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Abstract Rapeseed (Brassica napus L.) is a major oilseed crop in the middle and lower reaches of the Yangtze River in China. However, it is susceptible to waterlogging stress. This study aimed to investigate the physiological characteristics, cellular changes, and gene expression patterns of rapeseed under waterlogging stress, with the goal of providing a foundation for breeding waterlogging-tolerant rapeseed. The results revealed that waterlogging-tolerant rapeseed exhibited higher levels of soluble sugars and antioxidant enzyme activity, particularly in the roots. Conversely, waterlogging-sensitive rapeseed displayed greater changes in malondialdehyde, proline, and hydrogen peroxide levels. Cellular observations showed that after experiencing waterlogging stress, the intercellular space of rapeseed leaf cells expanded, leading to disintegration of mitochondria and chloroplasts. Moreover, the area of the root xylem increased, the number of vessels grew, and there were signs of mitochondrial disintegration and vacuole shrinkage, with more pronounced changes observed in waterlogging-sensitive rapeseed. Furthermore, significant differences were found in the transcription levels of genes related to anaerobic respiration and flavonoid biosynthesis, and different varieties demonstrated varied responses to waterlogging stress. In conclusion, there are differences in the response of different varieties to waterlogging stress at the levels of morphology, physiological characteristics, cell structure, and gene transcription. Waterlogging-tolerant rapeseed responds to waterlogging stress by regulating its antioxidant defense system. This study provides valuable insights for the development of waterlogging-tolerant rapeseed varieties.

The flesh color of pummelo (Citrus maxima) fruits is highly diverse and largely depends on the level of carotenoids, which are beneficial to human health. It is vital to investigate the regulatory network of carotenoid biosynthesis to improve the carotenoid content in pummelo. However, the molecular mechanism underlying carotenoid accumulation in pummelo is not fully understood. In this study, we identified a novel histone methyltransferase gene, CgSDG40, involved in carotenoid regulation by analyzing the flesh transcriptome of typical white-fleshed pummelo, red-fleshed pummelo and extreme-colored F1 hybrids from a segregated pummelo population. Expression of CgSDG40 corresponded to flesh color change and was highly coexpressed with CgPSY1. Interestingly, CgSDG40 and CgPSY1 are located physically adjacent to each other on the chromosome in opposite directions, sharing a partially overlapping promoter region. Subcellular localization analysis indicated that CgSDG40 localizes to the nucleus. Overexpression of CgSDG40 significantly increased the total carotenoid content in citrus calli relative to that in wild type. In addition, expression of CgPSY1 was significantly activated in overexpression lines relative to wild type. Taken together, our findings reveal a novel histone methyltransferase regulator, CgSDG40, involved in the regulation of carotenoid biosynthesis in citrus and provide new strategies for molecular design breeding and genetic improvement of fruit color and nutritional quality.

AbstractMacrophages play a crucial role in tumor initiation and progression, while macrophage-associated gene signature in colorectal cancer (CRC) patients has not been investigated. Our study aimed to identify macrophage-related molecular subgroups and develop a macrophage-related risk model to predict CRC prognosis. The mRNA expression profile and clinical information of CRC patients were obtained from TCGA and GEO databases. CRC patients from TCGA were divided into high and low macrophage subgroups based on the median macrophage score. The ESTIMATE and CIBERSORT algorithms were used to assess immune cell infiltration between subgroups. GSVA and GSEA analyses were performed to investigate differences in enriched pathways between subgroups. Univariate and LASSO Cox regression were used to build a prognostic risk model, which was further validated in the GSE39582 dataset. A high macrophage score subgroup was associated with poor prognosis, highly activated immune-related pathways and an immune-active microenvironment. A total of 547 differentially expressed macrophage-related genes (DEMRGs) were identified, among which seven genes (including RIMKLB, UST, PCOLCE2, ZNF829, TMEM59L, CILP2, DTNA) were identified by COX regression analyses and used to build a risk score model. The risk model shows good predictive and diagnostic values for CRC patients in both TCGA and GSE39852 datasets. Furthermore, multivariate Cox regression analysis showed that the risk score was an independent risk factor for overall survival in CRC patients. Our findings provided a novel insight into macrophage heterogeneity and its immunological role in CRC. This risk score model may serve as an effective prognostic tool and contribute to personalised clinical management of CRC patients.

Studies on odontogenesis are of great importance to treat dental abnormalities and tooth loss. However, the odontogenesis process was poorly studied in humans, especially at the early developmental stages. Here, we combined RNA sequencing (RNA-seq) with Laser-capture microdissection (LCM) to establish a spatiotemporal transcriptomic investigation for human deciduous tooth germs at the crucial developmental stage to offer new perspectives to understand tooth development and instruct tooth regeneration. Several hallmark events, including angiogenesis, ossification, axonogenesis, and extracellular matrix (ECM) organization, were identified during odontogenesis in human dental epithelium and mesenchyme from the cap stage to the early bell stage. ECM played an essential role in the shift of tooth-inductive capability. Species comparisons demonstrated these hallmark events both in humans and mice. This study reveals the hallmark events during odontogenesis, enriching the transcriptomic research on human tooth development at the early stage.

Glaucoma is a chronic ocular disease characterized by optic atrophy and visual field defect. The main risk factor for glaucoma onset and progression is elevated intraocular pressure, which is caused by increased aqueous humor outflow resistance. Currently, the primary method for glaucoma therapy is the use of intraocular pressure lowering drugs. However, these drugs, when administered through eye drops, have low bioavailability, require frequent administration, and often result in adverse effects. To overcome these challenges, the application of nanotechnology for drug delivery has emerged as a promising approach. Nanoparticles can physically adsorb, encapsulate, or chemically graft drugs, thereby improving their efficacy, retention time, and reducing adverse reactions. Moreover, nanotechnology has opened up new avenues for ocular administration. This article provides a comprehensive review of nano systems for intraocular pressure lowering drugs, encompassing cholinergic agonists, β-adrenergic antagonists, α-adrenergic agonists, prostaglandin analogs, carbonic anhydrase inhibitors, Rho kinase inhibitors, and complex preparations. The aim is to offer novel insights for the development of nanotechnology in the field of intraocular pressure lowering drugs.

Abstract Germline-somatic mutation interactions are universal and associated with tumorigenesis, but their role in breast cancer, especially in non-Caucasians, remains poorly characterized. We performed large-scale prospective targeted sequencing of matched tumor-blood samples from 4079 Chinese females, coupled with detailed clinical annotation, to map interactions between germline and somatic alterations. We discovered 368 pathogenic germline variants and identified 5 breast cancer DNA repair-associated genes (BCDGs; BRCA1/BRCA2/CHEK2/PALB2/TP53). BCDG mutation carriers, especially those with two-hit inactivation, demonstrated younger onset, higher tumor mutation burden, and greater clinical benefits from platinum drugs, PARP inhibitors, and immune checkpoint inhibitors. Furthermore, we leveraged a multiomics cohort to reveal that clinical benefits derived from two-hit events are associated with increased genome instability and an immune-activated tumor microenvironment. We also established an ethnicity-specific tool to predict BCDG mutation and two-hit status for genetic evaluation and therapeutic decisions. Overall, this study leveraged the large sequencing cohort of Chinese breast cancers, optimizing genomics-guided selection of DNA damaging-targeted therapy and immunotherapy within a broader population.

