing data governance and quality improvement in the bus transportation system.

Abstract Pseudomonas aeruginosa (P. aeruginosa) is a Gram-negative opportunistic pathogen that infects patients with cystic fibrosis, burn wounds, immunodeficiency, chronic obstructive pulmonary disorder (COPD), cancer, and severe infection requiring ventilation, such as COVID-19. P. aeruginosa is also a widely-used model bacterium for all biological areas. In addition to continued, intense efforts in understanding bacterial pathogenesis of P. aeruginosa including virulence factors (LPS, quorum sensing, two-component systems, 6 type secretion systems, outer membrane vesicles (OMVs), CRISPR-Cas and their regulation), rapid progress has been made in further studying host-pathogen interaction, particularly host immune networks involving autophagy, inflammasome, non-coding RNAs, cGAS, etc. Furthermore, numerous technologic advances, such as bioinformatics, metabolomics, scRNA-seq, nanoparticles, drug screening, and phage therapy, have been used to improve our understanding of P. aeruginosa pathogenesis and host defense. Nevertheless, much remains to be uncovered about interactions between P. aeruginosa and host immune responses, including mechanisms of drug resistance by known or unannotated bacterial virulence factors as well as mammalian cell signaling pathways. The widespread use of antibiotics and the slow development of effective antimicrobials present daunting challenges and necessitate new theoretical and practical platforms to screen and develop mechanism-tested novel drugs to treat intractable infections, especially those caused by multi-drug resistance strains. Benefited from has advancing in research tools and technology, dissecting this pathogen’s feature has entered into molecular and mechanistic details as well as dynamic and holistic views. Herein, we comprehensively review the progress and discuss the current status of P. aeruginosa biophysical traits, behaviors, virulence factors, invasive regulators, and host defense patterns against its infection, which point out new directions for future investigation and add to the design of novel and/or alternative therapeutics to combat this clinically significant pathogen.

Abstract The therapeutic use of messenger RNA (mRNA) has fueled great hope to combat a wide range of incurable diseases. Recent rapid advances in biotechnology and molecular medicine have enabled the production of almost any functional protein/peptide in the human body by introducing mRNA as a vaccine or therapeutic agent. This represents a rising precision medicine field with great promise for preventing and treating many intractable or genetic diseases. In addition, in vitro transcribed mRNA has achieved programmed production, which is more effective, faster in design and production, as well as more flexible and cost-effective than conventional approaches that may offer. Based on these extraordinary advantages, mRNA vaccines have the characteristics of the swiftest response to large-scale outbreaks of infectious diseases, such as the currently devastating pandemic COVID-19. It has always been the scientists’ desire to improve the stability, immunogenicity, translation efficiency, and delivery system to achieve efficient and safe delivery of mRNA. Excitingly, these scientific dreams have gradually been realized with the rapid, amazing achievements of molecular biology, RNA technology, vaccinology, and nanotechnology. In this review, we comprehensively describe mRNA-based therapeutics, including their principles, manufacture, application, effects, and shortcomings. We also highlight the importance of mRNA optimization and delivery systems in successful mRNA therapeutics and discuss the key challenges and opportunities in developing these tools into powerful and versatile tools to combat many genetic, infectious, cancer, and other refractory diseases.

Abstract Critical coronavirus disease 2019 (COVID-19) is associated with high mortality and potential genetic factors have been reported to be involved in the development of critical COVID-19. We performed a genome-wide association study to identify the genetic factors responsible for developing critical COVID-19. 632 critical patients with COVID-19 and 3021 healthy controls from the Chinese population were recruited. First, we identified a genome-wide significant difference of IL-6 rs2069837 (p = 9.73 × 10−15, OR = 0.41) between 437 critical patients with COVID-19 and 2551 normal controls in the discovery cohort. When replicated these findings in a set of 195 patients with critical COVID-19 and 470 healthy controls, we detected significant association of rs2069837 with COVID-19 (p = 8.89 × 10−3, OR = 0.67). This variant surpassed the formal threshold for genome-wide significance (combined p = 4.64 × 10−16, OR = 0.49). Further analysis revealed that there was a significantly stronger expression of IL-6 in the serum from patients with critical COVID-19 than in that from patients with asymptomatic COVID-19. An in vitro assay showed that the A to G allele changes in rs2069837 within IL-6 obviously decreased the luciferase expression activity. When analyzing the effect of this variant on the IL-6 in the serum based on the rs2069837 genotype, we found that the A to G variation in rs2069837 decreased the expression of IL-6, especially in the male. Overall, we identified a genetic variant in IL-6 that protects against critical conditions with COVID-19 though decreasing IL-6 expression in the serum.

