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Sugar preference is a key contributor to the overconsumption of sugar and the concomitant increase in the incidence of diabetes. However, the exact mechanism of its development remains ambiguous. Here we show that the expression of free fatty acid receptor Ffar4, a receptor for long-chain fatty acids, is decreased in patients and mouse models with diabetes, which is associated with high sugar intake. Deletion of intestinal Ffar4 in mice resulted in reduced gut Bacteroides vulgatus and its metabolite pantothenate, leading to dietary sugar preference. Pantothenate promoted the secretion of GLP-1 which inhibited sugar preference by stimulating hepatic FGF21 release, which in turn regulates energy metabolism. These findings uncover a previously unappreciated role of Ffar4 in negatively regulating sugar preference and suggest B. vulgatus-derived pantothenate as a potential therapeutic target for diabetes., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature Limited.)

The presence of high-risk human papillomavirus (HR-HPV) contributes to the development of cervical lesions and cervical cancer. Recent studies suggest that an imbalance in the cervicovaginal microbiota might be a factor in the persistence of HR-HPV infections. In this study, we collected 156 cervicovaginal fluid (CVF) of women with HR-HPV infection, which were divided into three groups (negative for intraepithelial lesions = 78, low/high-grade squamous intraepithelial lesions = 52/26). We performed metabolomics and 16 S rRNA sequencing to identify changes in metabolites and cervicovaginal microbiota among patients with HR-HPV infection and varying grades of cervical lesions. We detected 164 metabolites and 389 flora types in the three groups. Ten CVF metabolites-N-methylalanine, phenylacetaldehyde, succinic acid, 2-3-dihydroxypyridine, DL-p-hydroxylphenyllactic acid, gluconic acid lactone, guanine, glucose-6-phosphate, erythrose, and sucrose showed significant associations with disease severity and distinct separation patterns in HR-HPV-infected patients with LSIL and HSIL, with an area under the curve of 0.928. The most abundant microbial communities in the CVF were Gardnerella. Gardnerella was found to be associated with increased levels of succinic acid, thereby highlighting distinct metabolic profiles. These findings suggest that the development of cervical lesions resulting from persistent HR-HPV infection is associated with significant alterations in systemic metabolism and shifts in the cervicovaginal microbiota, providing valuable insights into the metabolic and microbiota changes linked to disease severity., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical statement: This study was conducted in accordance with the Declaration of Helsinki. The experimental procedures complied with relevant privacy protection laws and guidelines. Ethical approval was obtained from the Ethics Committee of the Affiliated Hospital of Nanjing University of Chinese Medicine (approval number 2021NL-025-03). All experiments were carried out in accordance with the relevant guidelines and regulations, and informed consent was obtained from each participant., (© 2025. The Author(s).)

Clostridioides difficile infection (CDI) is the most common nosocomial infection in the US. CDI has become a growing concern due to C. difficile's resistance to several antibiotics, including cephalosporins. Furthermore, patients administered cephalosporins are at higher risk of contracting CDI. Cephalosporins are β-lactam antibiotics, which prevent bacterial cell wall synthesis by inhibiting penicillin-binding proteins (PBPs). β-lactam-resistant bacteria evade these antibiotics by producing β-lactamases or by harboring low-affinity PBPs. A genomic analysis of C. difficile strain 630 identified 31 putative β-lactam resistance genes. Upon cefoxitin exposure, few C. difficile strain 630 putative antibiotic-resistant genes were overexpressed. Most notably, the β-lactamase blaCDD gene was upregulated approximately 600-fold, as previously reported. Deletion of the blaCDD locus did not change in cephalosporin susceptibility. Deletion of the second most upregulated gene, the PBP vanY, was also ineffective at decreasing cephalosporin resistance. Cefoxitin exposure of the C. difficile strain 630ΔblaCDD mutant did not increase upregulation of other putative antibiotic resistance genes compared to wildtype C. difficile strain 630. Transcriptomic analyses of wildtype C. difficile strain 630 exposed to cephradine, cefoxitin, ceftazidime, or cefepime revealed the shared upregulation of a putative heterodimeric ABC transporter encoded by loci CD630_04590 (ABC transporter ATP-binding protein) and CD630_04600 (ABC transporter permease). These genes are genomically located directly downstream of blaCDD (CD630_04580). The deletion mutant CD630_04600 remained resistant to a number of antibiotics. Thus, even though blaCDD, CD630_04590, and CD630_04600 are all upregulated when exposed to cephalosporins, they do not seem to be involved in antibiotic resistance in C. difficile strain 630., Competing Interests: Compliance with ethical standards. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.)

Depression frequently comorbidities with cancer, adversely affecting survivors' quality of life. Liver dysfunction is also prevalent among cancer survivors. However, the association between these two conditions remains unclear. This study aimed to explore the relationship between depression and liver function biomarkers in US cancer survivors. A cross-sectional study was conducted utilizing data from the National Health and Nutrition Examination Survey (NHANES) 2005-2020. Cancer survivors were screened and depression was assessed using the Patient Health Questionnaire-9 (PHQ-9), and 18 liver function biomarkers were included. Survey-weighted generalized linear models with multiple covariables adjusted were employed to examine the associations between depression and liver function biomarkers. A total of 4118 cancer survivors were included, representing a weighted population of 21 501 237. After adjusted with age, gender, race, marital status, education level, family income-to-poverty ratio, and number of cancer types, 8 biomarkers demonstrated positive correlations with depression in cancer survivors, included alanine aminotransferase (ALT, OR = 1.007, 95% CI: 1.000 to 1.013), alkaline phosphatase (ALP, 1.006 [1.002, 1.010]), gamma glutamyl transferase (GGT, 1.004 [1.001, 1.007]), lactate dehydrogenase (LDH, 1.004 [1.000, 1.009]), total protein (TP, 1.040 [1.009, 1.072]), globulin (GLB, 1.060 [1.030, 1.091]), total cholesterol (TC) to high-density lipoprotein cholesterol (HDL-C) ratio (1.162 [1.050, 1.286]), and low-density lipoprotein cholesterol (LDL-C) to HDL-C ratio (1.243 [1.012, 1.526]); while 4 other biomarkers exhibited negative correlations, included HDL-C (0.988 [0.980, 0.997]), total bilirubin (TBi, 0.501 [0.284, 0.883]), aspartate aminotransferase (AST) to ALT ratio (0.588 [0.351, 0.986]), albumin (ALB) to GLB ratio (0.384 [0.229, 0.642]). Following sensitivity analysis, 5 biomarkers included LDH, HDL-C, TBi, AST/ALT and LDL-C/HDL-C lost their statistical significance for the association. This study identified certain associations between 7 liver function biomarkers and depression in US cancer survivors. Further research, particularly prospective longitudinal studies, is warranted to elucidate the causal relationships and explore the potential of improving liver function for the management of depression in cancer patients., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics approval and consent to participate All the NHANES protocols were approved by the Ethics Review Board of U.S. National Center for Health Statistics, and written informed consents were obtained from all participants of NAHNES surveys., (© 2024. The Author(s).)