Abstract Apoptosis releases numerous apoptotic vesicles that regulate processes such as cell proliferation, immunity, and tissue regeneration and repair. Now, it has also emerged as an attractive candidate for biotherapeutics. However, apoptotic vesicles encompass a diverse range of subtypes, and it remains unclear which specific subtypes play a pivotal role. In this study, we successfully isolated different apoptotic vesicle subtypes based on their sizes and characterized them using NTA and TEM techniques, respectively. We compared the functional variances among the distinct subtypes of apoptotic vesicles in terms of stem cell proliferation, migration, and differentiation, as well as for endothelial cell and macrophage function, effectively identifying subtypes that exhibit discernible functional differences. ApoSEV (with diameter 1000 nm) played the opposite effect on cell function and tissue regeneration. Lastly, employing protein analysis and gene sequencing techniques, we elucidated the intrinsic mechanisms underlying these differences between different subtypes of apoEVs. Collectively, this study identified that apoptotic vesicle subtypes possessed distinct bio‐functions in regulating stem cell function and behaviour and modulating tissue regeneration, which primarily attribute to the distinct profiling of protein and mRNA in different subtypes. This comprehensive analysis of specific subtypes of apoEVs would provide novel insights for potential therapeutic applications in cell biology and tissue regeneration.

Extracellular polymeric substances (EPS) constitutes crucial elements within bacterial biofilms, facilitating accelerated antimicrobial resistance and conferring defense against the host's immune cells. Developing precise and effective antibiofilm approaches and strategies, tailored to the specific characteristics of EPS composition, can offer valuable insights for the creation of novel antimicrobial drugs. This, in turn, holds the potential to mitigate the alarming issue of bacterial drug resistance. Current analysis of EPS compositions relies heavily on colorimetric approaches with a significant bias, which is likely due to the selection of a standard compound and the cross-interference of various EPS compounds. Considering the pivotal role of EPS in biofilm functionality, it is imperative for EPS research to delve deeper into the analysis of intricate compositions, moving beyond the current focus on polymeric materials. This necessitates a shift from heavy reliance on colorimetric analytic methods to more comprehensive and nuanced analytical approaches. In this study, we have provided a comprehensive summary of existing analytical methods utilized in the characterization of EPS compositions. Additionally, novel strategies aimed at targeting EPS to enhance biofilm penetration were explored, with a specific focus on highlighting the limitations associated with colorimetric methods. Furthermore, we have outlined the challenges faced in identifying additional components of EPS and propose a prospective research plan to address these challenges. This review has the potential to guide future researchers in the search for novel compounds capable of suppressing EPS, thereby inhibiting biofilm formation. This insight opens up a new avenue for exploration within this research domain.

Recent developments on the electron optics simulator (EOS) are reported in this paper. The EOS is a finite element two-dimensional (2D) and three-dimensional (3D) electrostatic particle steady-state trajectory code that has been widely used for beam optics modeling of vacuum electronic devices. To extend the application scope and improve the computation efficiency, four significant advances have been made and are presented in this paper. First, the code is reprogrammed to consider physical models that contain dielectrics and to support charge excitation. Second, more primary particle emission models are added in EOS to meet the needs for simulating electron and ion optics devices for diverse applications. For the precise simulation of the secondary electron emission, the Vaughan model is improved, and the Furman model is newly added in EOS. Finally, the algebraic multigrid algorithm has been embedded in EOS, which can significantly improve the computation efficiency for problems with large-scale matrices. For these developments, the necessary principles and corresponding performance are shown in detail in this paper.

Stem cell senescence and exhaustion, a hallmark of aging, lead to declines in tissue repair and regeneration in aged individuals. Emerging evidence has revealed that epigenetic regulation plays critical roles in the self-renew, lineage-commitment, survival, and function of stem cells. Moreover, epigenetic alterations are considered important drivers of stem cell dysfunction during aging. In this review, we focused on current knowledge of the histone modifications in the aging of mesenchymal stem cells (MSCs). The aberrant epigenetic modifications on histones, including methylation and acetylation, have been found in aging MSCs. By disturbing the expression of specific genes, these epigenetic modifications affect the self-renew, survival, and differentiation of MSCs. A set of epigenetic enzymes that write or erase these modifications are critical in regulating the aging of MSCs. Furthermore, we discussed the rejuvenation strategies based on epigenetics to prevent stem cell aging and/or rejuvenate senescent MSCs.

Abstract Microbes well-adapted to the Arctic Ocean are promising for producing novel compounds, due to their fancy strategies for adaptation and being under-investigated. Two new phenazine alkaloids (1 and 2) and one new phenoxazine (3) were isolated from Nocardiopsis dassonvillei 502F, a strain originally isolated from Arctic deep-sea sediments. AntiSMASH analysis of the genome of Nocardiopsis dassonvillei 502F revealed the presence of 16 putative biosynthetic gene clusters (BGCs), including a phenazine BGC. Most of the isolated compounds were evaluated for their antibacterial, antiallergic, and cytotoxic activities. Among them, compounds 4 and 5 exhibited potent in vitro cytotoxic activities against osteosarcoma cell line 143B with IC50 values 0.16 and 20.0 μM, respectively. Besides, the results of antiallergic activities of compounds 6–8 exhibited inhibitory activities with IC50 values of 10.88 ± 3.05, 38.88 ± 3.29, and 2.44 ± 0.17 μg/mL, respectively (IC50 91.6 μM for the positive control loratadine). Graphical Abstract

(1) Background: A rise in intraocular pressure (IOP) and decreased retinal ganglion cells are frequent indicators of effective modeling of chronic ocular hypertension in mice. In this study, the sensitivity of the mouse model to pharmaceutical therapy to reduce intraocular tension was assessed, the model’s safety was confirmed using a cytotoxicity test, and the success rate of the mouse model of ocular hypertension was assessed by assessing alterations in IOP and neurons in the ganglion cell layer. (2) Methods: A mouse model of chronic ocular hypertension was produced in this study by employing photocrosslinkable sericin hydrogel injection and LED lamp irradiation. The eyes of 25 C57BL/6 male mice were subjected to 405 nm UV light from the front for 2 min after being injected with 5 μL of sericin hydrogel in the anterior chamber of the left eye. IOP in the mice was measured daily, and IOP rises greater than 5 mmHg were considered intraocular hypertension. When the IOP was lowered, the intervention was repeated once, but the interval between treatments was at least 2 weeks. The right eyes were not treated with anything as a normal control group. Mice eyeballs were stained with HE, Ni-type, and immunofluorescence to assess the model’s efficacy. Two common drugs (tafluprost eye drops and timolol eye drops) were provided for one week after four weeks of stable IOP, and IOP changes were assessed to determine the drug sensitivity of the mouse model of chronic ocular hypertension. Furthermore, CellTiter 96® AQueous One Solution Cell Proliferation Assay (MTS) was utilized to investigate the safety of the ocular hypertension model by evaluating the deleterious effects of photocrosslinkable sericin hydrogel on cells. (3) Results: Before injection, the basal IOP was (9.42 ± 1.28) mmHg (1 kPa = 7.5 mmHg) in the experimental group and (9.08 ± 1.21) in the control group. After injection, cataract occurred in one eye, corneal edema in one eye, endophthalmitis in one eye, iris incarceration in one eye, and eyeball atrophy in one eye. Five mice with complications were excluded from the experiment, and twenty mice were left. Four weeks after injection, the IOP of the experimental group was maintained at (19.7 ± 4.52) mmHg, and that of the control group was maintained at (9.92 ± 1.55) mmHg, and the difference between the two groups was statistically significant (p < 0.05). Before the intervention, the IOP in the experimental group was (21.7 ± 3.31) mmHg in the high IOP control group, (20.33 ± 2.00) mmHg in the tafluprost eye drops group, and (20.67 ± 3.12) mmHg in the timolol maleate eye drops group. The IOP after the intervention was (23.2 ± 1.03) mmHg, (12.7 ± 2.11) mmHg, and (10.4 ± 1.43) mmHg, respectively. Before and after the intervention, there were no significant differences in the high-IOP control group (p > 0.05), there were statistically significant differences in the timolol eye drops group (p < 0.05), and there were statistically significant differences in the tafluprost eye drops group (p < 0.05). One week after drug withdrawal, there was no significant difference in IOP among the three groups (p > 0.05). In the high-IOP group, the protein (sericin hydrogel) showed a short strips or fragmented structure in the anterior chamber, accompanied by a large number of macrophages and a small number of plasma cells. The shape of the chamber angle was normal in the blank control group. The number of retinal ganglion cells decreased significantly 8 weeks after injection of sericin hydrogel into the anterior chamber, and the difference was statistically significant compared with the blank control group (p < 0.05). After the cells were treated with photocrosslinkable sericin hydrogel, there was no significant difference in the data of the CellTiter 96® assay kit of MTS compared with the blank control group (p > 0.05). (4) Conclusions: A mouse model of chronic intraocular hypertension can be established successfully by injecting sericin in the anterior chamber and irradiating with ultraviolet light. The model can simulate the structural and functional changes of glaucoma and can effectively reduce IOP after the action of most antihypertensive drugs, and it is highly sensitive to drugs. Sericin has no obvious toxic effect on cells and has high safety.

