Search

Abstract The pursuit of innovative therapeutic strategies in oncology remains imperative, given the persistent global impact of cancer as a leading cause of mortality. Immunotherapy is regarded as one of the most promising techniques for systemic cancer therapies among the several therapeutic options available. Nevertheless, limited immune response rates and immune resistance urge us on an augmentation for therapeutic efficacy rather than sticking to conventional approaches. Ferroptosis, a novel reprogrammed cell death, is tightly correlated with the tumor immune environment and interferes with cancer progression. Highly mutant or metastasis-prone tumor cells are more susceptible to iron-dependent nonapoptotic cell death. Consequently, ferroptosis-induction therapies hold the promise of overcoming resistance to conventional treatments. The most prevalent post-transcriptional modification, RNA m6A modification, regulates the metabolic processes of targeted RNAs and is involved in numerous physiological and pathological processes. Aberrant m6A modification influences cell susceptibility to ferroptosis, as well as the expression of immune checkpoints. Clarifying the regulation of m6A modification on ferroptosis and its significance in tumor cell response will provide a distinct method for finding potential targets to enhance the effectiveness of immunotherapy. In this review, we comprehensively summarized regulatory characteristics of RNA m6A modification on ferroptosis and discussed the role of RNA m6A-mediated ferroptosis on immunotherapy, aiming to enhance the effectiveness of ferroptosis-sensitive immunotherapy as a treatment for immune-resistant malignancies.

Abstract We aimed to explore the mineralization characteristics of soil organic carbon(SOC) under different plant species in semi-arid grassland and provide basic soil carbon cycling data. Leymus chinensis, Stipa krylovii Roshev, Artemisia frigida, and Agrophorn cristam (L.) Gaertn were selected as the plant species. Incubation experiment were conducted on SOC mineralization in soil aggregates with particle sizes of > 2, 1–2, 0.25–1, and 2 mm was the highest, exceeding that of A. cristam (L.) Gaertn by approximately 136.14%. S. krylovii Roshev (70.73%), L. chinensis (58.05%), and A. frigida (33.73%) exhibited pronounced promotion effects on mineralization. The potential SOC mineralization of S. krylovii Roshev was the greatest among all species at the same soil particle size. The potential SOC mineralization was highest at a particle size of > 2 mm for all plant types. All plant types increased the SOC mineralization rate and cumulative mineralization in soils with large particle sizes, the mineralization reaction occurred more strongly. Organic carbon cumulative SOC mineralization rapidly increased in all tests during the first 20 days and gradually slowed thereafter.

Abstract Runoff and evapotranspiration (ET) are pivotal constituents of the water, energy, and carbon cycles. This research presents a 5-km monthly gridded runoff and ET dataset for 1998–2017, encompassing seven headwaters of Tibetan Plateau rivers (Yellow, Yangtze, Mekong, Salween, Brahmaputra, Ganges, and Indus) (hereinafter TPRED). The dataset was generated using the advanced cryosphere-hydrology model WEB-DHM, yielding a Nash coefficient ranging from 0.77 to 0.93 when compared to the observed discharges. The findings indicate that TPRED’s monthly runoff notably outperforms existing datasets in capturing hydrological patterns, as evidenced by robust metrics such as the correlation coefficient (CC) (0.944–0.995), Bias (−0.68-0.53), and Root Mean Square Error (5.50–15.59 mm). Additionally, TPRED’s monthly ET estimates closely align with expected seasonal fluctuations, as reflected by a CC ranging from 0.94 to 0.98 when contrasted with alternative ET products. Furthermore, TPRED’s annual values exhibit commendable concordance with operational products across multiple dimensions. Ultimately, the TPRED will have great application on hydrometeorology, carbon transport, water management, hydrological modeling, and sustainable development of water resources.

The Himalayas and their surrounding areas boast vast glaciers rivaling those in polar regions, supplying vital meltwater to the Indus, Ganges, and Brahmaputra rivers, supporting over a billion downstream inhabitants for drinking, power, and agriculture. With changing runoff patterns due to accelerated glacial melt, understanding and projecting glacio-hydrological processes in these basins is imperative. This review assesses the evolution, applications, and key challenges in diverse glacio-hydrology models across the Himalayas, varying in complexities like ablation algorithms, glacier dynamics, ice avalanches, and permafrost. Previous findings indicate higher glacial melt contributions to annual runoff in the Indus compared to the Ganges and Brahmaputra, with anticipated peak melting in the latter basins — having less glacier cover — before the mid-21st century, contrasting with the delayed peak expected in the Indus Basin due to its larger glacier area. Different modeling studies still have large uncertainties in the simulated runoff components in the Himalayan basins; and the projections of future glacier melt peak time vary at different Himalaya sub-basins under different Coupled Model Intercomparison Project (CMIP) scenarios. We also find that the lack of reliable meteorological forcing data (particularly the precipitation errors) is a major source of uncertainty for glacio-hydrological modeling in the Himalayan basins. Furthermore, permafrost degradation compounds these challenges, complicating assessments of future freshwater availability. Urgent measures include establishing comprehensive in situ observations, innovating remote-sensing technologies (especially for permafrost ice monitoring), and advancing glacio-hydrology models to integrate glacier, snow, and permafrost processes. These endeavors are crucial for informed policymaking and sustainable resource management in this pivotal, glacier-dependent ecosystem.

Highlights The SiO2 nanofiber membranes and MXene@c-MWCNT6:4 as one unit layer (SMC1) were bonded together with 5 wt% PVA solution. When the structural unit is increased to three layers, the resulting SMC3 has an average electromagnetic interference SET of 55.4 dB and a low thermal conductivity of 0.062 W m−1 K−1. SMCx exhibit stable electromagnetic interference shielding and excellent thermal insulation even in extreme heat and cold environment.

Abstract Citrus reticulata cv. Chachiensis (CRC) is an important medicinal plant, its dried mature peels named “Guangchenpi”, has been used as a traditional Chinese medicine to treat cough, indigestion, and lung diseases for several hundred years. However, the biosynthesis of the crucial natural products polymethoxylated flavonoids (PMFs) in CRC remains unclear. Here, we report a chromosome-scale genome assembly of CRC with the size of 314.96 Mb and a contig N50 of 16.22 Mb. Using multi-omics resources, we discover a putative caffeic acid O-methyltransferase (CcOMT1) that can transfer a methyl group to the 3-hydroxyl of natsudaidain to form 3,5,6,7,8,3’,4’-heptamethoxyflavone (HPMF). Based on transient overexpression and virus-induced gene silencing experiments, we propose that CcOMT1 is a candidate enzyme in HPMF biosynthesis. In addition, a potential gene regulatory network associated with PMF biosynthesis is identified. This study provides insights into PMF biosynthesis and may assist future research on mining genes for the biosynthesis of plant-based medicines.