Background: Neutrophil extracellular traps (NETs) are closely associated to tumorigenesis and development. However, the relationship between NETs-related long non-coding RNAs (lncRNAs) and the characteristics of breast tumor remains an enigma. This study aimed to explore the clinical prognostic value of NETs-related lncRNAs, their correlation with the tumor microenvironment (TME) and their predictive ability of drug sensitivity in patients with breast cancer (BC).Methods: The expression profiles of RNA-sequencing and relevant clinical data of BC patients were extracted from TCGA database. The co-expression network analysis, univariable, least absolute shrinkage and selection operator (LASSO) and multivariable Cox algorithms were employed to construct the NETs-related lncRNAs signature. A nomogram was established and validated to explore the clinical application. Furthermore, the immune microenvironment and drug sensitivity for BC with different prognostic risks were explored. Finally, the expression pattern of lncRNAs was validated using qRT-PCR in BC tissues and their adjacent non-cancerous tissues.Results: Based on NETs-related lncRNAs, a prognostic risk model consisted of 10 lncRNAs (SFTA1P, ACTA2-AS1, AC004816.2, AC000067.1, LINC01235, LINC01010, AL133467.1, AC092919.1, AL591468.1, and MIR200CHG) was established. The Kaplan-Meier analysis showed that the overall survival (OS) was significantly better in low-risk BC patients than in high-risk BC patients (Ptraining cohort < 0.001, Pvalidation cohort = 0.009). The nomogram also showed good predictive accuracy for OS of BC individuals in both training and validation cohorts. The function enrichment analysis revealed that high-risk group was mainly enriched in immune-related functions and pathways, and the tumor mutation burden in this group was markedly higher than that in the low-risk group (p = 0.022). Moreover, significant differences were observed in immune cells, immune functions and immune checkpoint genes among BC patients at different risks (p < 0.05). The response to chemotherapeutic agents and immunotherapy were also closely related with the expression of NETs-related lncRNAs (p < 0.001). The expression of lncRNAs from experimental validation were generally consistent with the bioinformatics analysis results.Conclusion: Our study provided a novel prognostic model for BC and yielded strong scientific rationale for individualized treatment strategies, elucidating immunotherapy in BC patients.

The role of MIR31 in the wound healing process, specifically in vocal fold wound healing (VFWH), remains uncertain despite its potential to facilitate the process. In this study, we first constructed a literature-based pathway to examine both the positive and negative effects of MIR31 on wound healing. We then conducted animal experiments on 20 rats to investigate MIR31 expression at different time points (1, 4, and 8 weeks) after vocal fold injury. Co-expression analysis and pathway analysis were performed to explore the potential function of MIR31 in VFWH. The literature-based pathway suggested that MIR31 could both impede and promote the wound healing process by regulating 14 and 47 wound healing upstream regulators, respectively. However, the rat experiment indicated that MIR31 expression significantly increased after vocal fold injury (p

The aim of this in vitro study was to evaluate the effect of three final irrigants, namely QMix, MTAD and EDTA, combined with three irrigation techniques, namely conventional needle irrigation (CNI), passive ultrasonic irrigation (PUI) and photon-induced photoacoustic streaming (PIPS), on smear layer removal, dentin mineral content and microhardness in oval-shaped canals. 130 decoronated premolars with single, oval root canals were equally divided into1 blank control group and 12 treatment groups (n=10) according to the final irrigation protocols. Roots in treatment groups were instrumented with ProTaper Gold to size F4 and subjected to final irrigation. Smear layer removal was assessed by using a four-level scoring system under an environmental scanning electron microscope. Energy dispersive X-ray spectroscopy was performed to measure the dentin mineral content. Dentin microhardness was measured by Knoop microhardness testing. Statistical analysis of the data was performed by using Kruskal-Wallis test, followed by Dunn’s post hoc test with Bonferroni correction. PUI- and PIPS-activated QMix and EDTA removed smear layer more effectively than MTAD groups (p

After years of service, bridges could lose their expected functions. Considering the significant number of bridges and the adverse inspecting environment, the urgent requirement for timely and efficient inspection solutions, such as computer vision techniques, have been attractive in recent years, especially for those bridge components with poor accessibility. In this paper, a lightweight procedure for bridge apparent-defect detection is proposed, including a crack annotation method and crack detection. First of all, in order to save computational costs and improve generalization performance, we propose herein a relative-breakpoint annotation method to build a crack instance segmentation dataset, a critical process for a supervised vision-based crack detection method. Then, the trained models based on classic Mask RCNN and Yolact are transferred to evaluate the effectiveness of the proposed method. To verify the correctness, universality and generality of the proposed crack-detection framework, approximately 800 images are used for model training, while nearly 100 images are saved for validation. Results show that the crack instance segmentation model can achieve a level of 90% for both accuracy and recall values, with a limited dataset.

Nematode-trapping fungi are widely studied due to their unique morphological structure, survival strategy, and potential value in the biological control of harmful nematodes. During the identification of carnivorous fungi preserved in our laboratory, five novel nematode-trapping fungi were established and placed in the genera Arthrobotrys and Drehslerella based on morphological and multigene (ITS, TEF, and RPB2) phylogenetic analyses. A. hengjiangensis sp. nov. and A. weixiensis sp. nov. are characterized by producing adhesive networks to catch nematodes. Dr. pengdangensis sp. nov., Dr. tianchiensis sp. nov., and Dr. yunlongensis sp. nov. are characterized by producing constricting rings. Morphological descriptions, illustrations, taxonomic notes, and phylogenetic analysis are provided for all new taxa; a key for Drechslerella species is listed; and some deficiencies in the taxonomy and evolution study of nematode-trapping fungi are also discussed herein.

