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PurposeThe purposes of this study were to determine whether biomechanical properties of mature oocytes could predict usable blastocyst formation better than morphological information or maternal factors, and to demonstrate the safety of the aspiration measurement procedure used to determine the biomechanical properties of oocytes.MethodsA prospective split cohort study was conducted with patients from two IVF clinics who underwent in vitro fertilization. Each patient's oocytes were randomly divided into a measurement group and a control group. The aspiration depth into a micropipette was measured, and the biomechanical properties were derived. Oocyte fertilization, day 3 morphology, and blastocyst development were observed and compared between measured and unmeasured cohorts. A predictive classifier was trained to predict usable blastocyst formation and compared to the predictions of four experienced embryologists.Results68 patients and their corresponding 1252 oocytes were included in the study. In the safety analyses, there was no significant difference between the cohorts for fertilization, while the day 3 and 5 embryo development were not negatively affected. Four embryologists predicted usable blastocyst development based on oocyte morphology with an average accuracy of 44% while the predictive classifier achieved an accuracy of 71%. Retaining the variables necessary for normal fertilization, only data from successfully fertilized oocytes were used, resulting in a classifier an accuracy of 81%.ConclusionsTo date, there is no standard guideline or technique to aid in the selection of oocytes that have a higher likelihood of developing into usable blastocysts, which are chosen for transfer or vitrification. This study provides a comprehensive workflow of extracting biomechanical properties and building a predictive classifier using these properties to predict mature oocytes' developmental potential. The classifier has greater accuracy in predicting the formation of usable blastocysts than the predictions provided by morphological information or maternal factors. The measurement procedure did not negatively affect embryo culture outcomes. While further analysis is necessary, this study shows the potential of using biomechanical properties of oocytes to predict embryo developmental outcomes.

Background: Sepsis commonly causes acute respiratory distress syndrome (ARDS), and ARDS contributes to poor prognosis in sepsis patients. Early prediction of ARDS for sepsis patients remains a clinical challenge. This study aims to develop and validate chest computed tomography (CT) radiomic-based signatures for early prediction of ARDS and assessment of individual severity in sepsis patients. Methods: In this ambispective observational cohort study, a deep learning model, a sepsis-induced acute respiratory distress syndrome (SI-ARDS) prediction neural network, will be developed to extract radiomics features of chest CT from sepsis patients. The datasets will be collected from these retrospective and prospective cohorts, including 400 patients diagnosed with sepsis-3 definition during a period from 1 May 2015 to 30 May 2022. 160 patients of the retrospective cohort will be selected as a discovering group to reconstruct the model and 40 patients of the retrospective cohort will be selected as a testing group for internal validation. Additionally, 200 patients of the prospective cohort from two hospitals will be selected as a validating group for external validation. Data pertaining to chest CT, clinical information, immune-associated inflammatory indicators and follow-up will be collected. The primary outcome is to develop and validate the model, predicting in-hospital incidence of SI-ARDS. Finally, model performance will be evaluated using the area under the curve (AUC) of receiver operating characteristic (ROC), sensitivity and specificity, using internal and external validations. Discussion: Present studies reveal that early identification and classification of the SI-ARDS is essential to improve prognosis and disease management. Chest CT has been sought as a useful diagnostic tool to identify ARDS. However, when characteristic imaging findings were clearly presented, delays in diagnosis and treatment were impossible to avoid. In this ambispective cohort study, we hope to develop a novel model incorporating radiomic signatures and clinical signatures to provide an easy-to-use and individualized prediction of SI-ARDS occurrence and severe degree in patients at early stage.

Abstract Background The expression of 2’-5’-oligoadenylate synthetase 1 (OAS1) in lung cancer has been validated in numerous studies. However, the prognostic value of OAS1 expression in lung adenocarcinoma (LUAD) still remains unclear. This study aimed to reveal the prognostic value and associated molecular mechanisms of OAS1 expression in LUAD. Methods Gene expression data of LUAD were extracted from online databases. Gene and protein expression levels of OAS1 in LUAD and normal samples were revealed, followed by prognostic analysis of OAS1. Next, we conducted a thorough bioinformatics analysis to examine the enrichment of key functional and biological signaling pathways and their correlation with the abundance of immune cells. The independent prognoses, drug responses, and PPI networks associated with OAS1 were analyzed. OAS1 expression was evaluated in LUAD tissues and cell lines. OAS1 was knocked down by siRNA transfection, followed by CCK8, colony formation, and wound-healing assays. Results Gene and protein expression levels of OAS1 in LUAD samples were significantly higher than those in normal samples (all P