Abstract Soil salinization is a growing issue that limits agriculture globally. Understanding the mechanism underlying salt tolerance in halophytic grasses can provide new insights into engineering plant salinity tolerance in glycophytic plants. Seashore paspalum (Paspalum vaginatum Sw.) is a halophytic turfgrass and genomic model system for salt tolerance research in cereals and other grasses. However, the salt tolerance mechanism of this grass largely unknown. To explore the correlation between Na+ accumulation and salt tolerance in different tissues, we utilized two P. vaginatum accessions that exhibit contrasting tolerance to salinity. To accomplish this, we employed various analytical techniques including ICP-MS-based ion analysis, lipidomic profiling analysis, enzyme assays, and integrated transcriptomic and metabolomic analysis. Under high salinity, salt-tolerant P. vaginatum plants exhibited better growth and Na+ uptake compared to salt-sensitive plants. Salt-tolerant plants accumulated heightened Na+ accumulation in their roots, leading to increased production of root-sourced H2O2, which in turn activated the antioxidant systems. In salt-tolerant plants, metabolome profiling revealed tissue-specific metabolic changes, with increased amino acids, phenolic acids, and polyols in roots, and increased amino acids, flavonoids, and alkaloids in leaves. High salinity induced lipidome adaptation in roots, enhancing lipid metabolism in salt-tolerant plants. Moreover, through integrated analysis, the importance of amino acid metabolism in conferring salt tolerance was highlighted. This study significantly enhances our current understanding of salt-tolerant mechanisms in halophyte grass, thereby offering valuable insights for breeding and genetically engineering salt tolerance in glycophytic plants.

ObjectiveThis systematic review and meta-analysis aimed to evaluate the prevalence of frailty and pre-frailty in older adults with diabetes; and to identify the risk factors associated with frailty in this population.DesignSystematic review and meta-analysis.Participants24,332 people aged 60 years and older with diabetes.MethodsSix databases were searched (PubMed, Embase, the Cochrane Library, Web of Science, China Knowledge Resource Integrated Database, and Chinese Biomedical Database) up to 15 January 2024. Random effects models were used in instances of significant heterogeneity. Subgroup analysis and meta-regression were conducted to identify the potential source of heterogeneity. The Agency for Healthcare Research and Quality (AHRQ) and the Newcastle-Ottawa Scale (NOS) were applied to assess the quality of included studies.Results3,195 abstracts were screened, and 39 full-text studies were included. In 39 studies with 24,332 older people with diabetes, the pooled prevalence of frailty among older adults with diabetes was 30.0% (95% CI: 23.6%-36.7%). Among the twenty-one studies involving 7,922 older people with diabetes, the pooled prevalence of pre-frailty was 45.1% (95% CI: 38.5%-51.8%). The following risk factors were associated with frailty among older adults with diabetes: older age (OR = 1.08, 95% CI: 1.04-1.13, pConclusionsThis suggests that clinical care providers should be vigilant in identifying frailty and risk factors of frailty while screening for and intervening in older adults with diabetes. However, there are not enough studies to identify comprehensive risk factors of frailty in older adults with diabetes.Trial registrationPROSPERO registration number: CRD42023470933.

IntroductionRadiation exposure in medical settings stands as the primary source of artificial radiation, compounded by the yearly rise in healthcare worker numbers. Ensuring radiation protection is crucial for safeguarding their occupational health. Nevertheless, existing studies on radiation protection behavior exhibit considerable heterogeneity due to various factors.ObjectiveThis scoping review aims to explore the current status of research on radiation protection behavior and identify research gaps, intending to guide future research directions.Methods and analysisThe scoping review will follow the Arksey and O'Malley framework and the Joanna Briggs Institute methodology. A systematic search will be conducted across English databases including PubMed, Web of Science, Embase, and Medline, as well as Chinese databases such as CNKI, Wanfang, VIP, and China Biomedical Literature Database. Two independent reviewers will screen the studies based on predefined eligibility criteria and extract the data. Any disagreements will be resolved through discussion by a third reviewer. The review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews.Strengths and limitations of this studyA stakeholder consultation will provide an opportunity to validate the findings and address any potential gaps in the article. In this scoping review, all types of studies will be considered. The effectiveness of the methodological quality of the included studies will not be reported, which may lead to some studies of poor quality being included. Only studies published in English or Chinese after 2010 will be considered in this review, potentially leading to the omission of relevant papers.

BackgroundCentral catheter bloodstream infections (CRBSI) is a major cause of healthcare-associated infections. However, few factors are generally accepted and some studies have conflicting finding about some factors, possibly caused by limitation associated with an individual study. This study was to identify risk factors for CRBSI in intensive care units.MethodsWe searched the PubMed, Cochrane Library, Web of science and EMBASE databases and the 4 top Chinese-language databases, including WanFang data, China National Knowledge Infrastructure (CNKI), and Chinese Science and Technology Journal Database (VIP), China Biology Medicine disc (CBM) as of July 2023. Case control and cohort studies were included. Two authors independently screened the literature and evaluated the quality of the studies using the Newcastle-Ottawa scale (NOS). The pooled effect size was estimated using the odds ratio (OR), and the corresponding 95% confidence interval (CI) was calculated. The Cochrane Q (χ2) and I2 tests were used to assess heterogeneity among studies, and each risk factor was tested for its robustness using fixed- or random-effects models.FindingsA total of 32 studies enrolled, among which eleven factors were identified, they were divided into two categories: modifiable and unmodifiable factors. Modifiable factors: duration of catheterization (≥ 5d) (OR: 2.07, 95%CI: 1.41-3.03), duration of catheterization (≥ 7d) (OR: 3.62, 95%CI: 2.65-4.97), duration of catheterization (≥ 14d)(OR: 4.85, 95%CI: 3.35-7.01), total parenteral nutrition (OR: 2.27,95%CI: 1.56-3.29), use of multiple-lumen catheters(OR: 3.41, 95%CI: 2.27-5.11), times of tube indwelling (OR: 3.50, 95%CI: 2.93-4.17), length of ICU stay (OR: 4.05, 95%CI: 2.41-6.80), the position of indwelling(OR: 2.41, 95%CI: 2.03-2.85); Unmodifiable factors: APACHEII scores (OR: 1.84, 95%CI: 1.54-2.20), Age≥ 60 years old (OR: 2.19, 95%CI: 1.76-2.73), the extensive use of antibiotic (OR: 3.54, 95%CI: 1.65-7.61), Diabetes mellitus (OR: 3.06, 95%CI: 2.56-3.66), Immunosuppression (OR: 2.87, 95%CI: 2.08-3.95).ConclusionsEffective interventions targeting the above modifiable factors may reduce the risk of developing CRBSI in ICU and improve the clinical outcome of patients. Further prospective studies are needed to confirm these findings.