MSS/pMMR patients are unresponsive to PD-1/PD-L1 blockade in colorectal cancer (CRC), but the mechanisms are unclear. A better understanding of immunotherapy resistance in CRC may lead to more precise treatment and expand the benefit of immunotherapy to patients. In this study, we constructed mouse model of subcutaneous CRC tumor received anti-PD-L1 treatment with or without fusobacterium nucleatum (F. nucleatum) infection. Then we used single-cell RNA sequencing (scRNA-seq) to explore the comprehensive landscape of the tumor microenvironment (TME). Our data delineated the composition, subclonal diversity and putative function of distinct cells, tracked the developmental trajectory of tumor cells and highlighted cell-cell interactions. We found different compositions and functions of both tumor cells and immune cells. Single anti-PD-L1 monoclonal antibody (mAb) treated tumor exhibited two specific clusters which might be resistant to PD-L1 blockade. The accumulation of immune cells, including T cell, NK cell and pro-inflammatory macrophage subset in tumors infected with F. nucleatum may be one of the reasons for the increased sensitivity to PD-L1 blockade. Thus, targeting F. nucleatum to change the composition of tumor cell subclusters and enliven the immune response might help to overcome immune checkpoint blockade (ICB) resistance.

Tumor immune microenvironment is crucial for diffuse large B-cell lymphoma (DLBCL) development. However, the mechanisms by which super-enhancers (SEs) regulate the interactions between DLBCL cells and tumor-infiltrating immune cells remains largely unknown. This study aimed to investigate the role of SE-controlled genes in regulating the interactions between DLBCL cells and tumor-infiltrating immune cells. Single-cell RNA-seq, bulk RNA-seq and H3K27ac ChIP-seq data were downloaded from the Heidelberg Open Research Data database and Gene Expression Omnibus database. HOMER algorithm and Seurat package in R were used for bioinformatics analysis. Cell proliferation and lactate dehydrogenase (LDH) release was detected by MTS and LDH release assays, respectively. Interaction between B cell cluster and CD8+ T cell and NK cell cluster was most obviously enhanced in DLBCL, with CD70-CD27, MIF-CD74/CXCR2 complex, MIF-CD74/CD44 complex and CCL3-CCR5 interactions were significantly increased. NK cell sub-cluster showed the strongest interaction with B cell cluster. ZZZ3 upregulated the transcription of CD70 by binding to its SE. Silencing CD70 in DOHH2 cells significantly promoted the proliferation of co-cultured NK92 cells and LDH release from DOHH2 cells, which was counteracted by ZZZ3 overexpression in DOHH2 cells. CD70 silencing combined with PD-L1 blockade promoted LDH release from DOHH2 cells co-cultured with NK92 cells. In conclusion, DLBCL cells inhibited the proliferation and killing of infiltrating NK cells by regulating ZZZ3/CD70 axis. Targeting ZZZ3/CD70 axis combined with PD-L1 blockade is expected to be a promising strategy for DLBCL treatment.

Background: Sivelestat, a neutrophil elastase inhibitor, is postulated to mitigate acute lung injury in patients following emergency surgery. However, its efficacy in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) induced by coronavirus disease 2019 (COVID-19) remains uncertain. This study aims to evaluate the pulmonary protective effects of sivelestat in COVID-19 patients with ALI/ARDS. Methods: A retrospective study was conducted involving 2454 COVID-19 patients between October 5, 2022, and February 1, 2023. Of these, 102 patients received sivelestat (0.2 mg/kg/h), while 2352 age- and sex-matched controls were identified. Propensity score matching (PSM) analysis was used to match sivelestat and non-sivelestat subgroups in ratios of 1:1 and 1:3 for sensitivity analysis. The primary outcome was a composite of effective outcomes, including 30-day mortality. Secondary outcomes included changes in partial pressure of arterial oxygen (PaO2), the ratio of PaO2 to the fraction of inspired oxygen (PaO2/FiO2), and various cytokine levels. Safety evaluations included assessments of liver function, kidney function, and leukopenia. Results: In the propensity score-matched analysis, the sivelestat group had a higher proportion of severe/critical patients (87.26 % vs. 51.02 %, P

Environmental chemicals and pollutants are increasingly recognized for their potential transgenerational effects. Acetyl tributyl citrate (ATBC), a widely used plasticizer substituting di-(2-ethylhexyl) phthalate (DEHP), was identified as an inducer of lipogenesis in male mice by our previous research. This study aimed to investigate the impact of ATBC exposure on the metabolic homeostasis of female mice and simultaneously evaluate its intergenerational effects.Female C57BL/6J mice were orally exposed to ATBC (0.01 or 1 μg/kg/day) for 10 weeks before mating with unexposed male mice. The resulting F1 female mice were bred with unexposed males to generate F2 offspring. Our results indicated that 10-week ATBC exposure disrupted glucose metabolism homeostasis and the reproductive system in F0 female mice. In F1 female mice, elevated liver lipid levels and mild insulin resistance were observed. In the F2 generation, maternal ATBC exposure resulted in increased weight gain, elevated liver triglycerides, and higher fasting blood glucose levels, primarily in F2 male mice. These findings suggest that maternal ATBC exposure may exert intergenerational disturbing effects on glucose metabolism across generations of mice. Further investigation is needed to evaluate the health risks associated with ATBC exposure.

Under the dual-carbon background, enterprises' ESG performance and sustainable development capability have become a topic of great concern to all sectors of society. The ESG industry in China is very young, and there isn't much research looking at how ESG performance relates to business risk for corporations. This paper empirically tests the impact of firms' ESG performance on their business risk. It discusses the mechanism from the viewpoints of financing constraints and agency costs, the moderating role of economic policy uncertainty, and the analysis of differences in corporate size. The results indicate that firms with strong ESG performance experience a significant reduction in business risk. These firms face lower financing constraints and agency costs, which contribute to the mitigation of business risk. Furthermore, economic policy uncertainty moderates the link between ESG performance and business risk. Additionally, the influence of ESG performance on business risk is more significant in larger-scale companies.