Using acrylic acid advanced ester and styrene as raw materials, the long-chain polyester polymer, polyacrylic acid advanced ester-styrene pour point depressant (P-PPD), was synthesized by molecular design, and its structure was characterized by infrared spectroscopy and nuclear magnetic resonance. In addition, this study experimentally investigated the effect of P-PPD on the phase equilibrium and induction time of natural gas hydrate inhibitors in deionized water (DW) and crude oil/water (O/W) systems, respectively. Polyvinylpyrrolidone (PVP) and mono ethylene glycol (EG) were selected as representatives of kinetic hydrate inhibitor (KHIs) and thermodynamic hydrate inhibitor (THIs), respectively. The results exhibit that P-PPD played a sight role in the phase equilibrium of hydrate, while the addition of P-PPD significantly prolonged the induction time of methane hydrate both in O/W + PVP, OW + EG and O/W + PVP + EG system, indicating that the addition of as-synthesized PPD has a synergistic inhibition effect on the nucleation ability of methane hydrate and can prevent hydrate from formatting during oil and gas transport process, and thus guarantee the flow assurance. The findings of this work will provide a data reference for the hybrid use of hydrate inhibitors and pour point depressants in oil and gas transport., (© 2024. The Author(s).)

Induced pluripotent stem cell (iPSC) technology, in combination with electrophysiological characterization via multielectrode array (MEA), has facilitated the utilization of iPSC-derived motor neurons (iPSC-MNs) as highly valuable models for underpinning pathogenic mechanisms and developing novel therapeutic interventions for motor neuron diseases (MNDs). However, the challenge of MN adherence to the MEA plate and the heterogeneity presented in iPSC-derived cultures raise concerns about the reproducibility of the findings obtained from these cellular models. We discovered that one novel factor modulating the electrophysiological activity of iPSC-MNs is the extracellular matrix (ECM) used in the coating to support in vitro growth, differentiation and maturation of iPSC-MNs. The current study showed that two coating conditions, namely, Poly-L-ornithine/Matrigel (POM) and Polyethyleneimine (PEI) strongly promoted attachment of iPSC-MNs on MEA culture dishes compared to three other coating conditions, and both facilitated the maturation of iPSC-MNs as characterized by the detection of extensive electrophysiological activities from the MEA plates. POM coating accelerated the maturation of the iPSC-MNs for up to 5 weeks, which suits modeling of neurodevelopmental disorders. However, the application of PEI resulted in more even distribution of the MNs on the culture dish and reduced variability of electrophysiological signals from the iPSC-MNs in 7-week cultures, which permitted the detection of enhanced excitability in iPSC-MNs from patients with amyotrophic lateral sclerosis (ALS). This study provides a comprehensive comparison of five coating conditions and offers POM and PEI as favorable coatings for in vitro modeling of neurodevelopmental and neurodegenerative disorders, respectively., (© 2024. The Author(s).)

Observational studies and clinical trials have suggested the relationship between the gut microbiome and respiratory diseases, but the causality between them remains unclear. Firstly, we selected eight respiratory diseases Genome-wide association study (GWAS) datasets mainly from the FinnGen collaboration as outcomes. The exposure was based on GWAS statistics about the gut microbiome, sourced from the MiBioGen consortium, including gut microbial taxa. The causal link between the gut microbiome and respiratory illnesses was then estimated using a Two-sample Mendelian randomization (MR) analysis, including the inverse-variance weighted (IVW), weighted median, MR-Egger, simple mode, and weighted mode. To ensure reliability, F-statistics and sensitivity tests were conducted. Furthermore, we performed a reverse MR analysis of the pre-Mendelian positive findings to possible reverse causality. For the 196 gut microbe taxa, the IVW analysis suggested 88 potential associations with eight clinically prevalent respiratory diseases. Among them, 30 causal associations were found in more than one MR method. Multiple statistical corrections have confirmed three causal associations: genus Holdemanella was a risk factor for chronic obstructive pulmonary disease (COPD) (P = 1.3 × 10 -4 , OR = 1.18), family FamilyXIII was a protective factor for COPD (P = 1.3 × 10 -3 , OR = 0.75), and genus Oxalobacter was a risk factor for asthma (P = 2.1 × 10 -4 , OR = 1.09). Our MR analysis results indicate that there would be a causal relationship between the gut microbiome and respiratory diseases, contributing to the gut-lung axis. This finding offers new insights into the gut microbiome's roles in respiratory diseases' clinical prevention, pathogenesis, and improvement of clinical symptoms. Further randomized controlled trials are necessary to clarify the protective effect of probiotics and fecal microbial transplantation on respiratory health., (© 2024. The Author(s).)

In this study, a feasibility of γ radiation detection using complementary metal-oxide semiconductor (CMOS) image sensors with a neural network algorithm to extract the γ rays interacted pixels has been investigated. The responses characteristics of the CMOS imaging sensor to γ-ray is studied by placed in a γ fields produced by standard 60 Co or 137 Cs isotope sources. The supported preview frame rate of the CMOS image sensor is 25 fps, establishing the functional relationship between the gray level histograms and the dose rate through the neural network, the high energy γ-ray from 60 Co and 137 Cs source radiation dose rate in µSv/h level can be detected using the CMOS imaging sensor. The results show that the proposed method can effectively identify the number of photon particles which detected by the radiation monitoring system based on CMOS image sensor, and infer that the CMOS imaging sensor with a radiation signal extraction algorithm can be used as a dose warner for radiation protection purpose., (© 2024. The Author(s).)

Type 2 diabetes (T2D) is a disease characterized by heterogeneously progressive loss of islet β cell insulin secretion usually occurring after the presence of insulin resistance (IR) and it is one component of metabolic syndrome (MS), and we named it metabolic dysfunction syndrome (MDS). The pathogenesis of T2D is not fully understood, with IR and β cell dysfunction playing central roles in its pathophysiology. Dyslipidemia, hyperglycemia, along with other metabolic disorders, results in IR and/or islet β cell dysfunction via some shared pathways, such as inflammation, endoplasmic reticulum stress (ERS), oxidative stress, and ectopic lipid deposition. There is currently no cure for T2D, but it can be prevented or in remission by lifestyle intervention and/or some medication. If prevention fails, holistic and personalized management should be taken as soon as possible through timely detection and diagnosis, considering target organ protection, comorbidities, treatment goals, and other factors in reality. T2D is often accompanied by other components of MDS, such as preobesity/obesity, metabolic dysfunction associated steatotic liver disease, dyslipidemia, which usually occurs before it, and they are considered as the upstream diseases of T2D. It is more appropriate to call "diabetic complications" as "MDS-related target organ damage (TOD)", since their development involves not only hyperglycemia but also other metabolic disorders of MDS, promoting an up-to-date management philosophy. In this review, we aim to summarize the underlying mechanism, screening, diagnosis, prevention, and treatment of T2D, especially regarding the personalized selection of hypoglycemic agents and holistic management based on the concept of "MDS-related TOD"., (© 2024. The Author(s).)

While immune checkpoint blockade (ICB) has shown promise for clinical cancer therapy, its efficacy has only been observed in a limited subset of patients and the underlying mechanisms regulating innate and acquired resistance to ICB of tumor cells remain poorly understood. Here, we identified ependymin-related protein 1 (EPDR1) as an important tumor-intrinsic regulator of PD-L1 expression and tumor immune evasion. Aberrant expression of EPDR1 in hepatocellular carcinoma is associated with immunosuppression. Mechanistically, EPDR1 binds to E3 ligase TRIM21 and disrupts its interaction with IkappaB kinase-b, suppressing its ubiquitylation and autophagosomal degradation and enhancing NF-κB-mediated transcriptional activation of PD-L1. Further, we validated through a mouse liver cancer model that EPDR1 mediates exhaustion of CD8 + T cells and promotes tumor progression. In addition, we observed a positive correlation between EPDR1 and PD-L1 expression in both human and mouse liver cancer samples. Collectively, our study reveals a previously unappreciated role of EPDR1 in orchestrating tumor immune evasion and cancer progression., (© 2024. The Author(s).)