AbstractThe southeastern margin of the Bayanhar block (BHB) is located at the junction of the Bayanhar block and the southern China block (SCB). Strong earthquakes occurred frequently in this region because of the intensive tectonic movement. The stress changes caused by strong earthquakes and the observed background seismicity can be used to forecast strong earthquake probability in this region. Therefore, we construct a 3D (three Dimension) viscoelastic finite element model that includes the complex fault system, inhomogeneous medium, tectonic stress, and gravity to simulate the evolutionary stress field when using the observed Global Positioning System (GPS) vectors as the boundary conditions. In addition, we calculate the strong earthquake probability based on the calculated stress and a Poisson probability distribution. The stress evolution result shows the Xianshuihe fault (XSHF), the Huya fault (HYF) and the southern segment except for the Yaan County of Longmenshan fault (LMSF) are located in the stress enhancement area indicating high seismic potential. However, the Minjiang fault (MJF) is located in the stress shadow area. After the Lushan and Jiuzhaigou earthquakes, there is still a high possibility of strong earthquakes in the MJF, HYF, and LMSF zone, according to the strong earthquake probability result.

Abstract Background To examine the levels of exosome-derived connexin 43 (Cx43) in plasma and estimate its forecast value in patients with melanoma. Methods We measured the plasma exosome-derived Cx43 levels in the plasma of 112 melanoma patients and 50 healthy controls. Results The plasma exosome-derived Cx43 levels in patients with melanoma were substantially downregulated as opposed to the levels in healthy controls (P

Residue contact maps provide a condensed two-dimensional representation of three-dimensional protein structures, serving as a foundational framework in structural modeling but also as an effective tool in their own right in identifying inter-helical binding sites and drawing insights about protein function. Treating contact maps primarily as an intermediate step for 3D structure prediction, contact prediction methods have limited themselves exclusively to sequential features. Now that AlphaFold2 predicts 3D structures with good accuracy in general, we examine (1) how well predicted 3D structures can be directly used for deciding residue contacts, and (2) whether features from 3D structures can be leveraged to further improve residue contact prediction. With a well-known benchmark dataset, we tested predicting inter-helical residue contact based on AlphaFold2’s predicted structures, which gave an 83% average precision, already outperforming a sequential features-based state-of-the-art model. We then developed a procedure to extract features from atomic structure in the neighborhood of a residue pair, hypothesizing that these features will be useful in determining if the residue pair is in contact, provided the structure is decently accurate, such as predicted by AlphaFold2. Training on features generated from experimentally determined structures, we leveraged knowledge from known structures to significantly improve residue contact prediction, when testing using the same set of features but derived using AlphaFold2 structures. Our results demonstrate a remarkable improvement over AlphaFold2, achieving over 91.9% average precision for a held-out subset and over 89.5% average precision in cross-validation experiments.

Abstract Background Triple‐negative breast cancer (TNBC) presents the most challenging subtype of all breast cancers because of its aggressive clinical phenotypes and absence of viable therapy targets. In order to identify effective molecular targets for treating patients with TNBC, we conducted an integration analysis of our recently published TNBC dataset of quantitative proteomics and RNA‐Sequencing, and found the abnormal upregulation of chromosome 9 open reading frame 142 (C9orf142) in TNBC. However, the functional roles of C9orf142 in TNBC are unclear. Methods In vitro and in vivo functional experiments were performed to assess potential roles of C9orf142 in TNBC. Immunoblotting, real‐time quantitative polymerase chain reaction (RT‐qPCR), and immunofluorescent staining were used to investigate the expression levels of C9orf142 and its downstream molecules. The molecular mechanisms underlying C9orf142‐regulated mouse double minute 2 (MDM2)‐binding protein (MTBP) were determined by chromatin immunoprecipitation (ChIP) and dual‐luciferase reporter assays. Results In TNBC tissues and metastatic lymph nodes, we observed that C9orf142 exhibited abnormal up‐regulation, and its elevated expression was indicative of unfavorable prognosis for TNBC patients. Both in vitro and in vivo functional experiments demonstrated that C9orf142 accelerated TNBC growth and metastasis. Further mechanism exploration revealed that C9orf142 transcriptionally activated MTBP, thereby regulating its downstream MDM2/p53/p21 signaling axis and the transition of cell cycle from G1 to S phase. Functional rescue experiment demonstrated that knockdown of MTBP attenuated C9orf142‐mediated tumour growth and metastasis. Furthermore, depletion of C9orf142 remarkably increased the responsiveness of TNBC cells to CDK4/6 inhibitor abemaciclib. Conclusions Together, these findings unveil a previously unrecognized effect of C9orf142 in TNBC progression and responsiveness to CDK4/6 inhibitor, and emphasize C9orf142 as a promising intervention target for TNBC treatment.

The international investment arbitration system between investors and host countries originated from the international commercial arbitration system. International investment disputes are usually disputes caused by the host country’s policies to protect public interests and the dissatisfaction of private investors caused by regulations. There are few methods for intelligently recommending judgment documents based on factual texts in international investment arbitration cases. Because of this, this paper proposes a recommendation algorithm for international investment arbitration adjudication documents based on multimodal feature fusion. This paper teaches the structural information of paragraph tags and the relationship between paragraph contexts and incomplete judgment documents. The algorithm achieves a good structuring effect of international investment arbitration documents.

Abstract Triple‐negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, which is characterized by high heterogeneity and metabolic dysregulation. Inositol monophosphatase 1(IMPA1) is critical for the metabolism of inositol, which has profound effects on gene expression and other biological processes. Here, we report for the first time that IMPA1 was upregulated in TNBC cell lines and tissues, and enhanced cell colony formation and proliferation in vitro and tumorigenicity in vivo. Additionally, IMPA1 promoted cell motility in vitro and metastatic lung colonization in vivo. Mechanistic investigations by transcriptome sequencing revealed that 4782 genes were differentially expressed between cells with IMPA1 knockdown and control cells. Among the differentially expressed genes after IMPA1 knockdown, five significantly altered genes were verified via qRT‐PCR assays. Morerover, we found that the expression profile of those five targets as a gene set was significantly associated with IMPA1 status in TNBC cells. As this gene set was associated with mTOR pathway and epithelial‐mesenchymal transition (EMT) process, we further confirmed that IMPA1 induced mTOR activity and EMT process, which at least in part contributed to IMPA1‐induced TNBC progression. Collectively, our findings reveal a previously unrecognized role of IMPA1 in TNBC progression and identify IMPA1 as a potential target for TNBC therapy.

Abstract Orthodontic tooth movement relies on bone remodeling and periodontal tissue regeneration in response to the complicated mechanical cues on the compressive and tensive side. In general, mechanical stimulus regulates the expression of mechano-sensitive coding and non-coding genes, which in turn affects how cells are involved in bone remodeling. Growing numbers of non-coding RNAs, particularly mechano-sensitive non-coding RNA, have been verified to be essential for the regulation of osteogenesis and osteoclastogenesis and have revealed how they interact with signaling molecules to do so. This review summarizes recent findings of non-coding RNAs, including microRNAs and long non-coding RNAs, as crucial regulators of gene expression responding to mechanical stimulation, and outlines their roles in bone deposition and resorption. We focused on multiple mechano-sensitive miRNAs such as miR-21, - 29, -34, -103, -494-3p, -1246, -138-5p, -503-5p, and -3198 that play a critical role in osteogenesis function and bone resorption. The emerging roles of force-dependent regulation of lncRNAs in bone remodeling are also discussed extensively. We summarized mechano-sensitive lncRNA XIST, H19, and MALAT1 along with other lncRNAs involved in osteogenesis and osteoclastogenesis. Ultimately, we look forward to the prospects of the novel application of non-coding RNAs as potential therapeutics for tooth movement and periodontal tissue regeneration.

