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Purpose: The purpose of this study was to determine whether contralateral cervical lymph node dissection is needed in patients with oropharyngeal squamous cell carcinoma (OPSCC) with contralateral cervical cN0. Methods: We searched the PubMed, Web of Science, Embase, Chinese Biomedical Literature Database (CBM) and Cochrane Library databases up to August 14, 2021 for studies examining the contralateral neck occult metastasis rate of patients with ipsilateral clinical neck-negative (cN0) OPSCC and the contralateral neck occult metastasis rate of patients with ipsilateral clinical neck-positive (cN1, cN2a, cN2b) OPSCC. This rate is used to determine whether patients with contralateral cN0 OPSCC need contralateral cervical lymph node dissection. Results: A total of 14 articles, including 532 cases, were included in the analysis. When studying the rate of ipsilateral cervical occult metastasis in patients with ipsilateral cN0, 163 cases were included in 11 studies. The results showed that the rate of contralateral cervical occult lymph node metastasis in patients with ipsilateral cN0 was 0.6816% (95% CI 0.0000–4.4880 (P = 0.3005)). In the study of ipsilateral cN+ (cN1, cN2a, cN2b), a total of 369 cases of 10 articles were included in the analysis. The results showed that the rate of contralateral cervical occult lymph node metastasis in patients with ipsilateral cN+ was 11.4920% [95% CI 7.8944–15.5223 (P = 0.0000)]. Conclusion: For cancer treatment, the ultimate goal is to achieve the best control of cancer and the lowest complications. It seems unnecessary to intervene in the contralateral neck of patients with OPSCC with ipsilateral cN0. For OPSCC with ipsilateral cN+ , this index is a factor that cannot be ignored when making clinical decisions. [ABSTRACT FROM AUTHOR]

Over the past few decades, RNA sequencing has significantly progressed, becoming a paramount approach for transcriptome profiling. The revolution from bulk RNA sequencing to single-molecular, single-cell and spatial transcriptome approaches has enabled increasingly accurate, individual cell resolution incorporated with spatial information. Cancer, a major malignant and heterogeneous lethal disease, remains an enormous challenge in medical research and clinical treatment. As a vital tool, RNA sequencing has been utilized in many aspects of cancer research and therapy, including biomarker discovery and characterization of cancer heterogeneity and evolution, drug resistance, cancer immune microenvironment and immunotherapy, cancer neoantigens and so on. In this review, the latest studies on RNA sequencing technology and their applications in cancer are summarized, and future challenges and opportunities for RNA sequencing technology in cancer applications are discussed. [ABSTRACT FROM AUTHOR]

• Ecological intensification (EI) approach successfully enhanced maize yield over farmer's practice (FP). • Lower abundance of microbial communities involved in N cycling was noted in EI approach as compared to FP. • Lower N 2 O emissions and greenhouse gas (GHG) emissions were found in EI approach than FP. There is global concern about the adverse impacts of conventional agricultural practices on the environment. Recent evidence has shown that ecological intensification (EI) of agriculture can safeguard the environment from negative impacts of agricultural practices and simultaneously produce substantially higher crop productivity. Here, we employed the concept of EI and compared it with conventional agriculture or farmer's practice (FP). We explored the effects of EI and FP treatments on maize yield, N losses via potential nitrification activity (PNA), potential denitrification activity (PDA), N 2 O emissions, greenhouse gas (GHG) emissions, and nitrogen (N) cycling microbial populations associated with nitrification and denitrification in fluvo-aquic soil and black soil of North China. There were four treatments, i.e., EI N-, FP N-, EI N+, FP N + at each site, - and + indicate no N addition and N addition, respectively. The results revealed that across the two soils, N addition increased PNA and PDA; however, compared with the FP N + treatment, lower PNA and PDA were observed in the EI N + treatment. Similarly, the abundance of N cycling genes, including AOA amoA and AOB amoA, for nitrification and nirS , nirK , and nosZ for denitrification were significantly increased under N addition, and compared with the FP N + treatment, reduced abundance was noted in the EI N + treatment. N 2 O and GHG emissions were quantified, and it was observed that, in comparison to the FP treatment, reduced N 2 O and GHG emissions occurred in EI treatments in the two locations. EI with best management practices also increased crop yield relative to FP. Owing to higher N rates in FP treatments, substantial soil acidification was noted in FP plots but not in EI plots. In addition, PNA and PDA were significantly positively linked with soil nitrifying and denitrifying communities, particularly in the black soil. Moreover, the N availability pathway rather than soil acidification mainly regulated N cycling microbial communities. Our results suggest that EI could be a sustainable and environmentally friendly approach due to higher crop productivity and lower N losses via PNA, PDA, N 2 O, and GHG emissions, thus preventing the negative impact of agricultural practices, especially N fertilization, on the environment. [ABSTRACT FROM AUTHOR]