Tumor microenvironment heterogeneity in hepatocellular carcinoma (HCC) on a spatial single-cell resolution is unclear. Here, we conducted co-detection by indexing to profile the spatial heterogeneity of 401 HCC samples with 36 biomarkers. By parsing the spatial tumor ecosystem of liver cancer, we identified spatial patterns with distinct prognosis and genomic and molecular features, and unveiled the progressive role of vimentin (VIM) high macrophages. Integration analysis with eight independent cohorts demonstrated that the spatial co-occurrence of VIM high macrophages and regulatory T cells promotes tumor progression and favors immunotherapy. Functional studies further demonstrated that VIM high macrophages enhance the immune-suppressive activity of regulatory T cells by mechanistically increasing the secretion of interleukin-1β. Our data provide deep insights into the heterogeneity of tumor microenvironment architecture and unveil the critical role of VIM high macrophages during HCC progression, which holds potential for personalized cancer prevention and drug discovery and reinforces the need to resolve spatial-informed features for cancer treatment., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Diffusion Kurtosis Imaging (DKI)-derived metrics are recognized as indicators of maturation in neonates with low-grade germinal matrix and intraventricular hemorrhage (GMH-IVH). However, it is not yet known if these factors are associated with neurodevelopmental outcomes. The objective of this study was to acquire DKI-derived metrics in neonates with low-grade GMH-IVH, and to demonstrate their association with later neurodevelopmental outcomes. In this prospective study, neonates with low-grade GMH-IVH and control neonates were recruited, and DKI were performed between January 2020 and March 2021. These neonates underwent the Bayley Scales of Infant Development test at 18 months of age. Mean kurtosis (MK), radial kurtosis (RK) and gray matter values were measured. Spearman correlation analyses were conducted for the measured values and neurodevelopmental outcome scores. Forty controls (18 males, average gestational age (GA) 30 weeks ± 1.3, corrected GA at MRI scan 38 weeks ± 1) and thirty neonates with low-grade GMH-IVH (13 males, average GA 30 weeks ± 1.5, corrected GA at MRI scan 38 weeks ± 1). Neonates with low-grade GMH-IVH exhibited lower MK and RK values in the PLIC and the thalamus (P < 0.05). The MK value in the thalamus was associated with Mental Development Index (MDI) (r = 0.810, 95% CI 0.695-0.13; P < 0.001) and Psychomotor Development Index (PDI) (r = 0.852, 95% CI 0.722-0.912; P < 0.001) scores. RK value in the caudate nucleus significantly and positively correlated with MDI (r = 0.496, 95% CI 0.657-0.933; P < 0.001) and PDI (r = 0.545, 95% CI 0.712-0.942; P < 0.001) scores. The area under the curve (AUC) were used to assess diagnostic performance of MK and RK in thalamus (AUC = 0.866, 0.787) and caudate nucleus (AUC = 0.833, 0.671) for predicting neurodevelopmental outcomes. As quantitative neuroimaging markers, MK in thalamus and RK in caudate nucleus may help predict neurodevelopmental outcomes in neonates with low-grade GMH-IVH., (© 2024. The Author(s).)

Ab initio calculations have an essential role in our fundamental understanding of quantum many-body systems across many subfields, from strongly correlated fermions 1-3 to quantum chemistry 4-6 and from atomic and molecular systems 7-9 to nuclear physics 10-14 . One of the primary challenges is to perform accurate calculations for systems where the interactions may be complicated and difficult for the chosen computational method to handle. Here we address the problem by introducing an approach called wavefunction matching. Wavefunction matching transforms the interaction between particles so that the wavefunctions up to some finite range match that of an easily computable interaction. This allows for calculations of systems that would otherwise be impossible owing to problems such as Monte Carlo sign cancellations. We apply the method to lattice Monte Carlo simulations 15,16 of light nuclei, medium-mass nuclei, neutron matter and nuclear matter. We use high-fidelity chiral effective field theory interactions 17,18 and find good agreement with empirical data. These results are accompanied by insights on the nuclear interactions that may help to resolve long-standing challenges in accurately reproducing nuclear binding energies, charge radii and nuclear-matter saturation in ab initio calculations 19,20 ., (© 2024. The Author(s).)

Accurate prediction of the remaining useful life (RUL) of lithium-ion batteries is advantageous for maintaining the stability of electrical systems. In this paper, an interpretable online method which can reflect capacity regeneration is proposed to accurately estimate the RUL. Firstly, four health indicators (HIs) are extracted from the charging and discharging process for online prediction. Then, the HIs model is trained using support vector regression to obtain future features. And the capacity model of Gaussian process regression (GPR) is trained and analyzed by Shapley additive explanation (SHAP). Meanwhile, the state space for capacity prediction is constructed with the addition of Gaussian non-white noise to simulate the capacity regeneration. And the modified predicted HIs and noise are obtained by unscented Kalman filter. Finally, according to SHAP explainer, the predicted HIs acting as the baseline and the modified HIs containing information on capacity regeneration are chosen to predict RUL. In addition, the bounds of confidence intervals (CIs) are calculated separately to reflect the regenerated capacity. The experimental results demonstrate that the proposed online method can achieve high accuracy and effectively capture the capacity regeneration. The absolute error of failure RUL is below 5 and the minimum confidence interval is only 2., (© 2024. The Author(s).)

Systemic therapy is typically the primary treatment choice for hepatocellular carcinoma (HCC) patients with extrahepatic metastases. Some patients may achieve partial response (PR) or complete response (CR) with systemic treatment, leading to the possibility of their primary tumor becoming resectable. This study aimed to investigate whether these patients could achieve longer survival through surgical resection of their primary tumor. We retrospectively collected data from 150 HCC patients with extrahepatic metastases treated at 15 different centers from January 1st, 2015, to November 30th, 2022. We evaluated their overall survival (OS) and progress-free survival (PFS) and analyzed risk factors impacting both OS and PFS were analyzed. Patients who received surgical treatment had longer OS compared to those who did not (median OS 16.5 months vs. 11.3 months). However, there was no significant difference in progression-free survival between the two groups. Portal vein invasion (P = 0.025) was identified as a risk factor for poor prognosis in patients, while effective first-line treatment (P = 0.039) and surgical treatment (P = 0.005) were protective factors. No factors showed statistical significance in the analysis of PFS. Effective first-line treatment (P = 0.027) and surgical treatment (P = 0.006) were both independent protective factors for prolonging patient prognosis, while portal vein invasion was an independent risk factor (P = 0.044). HCC patients with extrahepatic metastases who achieve PR/CR with conversion therapy may experience longer OS through surgical treatment. This study is the first to analyze the clinical outcomes of patients receiving surgical treatment for HCC with extrahepatic metastases., (© 2024. The Author(s).)