Background: Circular RNAs (circRNAs) have been identified as playing an integral role in the development of bladder cancer (BC). However, the mechanism by which circRNAs operate in the chemical carcinogenesis of BC remains unclear. Methods: To explore this mechanism, we used RNA high-throughput sequencing to identify differentially expressed circRNA in bladder epithelial cells and chemically induced malignant transformed BC cells. Subsequently, in vitro experiments were conducted to investigate the biological function and molecular mechanism of circLMBR1 in BC. Finally, animal experiments were conducted to examine the clinical relevance of circLMBR1 in vivo. Results: Our profiling of circular RNA expression during cellular malignant transformation induced by chemical carcinogens identified a subset of circRNAs associated with cell transformation. We verified that the expression of circLMBR1 in bladder epithelial malignant transformed cells was decreased compared with control cells, as well as in BC tissues and bladder cell lines. Furthermore, circLMBR1 was seen to inhibit the proliferation, invasion, and migration of BC cells both in vitro and in vivo. Mechanistically, circLMBR1 was found to exert its antitumor effect by binding to the protein ALDH1A3. Conclusions: Our findings have revealed that circLMBR1 inhibits the progression of BC cells by binding to ALDH1A3 and upregulating its expression. As such, circLMBR1 serves as a promising predictor of BC and may provide a novel therapeutic target for the treatment of BC.

Abstract Emerging evidence indicates that transfer RNA (tRNA)‐derived small RNAs (tsRNAs), originated from tRNA with high abundance RNA modifications, play an important role in many complex physiological and pathological processes. However, the biological functions and regulatory mechanisms of modified tsRNAs in cancer remain poorly understood. Here, it is screened for and confirmed the presence of a novel m7G‐modified tsRNA, m7G‐3′‐tiRNA LysTTT (mtiRL), in a variety of chemical carcinogenesis models by combining small RNA sequencing with an m7G small RNA‐modified chip. Moreover, it is found that mtiRL, catalyzed by the tRNA m7G‐modifying enzyme mettl1, promotes bladder cancer (BC) malignancy in vitro and in vivo. Mechanistically, mtiRL is found to specifically bind the oncoprotein Annexin A2 (ANXA2) to promote its Tyr24 phosphorylation by enhancing the interactions between ANXA2 and Yes proto‐oncogene 1 (Yes1), leading to ANXA2 activation and increased p‐ANXA2‐Y24 nuclear localization in BC cells. Together, these findings define a critical role for mtiRL and suggest that targeting this novel m7G‐modified tsRNA can be an efficient way for to treat BC.

Introduction: N6-methyladenosine (m6A) modification contributes to the pathogenesis and development of various cancers, including bladder cancer (BCa). In particular, integrin α6 (ITGA6) promotes BCa progression by cooperatively regulating multisite m6A modification. However, the therapeutic effect of targeting ITGA6 multisite m6A modifications in BCa remains unknown. Objectives: We aim to develop a multisite dCasRx– m6A editor for assessing the effects of the multisite dCasRx–m6A editor targeted m6A demethylation of ITGA6 mRNA in BC growth and progression. Methods: The multisite dCasRx– m6A editor was generated by cloning. m6A-methylated RNA immunoprecipitation (meRIP), luciferase reporter, a single-base T3 ligase-based qPCR-amplification, Polysome profiling and meRIP-seq experiments were performed to determine the targeting specificity of the multisite dCasRx–m6A editor. We performed cell phenotype analysis and used in vivo mouse xenograft models to assess the effects of the multisite dCasRx–m6A editor in BC growth and progression. Results: We designed a targeted ITGA6 multi-locus guide (g)RNA and established a bidirectional deactivated RfxCas13d (dCasRx)-based m6A-editing platform, comprising a nucleus-localized dCasRx fused with the catalytic domains of methyltransferase-like 3 (METTL3-CD) or α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5-CD), to simultaneously manipulate the methylation of ITGA6 mRNA at four m6A sites. The results confirmed the dCasRx–m6A editor modified m6A at multiple sites in ITGA6 mRNA, with low off-target effects. Moreover, targeted m6A demethylation of ITGA6 mRNA by the multisite dCasRx–m6A editor significantly reduced BCa cell proliferation and migration in vitro and in vivo. Furthermore, the dCasRx–ALKBH5-CD and ITGA6 multi-site gRNA delivered to 5-week-old BALB/cJNju-Foxn1nu/Nju nude mice via adeno-associated viral vectors significantly inhibited BCa cell growth. Conclusion: Our study proposes a novel therapeutic tool for the treatment of BC by applying the multisite dCasRx–m6A editor while highlighting its potential efficacy for treating other diseases associated with abnormal m6A modifications.