Liver fibrosis can develop into liver cirrhosis and hepatocellular carcinoma substantially without effective available treatment currently due to rarely characterized molecular pathogenesis. Indoleamine 2,3-dioxygenase 1(IDO1) can be detected on antigen-presenting cells (APCs) and modulates various immune responses. However, the role of IDO1 in the regulation of dendritic cells (DCs) during liver fibrosis is rarely reported. Here, we found that hepatic IDO1 was up-regulated during CCL4-induced liver fibrosis, which accompanied by a significant decrease in the frequencies of CD11c+CD80+, CD11c+CD86+, CD11c+CD40+ and CD11c+MHCII+ cells and a reduction in the subsequent T cell proliferation rate, whereas these changes were reversed significantly in IDO1−/− mice. Overexpressing IDO1 by adeno-associated viral vector serotype 9 (AAV9) significantly inhibited the maturation status of DCs, worsened fibrosis. In vitro studies showed that significantly elevated CD80, CD86, CD40 and MHCII expression were observed in BMDCs derived from IDO1−/− mice. Moreover, the maturation of BMDCs derived from WT mice were significantly increased after stimulated with IDO1 inhibitor (1-methyl- D -tryptophan). Nuclear factor E2-related factor 2 (Nrf2), a key regulator of the cellular adaptive response to oxidative insults and inflammation, exhibited a markedly decrease in the liver of WT fibrotic mice, nevertheless, knockout of IDO1 enhanced the protein level of Nrf2. Moreover, the expression of IDO1 and Nrf2 exhibited inverse colocalization pattern suggesting that ectopically expressed IDO1 down-regulated Nrf2. Additionally, up-regulation of IDO1 was also observed in the livers of Nrf2−/− fibrotic mice. Taken together, these data uncovered mutual antagonism between IDO1 and Nrf2 on the maturation status of DCs during hepatic fibrosis. Image 1 • Hepatic IDO1 was up-regulated during CCL4-induced liver fibrosis. • IDO1 functioned as a pro-fibrogenic factor via inhibited the maturation status of DCs. • IDO1 may form a protein complex with Nrf2 protein, and played antagonistically important roles during liver fibrosis. [ABSTRACT FROM AUTHOR]

Abstract Aims Alcoholic liver disease (ALD) is a leading health risk worldwide, which can induce hepatic steatosis, progressive fibrosis, cirrhosis and even carcinoma. As a potential therapeutic drug for ALD, naringin, an abundant flavanone in grapefruit, could improve resistance to oxidative stress and inflammation and protects against multiple organ injury. However, the specific mechanisms responsible for protection against alcoholic injury remain not fully understood. In this study, we aim to investigate the effect and the regulatory mechanisms of naringin in the liver and whole body after alcohol exposure under zebrafish larvae system. Main methods At 96 h post fertilization (hpf), larvae from wild-type (WT) and transgenic zebrafish, with liver-specific eGFP expression (Tg(lfabp10α:eGFP)), were exposed to 2% ethanol for 32 h to establish an ALD model. Different endpoints, such as morphological changes in liver shape and size, histological changes, oxidative stress-related free radical levels, apoptosis and the expression of certain genes, were chosen to verify the essential impact of naringin in alcohol-induced liver lesions. Key findings Subsequent experiments, including Oil red O, Nile red, pathological hematoxylin and eosin (H&E), and TUNEL staining and qPCR, revealed that naringin treatment reduced alcoholic hepatic steatosis, and this inhibitory effect was dose dependent. Specifically, a 25 mg/L dose resulted in an almost normal response. Significance This finding suggested that naringin may inhibit alcoholic-induced liver steatosis and injury by attenuating lipid accumulation and reducing oxidative stress and apoptosis. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