Conidia fusion (CF) is a commonly observed structure in fungi. However, it has not been systematically studied. This study examined 2457 strains of nematode-trapping fungi (NTF) to explore the species specificity, physiological period, and physiological significance of CF. The results demonstrated that only six species of Arthrobotrys can form CF among the sixty-five tested NTF species. The studies on the model species Arthrobotrys oligospora (DL228) showed that CF occurred in both shed and unshed plus mature and immature conidia. Additionally, the conidia fusion rate (CFR) increased significantly with the decrease of nutrient concentration in habitats. The studies on the conidia fusion body (CFB) produced by A. oligospora (DL228) revealed that the more conidia contained in the CFB, the faster and denser the mycelia of the CFB germinated in weak nutrient medium and soil plates. On the one hand, rapid mycelial extension is beneficial for the CFB to quickly find new nutrient sources in habitats with uneven nutrient distribution. On the other hand, dense mycelium increases the contact area with the environment, improving the nutrient absorption efficiency, which is conducive to improving the survival rate of conidia in the weak nutrient environment. In addition, all species that form CF produce smaller conidia. Based on this observation, CF may be a strategy to balance the defects (nutrient deficiency) caused by conidia miniaturization.

Sound has a potential impact on animal welfare and production, but the impacts of soundscapes on aquaculture species in different aquaculture production systems have been rarely studied. This study investigated the impact of varying aquaculture soundscapes on largemouth bass (Micropterus salmoides). Three soundscapes were administered to replicated tanks: Recirculating Aquaculture System (RAS:107.7 dB re 1 Pa RMS), In-Pond Raceway System (IPRS:115.1 dB re 1 Pa RMS), and Ambient (70.4 dB re 1 Pa RMS) as the control. The initial weight of fish in the three groups was 3.59 ± 0.30 g. Following a 50-day experimental period, the average weight of the Ambient group (14.08 ± 0.13 g) was significantly greater than that of the IPRS group (12.79 ± 0.08 g) (p < 0.05). Examination of physiological samples revealed that the soundscape negatively impacted the fish’s immunological, anti-oxidation, and digestive enzymes. Furthermore, the external noise also influenced the locomotive patterns of the fish aggregations. Fish polarity and cohesion were significantly more discrete (p < 0.05) in both the RAS (47.79 ± 2.34° and 98.52 ± 3.22 mm) and IPRS groups (48.04 ± 0.70° and 87.70 ± 7.31 mm) compared to the Ambient group (42.76 ± 1.42° and 85.73 ± 1.57 mm). These results highlight the significant impacts of the aquaculture soundscape on the development, physiological activities, and behavioral traits of largemouth bass. Future research should focus on determining and optimizing the impact of different equipment noise to ensure optimal welfare and production performance in aquaculture systems.

Trajectory similarity search (TSS) is a common operation for spatiotemporal data analysis. However, the existing TSS methods are mainly focused on GPS trajectories produced by moving objects such as vehicles. Further, these corresponding optimization strategies cannot be directly applied in the metro scenario because the metro passenger trajectory is totally different from the GPS trajectory. To fill this gap, we systematically analyze the unique spatiotemporal characteristics of metro passenger trajectories and propose a similarity search solution named PMMTss for the metro system. The core idea of this solution has two key points: first, we design a multi-layer index based on the spatiotemporal feature of metro trajectories, and all points of a trajectory are stored in this index. Second, we design a parallel multi-way merging-based trajectory similar search method, in which the candidate trajectory segments are merged and filtered. We evaluate this solution on a large dataset (Shenzhen Metro data for 3 consecutive months, 6.976 million trajectories with 260 million records). When lengths of input trajectories are 16, 32, and 64, respectively, the corresponding search times are 0.004 s, 0.016 s, and 0.036 s, respectively. Compared to the baseline PPJion+, the query times are reduced by 99.7%, 98.8%, and 97.6%, respectively.

The treatment of long-gap (>10 mm) peripheral nerve injury (PNI) and spinal cord injury (SCI) remains a continuous challenge due to limited native tissue regeneration capabilities. The current clinical strategy of using autografts for PNI suffers from a source shortage, while the pharmacological treatment for SCI presents dissatisfactory results. Tissue engineering, as an alternative, is a promising approach for regenerating peripheral nerves and spinal cords. Through providing a beneficial environment, a scaffold is the primary element in tissue engineering. In particular, scaffolds with anisotropic structures resembling the native extracellular matrix (ECM) can effectively guide neural outgrowth and reconnection. In this review, the anatomy of peripheral nerves and spinal cords, as well as current clinical treatments for PNI and SCI, is first summarized. An overview of the critical components in peripheral nerve and spinal cord tissue engineering and the current status of regeneration approaches are also discussed. Recent advances in the fabrication of anisotropic surface patterns, aligned fibrous substrates, and 3D hydrogel scaffolds, as well as their in vitro and in vivo effects are highlighted. Finally, we summarize potential mechanisms underlying the anisotropic architectures in orienting axonal and glial cell growth, along with their challenges and prospects.