1. Abstract: Objective: Bladder cancer is one of the most prominent malignancies affecting the urinary tract, characterized by a poor prognosis. Our previous research has underscored the pivotal role of m6A methylation in the progression of bladder cancer. Nevertheless, the precise relationship between N6-methyladenosine (m6A) regulation of long non-coding RNA (lncRNA) and bladder cancer remains elusive. Methods: This study harnessed sequencing data and clinical records from 408 bladder cancer patients in the TCGA database. Employing R software, we conducted bioinformatics analysis to establish an m6A-lncRNA co-expression network. Analyzing the differences between high and low-risk groups, particularly at the immunological level, and subsequently investigating the primary regulatory factors of these lncRNA, validating the findings through experiments, and exploring their specific cellular functions. Results: We identified 50 m6A-related lncRNA with prognostic significance through univariate Cox regression analysis. In parallel, we employed a LASSO-Cox regression model to pinpoint 11 lncRNA and calculate risk scores for bladder cancer patients. Based on the median risk score, patients were categorized into low-risk and high-risk groups. The high-risk cohort exhibited notably lower survival rates than their low-risk counterparts. Further analysis pointed to RBM15 and METTL3 as potential master regulators of these m6A-lncRNA. Experimental findings also shed light on the upregulated expression of METTlL3 and RBM15 in bladder cancer, where they contributed to the malignant progression of tumors. The experimental findings demonstrated a significant upregulation of METTL3 and RBM15 in bladder cancer specimens, implicating their contributory role in the oncogenic progression. Knockdown of METTL3 and RBM15 resulted in a marked attenuation of tumor cell proliferation, invasion, and migration, which was concomitant with a downregulation in the cellular m6A methylation status. Moreover, these results revealed that RBM15 and METTL3 function in a synergistic capacity, positing their involvement in cancer promotion via the upregulation of m6A modifications in long non-coding RNAs. Additionally, this study successfully developed an N-methyl-N-nitrosourea (MNU)-induced rat model of in situ bladder carcinoma, confirming the elevated expression of RBM15 and METTL3, which paralleled the overexpression of m6A-related- lncRNAs observed in bladder cancer cell lines. This congruence underscores the potential utility of these molecular markers in in vivo models that mirror human malignancies. Conclusion: This study not only offers novel molecular targets,but also enriches the research on m6A modification in bladder cancer, thereby facilitating its clinical translation.

BackgroundLockdowns in COVID-19 pandemic led to less physical activity and more intake of unhealthy food in children. The aim of this study was to investigate the negative impact of major lockdowns on the growth of children aged 3-6 years during COVID-19 pandemic period.MethodsPhysical examination results in 2019 to 2022 from 5834 eligible children (2972 males and 2862 females) from Southwestern China who were 3 years old in 2019 were retrospectively collected. Height and weight data points were extracted from the results, and percentiles of height (height%), weight (weight%), and BMI (BMI%), and rates of overweight and obesity were calculated and compared between different years during the pandemic.ResultsAfter analyzing the 15404 growth data points from 5834 children, a slowly increasing trend of height% from 2019 to 2022 was observed. Weight%, BMI%, overweight rate, obesity rate, and combined overweight and obesity rate had two peaks in 2020 and 2022 when major lockdowns were adopted and a drop in between (year 2021), except for obesity rate which did not drop in 2021. Similar results were shown after stratification by gender.ConclusionThe lockdowns in COVID-19 pandemic promoted obesity of kindergarten children, but did not show any negative impact on their height growth possibly due to over-nutrition of children during lockdowns. More efforts need to be made to limit the increase of obesity rate in kindergarten children during possible future lockdowns.