BackgroundThe ryanodine receptor 3 (RYR3) is involved in skeletal muscle contraction by releasing calcium from the sarcoplasmic reticulum and subsequent T-tubule depolarization. It is also expressed in the brain, and variants in the RYR3 gene can lead to congenital myopathy type 20 (MIM: #620310).MethodsWe retrospectively analyzed the clinical characteristics and prognosis of a case of West syndrome, developmental and epileptic encephalopathy (DEE) caused by a missense variant in the RYR3 gene. We also reviewed and summarized the literature on epilepsy cases caused by RYR3 gene variants.ResultsA 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. Treatment with various antiepileptic drugs resulted in initial improvement but ultimately failed to control the seizures. Whole-exome sequencing revealed a novel heterozygous variant c.10943C > T/p.T3648M in the RYR3 gene, and genome-wide sequencing ruled out other potentially pathogenic variants. Three previous reports have described RYR3 variants causing DEE, two of which were attributed to de novo heterozygous variants, and one was a compound heterozygote.ConclusionThe present case of DEE caused by a RYR3 heterozygous variant is consistent with previous rare cases of epilepsy caused by RYR3 gene variants in terms of pathogenesis and clinical features, but significantly different from congenital myopathy type 20. Our findings provide important evidence for the diagnosis of RYR3-related DEE, and we hypothesize that RYR3 gain-of-function variants resulting in “leaky” Ca2+ release channels may be a molecular genetic feature leading to DEE rather than myopathy.

Abstract The precise structural integration of single-atom and high-entropy-alloy features for energy electrocatalysis is highly appealing for energy conversion, yet remains a grand challenge. Herein, we report a class of single-atom Mo-tailored PdPtNiCuZn high-entropy-alloy nanosheets with dilute Pt-Pt ensembles and intrinsic tensile strain (Mo1-PdPtNiCuZn) as efficient electrocatalysts for enhancing the methanol oxidation reaction catalysis. The as-made Mo1-PdPtNiCuZn delivers an extraordinary mass activity of 24.55 A mgPt −1 and 11.62 A mgPd+Pt −1, along with impressive long-term durability. The planted oxophilic Mo single atoms as promoters modify the electronic structure of isolated Pt sites in the high-entropy-alloy host, suppressing the formation of CO adsorbates and steering the reaction towards the formate pathway. Meanwhile, Mo promoters and tensile strain synergistically optimize the adsorption behaviour of intermediates to achieve a more energetically favourable pathway and minimize the methanol oxidation reaction barrier. This work advances the design of atomically precise catalytic sites by creating a new paradigm of single atom-tailored high-entropy alloys, opening an encouraging pathway to the design of CO-tolerance electrocatalysts.

Abstract The Holocene temperature conundrum, the discrepancy between proxy-based Holocene global cooling and simulated global annual warming trends, remains controversial. Meanwhile, reconstructions and simulations show inconsistent spatial patterns of terrestrial temperature changes. Here we report Holocene alkenone records to address spatial patterns over mid-latitude Eurasia. In contrast with long-term cooling trends in warm season temperatures in northeastern China, records from southwestern Siberia are characterized by colder conditions before ~6,000 years ago, thus long-term warming trends. Together with existing records from surrounding regions, we infer that colder airmass might have prevailed in the interior of mid-latitude Eurasian continent during the early to mid-Holocene, perhaps associated with atmospheric response to remnant ice sheets. Our results challenge the proposed seasonality bias in proxies and modeled spatial patterns in study region, highlighting that spatial patterns of Holocene temperature changes should be re-considered in record integrations and model simulations, with important implications for terrestrial hydroclimate changes.

Abstract Fusobacterium nucleatum (F. nucleatum) promotes intestinal tumor growth and its relative abundance varies greatly among patients with CRC, suggesting the presence of unknown, individual-specific effectors in F. nucleatum-dependent carcinogenesis. Here, we identify that F. nucleatum is enriched preferentially in KRAS p.G12D mutant CRC tumor tissues and contributes to colorectal tumorigenesis in Villin-Cre/Kras G12D+/- mice. Additionally, Parabacteroides distasonis (P. distasonis) competes with F. nucleatum in the G12D mouse model and human CRC tissues with the KRAS mutation. Orally gavaged P. distasonis in mice alleviates the F. nucleatum-dependent CRC progression. F. nucleatum invades intestinal epithelial cells and binds to DHX15, a protein of RNA helicase family expressed on CRC tumor cells, mechanistically involving ERK/STAT3 signaling. Knock out of Dhx15 in Villin-Cre/Kras G12D+/- mice attenuates the CRC phenotype. These findings reveal that the oncogenic effect of F. nucleatum depends on somatic genetics and gut microbial ecology and indicate that personalized modulation of the gut microbiota may provide a more targeted strategy for CRC treatment.

Abstract The bridge bottom crack detection provides important state information for bridge disease control and safety assessment. This paper proposes a detection method based on deep learning Faster R‐CNN and BIM (Building Information Modeling). The UAV (Unmanned Aerial Vehicle) was used for close aerial photography to obtain high‐resolution crack images of the concrete surface at the bottom of a bridge. Through deep learning algorithms, a Faster R‐CNN model is trained and established for crack identifications. The crack identification accuracy rate and recall rate reach 92.03% and 96.54%, respectively. Crack images are mapped to a BIM model developed for the chosen bridge, and the box girder family with cracks and the three crack families of transverse cracks, longitudinal cracks and turtle cracks are established. The cracks are located and the visualization of the beam bridge with cracks was completed. In order to better assess the health condition of the bridge. The results show that the combination of UAV bridge crack detection and modelling solves the remote, visual and automated detection of cracks on the surface of bridge structures, which are difficult to reach manually, and has important scientific research and engineering application value.