This retrospective cohort study explored the relationship between monocular and interocular optical coherence tomography (OCT) parameters and stereopsis in 56 patients undergoing pars plana vitrectomy (PPV) for unilateral idiopathic epiretinal membrane (IERM). IERM impairs visual functions, with symptoms ranging from asymptomatic to severe impairment. Despite established surgical interventions, including PPV with membrane peeling, the impact on advanced three-dimensional visual functions such as stereopsis remains inadequately investigated. All subjects were assessed for stereopsis, visual acuity, and metamorphopsia, alongside spectral domain OCT parameters. These visual functions significantly improved 3-month postoperatively. Central retinal thickness at the fovea, parafovea, and perifovea (CFT, CRT-3 mm, and CRT-6 mm), ectopic inner foveal layer thickness, and retinal layer thickness notably decreased 1 week to 3 months after surgery. The interocular difference in OCT parameters between bilateral eyes was included as a parameter. Baseline CRT-3 mm difference and inner nuclear layer (INL) thickness were independently correlated with postoperative stereopsis on the Titmus Stereo Test, while baseline CRT-6 mm difference and INL thickness were independently related to stereopsis on the TNO stereotest. This study highlights the substantial enhancement in stereopsis post-IERM surgery, with both interocular and monocular OCT parameters independently influencing postoperative stereopsis. These findings underscore the importance of retinal microstructures in assessing and predicting stereopsis in IERM patients after vitrectomy., (© 2024. The Author(s).)

Despite epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have shown remarkable efficacy in patients with EGFR-mutant non-small cell lung cancer (NSCLC), acquired resistance inevitably develops, limiting clinical efficacy. We found that TET2 was poly-ubiquitinated by E3 ligase CUL7 FBXW11 and degraded in EGFR-TKI resistant NSCLC cells. Genetic perturbation of TET2 rendered parental cells more tolerant to TKI treatment. TET2 was stabilized by MEK1 phosphorylation at Ser 1107, while MEK1 inactivation promoted its proteasome degradation by enhancing the recruitment of CUL7 FBXW11 . Loss of TET2 resulted in the upregulation of TNF/NF-κB signaling that confers the EGFR-TKI resistance. Genetic or pharmacological inhibition of NF-κB attenuate the TKI resistance both in vitro and in vivo. Our findings exemplified how a cell growth controlling kinase MEK1 leveraged the epigenetic homeostasis by regulating TET2, and demonstrated an alternative path of non-mutational acquired EGFR-TKI resistance modulated by TET2 deficiency. Therefore, combined strategy exploiting EGFR-TKI and inhibitors of TET2/NF-κB axis holds therapeutic potential for treating NSCLC patients who suffered from this resistance., (© 2024. The Author(s).)

Chemical cleaning and disinfection are crucial steps for eliminating infection in root canal treatment. However, irrigant selection or irrigation procedures are far from clear. The vapor lock effect in the apical region has yet to be solved, impeding irrigation efficacy and resulting in residual infections and compromised treatment outcomes. Additionally, ambiguous clinical indications for root canal medication and non-standardized dressing protocols must be clarified. Inappropriate intracanal medication may present side effects and jeopardize the therapeutic outcomes. Indeed, clinicians have been aware of these concerns for years. Based on the current evidence of studies, this article reviews the properties of various irrigants and intracanal medicaments and elucidates their effectiveness and interactions. The evolution of different kinetic irrigation methods, their effects, limitations, the paradigm shift, current indications, and effective operational procedures regarding intracanal medication are also discussed. This expert consensus aims to establish the clinical operation guidelines for root canal irrigation and a position statement on intracanal medication, thus facilitating a better understanding of infection control, standardizing clinical practice, and ultimately improving the success of endodontic therapy., (© 2024. The Author(s).)

The bone marrow adjusts blood cell production to meet physiological demands in response to insults. The spatial organization of normal and stress responses are unknown owing to the lack of methods to visualize most steps of blood production. Here we develop strategies to image multipotent haematopoiesis, erythropoiesis and lymphopoiesis in mice. We combine these with imaging of myelopoiesis 1 to define the anatomy of normal and stress haematopoiesis. In the steady state, across the skeleton, single stem cells and multipotent progenitors distribute through the marrow enriched near megakaryocytes. Lineage-committed progenitors are recruited to blood vessels, where they contribute to lineage-specific microanatomical structures composed of progenitors and immature cells, which function as the production sites for each major blood lineage. This overall anatomy is resilient to insults, as it was maintained after haemorrhage, systemic bacterial infection and granulocyte colony-stimulating factor (G-CSF) treatment, and during ageing. Production sites enable haematopoietic plasticity as they differentially and selectively modulate their numbers and output in response to insults. We found that stress responses are variable across the skeleton: the tibia and the sternum respond in opposite ways to G-CSF, and the skull does not increase erythropoiesis after haemorrhage. Our studies enable in situ analyses of haematopoiesis, define the anatomy of normal and stress responses, identify discrete microanatomical production sites that confer plasticity to haematopoiesis, and uncover unprecedented heterogeneity of stress responses across the skeleton., (© 2024. The Author(s).)

Over half of hepatocellular carcinoma (HCC) cases diagnosed worldwide are in China 1-3 . However, whole-genome analysis of hepatitis B virus (HBV)-associated HCC in Chinese individuals is limited 4-8 , with current analyses of HCC mainly from non-HBV-enriched populations 9,10 . Here we initiated the Chinese Liver Cancer Atlas (CLCA) project and performed deep whole-genome sequencing (average depth, 120×) of 494 HCC tumours. We identified 6 coding and 28 non-coding previously undescribed driver candidates. Five previously undescribed mutational signatures were found, including aristolochic-acid-associated indel and doublet base signatures, and a single-base-substitution signature that we termed SBS&#95;H8. Pentanucleotide context analysis and experimental validation confirmed that SBS&#95;H8 was distinct to the aristolochic-acid-associated SBS22. Notably, HBV integrations could take the form of extrachromosomal circular DNA, resulting in elevated copy numbers and gene expression. Our high-depth data also enabled us to characterize subclonal clustered alterations, including chromothripsis, chromoplexy and kataegis, suggesting that these catastrophic events could also occur in late stages of hepatocarcinogenesis. Pathway analysis of all classes of alterations further linked non-coding mutations to dysregulation of liver metabolism. Finally, we performed in vitro and in vivo assays to show that fibrinogen alpha chain (FGA), determined as both a candidate coding and non-coding driver, regulates HCC progression and metastasis. Our CLCA study depicts a detailed genomic landscape and evolutionary history of HCC in Chinese individuals, providing important clinical implications., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Single-cell encapsulation in droplet microfluidics is commonly hindered by the tradeoff between cell suspension density and on-chip focusing performance. In this study, we introduce a novel droplet microfluidic chip to overcome this challenge. The chip comprises a double spiral focusing unit, a flow resistance-based sample enrichment module with fine-tunable outlets, and a crossflow droplet generation unit. Utilizing a low-density cell/bead suspension (2 × 10 6 objects/mL), cells/beads are focused into a near-equidistant linear arrangement within the double spiral microchannel. The excess water phase is diverted while cells/beads remain focused and sequentially encapsulated in individual droplets. Focusing performance was assessed through numerical simulations and experiments at three flow rates (40, 60, 80 μL/min), demonstrating successful focusing at 40 and 80 μL/min for beads and cells, respectively. In addition, both simulation and experimental results revealed that the flow resistance at the sample enrichment module is adjustable by punching different outlets, allowing over 50% of the aqueous phase to be removed. YOLOv8n-based droplet detection algorithms realized the counting of cells/beads in droplets, statistically demonstrating single-cell and bead encapsulation rates of 72.2% and 79.2%, respectively. All the results indicate that this on-chip sample enrichment approach can be further developed and employed as a critical component in single-cell encapsulation in water-in-oil droplets., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s) 2024.)