Simulations of the spontaneous rupture of potential earthquakes in the vicinity of reservoir dams can provide accurate parameters for seismic resilience assessment, which is essential for improving the seismic performance of reservoir dams. In simulations of potential spontaneous ruptures, fault geometry, regional stress fields, constitutive parameters of the fault friction law, and many other factors control the slip rate, morphology, and dislocation of the rupture, thereby affecting the simulated ground motion parameters. The focus of this study was to elucidate the effects of the background stress field on the nucleation and propagation of spontaneous ruptures based on the factors influencing potential M > 7 earthquake events on the Leibo Middle Fault (LBMF) and the Mabian-Yanjing Fault (MB-YJF) in the Xiluodu dam (XLD) region. Our simulation results show that the magnitude of the regional background stress field plays a decisive role in whether a destructive earthquake exceeding the critical magnitude will occur. We found that the direction and magnitude of the regional stress significantly affect the range of rupture propagation on the fault plane, and fault geometry affects the spatial distribution of the rupture range. Under the same regional stress field magnitude and orientation, a more destructive, high-magnitude earthquake is more likely to occur on the LBMF than on the MB-YJF.

Objective The ASTRUM-005 trial showed that serplulimab plus chemotherapy (SEP) significantly extended survival time compared with chemotherapy in the treatment of small cell lung cancer. But the survival benefits of SEP came at high costs, and its economy is not clear. Therefore, this study aimed to evaluate the cost-effectiveness of SEP from the perspective of the Chinese healthcare system.Design A partition survival model was built to simulate the outcomes. The clinical data came from the ASTRUM-005 trial, and only direct medical costs were included in the model. The utility values referred to the published literature. Scenario analyses 1 and 2 explored outcomes in the presence of a patient assistance plan (PAP) and different simulation periods, respectively. Scenario analysis 3 compared the cost-effectiveness of atezolizumab plus chemotherapy (AEP) with SEP by network meta-analysis. Sensitivity analyses were conducted to assess the robustness of the results.Outcome measures Total costs, incremental costs, life years, quality-adjusted life years (QALYs), incremental QALYs and incremental cost-effectiveness ratio (ICER).Results Compared with chemotherapy, SEP achieved an additional 0.34 QALYs at incremental costs of US$41 682.63, with an ICER of US$122 378.86/QALY. When PAP was available, ICER was US$58 316.46/QALY. In the simulation time of 5 years and 20 years, the ICER was US$132 637.97/QALY and US$118 054.59/QALY, respectively. When compared with AEP, SEP not only reduced the costs by US$47 244.87 but also gained 0.07 QALYs more. Sensitivity analyses showed that the price of serplulimab and the utility value of the progression-free survival stage were the main influencing parameters, and the results were stable.Conclusions Compared with chemotherapy, SEP was not cost-effective from the perspective of the Chinese healthcare system. However, SEP was absolutely dominant in comparison with AEP.

Very Low Frequency (VLF) waves radiated from ground-based transmitters are crucial for long-distance communication and underwater navigation. These waves can reflect between the Earth’s surface and the ionosphere for Earth–ionosphere waveguide propagation. Additionally, they can penetrate not only the ionosphere but also the magnetosphere, where they interact with high-energy particles in the radiation belt. Therefore, studying the spatial and temporal distribution of VLF radio signals holds significant importance. Such research enables us to understand the propagation characteristics of VLF signals, their interaction with radiation belt particles, and their response to space weather and lithospheric activity events. In this paper, we investigate the seasonal variations in the intensity of the Northwest Cape (NWC) transmitter (19.8 kHz) radio signals at satellite altitude and the displacement of the electric field’s peak center. Our analysis is based on the nightly China Seismo-Electromagnetic Satellite (CSES) data from 2019 to 2021. The results reveal the following: (1) There is no significant seasonal variation in the electric field strength within a small area (2.5° radius) around the NWC transmitter. However, a clear seasonal variation in the electric field strength is observed within a larger area (15° radius), with higher strength during winter compared with summer. (2) The power spectral density of the electric field remains constant within the peak central area (approximately 1~2° radius), but it decays with distance outside this region, showing a north–south asymmetry. Moreover, the decay rate of the radiation electric field is slower in the northern direction than in the southern direction. (3) The center of the electric field moves northward from summer to winter and southward from winter to summer. (4) In winter, VLF waves radiated by the NWC transmitter may predominantly propagate by being ducted toward the conjugate hemisphere.

In this study, we reported the complete genome sequence of Shewanella oncorhynchi for the first time. S. oncorhynchi Z-P2 is a bacterium that produces the siderophore putrebactin. Its genome consists of a circular chromosome of 5,034,612 bp with a G + C content of 45.4%. A total of 4544 protein-coding genes, 109 tRNAs and 31 rRNAs were annotated by the RAST. Five non-ribosomal peptide synthetase (NRPS) and polyketide synthetase (PKS) gene clusters were identified by the antiSMASH analysis. The pan-genome analysis of Z-P2 and 10 Shewanella putrefaciens revealed 9228 pan-gene clusters and 2681 core gene clusters, with Z-P2 having 618 unique gene clusters. Additionally, the gene cluster involved in putrebactin biosynthesis in Z-P2 was annotated, and the mechanism of putrebactin biosynthesis was analyzed. The putrebactin produced by Z-P2 was detected using UPLC-MS analysis, with an [M + H]+ molecular ion at m/z 373.21. These findings provide valuable support for further research on the genetic engineering of putrebactin biosynthetic genes of Z-P2 and their potential applications.

BMP7 as a regenerative signaling molecule mediates stem cell migration and odontoblastic differentiation (a) and as a pro-angiogenic factor promotes revascularization of endothelial cells (b). Collagen gel supports cell adhesion, spreading, and viability (c).

Objective The aim is to integrate quantitative and qualitative evidence to understand the effectiveness and experience of advance care planning (ACP) for frail elderly.Design A mixed-methods systematic review and meta-analysis was conducted. Quality evaluation was conducted using critical appraisal tools from the Joanna Briggs Institute. Data were synthesised and pooled for meta-analysis or meta-aggregation as needed.Data sources An electronic search of MEDLINE, CINAHL, Embase, PubMed, PsycINFO, and Cochrane Library databases from January 2003 to April 2022.Eligibility criteria for selecting studies We included experimental and mixed-methods studies. The quantitative component attempts to incorporate a broader study design. The qualitative component aids in comprehending the participant’s experience with ACP and its efficacy.Data extraction and synthesis Two independent reviewers undertook screening, data extraction and quality assessment. The quantitative and qualitative data were synthesised and integrated using a convergent segregated approach.Results There were 12 158 articles found, and 17 matched the inclusion criteria. The quality of the quantitative component of most included studies (6/10) was rated as low, and the qualitative component of half included studies (4/8) was rated as moderate. The meta-analysis showed that the intervention of ACP for frail elderly effectively increases readiness, knowledge and process of ACP behaviours. The meta-aggregation showed that the participants hold a positive attitude towards ACP and think it facilitates expressing their preferences for the medical decision.Conclusion ACP is an effective and feasible strategy to facilitate frail elderly to express their healthcare wishes timely and improve their outcomes. This study could provide proof for a better understanding of the subject and help direct future clinical practice. More well-designed randomised controlled trials evaluating the most effective ACP interventions and tools are needed for the frail elderly population.PROSPERO registration number CRD42022329615.

Cardiovascular disease (CVD) is the leading cause of death globally and poses at significant challenge in terms of effective medical treatment. Leonurus japonicus Houtt, a traditional Chinese herb, is widely used in China for the treatment of obstetrical and gynecological disorders, including menstrual disorders, dysmenorrhea, amenorrhea, blood stasis, postpartum bleeding, and blood-related diseases such as CVD. Stachydrine, the main alkaloid component of Leonurus, has been shown to exhibit a wide range of biological activities including anti-inflammatory, antioxidant, anti-coagulant, anti-apoptotic, vasodilator, angiogenic promoter. Additionally, it has been demonstrated to have unique advantages in the prevention and treatment of CVD through regulation of various disease-related signaling pathways and molecular targets. In this comprehensive review, we examine the latest pharmacological effects and molecular mechanisms of Stachydrine in treating cardiovascular and cerebrovascular diseases. Our aim is to solid scientific basis for the development of new CVD drug formulations.