Background: Clear cell renal cell carcinoma (ccRCC) is considered the second most common urogenital tract carcinoma, plaguing patients worldwide due to its high incidence and resistance to treatment. Thus, it is urgent to screen new biomarkers and decipher their molecular mechanisms to support early clinical diagnosis and targeted therapy of ccRCC. It is reported that epithelial membrane protein 3 (EMP3) acts as a tumor-promoting or suppressing factor in a variety of malignant tumors, but its relationship with ccRCC remains to be explored. Methods: The Cancer Genome Atlas (TCGA) and Oncomine database were utilized to screen the differentially expressed genes in ccRCC. Western blot and qPCR were used to verify the expression of our subject of interest, EMP3 in ccRCC tissues and cell lines. Next, a series of functional experiments were conducted to explore the biological functions of EMP3 in tumor cells, including cell counting kit-8, transwell, wound healing assays, Oil red O staining and triglyceride determination. Western blotting was used to explore the potential mechanism of EMP3 induced ccRCC deterioration. Finally, the TIMER2.0 database was used to explore the effect of EMP3 on tumor immune infiltration and its relationship with multiple immune checkpoints. Results: In this study, we uncovered that EMP3 was more prominently expressed in ccRCC and its expression level had a significant positive correlation with the clinical stage and histopathological grade of tumor patients. Based on the TCGA database, the Receiver operating characteristic (ROC) curves showed that EMP3 could be potentially utilized as a specific biomarker in diagnosing ccRCC patients. Meanwhile, six independent prognostic factors were determined and integrated into our nomogram, with an OS concordance index (C-index) of 0.760 (95% CI: 0.689–0.831). Furthermore, in vitro depletion of EMP3 could alleviate the proliferation, migration, invasion, and lipid storage in ccRCC cells. Mechanistically, EMP3 was shown to enhance the malignant potential of tumor cells by promoting epithelial-mesenchymal transition (EMT) and lipid accumulation. In addition, the expression of EMP3 was closely related to the infiltration of a variety of immune cells, and was positively related to PD-L1, suggesting that it may be a tight connection with tumor immune escape. Conclusions: Our results revealed that EMP3 might be a candidate biomarker and independent prognostic indicator, and related to EMT process, lipid accumulation, as well as immune infiltration in ccRCC. Targeted EMP3 therapy might be a promising and effective treatment strategy for ccRCC patients.

Recent progress in bioresorbable stents (BRSs) has provided a promising alternative for treating coronary artery disease. However, there is still lack of BRSs with satisfied compression and degradation performance for pediatric patients with congenital heart disease, leading to suboptimal therapy effects. Here, we developed a mechanically self-reinforced composite bioresorbable stent (cBRS) for congenital heart disease application. The cBRS consisted of poly(p-dioxanone) monofilaments and polycaprolactone/poly(p-dioxanone) core-shell composite yarns. Interlacing points in cBRS structure were partially bonded, offering the cBRS with significantly higher compression force compared to typical braids and remained good compliance. The suitable degradation profile of the cBRS can possibly preserve vascular remodeling and healing process. In addition, the controllable structural organization provides a method to customize the performance of the cBRS by altering the proportion of different components in the braids. The in vivo results suggested the cBRS supported the vessel wall similar to that of metallic stent. In both abdominal aorta and iliac artery of porcine, cBRS was entirely endothelialized within 1 month and maintained target vessels with good patency in the 12-month follow-up. The in vivo degradation profile of the cBRS is consistent with static degradation results in vitro. It is also demonstrated that there is minimal impact of pulsatile pressure of blood flow and variation of radial force on the degradation rate of the cBRS. Moreover, the lumen of cBRS implanted vessels were enlarged after 6 months, and significantly larger than the vessels implanted with metallic stent in 12 months.

Abstract SARS-CoV-2 mutations contribute to increased viral transmissibility and immune escape, compromising the effectiveness of existing vaccines and neutralizing antibodies. An in-depth investigation on COVID-19 pathogenesis is urgently needed to develop a strategy against SARS-CoV-2 variants. Here, we identified CD147 as a universal receptor for SARS-CoV-2 and its variants. Meanwhile, Meplazeumab, a humanized anti-CD147 antibody, could block cellular entry of SARS-CoV-2 and its variants—alpha, beta, gamma, and delta, with inhibition rates of 68.7, 75.7, 52.1, 52.1, and 62.3% at 60 μg/ml, respectively. Furthermore, humanized CD147 transgenic mice were susceptible to SARS-CoV-2 and its two variants, alpha and beta. When infected, these mice developed exudative alveolar pneumonia, featured by immune responses involving alveoli-infiltrated macrophages, neutrophils, and lymphocytes and activation of IL-17 signaling pathway. Mechanistically, we proposed that severe COVID-19-related cytokine storm is induced by a “spike protein-CD147-CyPA signaling axis”: Infection of SARS-CoV-2 through CD147 initiated the JAK-STAT pathway, which further induced expression of cyclophilin A (CyPA); CyPA reciprocally bound to CD147 and triggered MAPK pathway. Consequently, the MAPK pathway regulated the expression of cytokines and chemokines, which promoted the development of cytokine storm. Importantly, Meplazumab could effectively inhibit viral entry and inflammation caused by SARS-CoV-2 and its variants. Therefore, our findings provided a new perspective for severe COVID-19-related pathogenesis. Furthermore, the validated universal receptor for SARS-CoV-2 and its variants can be targeted for COVID-19 treatment.