[Display omitted] • The microbial cell membrane and cell wall biomarkers analysis were applied in the present study. • Mature walnut plantations were beneficial for improving microbial attributes and SOC storage. • The optimal microsites for microbes were found in the > 2 mm aggregates due to the better nutrient conditions. • The increased plantation ages and reduced aggregate sizes enlarged the microbial contribution to SOC stocks. • Walnut plantation ages affected aggregate-related C dynamics via altering microbial growth and metabolism. Soil aggregates and microbial attributes are of great importance to clarify soil C dynamics in agroecosystems. However, whether and how walnut plantation with different ages affects microbial-driven soil C dynamics, especially at the aggregate scales, remains unclear. In this study, the microbial community (as measured by phospholipid fatty acids analysis), exo -enzyme activities (micro-plate enzyme method), and microbial residues (amino sugar analysis) were determined in soil aggregates, which were collected from surface soils in walnut plantations of various ages (0-, 7-, 14-, and 21-year) in the areas of Lincheng county, China. According to the optimal-moisture sieving method, soil aggregates were divided into three parts, including > 2 mm, 2–0.25 mm, and < 0.25 mm aggregates. Results showed that long-term walnut cultivation (14- and 21-year) improved soil aggregate stability as well as its associated nutrient conditions, and these changes were mainly reflected in the larger (>2 mm and 2–0.25 mm) aggregates. Besides, long-term walnut cultivation was favorable to promoting microbial growth (as indicated by total PLFAs), functions (hydrolase activities), and metabolism (microbial residues C, MRC) within aggregates. Irrespective of the walnut plantation ages, the above-mentioned microbial attributes increased with increasing soil aggregate sizes, whereas oxidase activities decreased. We also found that the increased plantation ages and decreased aggregate sizes could enhance the microbial contributions to soil organic C (SOC) accumulation (as indicated by the MRC/SOC ratios), although higher SOC contents have been found in the larger aggregates. Notably, the partial least squares path model further emphasized that walnut plantation ages and aggregate sizes had strong effects on microbial attributes (e.g., microbial communities, exo -enzyme activities, and microbial residues), as well as their importance for soil C dynamics. Consequently, the mature walnut plantations were beneficial for improving soil structure, microbial attributes, and SOC sequestration in the East Taihang Mountains in Hebei, China. [ABSTRACT FROM AUTHOR]

• An enhanced morphological gradient operator (AEMGO) is constructed. • The concept of adaptive feature energy permutation entropy (FEPE) is defined. • A diagonal slice spectrum assisted optimal scale morphological filter is proposed. • The proposed method can detect two types of faults of rolling element bearings. Extraction of weak bearing failure signals remains a thorny issue in press lines. An adaptive enhanced morphological gradient operator (EMGO) fault feature diagnosis method based on third-order cumulant diagonal slice spectrum (AEMGO-TOCSS) is developed. Firstly, an EMGO is proposed to enhance the filtering ability of the operator according to the different features of the signal extracted by the basic morphological operator. Then, on account of the vital significance of structural element selection in filtering, a new adaptive feature energy permutation entropy (FEPE) selection strategy is put forward. Finally, the denoising performance of TOCSS is used to further improve the feature extraction ability of the EMGO operator for faulty information. Both simulation and experimental results verify that the EMGO is more effective and accurate than other morphological operators in identifying weak fault features of rolling bearings, and that it presents a broad application potential in practical engineering. [ABSTRACT FROM AUTHOR]

This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort (n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (β = −8.4, 95% CI −11.4–−5.4, p = 3.9 × 10−8) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3–6.7, p = 7.4 × 10−7) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: β = −1.5, 95% CI −5.3–2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8–3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies. [ABSTRACT FROM AUTHOR]