ABSTRACT: Fatty liver hemorrhagic syndrome is the main cause of noninfectious death of laying hens and results in substantial economic losses to the poultry industry. This study focused on evaluating the effects of Poly-dihydromyricetin-fused zinc nanoparticles (PDMY-Zn NPs) on antioxidant capacity, liver lipid metabolism, and intestinal health in laying hens. A total of 288 Jingfen laying hens (52 wk old) with similar body weights were randomly divided into 4 dietary groups with 6 replicates in each group for 8 wk. The control group received a basal diet, while the treatment groups were supplemented with PDMY-Zn NPs at levels of 200, 400, and 600 mg/kg, respectively. The results indicate that PDMY-Zn NPs supplementation can enhance antioxidant parameters (P < 0.05) in the blood and liver of laying hens. Simultaneously, it can mitigate vacuolar degeneration and inflammatory necrosis in hepatocytes, improve the relative expression level of related parameters associated with liver lipid metabolism and key regulatory genes (P < 0.05). Furthermore, it has been observed to reshape the composition and diversity of cecum microbes by increasing beneficial probiotics such as Lactobacillus and Prevotella, while also enhancing villi height and villi/crypt ratio in the duodenum and ileum (P < 0.05). Additionally, it elevates liver bile acid content along with the relative expression of key genes involved in liver synthesis (P < 0.05). In summary, PDMY-Zn NPs showed potential to alleviate fatty liver hemorrhagic syndrome by enhancing antioxidant capacity, regulating liver lipid metabolism, and maintaining intestinal health.

Soil alkalization is a major challenge for global crop production. This study reveals a novel defense mechanism in rice seedlings against alkaline stress, involving methyl jasmonate (MeJA) and auxin pathways. Under alkaline stress (15 mM Na2CO3), rice seedlings exhibited elevated levels of endogenous MeJA and upregulation of JA-responsive genes. Pre-treatment with MeJA (50 µM) significantly improved seedling survival, growth, and mitigated root damage under alkaline stress. This treatment also upregulated genes associated with cell death suppression (OsBI1) and stress tolerance (OsJRL, OsNAC). Notably, MeJA pre-treatment increased auxin (indole-3-acetic acid, IAA) levels in roots, and upregulated genes involved in IAA synthesis (OASA1, OASA2) and auxin signaling (Aux/IAA, ARFs). Blocking auxin transport with N-1-naphthylphthalamic acid intensified root damage under alkaline stress and diminished the protective effect of MeJA. These results highlight the crucial role of MeJA-induced activation of auxin pathway in enhancing rice tolerance to alkaline stress, and provide valuable insights for developing strategies to improve crop resilience in alkaline soils.

We present a case of Coccidioides posadasii infection which was contracted during study abroad. This coccidioidomycosis showed atypical manifestations and was diagnosed by a combination of tissue biopsy, metagenomic next–generation sequencing, internal transcribed spacer sequencing and culture. Initial treatment with fluconazole was not effective. Antifungal therapy was switched to voriconazole based on drug sensitivity results with good result. This case demonstrates the clinical significance of combining multiple diagnostic methods.

BackgroundObservational studies have indicated that immune dysregulation in primary sclerosing cholangitis (PSC) primarily involves intestinal-derived immune cells. However, the causal relationship between peripheral blood immune cells and PSC remains insufficiently understood.MethodsA bidirectional two-sample Mendelian randomization (MR) analysis was implemented to determine the causal effect between PBC and 731 immune cells. All datasets were extracted from a publicly available genetic database. The standard inverse variance weighted (IVW) method was selected as the main method for the causality analysis. Cochran’s Q statistics and MR-Egger intercept were performed to evaluate heterogeneity and pleiotropy.ResultsIn forward MR analysis, the expression ratios of CD11c on CD62L+ myeloid DC (OR = 1.136, 95% CI = 1.032–1.250, p = 0.009) and CD62L-myeloid DC AC (OR = 1.267, 95% CI = 1.086–1.477, p = 0.003) were correlated with a higher risk of PSC. Each one standard deviation increase of CD28 on resting regulatory T cells (Treg) (OR = 0.724, 95% CI = 0.630–0.833, p < 0.001) and CD3 on secreting Treg (OR = 0.893, 95% CI = 0.823–0.969, p = 0.007) negatively associated with the risk of PSC. In reverse MR analysis, PSC was identified with a genetic causal effect on EM CD8+ T cell AC, CD8+ T cell AC, CD28− CD127− CD25++ CD8+ T cell AC, CD28− CD25++ CD8+ T cell AC, CD28− CD8+ T cell/CD8+ T cell, CD28− CD8+ T cell AC, and CD45 RA− CD28− CD8+ T cell AC.ConclusionOur study indicated the evidence of causal effects between PSC and immune cells, which may provide a potential foundation for future diagnosis and treatment of PSC.

Abstract Background The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and its subsequent Omicron variant has raised concerns for chronic obstructive pulmonary disease (COPD) patients due to the potential risk of disruptions to healthcare services and unknown comorbidities between COPD and Omicron. Method In this study, we conducted a follow‐up investigation of 315 COPD patients during the Omicron outbreak at Shanxi Bethune Hospital to understand the impact of the pandemic on this vulnerable population. Among all patients, 228 were infected with Omicron, of which 82 needed hospitalizations. Result We found that COPD patients with high blood eosinophil (EOS) counts exhibited lower susceptibility to Omicron infection and were more likely to have milder symptoms that did not require hospitalization. Conversely, patients with low EOS counts showed higher rates of infection and hospitalization. Moreover, EOS count was positively correlated with T lymphocyte counts in hospitalized patients after Omicron infection, suggesting potential associations between EOS and specific immune responses in COPD patients during viral infections. Correlation analysis revealed a positive correlation between EOS count and lymphocyte and T‐cells, and a negative correlation between EOS count and age, neutrophil, and C‐reactive protein. Conclusion Overall, our study contributes to the knowledge of COPD management during the COVID‐19 Omicron outbreak and emphasizes the importance of considering individual immune profiles to improve care for COPD patients in the face of the ongoing global health crisis.