Abstract Background Microtubule‐targeing agents (MTAs), such as paclitaxel (PTX) and vincristine (VCR), kill cancer cells through activtion of the spindle assembly checkpoint (SAC) and induction of mitotic arrest, but the development of resistance poses significant clinical challenges. Methods Immunoblotting and RT‐qPCR were used to investigate potential function and related mechanism of MORC2. Flow cytometry analyses were carried out to determine cell cycle distribution and apoptosis. The effect of MORC2 on cellular sensitivity to PTX and VCR was determined by immunoblotting, flow cytometry, and colony formation assays. Immunoprecipitation assays and immunofluorescent staining were utilized to investigate protein‐protein interaction and protein co‐localization. Results Here, we identified microrchidia family CW‐type zinc finger 2 (MORC2), a poorly characterized oncoprotein, as a novel regulator of SAC activation, mitotic progression, and resistance of cancer cells to PTX and VCR. Mechanically, PTX and VCR activate cyclin‐dependent kinase 1, which in turn induces MORC2 phosphorylation at threonine 717 (T717) and T733. Phosphorylated MORC2 enhances its interation with HSPA8 and LAMP2A, two essential components of the chaperone‐mediated autophagy (CMA) mechinery, resulting in its autophagic degradation. Degradation of MORC2 during mitosis leads to SAC activation through stabilizing anaphase promoting complex/cyclosome activator protein Cdc20 and facilitating mitotic checkpoint complex assembly, thus contributing to mitotic arrest induced by PTX and VCR. Notably, knockdown of MORC2 promotes mitotic arrest induced by PTX and VCR and enhances the sensitivity of cancer cells to PTX and VCR. Conclusions Collectively, these findings unveil a previously unrecognized function and regulatory mechanism of MORC2 in mitotic progression and resistance of cancer cells to MTAs. These results also provide a new clue for developing combined treatmentstrategy by targeting MORC2 in combination with MTAs against human cancer.

Background and objectiveThe CHOICE-01 trial showed that toripalimab plus chemotherapy achieved satisfactory outcomes compared with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) who were negative for driver genes, but the economics of this regimen is unclear. Therefore, this study aimed to evaluate the cost-effectiveness of toripalimab in combination with chemotherapy in advanced NSCLC with negative driver genes from the perspective of the Chinese healthcare system.Materials and methodsA three-state partitioned survival model was developed to simulate the costs and outcomes associated with adding toripalimab to first-line chemotherapy. The clinical data in the model came from the CHOICE-01 trial, only direct medical costs were included, and utility values were referred to the literature. Four models were applied to explore the differences in the results of fitting and extrapolating K-M curves from different models, and cost-effectiveness subgroup analysis was performed. The incremental cost-effectiveness ratio (ICER) was used as the main outcome measure. Sensitivity analysis was performed to assess the impact of parameter uncertainty on the model.ResultsThe baseline analysis showed that toripalimab coupled with chemotherapy cost $21,052 more than chemotherapy ($43,197 vs. $22,145) and also gained 0.71 QALYs more (1.75 QALYs vs. 1.03 QALYs), with an ICER of $29,478/QALYs. At the current willingness-to-pay threshold ($35,108/QALY), the extra cost was well worth it. The results of fitting and extrapolating the survival curves using other models were consistent with the results of the standard parametric model. Subgroup analysis demonstrated that the addition of toripalimab to chemotherapy was economical. Sensitivity analysis showed that the utility values of PD and PFS stages had the greatest impact on the model.ConclusionFrom the viewpoint of the Chinese healthcare system, toripalimab combined with chemotherapy in the treatment of advanced NSCLC with negative driver genes was likely to be cost-effective compared with chemotherapy.

Abstract As global aging accelerates, the prevention and treatment of age-related bone diseases are becoming a critical issue. In the process of senescence, bone marrow mesenchymal stem cells (BMSCs) gradually lose the capability of self-renewal and functional differentiation, resulting in impairment of bone tissue regeneration and disorder of bone tissue homeostasis. Alteration in epigenetic modification is an essential factor of BMSC dysfunction during aging. Its transferability and reversibility provide the possibility to combat BMSC aging by reversing age-related modifications. Emerging evidence demonstrates that epigenetic therapy based on aberrant epigenetic modifications could alleviate the senescence and dysfunction of stem cells. This review summarizes potential therapeutic targets for BMSC aging, introduces some potential approaches to alleviating BMSC aging, and analyzes its prospect in the clinical application of age-related bone diseases.

Abstract Background Experiencing internship shapes nursing students’ professional commitment and aggravates its changes. However, few studies have been investigated how this changes empirically. Objectives The aims of this study are to investigate (a) what are the changes of professional commitment of nursing students before and after the internship? (b) Which of multiple independent variables is the strongest predictor? Methods A longitudinal study was conducted with 996 senior undergraduate nursing students (ready to enter clinical practice) in the China universities. The survey was conducted in the spring of 2015 and autumn of 2016. The data were collected by a paper-and-pencil questionnaire. The instruments used included Professional Commitment Scale and Perceived Stress Scale. Analysis of paired t-test and linear regression analysis were performed on the data. Results Nursing students showed lower professional commitment (2.79 ± 0.36) than they were (2.92 ± 0.36) before internship. Socio-demographic variables, pre-internship professional commitment and stress perceived during internship predicted 40.1% of the variance in the post-internship commitment. Discussion These data summarize the nursing students’ professional commitment changes and the main influential factors that contribute to post-internship professional commitment of undergraduate nursing student. The findings are timely, which indicate that senior nursing students’ professional commitment can be increased by enhancing pre-internship commitment and reducing students’ stress levels during internship.

Abstract Triple-negative breast cancer (TNBC) is a highly lethal disease due to aggressive clinical phenotype and the lack of validated therapeutic targets. Our recent quantitative proteomic analysis of 90 cases of TNBC tissues and 72 cases of matched adjacent normal tissues revealed that the expression levels of BPTF-associated protein of 18 KDa (BAP18), a component of the MLL1 and NURF chromatin complexes, were upregulated in TNBC tissues relative to normal tissues. However, the biological function and the underlying mechanism of BAP18 in TNBC progression remain unexplored. Here, we report that BAP18 promoted TNBC cell proliferation, migration, and invasion in vitro and xenograft tumor growth and lung colonization in vivo. Mechanistic investigations revealed that S100 calcium-binding protein A9 (S100A9), a member of the S100 protein family that is frequently upregulated in breast tumors and acts as an oncogenic driver in breast cancer progression, was a downstream target gene of BAP18. BAP18 was recruited to histone H3 trimethylation at lysine 4 (H3K4me3)-marked promoter of S100A9 and enhanced its promoter activities. Notably, knockdown of BAP18 by short hairpin RNA in TNBC cells suppressed xenograft tumor growth in mice, the noted effect was partially reverted by re-expression of S100A9 in BAP18-depleted cells. Taken together, these results suggest that BAP18 promotes TNBC progression through, at least in part, transcriptional activation of oncogene S100A9, and represents a potential therapeutic target for TNBC.