Background: Human scalp hair is a validated bio-substrate for monitoring various exposures in childhood including contextual stressors, environmental toxins, prescription or non-prescription drugs. Linear hair growth rates (HGR) are required to accurately interpret hair biomarker concentrations., Methods: We measured HGR in a prospective cohort of preschool children (N = 266) aged 9-72 months and assessed demographic factors, anthropometrics, and hair protein content (HPC). We examined HGR differences by age, sex, race, height, hair pigment, and season, and used univariable and multivariable linear regression models to identify HGR-related factors., Results: Infants below 1 year (288 ± 61 μm/day) had slower HGR than children aged 2-5 years (p = 0.0073). Dark-haired children (352 ± 52 μm/day) had higher HGR than light-haired children (325 ± 50 μm/day; p = 0.0019). Asian subjects had the highest HGR overall (p = 0.016). Younger children had higher HPC (p = 0.0014) and their HPC-adjusted HGRs were slower than older children (p = 0.0073). Age, height, hair pigmentation, and HPC were related to HGR in multivariable regression models., Conclusions: We identified age, height, hair pigment, and hair protein concentration as significant determinants of linear HGRs. These findings help explain the known hair biomarker differences between children and adults and aid accurate interpretation of hair biomarker results in preschool children., Impact: Discovery of hair biomarkers in the past few decades has transformed scientific disciplines like toxicology, pharmacology, epidemiology, forensics, healthcare, and developmental psychology. Identifying determinants of hair growth in children is essential for accurate interpretation of hair biomarker results in pediatric clinical studies. Childhood hair growth rates define the time-periods of biomarker incorporation into growing hair, essential for interpreting the biomarkers associated with environmental exposures and the mind-brain-body connectome. Our study describes age-, sex-, and height-based distributions of linear hair growth rates and provides determinants of linear hair growth rates in a large population of children. Age, height, hair pigmentation, and hair protein content are determinants of hair growth rates and should be accounted for in child hair biomarkers studies. Our findings on hair protein content and linear hair growth rates may provide physiological explanations for differences in hair growth rates and biomarkers in preschool children as compared to adults., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Prophages, which enables bacterial hosts to acquire novel traits, and increase genetic variation and evolutionary innovation, are considered to be one of the greatest drivers of bacterial diversity and evolution. Stenotrophomonas maltophilia is widely distributed and one of the most important multidrug resistant bacteria in hospitals. However, the distribution and genetic diversity of S. maltophilia prophages have not been elucidated. In this study, putative prophages were predicted in S. maltophilia genomes by using virus prediction tools, and the genetic diversity and phylogeny of S. maltophilia and the prophages they harbor were further analyzed. A total of 356 prophage regions were predicted from 88 S. maltophilia genomes. Among them, 144 were intact prophages, but 77.09% of the intact prophages did not match any known phage sequences in the public database. The number of prophage carried by S. maltophilia is related to its host habitat and is an important factor affecting the size of the host genome, but it is not related to the genetic diversity of the prophage. The prediction of auxiliary genes encoded by prophage showed that antibiotic resistance genes was not predicted for any of the prophages except for one questionable prophage, while 53 virulence genes and 169 carbohydrate active enzymes were predicted from 11.24 and 44.1% prophages, respectively. Most of the prophages (72.29%) mediated horizontal gene transfer of S. maltophilia genome, but only involved in 6.25% of the horizontal gene transfer events. In addition, CRISPR prediction indicated 97.75% S. maltophilia strains contained the CRISPR-Cas system containing 818 spacer sequences. However, these spacer sequences did not match any known S. maltophilia phages, and only a few S. maltophilia prophages. Comparative genomic analysis revealed a highly conserved and syntenic organization with genomic rearrangement between the prophages and the known related S. maltophilia phages. Our results indicate a high prevalence and genetic diversity of prophages in the genome of S. maltophilia, as well as the presence of a large number of uncharacterized phages. It provides an important complement to understanding the diversity and biological characteristics of phages, as well as the interactions and evolution between bacteria and phages., (© 2023. The Author(s).)

Supraglottic jet oxygenation/ventilation (SJOV) can reduce hypoxemia in sedated endoscopy but may increase minor side effects like pharyngalgia and xerostomia. This study aimed to identify risk factors for pharyngalgia/xerostomia with SJOV during gastrointestinal endoscopy. From January 1 to December 31, 2021, 5313 patients with propofol sedation and SJOV underwent gastrointestinal endoscopy or removal of gastrointestinal polyps was analyzed retrospectively. Data included patient characteristics, operation details, postoperative adverse events, and potential risk factors for postoperative adverse events. Parameters considered as potential risk factors were identified based on study results published previously and based on the researcher's idea and clinical experience. The patient factors and the incidence of pharyngalgia/xerostomia at 30 min post-procedure were assessed. Descriptive statistics were calculated using SPSS software. Evaluation potential risk factors using univariate and multivariate logistic regression. Pharyngalgia/xerostomia occurred in 18.7% of patients at 30 min after procedure. A multivariable analysis showed that procedure time and pharyngalgia/xerostomia within 2 weeks were independent risk factors. Procedure time had the strongest association with postoperative pharyngalgia/xerostomia (OR, 8.09 [95% CI, 4.197-6.312]). No factors were significantly associated with hypoxemia risk (1.7% incidence). There were no barotrauma or other serious morbidity or mortality. Procedure duration and recent pharyngalgia/xerostomia increased risk of pharyngalgia/xerostomia with SJOV during endoscopy. Limiting SJOV duration may reduce side effects in susceptible patients. No predictors of hypoxemia were identified., (© 2023. The Author(s).)

Trace-amine-associated receptors (TAARs), a group of biogenic amine receptors, have essential roles in neurological and metabolic homeostasis 1 . They recognize diverse endogenous trace amines and subsequently activate a range of G-protein-subtype signalling pathways 2,3 . Notably, TAAR1 has emerged as a promising therapeutic target for treating psychiatric disorders 4,5 . However, the molecular mechanisms underlying its ability to recognize different ligands remain largely unclear. Here we present nine cryo-electron microscopy structures, with eight showing human and mouse TAAR1 in a complex with an array of ligands, including the endogenous 3-iodothyronamine, two antipsychotic agents, the psychoactive drug amphetamine and two identified catecholamine agonists, and one showing 5-HT 1A R in a complex with an antipsychotic agent. These structures reveal a rigid consensus binding motif in TAAR1 that binds to endogenous trace amine stimuli and two extended binding pockets that accommodate diverse chemotypes. Combined with mutational analysis, functional assays and molecular dynamic simulations, we elucidate the structural basis of drug polypharmacology and identify the species-specific differences between human and mouse TAAR1. Our study provides insights into the mechanism of ligand recognition and G-protein selectivity by TAAR1, which may help in the discovery of ligands or therapeutic strategies for neurological and metabolic disorders., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Zinc toxicity affects crop productivity and threatens food security and human health worldwide. Unfortunately, the accumulation patterns of zinc and the harmful effects of excessive zinc on sweet potato have not been well explored. In the present research, two genotypes of sweet potato varieties with different accumulation patterns of zinc were selected to analyze the effects of excessive zinc on sweet potato via hydroponic and field cultivation experiments. The results indicated that the transfer coefficient was closely related to the zinc concentration in the storage roots of sweet potato. Excessive zinc inhibited the growth of sweet potato plants by causing imbalanced mineral concentrations, destroying the cellular structure and reducing photosynthesis. Furthermore, a total of 17,945 differentially expressed genes were identified in the two genotypes under zinc stress by transcriptomic analysis. Differentially expressed genes involved in the absorption and transport of zinc, defense networks and transcription factors played important roles in the response to zinc stress. In conclusion, this study provides a reference for the selection of sweet potato varieties in zinc contaminated soil and lays a foundation for investigating the tolerance of sweet potato to excessive zinc, which is meaningful for environmental safety and human health., (© 2023. The Author(s).)