• Aggregated yield over all crops were higher in the eastern coastal provinces of China and in south China than those in the inland provinces and west and north China. • The average aggregate yield increased in all provinces but the average annual growth rates varied. • Most of the regression models explained more than 60 % of the yield variance, except for rice, potato and cotton models. • Agricultural management practices (AMP), soil and economic covariates were the most important factors in all models. • The model performance for the aggregate yield was different for each province in individual years. With increasing discrepancies between population growth and food production in China, the monitoring of crop yield is essential to support food security policies. However, current studies about spatio-temporal variation of yield mainly focus on the influence of climatic factors on grain crops, and do not explore the contributions of agricultural, environmental and economic factors on crop yield in China. In this study, a large yield dataset, covering 31 provinces and a 38-year period from 1978 to 2015, and related explanatory variables were collected for analyzing the spatio-temporal variation of different yield aggregations using stepwise multiple linear regression. At the national scale, the average aggregate yield increased from 3.04 Mg ha−1 in 1978 to 10.04 Mg ha−1 in 2015. Overall, the average aggregate yield increased in all provinces but the average annual growth rates varied: it was smaller than 2.5 % in Heilongjiang, Guizhou, Beijing, Qinghai and Jilin, more than 4.0 % in Hainan, Guangxi, Ningxia, Hebei and Shaanxi, and between 2.5 % and 4.0 % in other provinces. The spatial patterns of the average yield from 1978 to 2015 were different for different crop aggregations. Most of the regression models explained more than 60 % of the yield variance, except for rice, potato and cotton models. Agricultural management practices, soil and economic covariates were important explanatory variables in all models. Topography and climatic covariates were also important for some of the crop models. The regression model of the aggregate yield for all crops explained 95 % of the yield variance, which was mainly explained by planting area index of vegetables (20 %), followed by farmer income (14 %), planting area index of other crops (orchards 11 %, melons 8 %, sugar 6 %, cereals 6 %), and density of agricultural diesel engines (5 %). Although the regression residual of the aggregate yield model was zero on average, the trends were different in different provinces: most provinces demonstrated a small negative or positive residual; the yield was substantially lower (< -0.20 Mg ha−1 y−1) than predicted by the regression model in three provinces in central China (Hebei, Shaanxi and Anhui) and substantially higher (> 0.20 Mg ha−1 y−1) in four provinces (Shanxi, Shandong, Sichuan and Guangdong). These systematic over- and underpredictions may be caused by other factors, such as plagues, pests, natural hazards, market structures (such as competition for labor or impediments to market access) and farmer's management skills. With the increasing population and limited agricultural land resources, enhancing economic growth might be an adequate solution to meet the growing demand for food. It can also promote agricultural efficiency in China, certainly when combined with better management practices, crop composition, breeding and planting technologies. [ABSTRACT FROM AUTHOR]

• Previous studies included the tongue, mouth floor, buccal mucosa sites, etc. • The mircobial correlation between GSCC and periodontitis has not been illustrated. • 10 GSCC patients, 15 periodontitis patients, and 15 healthy individuals were recruited. • Subgingival plaque, saliva, swabs, etc. were collected for 16S rDNA sequencing. • A high level of Atopobium and LPS biosynthesis potentially increase the risk of GSCC. Previous studies have proved that periodontitis is an independent risk factor of oral squamous cell carcinoma (OSCC) epidemiologically. Along with the important role of microbiota in the cancer process and the specific anatomical position, our study explored the microbial composition and functions in periodontitis and gingival squamous cell carcinoma (GSCC). GSCC patients (n = 10), matched periodontitis patients (n = 15), and healthy individuals (n = 15) were recruited. Saliva, subgingival plaque, tongue dorsum, buccal mucosa, cancerous tissue, and paracancerous tissue samples were collected. 16S rDNA amplicon sequencing and functional prediction were applied for the taxonomic analysis. Periodontal pathogens occupied 46% in GSCC. Besides, the mutual operational taxonomy unites (OTU) generated from the subgingival plaque occupied 38.36% and 44.13% from saliva. Fusobacterium , Peptostreptococcus , and Prevotella were more abundant in cancerous tissues, while Streptococcus , Neisseria , and Haemophilus were more enriched in saliva or soft mucosa. PCoA exhibited similar cluster between tongue dorsum and saliva in GSCC. GSCC showed lower richness than periodontitis. In saliva and subgingival plaque, Atopobium was more prevalent in GSCC than periodontitis and controls in descending order. Lipopolysaccharide (LPS) biosynthesis increased in subgingival plaque of GSCC compared with the other two groups. Periodontal pathogens were abundant in GSCC. Cancerous tissues harbor enriched periodontal pathogens while saliva or soft mucosa harbored more periodontal health related bacteria. A high level of Atopobium in saliva and LPS biosynthesis have the potential for increasing the risk of suffering from GSCC in individuals with periodontitis, which needs more evidence to clarify it. [ABSTRACT FROM AUTHOR]