BackgroundBaitouweng decoction (BTW) is a classic botanical drugs formula that has been widely used clinically for the treatment of gut-related disorders in China. However, its role in ameliorating ulcerative colitis (UC) remains to be explored.PurposeThe study aimed to determine the therapeutic efficacy and potential mechanism of action of BTW on dextran sodium sulfate (DSS)-induced colitis mice.MethodsIn vivo: 3.5% DSS-induced experimental colitis mice were treated with BTW (Pulsatilla chinensis (Bunge) Regel, Phellodendron chinense C. K. Schneid, Coptis chinensis Franch and Fraxinus chinensis Roxb), kynurenine or DOPA decarboxylase (DDC) inhibitor (carbidopa). In vitro: Caco-2 cells were stimulated with TNF-α to activate inflammation and later treated with various concentrations of BTW and carbidopa. Model evaluation included body weight, disease activity index (DAI) score, colon length and histopathology. Cytokine levels were measured by flow cytometry. Protein levels were analyzed by proteomics and functionally annotated. The levels of tryptophan metabolites in mouse serum and colon were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Alcian Blue/Phosphate Acid Schiff (AB/PAS) staining, immunohistochemistry and western blot were used to assess the intestinal barrier function and detect the protein expression levels.ResultsBTW significantly reduced the DAI, ameliorated colonic injury and regulated inflammatory cytokines in DSS-induced colitis mice. The botanical drugs formula also promoted intestinal epithelial barrier repair by enhancing the expression of the tight junction (TJ) proteins. Tryptophan metabolic signaling pathway was significantly enriched in DSS-induced UC mice, and BTW decreased the level of kynurenine, increased indole metabolites. The therapeutic effect of BTW was evidently reduced when kynurenine was given to mice. Also, BTW promoted DDC protein expression and activated the aryl hydrocarbon receptor (AHR)/IL-22 signaling pathway.ConclusionBTW improves ulcerative colitis by promoting DDC expression, regulating the conversion of tryptophan metabolism from the kynurenine pathway to the indole metabolism pathway, thereby modulating tryptophan metabolism to increase indole metabolites, and activating AHR receptors to restore intestinal barrier function.

Summary: Background: In ORIENT-15 study, sintilimab plus chemotherapy demonstrated significant improvement on overall survival (OS) versus placebo plus chemotherapy in first-line treatment of advanced esophageal squamous cell carcinoma (ESCC). Here, we report effect of sintilimab plus chemotherapy on health-related quality of life (HRQoL) in patients with advanced ESCC. Methods: From December 14, 2018 to August 28, 2022, HRQoL was evaluated in all randomized patients using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), EORTC Quality of Life Questionnaire Oesophageal Cancer Module 18 items (QLQ-OES18), and visual analogue scale (VAS) of the EuroQol five-dimensional five-level questionnaire (EQ-5D-5L). Mean scores of each scale were described by treatment group through week 60. Least-squares mean (LSM) score change from baseline through week 24 were analyzed using the mixed-model repeated-measures method. Time to the first onset of deterioration (TTD) and OS for each scale were estimated. Clinical Trials Registration: NCT03748134. Findings: As of August 28, 2022, 689 of 690 enrolled patients were assessed for HRQoL analysis (sintilimab group: 340, placebo group: 349). Median follow-up was 32.2 months. Differences in LSM favored sintilimab over placebo for QLQ-C30 social functioning (LSM difference: 3.06, 95% CI: 0.55 to 5.57; P = 0.0170), pain (−2.24, 95% CI: −4.30 to −0.17; P = 0.0337), fatigue (−2.24, 95% CI: −4.46 to −0.02; P = 0.0479), constipation (−3.27, 95% CI −5.49 to −1.05; P = 0.0039), QLQ-OES18 pain (−1.77, 95% CI −3.11 to −0.43; P = 0.0097), trouble swallowing saliva (−2.09, 95% CI: −3.77 to −0.42; P = 0.0146), and choked when swallowing (−3.23, 95% CI: −5.60 to −0.86; P = 0.0076). TTD favored sintilimab over placebo for QLQ-OES18 dysphagia (Hazard ratio [HR]: 0.76, 95% CI: 0.61–0.94, P = 0.0104), and trouble swallowing saliva (HR: 0.48, 95% CI: 0.35–0.67, P

In recent years, significant advancements in nanotechnology have yielded remarkable improvements in biomedical applications. Nanocarriers, harnessed from the principles of nanotechnology, have garnered widespread utilization in medicine delivery and diagnostics. However, the progression of nanocarriers has been hindered by two key challenges: low drug loading capacity and the potential for carrier-induced toxicity. To surmount these obstacles, the rapid development and expansion of carrier-free drug delivery systems (CFDDSs) composed of pure drugs and prodrugs have emerged as a promising solution. Extensive endeavors have been undertaken to explore novel excipients, therapeutic agents, self-assembly processes, and therapeutic mechanisms, aimed at expanding the horizons of CFDDSs and enhancing their therapeutic efficacy. This comprehensive review provides an overview of CFDDSs, elucidating their self-assembly mechanisms. Additionally, we examine their diverse biomedical applications while shedding light on the challenges ahead for the future development and clinical implementation of CFDDSs. This review serves to enhance our understanding of the intricate mechanisms governing drug nanoassembly formation and fosters the advancement of CFDDSs in the expansive realm of biomedical research.

As the inflammatory subtype of nonalcoholic fatty liver disease (NAFLD), the progression of nonalcoholic steatohepatitis (NASH) is associated with disorders of glycerophospholipid metabolism. Scoparone is the major bioactive component in Artemisia capillaris which has been widely used to treat NASH in traditional Chinese medicine. However, the underlying mechanisms of scoparone against NASH are not yet fully understood, which hinders the development of effective therapeutic agents for NASH. Given the crucial role of glycerophospholipid metabolism in NASH progression, this study aimed to characterize the differential expression of glycerophospholipids that is responsible for scoparone’s pharmacological effects and assess its efficacy against NASH. Liquid chromatography-multiple reaction monitoring-mass spectrometry (LC-MRM-MS) was performed to get the concentrations of glycerophospholipids, clarify mechanisms of disease, and highlight insights into drug discovery. Additionally, pathologic findings also presented consistent changes in high-fat diet-induced NASH model, and after scoparone treatment, both the levels of glycerophospholipids and histopathology were similar to normal levels, indicating a beneficial effect during the observation time. Altogether, these results refined the insights on the mechanisms of scoparone against NASH and suggested a route to relieve NASH with glycerophospholipid metabolism. In addition, the current work demonstrated that a pseudotargeted lipidomic platform provided a novel insight into the potential mechanism of scoparone action.