Triple-negative breast cancer (TNBC) is the most fatal subtype of breast cancer; however, effective treatment strategies for TNBC are lacking. Therefore, it is important to explore the mechanism of TNBC metastasis and identify its therapeutic targets. Dysregulation of ETHE1 leads to ethylmalonic encephalopathy in humans; however, the role of ETHE1 in TNBC remains elusive. Stable cell lines with ETHE1 overexpression or knockdown were constructed to explore the biological functions of ETHE1 during TNBC progression in vitro and in vivo. Mass spectrometry was used to analyze the molecular mechanism through which ETHE1 functions in TNBC progression. ETHE1 had no impact on TNBC cell proliferation and xenograft tumor growth but promoted TNBC cell migration and invasion in vitro and lung metastasis in vivo. The effect of ETHE1 on TNBC cell migratory potential was independent of its enzymatic activity. Mechanistic investigations revealed that ETHE1 interacted with eIF2α and enhanced its phosphorylation by promoting the interaction between eIF2α and GCN2. Phosphorylated eIF2α in turn upregulated the expression of ATF4, a transcriptional activator of genes involved in cell migration and tumor metastasis. Notably, inhibition of eIF2α phosphorylation through ISRIB or ATF4 knockdown partially abolished the tumor-promoting effect of ETHE1 overexpression. ETHE1 has a functional and mechanistic role in TNBC metastasis and offers a new therapeutic strategy for targeting ETHE1-propelled TNBC using ISRIB.

Interference with quorum sensing (QS) represents an antivirulence strategy with a significant promise for the treatment of bacterial infections and a new approach to restoring antibiotic tolerance. Over the past two decades, a novel series of studies have reported that quorum quenching approaches and the discovery of quorum sensing inhibitors (QSIs) have a strong impact on the discovery of anti-infective drugs against various types of bacteria. The discovery of QSI was demonstrated to be an appropriate strategy to expand the anti-infective therapeutic approaches to complement classical antibiotics and antimicrobial agents. For the discovery of QSIs, diverse approaches exist and develop in-step with the scale of screening as well as specific QS systems. This review highlights the latest findings in strategies and methodologies for QSI screening, involving activity-based screening with bioassays, chemical methods to seek bacterial QS pathways for QSI discovery, virtual screening for QSI screening, and other potential tools for interpreting QS signaling, which are innovative routes for future efforts to discover additional QSIs to combat bacterial infections.

In this paper, a two-stage equalization topology based on Zero-Voltage Switching Quasi-Resonant Converter (ZVS QRC) is proposed to solve the problems of long equalization time and low energy utilization of series lithium-ion battery packs. The equalization topology is divided into two forms: intra-group and inter-group, ZVS QRCs are adopted in both intra-group and inter-group, which can equalize any single cell within a group, and the equalization circuit within each pack can equalize simultaneously, which greatly reduces the equalization time, and reduces the switching loss during the equalization process by introducing quasi-resonant circuit to improve the energy utilization. Taking the State of Charge (SOC) as the equalization target, a group equalization strategy based on the Credibility Factor (C-F) inference model is proposed. The strategy defines the SOC unbalance degree of a single battery, gets the group unbalance degree according to the C-F inference model, and gets the group equalization state from the unbalance degree, to control the group for equalization. Matlab/Simulink software is used to build the model and simulate it. The experimental results demonstrate that the proposed topology saves approximately 25% of the equalization time compared to the traditional Buck-Boost group equalization topology. Under the same static and charge/discharge conditions, the equalization time is reduced by about 21% and the energy utilization is improved by about 6% after using the C-F inference model for equalization compared to the fixed-threshold method.

ABSTRACT Small RNAs (sRNAs) play a very important role in gene regulation at the posttranscriptional level. However, sRNAs from nonmodel microorganisms, extremophiles in particular, have been rarely explored. We discovered a putative sRNA, termed Pf1 sRNA, in Pseudoalteromonas fuliginea BSW20308 isolated from the polar regions in our previous work. In this study, we identified the sRNA and investigated its regulatory role in gene expression under different temperatures. Pf1 sRNA was confirmed to be a new member of the CsrB family but has little sequence similarity with Escherichia coli CsrB. However, Pf1 sRNA was able to bind to CsrA from E. coli and P. fuliginea BSW20308 to regulate glycogen synthesis. The Pf1 sRNA knockout strain (ΔPf1) affected motility, fitness, and global gene expression in transcriptomes and proteomes at 4°C and 32°C. Genes related to carbon metabolism, amino acid metabolism, salinity tolerance, antibiotic resistance, oxidative stress, motility, chemotaxis, biofilm, and secretion systems were differentially expressed in the wild-type strain and the ΔPf1 mutant. Our study suggested that Pf1 sRNA might play an important role in response to environmental changes by regulating global gene expression. Specific targets of the Pf1 sRNA-CsrA system were tentatively proposed, such as genes involved in the type VI secretion system, TonB-dependent receptors, and response regulators, but most of them have an unknown function. Since this is the first study of CsrB family sRNA in Pseudoalteromonas and microbes from the polar regions, it provides a novel insight at the posttranscriptional level into the responses and adaptation to temperature changes in bacteria from extreme environments. This study also sheds light on the evolution of sRNA in extreme environments and expands the bacterial sRNA database. IMPORTANCE Previous research on microbial temperature adaptation has focused primarily on functional genes, with little attention paid to posttranscriptional regulation. Small RNAs, the major posttranscriptional modulators of gene expression, are greatly underexplored, especially in nonpathogenic and nonmodel microorganisms. In this study, we verified the first Csr sRNA, named Pf1 sRNA, from Pseudoalteromonas, a model genus for studying cold adaptation. We revealed that Pf1 sRNA played an important role in global regulation and was indispensable in improving fitness. This study provided us a comprehensive view of sRNAs from Pseudoalteromonas and expanded our understanding of bacterial sRNAs from extreme environments.

The establishment of effective vascularization represents a key challenge in regenerative medicine. Adequate sources of vascular cells and intact vessel fragments have not yet been explored. We herein examined the potential application of microvessels induced from hiPSCs for rapid angiogenesis and tissue regeneration. Microvessels were generated from human pluripotent stem cells (iMVs) under a defined induction protocol and compared with human adipose tissue-derived microvessels (ad-MVs) to illustrate the similarity and differences of the alternative source. Then, the therapeutic effect of iMVs was detected by transplantation in vivo. The renal ischemia-reperfusion model and skin damage model were applied to explore the potential effect of vascular cells derived from iMVs (iMVs-VCs). Besides, the subcutaneous transplantation model and muscle injury model were established to explore the ability of iMVs for angiogenesis and tissue regeneration. The results revealed that iMVs had remarkable similarities to natural blood vessels in structure and cellular composition, and were potent for vascular formation and self-organization. The infusion of iMVs-VCs promoted tissue repair in the renal and skin damage model through direct contribution to the reconstruction of blood vessels and modulation of the immune microenvironment. Moreover, the transplantation of intact iMVs could form a massive perfused blood vessel and promote muscle regeneration at the early stage. The infusion of iMVs-VCs could facilitate the reconstruction and regeneration of blood vessels and modulation of the immune microenvironment to restore structures and functions of damaged tissues. Meanwhile, the intact iMVs could rapidly form perfused vessels and promote muscle regeneration. With the advantages of abundant sources and high angiogenesis potency, iMVs could be a candidate source for vascularization units for regenerative medicine.

ObjectiveTo evaluate the economics of sugemalimab plus chemotherapy in the first-line treatment of metastatic non-small cell lung cancer, and to provide a reference for the formulation of relevant medical insurance policies and rational drug use.MethodsFrom the perspective of the Chinese health system, a three-state partitioned survival model was constructed based on data from a phase III randomized clinical trial (GEMSTONE 302) to evaluate the cost-utility of sugemalimab plus chemotherapy compared with chemotherapy in first-line treatment of metastatic non-small cell lung cancer. Model results were expressed as total cost, life years, quality-adjusted life years, and incremental cost-effectiveness ratio. The robustness of the underlying analysis results was verified using one-way sensitivity analysis and probabilistic sensitivity analysis.ResultsThe results of the base-case analysis showed that sugemalimab plus chemotherapy yielded 1.63 QALYs at a total cost of 130,667.70 USD, chemotherapy yielded 1.04 QALYs at a total cost of 64,001.02 USD, and the ICER was 113,155.52 USD/QALY, which was well above the current willingness-to-pay threshold in China (3 times 2021 per capita GDP) (36,203.88 USD).ConclusionThis study suggests that sugemalimab in combination with a chemotherapy regimen is more effective but not economical for patients with metastatic non-small cell lung cancer receiving first-line therapy in China and that a reasonable reduction in drug prices could improve the probability of it being economical.