In order to obtain the optimal conditions for ammonia nitrogen (AN) wastewater treatment by bio filter (BF), the effects of ratio of carbon to nitrogen (C/N), pH, and hydraulic load (HL) on the AN degradation were studied by Response Surface Methodology (RSM). Central Composite Design (CCD) experiments were conducted, and the response of the AN removal rates were fitted to a second-order polynomial model. The analysis of variance showed that the model was accurate and reliable. Through model fitting, the optimal condition for AN removal was: C/N of 18.95, pH of 7.78, and HL of 1.04 d -1 . The maximum AN removal rate predicted by the model was 91.90%, accorded with the experimental verification value of 91.37% under the optimal condition. The research provided valuable demonstration for optimizing process parameters on AN removal in BF., (© 2023. Springer Nature Limited.)

There are concerns about the risk of injuries caused by marathons in China. Since male and female runners have different injury risks, gender differences in running shoe functionality should be further complemented. A supervised questionnaire survey of 626 marathon runners was collected. The questionnaire was categorized into four sections: (1) participant profile, (2) importance of shoe properties, (3) functional evaluation of shoe properties and (4) importance ranking of shoe properties. The Mann-Whitney U test, Fisher's exact test of cross tabulation and Chi-square test, and two-way ANOVA were used to analyze the results of this survey. The significance level was set at P < 0.05. The full marathon participants were older than the half marathon participants. There was no gender difference in the importance of shoe features to elite runners. In addition, women are more concerned about upper elasticity and have higher requirements for running shoes than men. Women were more focused on injury prevention, while men were more focused on running performance. Heel cushioning was identified by all participants as the most important running shoe feature. There were no gender differences between elite players' demand for running shoes, but significant gender differences were found between genders at other running levels., (© 2023. Springer Nature Limited.)

Cell death is the irreversible stop of life. It is also the basic physiological process of all organisms which involved in the embryonic development, organ maintenance and autoimmunity of the body. In recent years, we have gained more comprehension of the mechanism in cell death and have basically clarified the different types of "programmed cell death", such as apoptosis, necroptosis, autophagy, and pyroptosis, and identified some key genes in these processes. However, in these previous studies, the conversion between different cell death modes and their application in diseases are rarely explored. To sum up, although many valued discoveries have been discovered in the field of cell death in recent years, there are still many unknown problems to be solved in this field. Facts have proved that cell death is a very complex game, and a series of core players have the ability to destroy the delicate balance of the cell environment, from survival to death, from anti-inflammatory to pro-inflammatory. With the thorough research of the complex regulatory mechanism of cell death, there will certainly be exciting new research in this field in the next few years. The sake of this paper is to emphasize the complex mechanism of overturning the balance between different cell fates and provide relevant theoretical basis for the connection between cell death transformation and disease treatment in the future., (© 2023. Cell Death Differentiation Association (ADMC).)

SARS-CoV-2 vaccines are useful tools to combat the Coronavirus Disease 2019 (COVID-19) pandemic, but vaccine reluctance threatens these vaccines' effectiveness. To address COVID-19 vaccine reluctance and ensure equitable distribution, understanding the extent of and factors associated with vaccine acceptance and uptake is critical. We report the results of a large nationwide study in the US conducted December 2020-May 2021 of 36,711 users from COVID-19-focused smartphone-based app How We Feel on their willingness to receive a COVID-19 vaccine. We identified sociodemographic and behavioral factors that were associated with COVID-19 vaccine acceptance and uptake, and we found several vulnerable groups at increased risk of COVID-19 burden, morbidity, and mortality were more likely to be reluctant to accept a vaccine and had lower rates of vaccination. Our findings highlight specific populations in which targeted efforts to develop education and outreach programs are needed to overcome poor vaccine acceptance and improve equitable access, diversity, and inclusion in the national response to COVID-19., (© 2023. The Author(s).)

Myocardial infarction that causes damage to heart muscle can lead to heart failure. The identification of molecular mechanisms promoting myocardial regeneration represents a promising strategy to improve cardiac function. Here we show that IGF2BP3 plays an important role in regulating adult cardiomyocyte proliferation and regeneration in a mouse model of myocardial infarction. IGF2BP3 expression progressively decreases during postnatal development and becomes undetectable in the adult heart. However, it becomes upregulated after cardiac injury. Both gain- and loss-of-function analyses indicate that IGF2BP3 regulates cardiomyocyte proliferation in vitro and in vivo. In particular, IGF2BP3 promotes cardiac regeneration and improves cardiac function after myocardial infarction. Mechanistically, we demonstrate that IGF2BP3 binds to and stabilizes MMP3 mRNA through interaction with N 6 -methyladenosine modification. The expression of MMP3 protein is also progressively downregulated during postnatal development. Functional analyses indicate that MMP3 acts downstream of IGF2BP3 to regulate cardiomyocyte proliferation. These results suggest that IGF2BP3-mediated post-transcriptional regulation of extracellular matrix and tissue remodeling contributes to cardiomyocyte regeneration. They should help to define therapeutic strategy for ameliorating myocardial infarction by inducing cell proliferation and heart repair., (© 2023. The Author(s).)

The vein pattern in insect wings allows this lightweight structure to carry multiple biological functions. Here, an investigation of the angular distribution of the vein struts in dragonfly wings revealed that the golden angle or golden ratio dominates the venation patterns. We find that the golden angle dominates the intervein angles in regions where thin veins and membranes demand strength reinforcement. A golden ratio partition method has thus been developed that explains a set of preferred intervein angles in distorted polygon-shaped venation cells throughout the venation pattern in dragonfly wings. These observations provide new evidence that the wing structure is spatially optimized, by the golden rule in nature, for supporting biomechanical functions of dragonfly wings., (© 2023. The Author(s).)

Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most exciting classes of targeted therapy agents for cancers with homologous recombination (HR) deficiency. However, many patients without apparent HR defects also respond well to PARP inhibitors/cisplatin. The biomarker responsible for this mechanism remains unclear. Here, we identified a set of ribosomal genes that predict response to PARP inhibitors/cisplatin in HR-proficient patients. PARP inhibitor/cisplatin selectively eliminates cells with high expression of the eight genes in the identified panel via DNA damage (ATM) signaling-induced pro-apoptotic ribosomal stress, which along with ATM signaling-induced pro-survival HR repair constitutes a new model to balance the cell fate in response to DNA damage. Therefore, the combined examination of the gene panel along with HR status would allow for more precise predictions of clinical response to PARP inhibitor/cisplatin. The gene panel as an independent biomarker was validated by multiple published clinical datasets, as well as by an ovarian cancer organoids library we established. More importantly, its predictive value was further verified in a cohort of PARP inhibitor-treated ovarian cancer patients with both RNA-seq and WGS data. Furthermore, we identified several marketed drugs capable of upregulating the expression of the genes in the panel without causing HR deficiency in PARP inhibitor/cisplatin-resistant cell lines. These drugs enhance PARP inhibitor/cisplatin sensitivity in both intrinsically resistant organoids and cell lines with acquired resistance. Together, our study identifies a marker gene panel for HR-proficient patients and reveals a broader application of PARP inhibitor/cisplatin in cancer therapy., (© 2023. The Author(s).)