Background: With the increasing use of lung cancer screening, the detection of ground glass nodules (GGNs) has risen. However, the natural course of GGNs and their relationship to pathologic features remains unclear. Differentiating between invasive and pre-invasive lesions based on GGN growth may improve clinical intervention timing. Ki-67, a proliferation marker, holds value in assessing tumor malignancy. This study analyzes the association between GGN growth, pathology, and Ki-67 expression to provide new insights into early-stage lung cancer management., Methods: We retrospectively evaluated 183 GGNs with at least two preoperative CT scans. Nodule location, type, natural course, and volume doubling time (VDT) were compared between invasive adenocarcinoma (IAC) and pre-IAC groups. We also assessed differences in Ki-67 expression and correlated VDT with Ki-67 levels., Results: A total of 183 nodules were finally included; gender, nodule location, smoking history, and duration of follow-up did not differ between the IAC group and the pre-IAC group, whereas age was statistically different between the two groups. Of the 183 nodules, 52 showed growth and the predominant pathologic type was IAC, these IACs showed more PSN in nodule type, while the IAC group showed more significant differences in nodule type, nodules growth, and VDT than the pre-IAC group. There were also differences in pathologic type and VDT between different Ki-67 expression groups, and Ki-67 expression gradually increased as VDT decreased., Conclusion: Lung adenocarcinoma (LUAD) presenting as GGNs exhibit distinct natural courses among pathologic subtypes. VDT effectively distinguishes these growth characteristics, with IACs showing shorter VDT. The significant correlation between VDT and Ki-67 expression suggests that combining these parameters may provide valuable insights into the biological behavior and invasiveness of LUAD., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background and Aim: Endoscopic submucosal dissection (ESD) is commonly employed in the treatment of epithelial gastrointestinal tumors, but few studies have explored ESD for treatment of duodenal papillary adenomas (PAs). In this study, we aim to evaluate the feasibility of a modified ESD method as an alternative modality in the resection of PAs. Methods: We evaluated potential advantages of modified ESD for resection of sporadic duodenal PAs through retrospective analysis of 10 PAs resected via ESD compared to paired lesions undergoing endoscopic papillectomy (EP). Results: All lesions undergoing ESD were resected en bloc with negative margins, compared to 60% of lesions undergoing EP. Within the experimental group, there was one case each of melena and pancreatitis compared to four bleeds and one case of pancreatitis in the control group. No recurrence was detected within the ESD group after a mean follow-up time of 11.2 months compared to three recurrences within a mean follow-up time of 27.7 months. Conclusions: From our preliminary experience, ESD is a promising alternative in the treatment of superficial duodenal PAs; however, further investigation is needed., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Zelong Han et al.)