Invasive species have caused severe impacts on biodiversity and human society. Although the estimation of environmental impacts caused by invasive species has increased in recent years, economic losses associated with biological invasions are only sporadically estimated in space and time. In this study, we synthesized the losses incurred by invasions in Asia, based on the most comprehensive database of economic costs of invasive species worldwide, including 560 cost records for 88 invasive species in 22 countries. We also assessed the differences in economic costs across taxonomic groups, geographical regions and impacted sectors, and further identified the major gaps of current knowledge in Asia. Reported economic costs of biological invasions were estimated between 1965 and 2017, and reached a total of US$ 432.6 billion (2017 value), with dramatic increases in 2000–2002 and in 2004. The highest costs were recorded for terrestrial ectotherms, for species estimated in South Asia, and for species estimated at the country level, and were related to more than one impacted sector. Two taxonomic groups with the highest reported costs were insects and mammals, and two countries with the highest costs were India and China. Non-English data covered all of 12 taxonomic groups, whereas English data only covered six groups, highlighting the importance of considering data from non-English sources to have a more comprehensive estimation of economic costs associated with biological invasions. However, we found that the estimation of economic costs was lacking for most Asian countries and for more than 96% of introduced species in Asia. Further, the estimation is heavily biased towards insects and mammals and is very limited concerning expenditures on invasion management. To optimize the allocation of limited resources, there is an important need to better and more widely study the economic costs of invasive alien species. In this way, improved cost reporting and more collaborations between scientists and stakeholders are needed across Asia.

Fusarium crown rot (FCR) caused by Fusarium pseudograminearum is one of the most serious soil-borne diseases of wheat. Among 58 bacterial isolates from the rhizosphere soil of winter wheat seedlings, strain YB-1631 was found to have the highest in vitro antagonism to F. pseudograminearum growth. LB cell-free culture filtrates inhibited mycelial growth and conidia germination of F. pseudograminearum by 84.14% and 92.23%, respectively. The culture filtrate caused distortion and disruption of the cells. Using a face-to-face plate assay, volatile substances produced by YB-1631 inhibited F. pseudograminearum growth by 68.16%. In the greenhouse, YB-1631 reduced the incidence of FCR on wheat seedlings by 84.02% and increased root and shoot fresh weights by 20.94% and 9.63%, respectively. YB-1631 was identified as Bacillus siamensis based on the gyrB sequence and average nucleotide identity of the complete genome. The complete genome was 4,090,312 bp with 4357 genes and 45.92% GC content. In the genome, genes were identified for root colonization, including those for chemotaxis and biofilm production, genes for plant growth promotion, including those for phytohormones and nutrient assimilation, and genes for biocontrol activity, including those for siderophores, extracellular hydrolase, volatiles, nonribosomal peptides, polyketide antibiotics, and elicitors of induced systemic resistance. In vitro production of siderophore, β-1, 3-glucanase, amylase, protease, cellulase, phosphorus solubilization, and indole acetic acid were detected. Bacillus siamensis YB-1631 appears to have significant potential in promoting wheat growth and controlling wheat FCR caused by F. pseudograminearum.

Prefabricated concrete hollow slab bridges are widely used in short- and medium-span highway bridges in China due to the advantages of high production quality, installation convenience, and low construction cost. Field investigation shows that severe hinge joint damage occurred during the service life, and mechanical performance of the bridges also deteriorated with the weakened joints. It is important to accurately evaluate the performance of hollow slab bridges to ensure the safety of the highway system. In this paper, transverse connectivity and durability of the concrete hollow slab bridges are investigated in a field test using the surface damage and neural networks. Hollow slab bridges in the Wu-He highway system were taken as the background bridge. Surface damage was visually checked and statistically analyzed. Static load test was conducted to evaluate the transverse connectivity of the hinge joints based on the girder responses. The hollow slab bridges were then demolished, and a total of 75 concrete girder segments were cut off. Durability of the girders was evaluated based on the conditions of concrete and rebars, and the analytic hierarchy process along with the fuzzy comprehensive evaluation method was employed. Results showed that there were two main types of the defects in the hollow slab bridges, i.e., the transverse cracks on the bottom plates of the girders and the longitudinal cracks in the hinge joints. The distribution of the deflection of each girder was non-uniform due to the weakening of the transverse connectivity, and the girders in the background bridges were within the moderate deterioration condition after 25 years’ service life. An evaluation method of the hollow slab girders using the neural networks and surface damage was verified by the field test data. The maximum crack width at different locations of the bridges was used in the input layer of the neural network, and the hinge joint damage or the durability was considered as the output results. The prediction error of the method in the test set was within 15.0% for the hinge joint damage and within 40% for the durability result of the girder, indicating the feasibility of the evaluation method.