Isolation and manipulation of single cells play a crucial role in drug screening. However, previously reported single-cell drug screening lacked multiple-dose concentration gradient studies, which limits their ability to predict drug performance accurately. To solve this problem, we constructed a multiconcentration gradient generator in which a Tai Chi-spiral mixer can accelerate solution mixing in a short time and produce a linear concentration gradient. Later, a gradient generator combined with a single-cell capture array was adopted to investigate the effects of single or combined doses of 5-fluorouracil and cisplatin on human hepatoma cells and human breast carcinoma cells (at the single-cell level). The results showed that both drugs were effective in inhibiting the growth of cancer cells, and the combination was more effective for human hepatoma cells. In addition, the relationship between the biomechanical heterogeneity (e.g., deformability and size) of tumor cells and potential drug resistance at the single-cell level was investigated, indicating that small and/or deformable cells were more resistant than large and/or less deformable cells. The device provides a simple and reliable platform for studying the optimal dosage of different drug candidates at the single-cell level and effectively screening single-agent chemotherapy regimens and combination therapies., Competing Interests: Competing interestsThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© The Author(s) 2023.)

Brain metastasis, most commonly originating from lung cancer, increases cancer morbidity and mortality. Although metastatic colonization is the rate-limiting and most complex step of the metastatic cascade, the underlying mechanisms are poorly understood. Here, in vivo genome-wide CRISPR-Cas9 screening revealed that loss of interferon-induced transmembrane protein 1 (IFITM1) promotes brain colonization of human lung cancer cells. Incipient brain metastatic cancer cells with high expression of IFITM1 secrete microglia-activating complement component 3 and enhance the cytolytic activity of CD8 + T cells by increasing the expression and membrane localization of major histocompatibility complex class I. After activation, microglia (of the innate immune system) and cytotoxic CD8 + T lymphocytes (of the adaptive immune system) were found to jointly eliminate cancer cells by releasing interferon-gamma and inducing phagocytosis and T-cell-mediated killing. In human cancer clinical trials, immune checkpoint blockade therapy response was significantly correlated with IFITM1 expression, and IFITM1 enhanced the brain metastasis suppression efficacy of PD-1 blockade in mice. Our results exemplify a novel mechanism through which metastatic cancer cells overcome the innate and adaptive immune responses to colonize the brain, and suggest that a combination therapy increasing IFITM1 expression in metastatic cells with PD-1 blockade may be a promising strategy to reduce metastasis., (© 2023 The Authors.)

Rapid demographic ageing substantially affects socioeconomic development 1-4 and presents considerable challenges for food security and agricultural sustainability 5-8 , which have so far not been well understood. Here, by using data from more than 15,000 rural households with crops but no livestock across China, we show that rural population ageing reduced farm size by 4% through transferring cropland ownership and land abandonment (approximately 4 million hectares) in 2019, taking the population age structure in 1990 as a benchmark. These changes led to a reduction of agricultural inputs, including chemical fertilizers, manure and machinery, which decreased agricultural output and labour productivity by 5% and 4%, respectively, further lowering farmers' income by 15%. Meanwhile, fertilizer loss increased by 3%, resulting in higher pollutant emissions to the environment. In new farming models, such as cooperative farming, farms tend to be larger and operated by younger farmers, who have a higher average education level, hence improving agricultural management. By encouraging the transition to new farming models, the negative consequences of ageing can be reversed. Agricultural input, farm size and farmer's income would grow by approximately 14%, 20% and 26%, respectively, and fertilizer loss would reduce by 4% in 2100 compared with that in 2020. This suggests that management of rural ageing will contribute to a comprehensive transformation of smallholder farming to sustainable agriculture in China., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Understanding the molecular mechanisms of pathological vascular remodeling is important for treating cardiovascular diseases and complications. Recent studies have highlighted a role of deubiquitinases in vascular pathophysiology. Here, we investigate the role of a deubiquitinase, OTUD1, in angiotensin II (Ang II)-induced vascular remodeling. We detect upregulated OTUD1 in the vascular endothelium of Ang II-challenged mice and show that OTUD1 deletion attenuates vascular remodeling, collagen deposition, and EndMT. Conversely, OTUD1 overexpression aggravates these pathological changes both in vivo and in vitro. Mechanistically, SMAD3 is identified as a substrate of OTUD1 using co-immunoprecipitation followed by LC-MS/MS. We find that OTUD1 stabilizes SMAD3 and facilitates SMAD3/SMAD4 complex formation and subsequent nuclear translocation through both K48- and K63-linked deubiquitination. OTUD1-mediated SMAD3 activation regulates transcription of genes involved in vascular EndMT and remodeling in HUVECs. Finally, SMAD3 inhibition reverses OTUD1-promoted vascular remodeling. Our findings demonstrate that endothelial OTUD1 promotes Ang II-induced vascular remodeling by deubiquitinating SMAD3. We identify SMAD3 as a target of OTUD1 and propose OTUD1 as a potential therapeutic target for diseases related to vascular remodeling., (© 2022 The Authors.)