Purpose: To determine the effect of general anesthesia on intraocular pressure (IOP) in children with no intraocular pathology and determine which postanesthetic time point is most predictive of preinduction IOP. Design: Prospective observational study. Participants: Children with no intraocular pathology ≤ 18 years scheduled for general anesthesia as part of their routine care followed by a pediatric ophthalmologist at Nanjing Medical University. Methods: Participants underwent a standardized general anesthetic protocol using a mask induction with sevoflurane and propofol maintenance. Intraocular pressure was measured at the following 7 time points: preinduction (taken in the preoperative area), postinduction minutes 1, 3, and 5, and postairway placement minutes 1, 3, and 5 for a total time period of 10 minutes after induction. A generalized estimating equation was used to evaluate the effect of anesthesia on IOP and the effect of patient factors (age, gender, vital signs, and airway type) on preanesthetic and postanesthetic IOP. An IOP prediction model was developed using the postanesthesia IOP measurements for predicting preinduction IOP. Main Outcome Measures: Intraocular pressure and change in IOP at prespecified time points. Results: Eighty-five children were enrolled with a mean ± standard deviation (SD) age of 7.5 ± 2.9 years. Mean ± SD preinduction IOP was 20.1 ± 3.7 mmHg. Overall, IOP was lowest at 3 minutes postinduction, decreased to a mean of 13.4 ± 3.7 mmHg (P < 0.001). After this, IOP rose 5 minutes postinduction to 16.5 ± 4.2 mmHg, which did not reach preinduction IOP levels (P < 0.001). The IOP prediction model showed that combining 1 minute postinduction and 3 minutes postairway was most predictive (R2 = 0.13), whereas 1 minute postairway was least predictive of preinduction IOP (R2 = 0.01). Conclusions: After the induction of general anesthesia in children, IOP temporarily decreases with a trough at 3 minutes postinduction before increasing and remaining stable just below preinduction levels. Intraocular pressure measurements taken 1 minute after induction with 3 minutes after airway placement are most predictive of preinduction IOP, though predictive value is relatively low. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Abstract Chemotherapy can cause severe pain for patients, but there are currently no satisfactory methods of pain relief. Enhancing the efficacy of chemotherapy to reduce the side effects of high-dose chemotherapeutic drugs remains a major challenge. Moreover, the treatment of chemotherapy-induced peripheral neuropathic pain (CIPNP) is separate from chemotherapy in the clinical setting, causing inconvenience to cancer patients. In view of the many obstacles mentioned above, we developed a strategy to incorporate local anesthetic (LA) into a cisplatin-loaded PF127 hydrogel for painless potentiated chemotherapy. We found that multiple administrations of cisplatin-loaded PF127 hydrogels (PFC) evoked severe CIPNP, which correlated with increased pERK-positive neurons in the dorsal root ganglion (DRG). However, incorporating ropivacaine into the PFC relieved PFC-induced CIPNP for more than ten hours and decreased the number of pERK-positive neurons in the DRG. Moreover, incorporating ropivacaine into the PFC for chemotherapy is found to upregulate major histocompatibility complex class I (MHC-I) expression in tumor cells and promote the infiltration of cytotoxic T lymphocytes (CD8+ T cells) in tumors, thereby potentiating chemotherapy efficacy. This study proposes that LA can be used as an immunemodulator to enhance the effectiveness of chemotherapy, providing new ideas for painless cancer treatment.

Flexible pressure sensors have attracted wide attention due to their applications to electronic skin, health monitoring, and human-machine interaction. However, the tradeoff between their high sensitivity and wide response range remains a challenge. Inspired by human skin, we select commercial silicon carbide sandpaper as a template to fabricate carbon nanotube (CNT)/polydimethylsiloxane (PDMS) composite film with a hierarchical structured surface (h-CNT/PDMS) through solution blending and blade coating and then assemble the h-CNT/PDMS composite film with interdigitated electrodes and polyurethane (PU) scotch tape to obtain an h-CNT/PDMS-based flexible pressure sensor. Based on in-situ optical images and finite element analysis, the significant compressive contact effect between the hierarchical structured surface of h-CNT/PDMS and the interdigitated electrode leads to enhanced pressure sensitivity and a wider response range (0.1661 ​kPa−1, 0.4574 ​kPa−1 and 0.0989 ​kPa−1 in the pressure range of 0–18 ​kPa, 18–133 ​kPa and 133–300 ​kPa) compared with planar CNT/PDMS composite film (0.0066 ​kPa−1 in the pressure range of 0–240 ​kPa). The prepared pressure sensor displays rapid response/recovery time, excellent stability, durability, and stable response to different loading modes (bending and torsion). In addition, our pressure sensor can be utilized to accurately monitor and discriminate various stimuli ranging from human motions to pressure magnitude and spatial distribution. This study supplies important guidance for the fabrication of flexible pressure sensors with superior sensing performance in next-generation wearable electronic devices.

AIM: To revise the referral criteria for the SPOT Vision Screener in children under 6 years old and assessed its accuracy based on the American Association for Pediatric Ophthalmology and Strabismus(AAPOS)uniform guidelines for instrument-based pediatric vision screen validation 2021.METHODS: Children who visited the Maternal and Child Health Center of Yuhuatai District in Nanjing city from January 2022 to April 2023 were included in the study and underwent SPOT refractive screening, cycloplegic retinoscopy, and other examinations. Abnormal children were defined according to AAPOS guidelines with amblyopia risk factors(ARFs)and visually significant refractive error(VSRE). Receiver operating characteristic(ROC)curve was used to calculate the optimal referral criteria and compared with manufacturer criteria, Wu's criteria, and Peterseim's criteria.RESULTS: A total of 959 children were examined, with 342 in the

An accurate estimation of net energy (NE) of wheat bran is essential for precision feeding of sows. However, the effects of inclusion level on NE of wheat bran have not been reported. Inclusion level was hypothesized to impact NE of wheat bran by regulating gut microbiota and partitioning of heat production. Therefore, twelve multiparous sows (Yorkshire × Landrace; 2 to 4 parity) were assigned to a replicated 3 × 6 Youden square with 3 successive periods and 6 diets in each square. The experiment included a corn-soybean meal diet (WB0) and five diets including 9.8% (WB10), 19.5% (WB20), 29.2% (WB30), 39.0% (WB40) and 48.7% wheat bran (WB50), respectively. Each period included 6 d of adaptation to diets followed by 6 d for heat production measurement using open-circuit respiration chambers. Compared with other groups, WB30, WB40, and WB50 enriched different fiber-degrading bacteria genera (P

The distribution network can continue to operate for a short time once a single-phase grounding fault arises, but if the defect is not monitored and corrected right away, it might cause serious harm. However, the bulk of fault monitoring algorithms struggle to identify faults when applied to complex distribution networks with a tree structure. In this article, a fault online monitoring method based on power line communication equipment is proposed. The method identifies the fault by monitoring the change of channel frequency response (CFR) of the distribution network in real-time, locates the fault branch by comparing the change amplitude of CFR of different receiving devices, calculates the impedance amplitude of the fault branch, and combines the relation between impedance and distance to further realize the accurate location of the fault point. A large number of simulations show that the method is accurate and stable, and can effectively monitor both high and low-resistance ground faults. Under the simulation conditions without considering signal interference, the fault branch detection accuracy reaches 100%, and the average error of fault distance localization is 19.38 m (1.98%). Compared with other methods, this method is highly applicable, with good real-time performance and high positioning accuracy.