Abstract Background Inference of protein’s membership in metabolic pathways has become an important task in functional annotation of protein. The membership information can provide valuable context to the basic functional annotation and also aid reconstruction of incomplete pathways. Previous works have shown success of inference by using various similarity measures of gene ontology. Results In this work, we set out to explore integrating ontology and sequential information to further improve the accuracy. Specifically, we developed a neural network model with an architecture tailored to facilitate the integration of features from different sources. Furthermore, we built models that are able to perform predictions from pathway-centric or protein-centric perspectives. We tested the classifiers using 5-fold cross validation for all metabolic pathways reported in KEGG database. Conclusions The testing results demonstrate that by integrating ontology and sequential information with a tailored architecture our deep neural network method outperforms the existing methods significantly in the pathway-centric mode, and in the protein-centric mode, our method either outperforms or performs comparably with a suite of existing GO term based semantic similarity methods.

Seashore paspalum (Paspalum vaginatum) is a halophytic, warm-season grass which is closely related to various grain crops. Gene duplication plays an important role in plant evolution, conferring significant plant adaptation at the genomic level. Here, we identified 2,542 tandem duplicated genes (TDGs) in the P. vaginatum genome and estimated the divergence time of pairs of TDGs based on synonymous substitution rates (Ks). Expression of P. vaginatum TDGs resulted in enrichment in many GO terms and KEGG pathways when compared to four other closely-related species. The GO terms included: “ion transmembrane transporter activity,” “anion transmembrane transporter activity” and “cation transmembrane transport,” and KEGG pathways included “ABC transport.” RNA-seq analysis of TDGs showed tissue-specific expression under salt stress, and we speculated that P. vaginatum leaves became adapted to salt stress in the earlier whole-genome duplication (WGD; ~83.3 million years ago; Ma), whereas the entire P. vaginatum plant acquired a large number of TDGs related to salt stress in the second WGD (~23.3 Ma). These results can be used as a reference resource to accelerate salt-resistance research in other grasses and crops.

Abstract Background The biofilm state of pathogens facilitates antimicrobial resistance which makes difficult-to-treat infections. In this regard, it has been found that the compounds screened from plant extracts represent one category of the most promising antibiofilm agents. However, the antibiofilm activities and the active ingredients of plant extracts remain largely unexplored. In this background, the study is (1) to screen out the plant extracts with antibiofilm ability against Pseudomonas aeruginosa, and (2) to identify the active ingredients in the plant extracts and elucidate the underlying mechanism of the antibiofilm activities. Methods Micro-broth dilution method, in vitro biofilm model, LC–MS/MS analysis and P. aeruginosa-mouse infection model were adopted to assess the antibiofilm activity. GC–MS analysis was performed to detect the active ingredients in plasma. RNA-Seq, GO analysis, KEGG analysis and RT-qPCR were adopted to elucidate the underlying mechanism of antibiofilm activities against P. aeruginosa. Results Lonicerae Japonicae Flos (LJF) among 13 plants could exert significant inhibitory effects on bacterial biofilm formation, mobility and toxin release in vitro, and it could exert antibiofilm effect in vivo too. Moreover, quinic acid, as one metabolite of chlorogenic acid, was found as an active ingredient in LJF against the biofilm of P. aeruginosa. The active ingredient significantly inhibited EPS secretion in biofilm formation and maturity and could achieve synergistic antibiofilm effect with levofloxacin. It reduced the biofilm formation by regulating core targets in quorum sensing system. In GO process, it was found that the core targets were significantly enriched in multiple biological processes involving locomotion, chemotaxis and motility mediated by flagellum/cilium, which was related to KEGG pathways such as bacterial chemotaxis, oxidative phosphorylation, ribosome, biofilm formation, cyanoamino acid metabolism and quorum sensing. Finally, the binding of quinic acid with core targets rhlA, rhlR and rhlB were validated by molecular docking and RT-qPCR. Conclusions In summary, the study verified the in vitro and in vivo antibiofilm effects of LJF against P. aeruginosa and elucidated the active ingredients in LJF and its conceivable pharmacological mechanism, indicating that quinic acid could have the potential of an antibiofilm agent against P. aeruginosa and related infections. Graphic abstract

N6-methyladenine (6mA) DNA modification has been detected in several eukaryotic organisms, in some of them, it plays important role in the regulation process of stress-resistance response. However, the genome-wide distribution patterns and potential functions of 6mA DNA modification in halophyte Seashore paspalum (Paspalum vaginatum) remain largely unknown. Here, we examined the 6mA landscape in the P. vaginatum genome by adopting single molecule real-time sequencing technology and found that 6mA modification sites were broadly distributed across the P. vaginatum genome. We demonstrated distinct 6mA methylation levels and 6mA distribution patterns in different types of transcription genes, which hinted at different epigenetic rules. Furthermore, the moderate 6mA density genes in P. vaginatum functionally correlated with stress resistance, which also maintained a higher transcriptional level. On the other hand, a specific 6mA distribution pattern in the gene body and near TSS was observed in gene groups with higher RNA expression, which maybe implied some kind of regularity between 6mA site distribution and the protein coding genes transcription was possible. Our study provides new insights into the association between 6mA methylation and gene expression, which may also contribute to key agronomic traits in P. vaginatum.

AIM: To describe the clinical features of acute myopic onset of optic neuropathy and observe the effects of retrobulbar and systemic glucocorticoid therapy in a real-world setting. METHODS: A retrospective observational case series included 18 patients with a clinical diagnosis of acute onset of myopic optic neuropathy in a real-world setting. While the patients were using retrobulbar and systemic glucocorticoid therapy, various imaging examination data were analysed, and the clinical features of myopic optic neuropathy were summarized for 6mo to 2y. RESULTS: The included group of patients with acute onset of myopic optic neuropathy consisted mostly of females (n=11). The visual field (VF) showed abnormalities in bilateral eyes, including the spread of physiological blind spots, central and paracentral dark spots, and centripetal peripheral VF reduction; but central vision with no subjective changes. The visual evoked potential (VEP) was abnormal in all eyes with vision loss. The best corrected visual acuity (BCVA) was improved from 1.04±0.63 to 0.47±0.57 (logMAR) after glucocorticoid treatment (P0.05). There was no recurrence during long-term follow-up observation. CONCLUSION: The acute onset of myopic optic neuropathy is characterized by BCVA and VF abnormalities in bilateral eyes. Retrobulbar and systemic glucocorticoid therapy is effective.

Abstract Background The low survival rate or dysfunction of extracellular matrix (ECM)-based engineered organs caused by the adverse effects of unfavourable local microenvironments on seed cell viability and stemness, especially the effects of excessive reactive oxygen species (ROS), prompted us to examine the importance of controlling oxidative damage for tissue transplantation and regeneration. We sought to improve the tolerance of seed cells to the transplant microenvironment via antioxidant pathways, thus promoting transplant efficiency and achieving better tissue regeneration. Methods We improved the antioxidative properties of ECM-based bioroots with higher glutathione contents in dental follicle stem cells (DFCs) by pretreating cells or loading scaffolds with the antioxidant NAC. Additionally, we developed an in situ rat alveolar fossa implantation model to evaluate the long-term therapeutic effects of NAC in bioroot transplantation. Results The results showed that NAC decreased H2O2-induced cellular damage and maintained the differentiation potential of DFCs. The transplantation experiments further verified that NAC protected the biological properties of DFCs by repressing replacement resorption or ankylosis, thus facilitating bioroot regeneration. Conclusions The following findings suggest that NAC could significantly protect stem cell viability and stemness during oxidative stress and exert better and prolonged effects in bioroot intragrafts.