The evolution of carnivorous fungi in deep time is still poorly understood as their fossil record is scarce. The approximately 100-million-year-old Cretaceous Palaeoanellus dimorphus is the earliest fossil of carnivorous fungi ever discovered. However, its accuracy and ancestral position has been widely questioned because no similar species have been found in modern ecosystems. During a survey of carnivorous fungi in Yunnan, China, two fungal isolates strongly morphologically resembling P. dimorphus were discovered and identified as a new species of Arthrobotrys (Orbiliaceae, Orbiliomycetes), a modern genus of carnivorous fungi. Phylogenetically, Arthrobotrys blastospora sp. nov. forms a sister lineage to A. oligospora. A. blastospora catches nematodes with adhesive networks and produces yeast-like blastospores. This character combination is absent in all other previously known modern carnivorous fungi but is strikingly similar to the Cretaceous P. dimorphus. In this paper, we describe A. blastospora in detail and discuss its relationship to P. dimorphus.

High accumulation of hyaluronan (HA) in the tumor microenvironment leads to an increase in the interstitial pressure and reduction perfusion of drugs. Furthermore, high molecular-weight (HMW)-HA suppresses M1 macrophage polarization, enhances M2 polarization, and induces immunosuppression. Hyaluronidase treatment have attempted to decrease the quantity of HA in tumors. However, hyaluronidase-driven HA degradation driven accelerates tumor cell metastasis, which is a major cause of mortality in cancer patients. Thus, we designed a novel exosome-based drug delivery system (DDS), named Exos-PH20-FA, using genetic engineering to express human hyaluronidase (PH20) and self-assembly techniques to modify the exosomes with folic acid (FA). Our results show that Exos-PH20-FA degraded HMW-HA to low-molecular-weight (LMW)-HA. Moreover, LMW-HA polarized macrophages to the M1 phenotype and reduced the number of relevant immunosuppressive immunocytes which changed the immune microenvironment from an immunosuppressive to immunosupportive phenotype. Furthermore, we demonstrated Exos-PH20-FA directly reduced hyaluronidase-induced metastasis of tumor cells. This tumor treatment also allowed an enhanced delivery of chemotherapy by tumor-targeting effect with FA modification. Our findings indicate that Exos-PH20-FA improves tumor treatment efficiency and reduces the side effects of hyaluronidase treatment, namely tumor cell metastasis. This all-in-one exosome-based HA targeting DDS maybe a promising treatment that yields more efficient and safer results.

The large number of dormant microorganisms present in the environment is an important component of microbial diversity, and neglecting dormant microorganisms would be disruptive to all research under the science of microbial diversity. However, current methods can only predict the dormancy potential of microorganisms in a sample and are not yet able to monitor dormant microorganisms directly and efficiently. Based on this, this study proposes a new method for the identification of dormant microorganisms based on high-throughput sequencing technology: Revived Amplicon sequence variants (ASV) Monitoring (RAM). Pao cai (Chinese fermented vegetables) soup was used to construct a closed experimental system, and sequenced samples were collected at 26 timepoints over a 60-day period. RAM was used to identify dormant microorganisms in the samples. The results were then compared with the results of the currently used gene function prediction (GFP), and it was found that RAM was able to identify more dormant microorganisms. In 60 days, GFP monitored 5045 ASVs and 270 genera, while RAM monitored 27,415 ASVs and 616 genera, and the RAM results were fully inclusive of the GFP results. Meanwhile, the consistency of GFP and RAM was also found in the results. The dormant microorganisms monitored by both showed a four-stage distribution pattern over a 60-day period, with significant differences in the community structure between the stages. Therefore, RAM monitoring of dormant microorganisms is effective and feasible. It is worth noting that the results of GFP and RAM can complement and refer to each other. In the future, the results obtained from RAM can be used as a database to extend and improve the monitoring of dormant microorganisms by GFP, and the two can be combined with each other to build a dormant microorganism detection system.

Overarching themes in the terminal differentiation of the enteric nervous system, an autonomously acting unit of animal nervous systems, have so far eluded discovery. We describe here the overall regulatory logic of enteric nervous system differentiation of the nematode Caenorhabditis elegans that resides within the foregut (pharynx) of the worm. A C. elegans homolog of the Drosophila Sine oculis homeobox gene, ceh-34, is expressed in all 14 classes of interconnected pharyngeal neurons from their birth throughout their life time, but in no other neuron type of the entire animal. Constitutive and temporally controlled ceh-34 removal shows that ceh-34 is required to initiate and maintain the neuron type-specific terminal differentiation program of all pharyngeal neuron classes, including their circuit assembly. Through additional genetic loss of function analysis, we show that within each pharyngeal neuron class, ceh-34 cooperates with different homeodomain transcription factors to individuate distinct pharyngeal neuron classes. Our analysis underscores the critical role of homeobox genes in neuronal identity specification and links them to the control of neuronal circuit assembly of the enteric nervous system. Together with the pharyngeal nervous system simplicity as well as its specification by a Sine oculis homolog, our findings invite speculations about the early evolution of nervous systems.