Abstract Intrahepatic cholangiocarcinoma (ICC) accounts for 20% of liver malignancies with a 5-year survival rate of 35% at best with limited prognostic predictors. Lung Immune Prognostic Index (LIPI) is a novel prognostic factor in pulmonary cancers. In this study, we developed a modified prognostic model from LIPI called intrahepatic immune prognostic index (IIPI) for ICC. A retrospectively study was conducted at Liver Transplant Center of West China Hospital between January 2015 and January 2023. Hematological factors and clinical features of ICC patients were collected and analyzed. The area under curve (AUC) and optimal cuff-off of each single hematological factor was calculated. In this study, derived neurtrophil to lymphocyte ratio (dNLR), arbohydrate antigen199 (CA199) and carcinoembryonic antigen (CEA) have higher AUC values. LIPI was composed of dNLR and was further modified by combing CA199 and CEA, forming the IIPI. The IIPI consists of four grades which are None, Light, Moderate and Severe. Compared to other prognostic factors, IIPI exhibited better ability to predict overall survival. The multivariate analysis indicated that cirrhosis, differentiation, hilar invasion and IIPI were independent prognostic factors for ICC patients. An IIPI-based nomogram was also established and could predict the overall survival. In addition, the subgroup analyses based on clinical prognostic factors showed that the IIPI exhibited excellent prognostic influence. IIPI model is suitable for predicting the prognosis of postoperative ICC patients. Further research is needed to explore the relationship between postoperative recurrence and metastasis of ICC patients and IIPI.

The ANGPT1 gene plays a crucial role in the regulation of angiogenesis and muscle growth, with previous studies identifying copy number variations (CNVs) within this gene among Leizhou black goats. In this study, we investigated three ANGPT1 CNVs in 417 individuals of LZBG using quantitative PCR (qPCR), examining the impact of different CNV types on the ANGPT1 gene expression and their associations with growth and meat quality traits. Notably, the ANGPT1 CNV-1 (ARS1_chr14:24950001-24953600) overlaps with protein-coding regions and conserved domains; its gain-of-copies genotype (copies ≥ 3) was significantly correlated with ANGPT1 mRNA expression in muscle tissue (p < 0.01). Furthermore, the gain-of-copies genotype of CNV-1 demonstrated significant correlations with various phenotypic traits, including carcass weight, body weight, shear stress, chest circumference, and cross-sectional area of longissimus dorsi muscle. These findings indicate that the CNV-1 gain-of-copies genotype in the ANGPT1 gene may serve as a valuable marker for selecting Leizhou black goats exhibiting enhanced growth and muscular development characteristics, thereby holding potential applications in targeted breeding programs aimed at improving meat quality.

The convolutional neural network (CNN) has been widely applied in medical image segmentation due to its outstanding nonlinear expression ability. However, applications of CNN are often limited by the receptive field, preventing it from modeling global dependencies. The recently proposed transformer architecture, which uses a self-attention mechanism to model global context relationships, has achieved promising results. Swin-Unet is a Unet-like simple transformer semantic segmentation network that combines the dominant feature of both the transformer and Unet. Even so, Swin-Unet has some limitations, such as only learning single-scale contextual features, and it lacks inductive bias and effective multi-scale feature selection for processing local information. To solve these problems, the Residual Local induction bias-Unet (RL-Unet) algorithm is proposed in this paper. First, the algorithm introduces a local induction bias module into the RLSwin-Transformer module and changes the multi-layer perceptron (MLP) into a residual multi-layer perceptron (Res-MLP) module to model local and remote dependencies more effectively and reduce feature loss. Second, a new densely connected double up-sampling module is designed, which can further integrate multi-scale features and improve the segmentation accuracy of the target region. Third, a novel loss function is proposed that can significantly enhance the performance of multiple scales segmentation and the segmentation results for small targets. Finally, experiments were conducted using four datasets: Synapse, BraTS2021, ACDC, and BUSI. The results show that the performance of RL-Unet is better than that of Unet, Swin-Unet, R2U-Net, Attention-Unet, and other algorithms. Compared with them, RL-Unet produces significantly a lower Hausdorff Distance at 95% threshold (HD95) and comparable Dice Similarity Coefficient (DSC) results. Additionally, it exhibits higher accuracy in segmenting small targets.

Hydrogen safety remains a paramount concern in pipeline transportation. Once hydrogen leaks and ignites, it quickly escalates into a jet fire incident. The substantial thermal radiation released poses significant risks of fire and explosion. Therefore, studying the thermal radiation characteristics of hydrogen jet fires and developing accurate prediction models are crucial for establishing relevant safety standards. To address the oversimplified consideration of weighted coefficients in thermal radiation prediction models, this study investigated the thermal radiation characteristics of hydrogen jet fire by carrying out experiments and numerical simulations. The results reveal the significant impacts of the leakage diameter and pressure on thermal radiation. Increases in both the leakage diameter and pressure lead to a rapid escalation in the thermal radiation release, highlighting their critical importance in establishing safety standards for hydrogen pipeline transportation. Additionally, this study optimized the weight coefficients in the multi-point source prediction model based on temperature distribution along the flame axis. The optimized model was validated through comparison with experimental data. After optimization, the prediction error of the multi-point source radiation model was reduced from 19.5% to 13.9%. This model provides significant support for accurately evaluating the risk of hydrogen jet fire.