The small molecule epiberberine (EPI) is a natural alkaloid with versatile bioactivities against several diseases including cancer and bacterial infection. EPI can induce the formation of a unique binding pocket at the 5' side of a human telomeric G-quadruplex (HTG) sequence with four telomeric repeats (Q4), resulting in a nanomolar binding affinity ( K D approximately 26 nM) with significant fluorescence enhancement upon binding. It is important to understand (1) how EPI binding affects HTG structural stability and (2) how enhanced EPI binding may be achieved through the engineering of the DNA binding pocket. In this work, the EPI-binding-induced HTG structure stabilization effect was probed by a peptide nucleic acid (PNA) invasion assay in combination with a series of biophysical techniques. We show that the PNA invasion-based method may be useful for the characterization of compounds binding to DNA (and RNA) structures under physiological conditions without the need to vary the solution temperature or buffer components, which are typically needed for structural stability characterization. Importantly, the combination of theoretical modeling and experimental quantification allows us to successfully engineer Q4 derivative Q4-ds-A by a simple extension of a duplex structure to Q4 at the 5' end. Q4-ds-A is an excellent EPI binder with a K (Huang Lian) extracts.D of 8 nM, with the binding enhancement achieved through the preformation of a binding pocket and a reduced dissociation rate. The tight binding of Q4 and Q4-ds-A with EPI allows us to develop a novel magnetic bead-based affinity purification system to effectively extract EPI from Rhizoma coptidis (Huang Lian) extracts.

Introduction: Linear-array endoscopic ultrasound (EUS) and narrow-band imaging (NBI) are both used to estimate the invasion depth of nonpedunculated rectal lesions (NPRLs). However, it is unclear which procedure is more accurate. This randomized controlled trial aimed to compare the diagnostic accuracy of linear EUS and NBI for estimating the invasion depth of NPRLs., Methods: This study is a single-center, randomized, tandem trial. Eligible patients with NPRLs were randomly assigned to A group (assessment with EUS followed by NBI) or B group (assessment with NBI followed by EUS). The invasion depth of each lesion was independently measured by each procedure and categorized as mucosal to slight submucosal (M-SM s , invasion depth <1,000 μm) or deep submucosal (SM d , invasion depth ≥1,000 μm) invasion, with postoperative pathology as the standard of measurement. The primary outcome was diagnostic accuracy, and secondary outcomes included sensitivity, specificity, and procedure time., Results: Eighty-six patients with NPRLs were enrolled, and 79 patients were finally analyzed, including 39 cases in the A group and 40 cases in the B group. Comparable diagnostic accuracies were observed between EUS and NBI (96.2% vs 93.7%, P = 0.625). EUS identified lesions with deep submucosal invasion with 81.8% sensitivity while that of NBI was 63.6% ( P = 0.500). The specificity of both EUS and NBI was 98.5%. The procedure time was also similar between EUS and NBI (5.90 ± 3.44 vs 6.4 ± 3.94 minutes, P = 0.450). Furthermore, the combined use of EUS and NBI did not improve diagnostic accuracy compared with EUS or NBI alone (94.9% vs 96.2% vs 93.7%, P = 0.333)., Discussion: Linear EUS and NBI measure the invasion depth of NPRLs with comparable accuracy. The combination of the 2 methods does not improve the diagnostic accuracy. Single NBI should be preferred, considering its simplicity and convenience in clinical practice., (Copyright © 2024 by The American College of Gastroenterology.)