The dysregulation of iron homeostasis has been explored in malignancies. However, studies focusing on the association between the serum iron level and prognosis of patients with early-stage triple-negative breast cancer (TNBC) are scarce. Accordingly, in current study, 272 patients with early-stage TNBC treated at Sun Yat-sen University Cancer Center (SYSUCC) between September 2005 and October 2016 were included as a training cohort, another 86 patients from a previous randomized trial, SYSUCC-001, were analyzed as a validation cohort (SYSUCC-001 cohort). We retrospectively collected their clinicopathological data and tested the serum iron level using blood samples at the diagnosis. In the training cohort, patients were divided into low-iron and high-iron groups according to the serum iron level cut-off of 17.84 μmol/L determined by maximally selected rank statistics. After a median follow-up of 87.10 months, patients with a low iron had a significantly longer median disease-free survival (DFS) of 89.13 [interquartile range (IQR): 66.88–117.38] months and median overall survival (OS) of 92.85 (IQR: 68.83–117.38) months than those in the high-iron group (median DFS: 75.25, IQR: 39.76–105.70 months, P = 0.015; median OS: 77.17, IQR: 59.38–110.28 months, P = 0.015). Univariate and multivariate Cox analysis demonstrated the serum iron level to be an independent predictor for DFS and OS. Then, a prognostic nomogram incorporating the serum iron level, T stage and N stage was developed for individualized prognosis predictions. It had good discriminative ability with a C-index of DFS (0.729; 95% CI 0.666–0.792) and OS (0.739; 95% CI 0.666–0.812), respectively. Furtherly, we validated the predictive model in the SYSUCC-001 cohort, which also showed excellent predictive performance with a C-index of DFS (0.735; 95% CI 0.614–0.855) and OS (0.722; 95% CI 0.577–0.867), respectively. All these suggested that the serum iron level might be a potential prognostic biomarker for patients with early-stage TNBC, the predictive model based on it might be served as a practical tool for individualized survival predictions.

Background: Altered copper levels have been observed in several cancers, but studies on the relationship between serum copper and early-stage triple-negative breast cancer (TNBC) remain scare. We sought to establish a predictive model incorporating serum copper levels for individualized survival predictions.Methods: We retrospectively analyzed clinicopathological information and baseline peripheric blood samples of patients diagnosed with early-stage TNBC between September 2005 and October 2016 at Sun Yat-sen University Cancer Center. The optimal cut-off point of serum copper level was determined using maximally selected log-rank statistics. Kaplan-Meier curves were used to estimate survival probabilities. Independent prognostic indicators associated with survival were identified using multivariate Cox regression analysis, and subsequently, prognostic nomograms were established to predict individualized disease-free survival (DFS) and overall survival (OS). The nomograms were validated in a separate cohort of 86 patients from the original randomized clinical trial SYSUCC-001 (SYSUCC-001 cohort).Results: 350 patients were eligible in this study, including 264 in the training cohort and 86 in the SYSUCC-001 cohort. An optimal cut-off value of 21.3 μmol/L of serum copper was determined to maximally divide patients into low- and high-copper groups. After a median follow-up of 87.1 months, patients with high copper levels had significantly worse DFS (p = 0.002) and OS (p < 0.001) than those with low copper levels in the training cohort. Multivariate Cox regression analysis revealed that serum copper level was an independent factor for DFS and OS. Further, prognostic models based on serum copper were established for individualized predictions. These models showed excellent discrimination [C-index for DFS: 0.689, 95% confidence interval (CI): 0.621–0.757; C-index for OS: 0.728, 95% CI: 0.654–0.802] and predictive calibration, and were validated in the SYSUCC-001 cohort.Conclusion: Serum copper level is a potential predictive biomarker for patients with early-stage TNBC. Predictive nomograms based on serum copper might be served as a practical tool for individualized prognostication.

The mechanistic target of rapamycin (mTOR) complex 1, mTORC1, integrates nutrient and growth factor signals with cellular responses and plays critical roles in regulating cell growth, proliferation, and lifespan. mTORC1 signaling has been reported as a central regulator of autophagy by modulating almost all aspects of the autophagic process, including initiation, expansion, and termination. An increasing number of studies suggest that mTORC1 and autophagy are critical for the physiological function of skeletal muscle and are involved in diverse muscle diseases. Here, we review recent insights into the essential roles of mTORC1 and autophagy in skeletal muscles and their implications in human muscle diseases. Multiple inhibitors targeting mTORC1 or autophagy have already been clinically approved, while others are under development. These chemical modulators that target the mTORC1/autophagy pathways represent promising potentials to cure muscle diseases.