One critical bottleneck that impedes the development and deployment of autonomous vehicles is the prohibitively high economic and time costs required to validate their safety in a naturalistic driving environment, owing to the rarity of safety-critical events 1 . Here we report the development of an intelligent testing environment, where artificial-intelligence-based background agents are trained to validate the safety performances of autonomous vehicles in an accelerated mode, without loss of unbiasedness. From naturalistic driving data, the background agents learn what adversarial manoeuvre to execute through a dense deep-reinforcement-learning (D2RL) approach, in which Markov decision processes are edited by removing non-safety-critical states and reconnecting critical ones so that the information in the training data is densified. D2RL enables neural networks to learn from densified information with safety-critical events and achieves tasks that are intractable for traditional deep-reinforcement-learning approaches. We demonstrate the effectiveness of our approach by testing a highly automated vehicle in both highway and urban test tracks with an augmented-reality environment, combining simulated background vehicles with physical road infrastructure and a real autonomous test vehicle. Our results show that the D2RL-trained agents can accelerate the evaluation process by multiple orders of magnitude (10 3 to 10 5 times faster). In addition, D2RL will enable accelerated testing and training with other safety-critical autonomous systems., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Our meta-analysis aimed to evaluate the diagnostic performance of 68 Ga-PSMA-11 PET/CT vs. 68 Ga-PSMA-11 PET/MRI for biochemical recurrence of prostate cancer., Methods: We searched for relevant articles in PubMed and Embase until February 2022. Studies evaluating head-to-head comparison of 68 Ga-PSMA-11 PET/CT and 68 Ga-PSMA-11 PET/MRI in men with prostate cancer biochemical recurrence were included. The quality of each study was assessed using the Quality Assessment of Diagnostic Performance Studies-2 (QUADAS-2) tool., Results: A total of 5 studies with 219 patients were included in the analysis. The pooled overall detection rates of 68 Ga-PSMA-11 PET/CT and 68 Ga-PSMA-11 PET/MRI in detecting recurrent PCa after definitive treatment were 0.89 (95% CI: 0.65-1.00), 0.92 (95% CI: 0.77-1.00), while the detection rates were 0.20 (95% CI: 0.05-0.41) and 0.29 (95% CI: 0.10-0.53) in local recurrence, 0.51 (95% CI: 0.33-0.69) and 0.52 (95% CI: 0.44-0.61) in lymph node metastasis, 0.18 (95% CI: 0.07-0.33) and 0.20 (95% CI: 0.09-0.35) in bone metastasis. There was no significant difference between the two imaging modalities in the overall detection rate (P = 0.82). In addition, detection rates were also not significantly different in local recurrence, lymph node metastasis, or bone metastasis (P = 0.54, 1.00, 0.82)., Conclusions: 68 Ga-PSMA-11 PET/CT and 68 Ga-PSMA-11 PET/MRI seem to have equivalent performance in detecting biochemical recurrence in prostate cancer. However, the results of the meta-analysis were drawn from studies with small samples. Further larger studies in this setting are warranted., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Fusobacterium nucleatum (F. nucleatum) is an early pathogenic colonizer in periodontitis, but the host response to infection with this pathogen remains unclear. In this study, we built an F. nucleatum infectious model with human periodontal ligament stem cells (PDLSCs) and showed that F. nucleatum could inhibit proliferation, and facilitate apoptosis, ferroptosis, and inflammatory cytokine production in a dose-dependent manner. The F. nucleatum adhesin FadA acted as a proinflammatory virulence factor and increased the expression of interleukin(IL)-1β, IL-6 and IL-8. Further study showed that FadA could bind with PEBP1 to activate the Raf1-MAPK and IKK-NF-κB signaling pathways. Time-course RNA-sequencing analyses showed the cascade of gene activation process in PDLSCs with increasing durations of F. nucleatum infection. NFκB1 and NFκB2 upregulated after 3 h of F. nucleatum-infection, and the inflammatory-related genes in the NF-κB signaling pathway were serially elevated with time. Using computational drug repositioning analysis, we predicted and validated that two potential drugs (piperlongumine and fisetin) could attenuate the negative effects of F. nucleatum-infection. Collectively, this study unveils the potential pathogenic mechanisms of F. nucleatum and the host inflammatory response at the early stage of F. nucleatum infection., (© 2023. The Author(s).)

Coagulation/flocculation is one of the most widely used and cost-effective pretreatment methods for improving the dewaterability of sludge. In this study, a cationic modified starch-based flocculant (St-CTA) in conjunction with a popular clay, attapulgite (ATP), was used for the conditioning of waste-activated sludge. The dewatering properties, including the filter cake moisture content, filtration specific resistance, capillary suction time, filtration rate and compressibility coefficient, were measured and compared by varying the doses of St-CTA and ATP. By combination of the apparent dewatering performance and the changes in the contents and distributions of the extracellular polymeric substance (EPS) fractions and components, sludge flocs, and microstructures of sludge cakes, the dewatering mechanisms were discussed in detail. St-CTA in conjunction with ATP can exhibit an enhanced dewaterability of sludge and the water content in final sludge cake can be stably reduced below 80% owing to the synergistic effects of St-CTA and ATP. In addition to the efficient charge neutralization of St-CTA, ATP not only acts as a skeleton builder in the sludge dewatering process which makes the sludge flocs more compact and improves the filterability and permeability, but also tightly interacts with the proteins in EPS of the sludge which reduces the protein content and further enhances the dewatering effect. This study provides an economical, green, and effective way to further improve the dewaterability of sludge., (© 2023. The Author(s).)

Mutations of the RAS oncogene are found in around 30% of all human cancers yet direct targeting of RAS is still considered clinically impractical except for the KRAS G12C mutant. Here we report that RAS-ON (RASON), a novel protein encoded by the long intergenic non-protein coding RNA 00673 (LINC00673), is a positive regulator of oncogenic RAS signaling. RASON is aberrantly overexpressed in pancreatic ductal adenocarcinoma (PDAC) patients, and it promotes proliferation of human PDAC cell lines in vitro and tumor growth in vivo. CRISPR/Cas9-mediated knockout of Rason in mouse embryonic fibroblasts inhibits KRAS-mediated tumor transformation. Genetic deletion of Rason abolishes oncogenic KRAS-driven pancreatic and lung cancer tumorigenesis in LSL-Kras G12D ; Trp53 R172H/+ mice. Mechanistically, RASON directly binds to KRAS G12D/V and inhibits both intrinsic and GTPase activating protein (GAP)-mediated GTP hydrolysis, thus sustaining KRAS G12D/V in the GTP-bound hyperactive state. Therapeutically, deprivation of RASON sensitizes KRAS mutant pancreatic cancer cells and patient-derived organoids to EGFR inhibitors. Our findings identify RASON as a critical regulator of oncogenic KRAS signaling and a promising therapeutic target for KRAS mutant cancers., (© 2022. The Author(s).)

Aberrant self-renewal of leukemia initiation cells (LICs) drives aggressive acute myeloid leukemia (AML). Here, we report that UHRF1, an epigenetic regulator that recruits DNMT1 to methylate DNA, is highly expressed in AML and predicts poor prognosis. UHRF1 is required for myeloid leukemogenesis by maintaining self-renewal of LICs. Mechanistically, UHRF1 directly interacts with Sin3A-associated protein 30 (SAP30) through two critical amino acids, G572 and F573 in its SRA domain, to repress gene expression. Depletion of UHRF1 or SAP30 derepresses an important target gene, MXD4, which encodes a MYC antagonist, and leads to suppression of leukemogenesis. Further knockdown of MXD4 can rescue the leukemogenesis by activating the MYC pathway. Lastly, we identified a UHRF1 inhibitor, UF146, and demonstrated its significant therapeutic efficacy in the myeloid leukemia PDX model. Taken together, our study reveals the mechanisms for altered epigenetic programs in AML and provides a promising targeted therapeutic strategy against AML., (© 2022. The Author(s).)

Continuing studies imply that m 6 A RNA modification is involved in the development of cervical cancer (CC), but lack strong support on recurrence and diagnosis prediction. In this research, a comprehensive analysis of 33 m 6 A regulators was performed to fulfill them. Here, we performed diagnostic and prognosis models and identified key regulators, respectively. Then the CC patients were separated into two clusters in accordance with 33 regulators, and participants in the cluster 1 had a worse prognosis. Subsequently, the m 6 AScore was calculated to quantify the m 6 A modification pattern based on regulators and we found that patients in cluster 1 had higher m 6 AScore. Afterwards, immune microenvironment, cell infiltration, escape analyses and tumor burden mutation analyses were executed, and results showed that m 6 AScore was correlated with them, but to a limited extent. Interestingly, HLAs and immune checkpoint expression, and immunophenoscore in patients with high-m 6 AScores were significantly lower than those in the low-m 6 AScore group. These suggested the m 6 AScores might be used to predict the feasibility of immunotherapy in patients. Results provided a distinctive perspective on m 6 A modification and theoretical basis for CC diagnosis, prognosis, clinical treatment strategies, and potential mechanism exploration., (© 2022. The Author(s).)