Cerebrovascular disease refers to damage to brain tissue caused by impaired intracranial blood circulation. It usually presents clinically as an acute nonfatal event and is characterized by high morbidity, disability, and mortality. Transcranial Doppler (TCD) ultrasonography is a non-invasive method for the diagnosis of cerebrovascular disease that uses the Doppler effect to detect the hemodynamic and physiological parameters of the major intracranial basilar arteries. It can provide important hemodynamic information that cannot be measured by other diagnostic imaging techniques for cerebrovascular disease. And the result parameters of TCD ultrasonography such as blood flow velocity and beat index can reflect the type of cerebrovascular disease and serve as a basis to assist physicians in the treatment of cerebrovascular diseases. Artificial intelligence (AI) is a branch of computer science which is used in a wide range of applications in agriculture, communications, medicine, finance, and other fields. In recent years, there are much research devoted to the application of AI to TCD. The review and summary of related technologies is an important work to promote the development of this field, which can provide an intuitive technical summary for future researchers. In this paper, we first review the development, principles, and applications of TCD ultrasonography and other related knowledge, and briefly introduce the development of AI in the field of medicine and emergency medicine. Finally, we summarize in detail the applications and advantages of AI technology in TCD ultrasonography including the establishment of an examination system combining brain computer interface (BCI) and TCD ultrasonography, the classification and noise cancellation of TCD ultrasonography signals using AI algorithms, and the use of intelligent robots to assist physicians in TCD ultrasonography and discuss the prospects for the development of AI in TCD ultrasonography.

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Abstract Background Iron deficiency (ID) impairs patient physical activity, recognition and life quality, which is difficult to perceive but should not be underestimated. Worldwide efforts have been made to lower ID burden, however, whether it decreased equally in different regions and sexes is unclear. This study is to examine regional and sex inequalities in global ID from 1990 to 2017. Methods We conducted a longitudinal, comparative burden-of-disease study. Disability-adjusted life-years (DALYs) of ID were obtained from Global Burden of Disease Report 2017. Human Development Index (HDI) data were obtained from Human Development Report 2017. Gini coefficient and the concentration index were calculated to assess the equities in global burden of ID. Results A downward trend of global ID burden (from 569.3 (95% Uncertainty Interval [UI]: 387.8–815.6) to 403.0 (95% UI: 272.4–586.6), p

Abstract Background Oncogenic metabolic reprogramming contributes to tumor growth and immune evasion. The intertumoral metabolic heterogeneity and interaction of distinct metabolic pathways may determine patient outcomes. In this study, we aim to determine the clinical and immunological significance of metabolic subtypes according to the expression levels of genes related to glycolysis and cholesterol-synthesis in bladder cancer (BCa). Methods Based on the median expression levels of glycolytic and cholesterogenic genes, patients were stratified into 4 subtypes (mixed, cholesterogenic, glycolytic, and quiescent) in an integrated cohort including TCGA, GSE13507, and IMvigor210. Clinical, genomic, transcriptomic, and tumor microenvironment characteristics were compared between the 4 subtypes. Results The 4 metabolic subtypes exhibited distinct clinical, molecular, and genomic patterns. Compared to quiescent subtype, mixed subtype was more likely to be basal tumors and was significantly associated with poorer prognosis even after controlling for age, gender, histological grade, clinical stage, and molecular phenotypes. Additionally, mixed tumors harbored a higher frequency of RB1 and LRP1B copy number deletion compared to quiescent tumors (25.7% vs. 12.7 and 27.9% vs. 10.2%, respectively, both adjusted P value