Rhizopus stolonifer is one of the main pathogens in postharvest storage logistics of more than 100 kinds of fruit, such as strawberries, tomatoes and melons. In this paper, the research on the morphology and detection, pathogenicity and infection mechanism of Rhizopus stolonifer was reviewed. The control methods of Rhizopus stolonifer in recent years was summarized from three dimensions of physics, chemistry and biology, including the nanomaterials, biological metabolites, light control bacteria, etc. Future direction of postharvest Rhizopus stolonifer infection control was analyzed from two aspects of pathogenic mechanism research and new composite technology. The information provided in this review will help researchers and technicians to deepen their understanding of the pathogenicity of Rhizopus stolonifer, and develop more effective control methods in the future.

Abstract The water resources of the Third Pole (TP), highly sensitive to climate change and glacier melting, significantly impact the water and food security of millions in Asia. However, projecting future spatial‐temporal runoff changes for TP's mountainous basins remains a formidable challenge. Here, we've leveraged the long short‐term memory model (LSTM) to craft a grid‐scale artificial intelligence (AI) model named LSTM‐grid. This model has enabled the production of hydrological projections for the seven major river basins of TP. The LSTM‐grid model integrates monthly precipitation, air temperature, and total glacier mass changes (total_GMC) data at a 0.25‐degree model grid. Training the LSTM‐grid model employed gridded historical monthly runoff and evapotranspiration data sets generated by an observation‐constrained cryosphere‐hydrology model at the headwaters of seven TP river basins during 2000–2017. Our results demonstrate the LSTM grid's effectiveness and usefulness, exhibiting a Nash‐Sutcliffe Efficiency coefficient exceeding 0.92 during the verification periods (2013–2017). Moreover, river basins in the monsoon region exhibited a higher rate of runoff increase compared to those in the westerlies region. Intra‐annual projections indicated notable increases in spring runoff, especially in basins where glacier meltwater significantly contributes to runoff. Additionally, the LSTM‐grid model aptly captures the runoff changes before and after the turning points of glacier melting, highlighting the growing influence of precipitation on runoff after reaching the maximum total_GMC. Therefore, the LSTM‐grid model offers a fresh perspective for understanding the spatiotemporal distribution of water resources in high‐mountain glacial regions by tapping into AI's potential to drive scientific discovery and provide reliable data.

Riemannian geometry-based classification (RGBC) gained popularity in the field of brain-computer interfaces (BCIs) lately, due to its ability to deal with non-stationarities arising in electroencephalography (EEG) data. Domain adaptation, however, is most often performed on sample covariance matrices (SCMs) obtained from EEG data, and thus might not fully account for components affecting covariance estimation itself, such as regional trends. Detrended cross-correlation analysis (DCCA) can be utilized to estimate the covariance structure of such signals, yet it is computationally expensive in its original form. A recently proposed online implementation of DCCA, however, allows for its fast computation and thus makes it possible to employ DCCA in real-time applications. In this study we propose to replace the SCM with the DCCA matrix as input to RGBC and assess its effect on offline and online BCI performance. First we evaluated the proposed decoding pipeline offline on previously recorded EEG data from 18 individuals performing left and right hand motor imagery (MI), and benchmarked it against vanilla RGBC and popular MI-detection approaches. Subsequently, we recruited eight participants (with previous BCI experience) who operated an MI-based BCI (MI-BCI) online using the DCCA-enhanced Riemannian decoder. Finally, we tested the proposed method on a public, multi-class MI-BCI dataset. During offline evaluations the DCCA-based decoder consistently and significantly outperformed the other approaches. Online evaluation confirmed that the DCCA matrix could be computed in real-time even for 22-channel EEG, as well as subjects could control the MI-BCI with high command delivery (normalized Cohen's κ: 0.7409 ± 0.1515) and sample-wise MI detection (normalized Cohen's κ: 0.5200 ± 0.1610). Post-hoc analysis indicated characteristic connectivity patterns under both MI conditions, with stronger connectivity in the hemisphere contralateral to the MI task. Additionally, fractal scaling exponent of neural activity was found increased in the contralateral compared to the ipsilateral motor cortices (C4 and C3 for left and right MI, respectively) in both classes. Combining DCCA with Riemannian geometry-based decoding yields a robust and effective decoder, that not only improves upon the SCM-based approach but can also provide relevant information on the neurophysiological processes behind MI.

Weaned stress may damage the tissue development, barrier function, and balance of microbiota of gut, resulting in the diarrhea and reduced growth performance of piglets. Probiotics with excellent characteristics can enhance the resistance of piglets to weaned stress. Under a poor sanitary condition, the Limosilactobacillus reuteri (L. reuteri) SLZX19-12 was supplemented to check its effects for piglets. Results showed that supplementation of L. reuteri significantly decreased the diarrhea incident, improved the growth performance, and enhanced the barrier integrity of gut. In ileum, L. reuteri decreased inflammation by NFκB p65 pathway, increased propionate, TCDCA, and THDCA contents, and regulated microbiota. In colon, L. reuteri decreased the inflammation by NFκB p65 pathway, reduced DCA content, and regulated microbiota. Therefore, the supplementation of L. reuteri may alleviate weaned stress by improving immune function and regulating the gut microbiota in piglets.

Objective: To further evaluate the connection between obesity and Parkinson's disease, we utilized A body shape index which normalizes waist circumference for Body mass index. Derived from the National Health and Nutrition Examination Survey. Methods: Based on National Health and Nutrition Examination Survey data from 2005 to 2018, this study included 31,933 adult participants in total. First, all the participants were divided into the Parkinson's disease group and non-Parkinson's disease group, respectively. Next, according to their quartiles of A body shape index levels, they were further classified into Q1 group (0.058–0.077), Q2 group (0.078–0.081), Q3 group (0.082–0.084), and Q4 group (0.085–0.117). A body shape index was the primary exposure, while Parkinson's disease was the primary outcome. A body shape index is defined by waist circumference divided by Body mass index2/3 × height1/2, and the expected value of waist circumference based on height and weight derived empirically from National Health and Nutrition Examination Survey. Consequently, A body shape index and Parkinson's disease were analyzed through multifactor logistic regression. Results: According to the unadjusted multivariate logistic analysis, the Q4 group had a greater likelihood of acquiring Parkinson's disease than the Q1 group [OR = 4.519, 95% CI: 3.094–6.600; P