The emergence of multidrug-resistant (MDR) bacteria poses a significant challenge to global health. Due to a shortage of antibiotics, alternative therapeutic strategies are urgently needed. Unfortunately, colistin, the last-resort antibiotic, has unavoidable nephrotoxicity and hepatotoxicity, and its single killing mechanism is prone to drug resistance. To address this challenge, a promising combinatorial approach that includes colistin, a membrane-disrupting antimicrobial agent, and chelerythrine (CHE), a FtsZ protein inhibitor is proposed. This approach significantly reduces antibiotic dose and development of resistance, leading to almost complete inactivation of MDR pathogens in vitro. To address solubility issues and ensure transport, the antimicrobial hydrogel system LNP-CHE-CST@hydrogel, which induced reactive oxygen species (ROS) and apoptosis-like cell death by targeting the FtsZ protein, is used. In an in vivo mouse skin infection model, the combination therapy effectively eliminated MDR bacteria within 24 h, as monitored by fluorescence tracking. The findings demonstrate a promising approach for developing multifunctional hydrogels to combat MDR bacterial infections., (© 2024 The Authors. Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Soil-based irrigation and the partial substitution of chemical fertilizers with manure are promising practices to improve water and nitrogen (N) use efficiency. We hypothesize that their combination would simultaneously benefit potato production, tuber quality and profitability. A two-year experiment was conducted in semiarid northern China to investigate the combined effects of three water treatments [rainfed (W0), soil-based irrigation (W1), conventional irrigation (W2)] and three N treatments [no N (N0), chemical N (N1), 25% manure substitution (N2)] on these indicators, and to perform a comprehensive evaluation and correlation analysis. The results showed that water and N treatments separately affected all indicators except vitamin C content. Compared to W2, W1 significantly increased water productivity by 12% and irrigation water use efficiency (IWUE) by 30% due to 10% lower evapotranspiration and 21% lower water use. However, W1 and W2 negatively affected crude protein content. Conversely, this was compensated by the combination with N1 and N2. There were slight differences between N1 and N2 for all indicators on average across water treatments, while under W1, N2 significantly increased leaf area index (LAI) and N recovery efficiency (REN) by 18% and 29.4%, respectively, over N1. Also, comprehensive evaluations showed that W1N2 performed best, with the highest tuber yield, profit and acceptable quality. This can be explained by the increase in LAI, IWUE and REN due to the positive correlations with tuber yield and net return. Consequently, soil-based irrigation combined with 25% manure substitution had complementary effects on tuber quality and synergistic effects on potato productivity and profitability.

Achieving ultrabright fluorogens is a key issue for fluorescence-guided surgery (FGS). Fluorogens with aggregation-induced emission (AIEgens) are potential agents for FGS on the benefit of the bright fluorescence in physiological conditions. Herein, the fluorescence brightness of AIEgen is further improved by preparing the nanoparticle using a polystyrene-based matrix and utilizing it for tumor FGS with a high signal-to-background ratio. After encapsulating AIEgen into polystyrene-poly (ethylene glycol) (PS-PEG), the fluorescence intensity of the prepared AIE@PS-PEG nanoparticles is multiple times that of nanoparticles in 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-poly (ethylene glycol) (DSPE-PEG), a commonly used polymer matrix for nanoparticle preparation. Molecular dynamics simulations suggest that higher free energy is required for the outer rings of AIEgen to rotate in polystyrene than in the DSPE, indicating that the benzene rings in polystyrene can restrict the intramolecular motions of AIEgen better than the alkyl chain in DSPE-PEG. Fluorescence correlation microscopy detections suggest that the triplet excited state of AIEgens is less in PS-PEG than in DSPE-PEG. The restricted intramolecular motions and suppressed triplet excited state result in ultrabright AIE@PS-PEG nanoparticles, which are more conducive to illuminating tumor tissues in the intestine for FGS. The illumination of metastatic tumors in lungs by AIE@PS-PEG nanoparticles is also tried., (© 2023 Wiley‐VCH GmbH.)