PurposeThis current study aimed to explore early prelingual auditory development (EPLAD) and early language development in Mandarin-speaking children who received simultaneous bilateral cochlear implants (BICI) during the first year of cochlear implantation and compare the performance of the children who received BICI with those received unilateral cochlear implant (UCI).Methods39 Mandarin-speaking children who received BICIs simultaneously and 36 children with UCIs were enrolled in this study. To access the EPLAD, the Infant-Toddler Meaningful Auditory Integration Scale (IT/MAIS) was conducted, and a subtest of the simplified short-form version of the Mandarin Communicative Development Inventory (SSF-MCDI) was used to evaluate the development of expressive and receptive vocabulary for the children at indicated time points after surgery.ResultsIn both the simultaneous BICI and UCI groups, we observed significantly increased scores of the SSF-MCDI and IT/MAIS 1 year after the surgery. There are indications of early advantages in children with BICI in IT/MAIS scores (at 1, 3, and 6 months after activation). For early development of language, a great difference between the expressive vocabulary scores and the receptive vocabulary scores was observed in both groups. We found there were not significant differences between the two groups on expressive or receptive vocabulary scores, the use of more differentiated measures might be required in future research. We further found that the development of the receptive or expressive vocabulary is dramatically correlated with the age at implantation and the total scores of IT/MAIS for children with simultaneous BICIs.ConclusionThese results may supplement the skills development of early language and auditory in Mandarin-native children with simultaneous CIs. It is obvious that children with normal hearing have mastery of receptive vocabulary before that of expressive vocabulary, which is the same as children with unilateral and bilateral CIs in this research. IT/MAIS total scores and age at CI were important factors for early language performance in children with simultaneous BICIs.

This study aimed to investigate anemia treatment and other potential effects of two food-derived bioactive oligopeptide iron complexes on pregnant rats with iron deficiency anemia (IDA) and their offspring. Rats with IDA were established with a low iron diet and then mated. There were one control group and seven randomly assigned groups of pregnant rats with IDA: Control group [Control, 40 ppm ferrous sulfate (FeSO4)]; IDA model group (ID, 4 ppm FeSO4), three high-iron groups (H-FeSO4, 400 ppm FeSO4; MCOP-Fe, 400 ppm marine fish oligopeptide iron complex; WCOP-Fe, 400 ppm whey protein oligopeptide iron complex) and three low-iron groups (L-FeSO4, 40 ppm FeSO4; MOP-Fe, 40 ppm marine fish oligopeptide iron complex; WOP-Fe, 40 ppm whey protein oligopeptide iron complex). Rats in each group were fed the corresponding special diet during pregnancy until the day of delivery. After different doses of iron supplement, serum hemoglobin, iron, and ferritin levels in rats with IDA were significantly increased to normal levels (P < 0.05). Serum iron levels were significantly lower in two food-derived bioactive oligopeptide low-iron complex groups than in the low FeSO4 group (P

Spinal cord injury (SCI) is a devastating and common neurological disorder that is difficult to treat. The pain can sustain for many years, making the sufferer extremely painful. Nerve stimulation was first reported half a century ago as a treatment for neuropathic pain. Since then, the method of electrical stimulation through leads placed in the epidural space on the dorsal side of the spinal cord has become a valuable therapeutic tool for SCI. But nerve stimulation equipment is expensive, and the stimulator design and treatment plan are complicated, which hinders its development. In recent years, wearable and implantable triboelectric nanogenerators (TENGs) developed rapidly, and their low cost and safety have brought a new turning point for the development of nerve stimulation. Nanofibrous membrane has been proved that it is a flexible material with the advantages of ultrathin diameter, good connectivity, easy scale-up, tunable wettability, fine flexibility, tunable porosity, controllable composition and so on. In this paper, we discuss the technology of using nanofiber membrane on clothing to create TENGs to provide continuous electrical energy for nerve stimulation to treat SCI in patients by analyzing previous research.

The expansion of urban areas has resulted in a substantial increase in demand for water ecosystem services. To address this issue, this study aims to investigate how the interaction between urbanization and water ecosystem services changed in response to different levels of urbanization in the Dongjiang River Basin from 1985 to 2020. The research examines four water ecosystem services (water yield, soil retention, and water purifications of N and P) and three types of urbanizations (population urbanization, economic urbanization, and land urbanization) to identify spatial heterogeneities among developed urban areas, developing urban areas, and rural regions, as well as their dynamic interactions. The findings indicate that water ecosystem services and urbanizations tend to be spatially polarized, with high values downstream and low values upstream. Although they have become more closely aligned, there is a local mismatch under basin-level homogeneity. Urbanization has migrated and centralized in a southward direction, while water ecosystem services have moved westward. This difference of migration results in an increasing trade-off in the west band of Dongjiang River. In particular, the developing urban area has been strengthening the function of the transition zone between the developed urban area and rural area, resulting in a dramatic decrease in synergy. The synergy of the rural area dominates the increasing synergy of the entire basin, but the developed urban area tends to lower the water ecosystem services that lag behind urbanization. The study recommends that policymakers consider different urban levels when developing urbanization plans and water resource management strategies, and implement measures to maintain the synergy in the rural area and mitigate the trade-off in the developing area.