Background: Endoplasmic reticulum stress (ERS) is a key part of the apoptotic cascade that is initiated after cerebral ischemia-reperfusion injury and is very important for research on poststroke rehabilitation. In addition, the unfolded protein response (UPR) plays an important role in ERS because it activates downstream apoptotic signal transduction and induces apoptosis through the glucose-regulated protein 78 (GRP78)/protein kinase R (PKR)-like ER kinase (PERK)/activating transcription factor 4 (ATF4) pathway. The Gua Lou Gui Zhi Decoction (GLGZD) ameliorated neuronal apoptosis of ischemia-reperfusion injury caused by middle cerebral artery occlusion (MCAO) had been proved in our previous study. The present study aims to underly the regulatory ability of GLGZD in ERS-induced apoptosis mediated by the GRP78/PERK/ATF4 pathway. Methods: GLGZD was analyzed by HPLC. The effects of GLGZD were obversed on MCAO-induced ischemic rats. The cerebral infarct volume was detected by 2,3,5-Triphenyl-2H-Tetrazolium Chloride (TTC) Staining. Terminal Deoxynucleotidyl Transferase-Mediated dUTP-Biotin Nick End Labeling (TUNEL) were used to detect apoptosis. Transmission Electron Microscopy (TEM), Ca2+ levels and reactive oxygen species (ROS) detection were used to determine the function of endoplasmic reticulum. The GRP78/PERK/ATF4 signaling pathway was assessed by western blotting and immunohistochemistry. Results: Our results showed that GLGZD exerted its effects on ischemia-reperfusion injury by significantly promoting the restoration of the quantity and morphology of the rough ER and reducing the neuronal apoptosis rate in the ischemic cortex. Moreover, both of the intracellular ROS and Ca2+ levels in ischemic cortical cells were found significantly reduced by GLGZD. The GLGZD-treated group showed increased levels of phosphorylation in both of PERK and eukaryotic translation initiation factor 2α (eIF2α), activation of cysteinyl aspartate-specific proteinase-3 (Caspase-3), upregulation of the total protein levels of sarcoplasmic/endoplasmic Ca2+ ATPase 2α (SERCA 2α) and B-cell leukemia/lymphoma gene 2 (Bcl-2). Conclusions: These findings suggest that GLGZD reduces oxidative stress-induced injury and promotes a dynamic calcium balance, thereby inhibiting ERS and exerting an antiapoptotic effect on neuronal ischemic injury, which are closely related to the activation of GRP78/PERK/ATF4 signaling pathway.

The mechanisms that underpin the species–area relationship (SAR) are crucial for both the development of biogeographic theory and the application of biodiversity conservation. Since its origin, the resource hypothesis, which proposes that rich resources in vast ecosystems will lower extinction rates and shape the SAR, has not been tested. The impossibility to quantify resources and extinction rates using plants and animals as research subjects, as well as the inability to rule out the influences of the area per se, habitat diversity, dispersal, and the historical background of biodiversity, make testing this hypothesis problematic. To address these challenges and test this hypothesis, two sets of microbial microcosm experimental systems with positive and negative correlated resources and volumes were created in this work. The results of 157 high-throughput sequencing monitoring sessions at 11 time points over 30 consecutive days showed that neither of the experimental groups with positive or negative correlations between total resources and microcosm volume had a significant SAR, and there were no negative correlations between extinction rates and resources. Therefore, in our microcosmic system, resources do not influence extinction rates or shape the SAR. Dispersal should be the principal mode of action if the resource theory is correct.

Small waterbodies are a unique aquatic ecosystem with an increasing recognition for their important role in maintaining regional biodiversity and delivering ecosystem services. However, small waterbodies in Northwest Yunnan, one of the most concerned global biodiversity hot-spots, remain largely unknown. Here, we investigated the community structure of crustacean zooplankton and their relationships with limnological, morphometric and spatial variables in the highland small waterbodies in Northwest Yunnan in both the dry (October 2015) and rainy (June 2016) seasons. A total of 38 species of crustacean zooplankton were identified in our study, which is significantly higher than many other reported waterbodies in the Yunnan–Guizhou plateau as well as in the Yangtze River basin. This suggests that the highland small waterbodies are critical in maintaining regional zooplankton diversity in Northwest Yunnan. Meanwhile, we found limnological variables could explain most variation of crustacean zooplankton community, comparing to the morphometric and spatial variables in both the rainy and dry seasons. Our study revealed the diversity and community structure of crustacean zooplankton in the highland small waterbodies in Northwest Yunnan and highlighted the importance of small waterbodies in maintaining regional biodiversity.

The aim of this study is to predict the influenced zone of deep excavation on adjacent tunnel displacement, evaluate the control effect of ground improvement, and give the optimal parameters for ground improvement. Based on the current research, a series of finite element method (FEM) numerical simulations were conducted to study the deep excavation-induced tunnel displacement behaviors, considering different tunnel positions outside the pit. On this basis, the influenced zone of deep excavation on an adjacent tunnel was divided corresponding to 3-level tunnel displacement control standards. Then, the commonly used control measure of ground improvement was chosen to study the effects of strength, depth, and width of the improved soil outside the pit on the displacement behaviors of the tunnel. An index of tunnel displacement control effectiveness (η) was proposed to quantitively characterize the control effect on tunnel displacement. Considering the control effect and engineering economy, the suggested values of strength, depth, and width of the improved soil were provided. Finally, the control effect of ground improvement outside the pit on the influenced zone of deep excavation was studied using the suggested parameters. The research indicates that the range outside the pit can be divided into: I—primary influenced zone, II—secondary influenced zone, III—general influenced zone, and IV—weak influenced zone. Considering the control effect and engineering economy, it is suggested that the ground improvement strength should be kept within 1.5~2 MPa, the ground improvement depth should be 2 times the excavation depth, and the ground improvement width should be increased as much as possible if the site condition allows. After the ground improvement using the suggested parameters, the scope of the influenced zone of deep excavation is reduced and the I—primary influenced zone no longer exists.