Abstract Accumulating evidence has revealed significant roles for N6-methyladenosine (m 6 A) modification in the development of various cancers. We previously demonstrated an oncogenic role of m 6 A-modified CUB domain containing protein 1 (CDCP1) in bladder cancer (BC) progression. However, the biological functions and underlying molecular mechanisms of engineered programmable m 6 A modification of CDCP1 mRNA in BC remain obscure. Here, we established a targeted m 6 A RNA methylation system by fusing the catalytic domain of methyltransferase like 3 (METTL3CD) to RCas9 as the RNA-targeting module. The constructed RCas9- METTL3 retained methylation activity and mediated efficient site-specific m 6 A installation in the presence of a cognate single guide RNA and short protospacer adjacent motif-containing ssDNA molecule . Subsequently, targeting m 6 A installation onto the 3′ untranslated region of CDCP1 promoted CDCP1 mRNA translation and facilitated BC development in vitro and in vivo. Our findings demonstrate that the RCas9-METTL3 system mediates efficient sitespecific m 6 A installation on CDCP1 mRNA and promotes BC development. Thus, the RCas9-METTL3 system provides a new tool for studying m 6 A function and a potential strategy for BC epitranscriptome-modulating therapies.

IntroductionAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is relatively rare in children. This article aimed to analyze clinical and renal histology findings and different responses to induction treatment associated with the long-term renal outcomes in children with AAV in a single center.MethodsAll pediatric patients with AAV admitted to Tongji Hospital from January 2002 to January 2021 were included in the study. The demographic, clinical, pathological, laboratory, and treatment data and outcomes were collected and analyzed to identify predictors associated with response to induction treatment and progression to end-stage renal disease (ESRD).ResultsIn total, 48 children with AAV were included in this cohort; 81.25% of them were women, and 91.7% were microscopic polyangiitis (MPA). Kidney involvement was found in 45 patients (93.75%). The most common histopathological subtype was crescentic form in this cohort according to Berden’s classification. In total, 34 patients (70.8%) showed eGFR

Abstracts Background Interleukin-6 (IL-6) is commonly highly secreted in the breast cancer (BrCA) microenvironment and implicated in disease development. In this study, we aimed to determine the role of the IL-6/pSTAT3/HIC1 axis in the breast cancer microenvironment, including in cancer-associated fibroblasts (CAFs) and breast cancer cells. Methods Stromal fibroblasts from the breast cancer tissue were isolated, and the supernatants of the fibroblasts were analyzed. Recombinant human IL-6 (rhIL-6) was applied to simulate the effect of CAF-derived IL-6 to study the mechanism of HIC1 (tumor suppressor hypermethylated in cancer 1) downregulation. IL-6 was knocked down in the high IL-6-expressing BrCA cell line MDA-MB-231, which enabled the investigation of the IL-6/pSTAT3/HIC1 axis in the autocrine pathway. Results Increased IL-6 was found in the supernatant of isolated CAFs, which suppressed HIC1 expression in cancer cells and promoted BrCA cell proliferation. After stimulating the BrCA cell line SK-BR-3 (where IL-6R is highly expressed) with rhIL-6, signal transducers and activators of transcription 3 (STAT3) was found to be phosphorylated and HIC1 decreased, and a STAT3 inhibitor completely rescued HIC1 expression. Moreover, HIC1 was restored upon knocking down IL-6 expression in MDA-MB-231 cells, accompanied by a decrease in STAT3 activity. Conclusions These findings indicate that IL-6 downregulates the tumor suppressor HIC1 and promotes BrCA development in the tumor microenvironment through paracrine or autocrine signaling.

Both lncRNAs and the N6-methyladenosine (m6A) modification are key regulators of tumorigenesis and innate immunity. However, little is known about the m6A modification of lncRNAs and their clinical and immune relevance in bladder cancer. In this study, we identified m6A-related lncRNAs using Pearson correlation analysis in The Cancer Genome Atlas (TCGA) and the IMvigor210 datasets. Next, univariate Cox regression was performed using the TCGA dataset to filter prognostic m6A-related lncRNAs, which were further subjected to the least absolute shrinkage and selection operator (LASSO) Cox regression to establish a 12 m6A-related lncRNA prognostic score (m6A-LRS). The m6A-LRS was validated in the IMvigor210 dataset. In addition, high m6A-LRS tumors, characterized by decreased tumor mutation load and neoantigen load, showed poorer response to immunotherapy than those with low m6A-LRS in the IMvigor210 dataset. Further, we constructed an m6A-LRS-based nomogram that demonstrated a strong ability to predict overall survival in patients with bladder cancer. Moreover, enrichment analysis revealed that tumor-associated biological processes, oncogenic signaling, and tumor hallmarks were commonly associated with a high m6A-LRS. Gene set variation analysis also indicated that high m6A-LRS was associated with activation of canonical oncogenic signatures, such as the epithelial-to-mesenchymal transition, cell cycle regulators, and DNA replication, as well as activation of immunosuppressive signatures, such as the T-cell exhaustion and pan-fibroblast-TGF-β response signatures. Furthermore, we observed distinct tumor microenvironment cell infiltration characteristics between high- and low-risk tumors. High m6A-LRS tumors showed reduced infiltration of CD8+ T-cells and enhanced infiltration of macrophages and fibroblasts. Additionally, we established a competing endogenous RNA network based on the12 m6A-related lncRNAs. Finally, three lncRNAs (SNHG16, SBF2-AS1, and BDNF-AS) were selected for further validation. The qualitative PCR assay on 10 pairs of bladder cancer and adjacent normal control samples validated the differential expression, and methylated RNA immunoprecipitation (MeRIP) analysis demonstrated a robust m6A enrichment in T24 bladder cancer cells compared with normal uroepithelial cells (SVHUC-1). In conclusion, this study introduced an m6A-related lncRNA signature that identified a subgroup of patients with poor prognoses and suboptimal immune responses, thus providing novel approaches for treatment response prediction and patient stratification in bladder cancer.

Satellite-based remote sensing is important for monitoring the spatial distribution of water resources. The water index is currently one of the most widely used water body extraction methods. Based on Sentinel-2 remote sensing image, this study combines area-to-point regression kriging interpolation, bilinear interpolation, and the Gram–Schmidt (GS) pan-sharpening method with the water indices MNDWI, AWEIsh and WI2015 to compare different water body extraction methods. The experimental results showed that all water indices have satisfactory extraction ability, with the kappa coefficient as an accuracy threshold above 0.8. Moreover, the GS downscaling method combined with the WI2015 yielded the best performance. This research demonstrates the efficacy of the WI2015 method to extract water bodies in urban areas and its ability to comprehensively describe river water bodies. The findings indicate that high-resolution band information is particularly important for improving low-resolution band downscaling results and can significantly minimize erroneous water body extraction.

Background: Accumulating evidence has revealed the critical roles of N6-methyladenosine (m6A) modification of mRNA in various cancers. However, the biological function and regulation of m6A in bladder cancer (BC) are not yet fully understood. Methods: We performed cell phenotype analysis and established in vivo mouse xenograft models to assess the effects of m6A-modified ITGA6 on BC growth and progression. Methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation and luciferase reporter and mutagenesis assays were used to define the mechanism of m6A-modified ITGA6. Immunohistochemical analysis was performed to assess the correlation between METTL3 and ITGA6 expression in bladder cancer patients. Findings: We show that the m6A writer METTL3 and eraser ALKBH5 altered cell adhesion by regulating ITGA6 expression in bladder cancer cells. Moreover, upregulation of ITGA6 is correlated with the increase in METTL3 expression in human BC tissues, and higher expression of ITGA6 in patients indicates a lower survival rate. Mechanistically, m6A is highly enriched within the ITGA6 transcripts, and increased m6A methylations of the ITGA6 mRNA 3’UTR promotes the translation of ITGA6 mRNA via binding of the m6A readers YTHDF1 and YTHDF3. Inhibition of ITGA6 results in decreased growth and progression of bladder cancer cells in vitro and in vivo. Furthermore, overexpression of ITGA6 in METTL3-depleted cells partially restores the BC adhesion, migration and invasion phenotypes. Interpretation: Our results demonstrate an oncogenic role of m6A-modified ITGA6 and show its regulatory mechanisms in BC development and progression, thus identifying a potential therapeutic target for BC. Fund: This work was supported by National Natural Science Foundation of China (81772699, 81472999). Keywords: N6-methyladenosine, ITGA6, METTL3, Progression, Bladder cancer

Yersinia pestis, a Gram-negative bacterium and the etiologic agent of plague, has evolved from Yersinia pseudotuberculosis, a cause of a mild enteric disease. However, the molecular and biological mechanisms of how Y. pseudotuberculosis evolved to such a remarkably virulent pathogen, Y. pestis, are not clear. The ability to initiate a rapid bacterial dissemination is a characteristic hallmark of Y. pestis infection. A distinguishing characteristic between the two Yersinia species is that Y. pseudotuberculosis strains possess an O-antigen of lipopolysaccharide (LPS) while Y. pestis has lost the O-antigen during evolution and therefore exposes its core LPS. In this study, we showed that Y. pestis utilizes its core LPS to interact with SIGNR1 (CD209b), a C-type lectin receptor on antigen presenting cells (APCs), leading to bacterial dissemination to lymph nodes, spleen and liver, and the initiation of a systemic infection. We therefore propose that the loss of O-antigen represents a critical step in the evolution of Y. pseudotuberculosis into Y. pestis in terms of hijacking APCs, promoting bacterial dissemination and causing the plague.

Panicle traits are among the most important agronomic characters which directly relate to yield in rice. Grain number (GN), panicle length (PL), primary branch number (PBN), and secondary branch number (SBN) are the major components of rice panicle structure, and are all controlled by quantitative trait loci (QTLs). In our research, four advanced backcross overlapping populations (BIL152, BIL196a, BIL196b, and BIL196b-156) carrying introgressed segments from chromosome 6 were derived from an indica/japonica cross that used the super-hybrid rice restorer line HR1128 and the international sequenced japonica cultivar 'Nipponbare' as the donor and recurrent parents, respectively. The four panicle traits, GN, PL, PBN, and SBN, were evaluated for QTL effects using the inclusive composite interval mapping (ICIM) method in populations over two years at two sites. Results showed that a total of twelve QTLs for GN, PL, PBN, and SBN were detected on chromosome 6. Based on marker loci physical positions, the QTLs were found to be tightly linked to three important chromosomal intervals described as RM7213 to RM19962, RM20000 to RM20210, and RM412 to RM20595. Three QTLs identified in this study, PL6-5, PBN6-1, and PBN6-2, were found to be novel compared with previous studies. A major QTL (PL6-5) for panicle length was detected in all four populations at two locations, and its position was narrowed down to a 1.3Mb region on chromosome 6. Near isogenic lines (NILs) carrying PL6-5 will be developed for fine mapping of the QTL, and our results will provide referable information for gene excavation of panicle components in rice.

Neuronal restricted progenitors (NRPs) represent a type of transitional intermediate cells that lie between multipotent neural progenitors and terminal differentiated neurons during neurogenesis. These NRPs have the ability to self-renew and differentiate into neurons, but not into glial cells, which is considered an advantage for cellular therapy of human neurodegenerative diseases. However, difficulty in the extraction of highly purified NRPs from normal nervous tissue prevents further studies and applications. In this study, we report the conversion of human fetal fibroblasts into human induced NRPs (hiNRPs) in 11 days by using just three defined factors: Sox2, c-Myc, and either Brn2 or Brn4. The hiNRPs exhibited distinct neuronal characteristics, including cell morphology, multiple neuronal marker expression, self-renewal capacity, and a genome-wide transcriptional profile. Moreover, hiNRPs were able to differentiate into various terminal neurons with functional membrane properties but not glial cells. Direct generation of hiNRPs from somatic cells will provide a new source of cells for cellular replacement therapy of human neurodegenerative diseases. [ABSTRACT FROM AUTHOR]