Abstract and Aim: Cholangiocarcinoma (CCA) is a highly aggressive and lethal cancer that originates from the biliary epithelium. Systemic treatment options for CCA are currently limited, and the first targeted drug of CCA, pemigatinib, emerged in 2020 for CCA treatment by inhibiting FGFR2 phosphorylation. However, the regulatory mechanism of FGFR2 phosphorylation is not fully elucidated., Approach and Results: Here we screened the FGFR2-interacting proteins and showed that protein tyrosine phosphatase (PTP) N9 interacts with FGFR2 and negatively regulates FGFR2 pY656/657 . Using phosphatase activity assays and modeling the FGFR2-PTPN9 complex structure, we identified FGFR2 pY656/657 as a substrate of PTPN9, and found that sec. 14p domain of PTPN9 interacts with FGFR2 through ACAP1 mediation. Coexpression of PTPN9 and ACAP1 indicates a favorable prognosis for CCA. In addition, we identified key amino acids and motifs involved in the sec. 14p-APCP1-FGFR2 interaction, including the "YRETRRKE" motif of sec. 14p, Y471 of PTPN9, as well as the PH and Arf-GAP domain of ACAP1. Moreover, we discovered that the FGFR2 I654V substitution can decrease PTPN9-FGFR2 interaction and thereby reduce the effectiveness of pemigatinib treatment. Using a series of in vitro and in vivo experiments including patient-derived xenografts (PDX), we showed that PTPN9 synergistically enhances pemigatinib effectiveness and suppresses CCA proliferation, migration, and invasion by inhibiting FGFR2 pY656/657 ., Conclusions: Our study identifies PTPN9 as a negative regulator of FGFR2 phosphorylation and a synergistic factor for pemigatinib treatment. The molecular mechanism, oncogenic function, and clinical significance of the PTPN9-ACAP1-FGFR2 complex are revealed, providing more evidence for CCA precision treatment., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background Aims: Cholangiocarcinoma (CCA) is a highly lethal malignancy originating from the biliary ducts. Current CCA diagnostic and prognostic assessments cannot satisfy the clinical requirement. Bile detection is rarely performed, and herein, we aim to estimate the clinical significance of bile liquid biopsy by assessing bile exosomal concentrations and components., Approach Results: Exosomes in bile and sera from CCA, pancreatic cancer, and common bile duct stone were identified and quantified by transmission electronmicroscopy, nanoparticle tracking analysis, and nanoFCM. Exosomal components were assessed by liquid chromatography with tandem mass spectrometry and microRNA sequencing (miRNA-seq). Bile exosomal concentration in different diseases had no significant difference, but miR-182-5p and miR-183-5p were ectopically upregulated in CCA bile exosomes. High miR-182/183-5p in both CCA tissues and bile indicates a poor prognosis. Bile exosomal miR-182/183-5p is secreted by CCA cells and can be absorbed by biliary epithelium or CCA cells. With xenografts in humanized mice, we showed that bile exosomal miR-182/183-5p promotes CCA proliferation, invasion, and epithelial-mesenchymal transition (EMT) by targeting hydroxyprostaglandin dehydrogenase in CCA cells and mast cells (MCs), and increasing prostaglandin E2 generation, which stimulates PTGER1 and increases CCA stemness. In single-cell mRNA-seq, hydroxyprostaglandin dehydrogenase is predominantly expressed in MCs. miR-182/183-5p prompts MC to release VEGF-A release from MC by increasing VEGF-A expression, which facilitates angiogenesis., Conclusions: CCA cells secret exosomal miR-182/183-5p into bile, which targets hydroxyprostaglandin dehydrogenase in CCA cells and MCs and increases prostaglandin E2 and VEGF-A release. Prostaglandin E2 promotes stemness by activating PTGER1. Our results reveal a type of CCA self-driven progression dependent on bile exosomal miR-182/183-5p and MCs, which is a new interplay pattern of CCA and bile., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Immunotherapy is restricted by a complex tumor immunosuppressive microenvironment (TIM) and low drug delivery efficiency. Herein, a multifunctional adjuvant micelle nanosystem (PPD/MPC) integrated with broken barriers and re-education of three classes of immune-tolerant cells is constructed for cancer immunotherapy. The nanosystem significantly conquers the penetration barrier via the weakly acidic tumor microenvironment-responsive size reduction and charge reversal strategy. The detached core micelle MPC could effectively be internalized by tumor-associated macrophages (TAMs), tumor-infiltrating dendritic cells (TIDCs), and myeloid-derived suppressor cells (MDSCs) via mannose-mediated targeting endocytosis and electrostatic adsorption pathways, promoting the re-education of immunosuppressive cells for allowing them to reverse from pro-tumor to antitumor phenotypes by activating TLR4/9 pathways. This process in turn leads to the remodeling of TIM. In vitro and in vivo studies collectively indicate that the adjuvant micelle-based nanosystem not only relieves the intricate immune tolerance and remodels TIM via reprogramming the three types of immunosuppressive cells and regulating the secretion of relevant cytokines/immunity factors but also strengthens immune response and evokes immune memory, consequently suppressing the tumor growth and metastasis.

Cholangiocarcinoma (CCA) is a highly aggressive malignant tumor that originates from the biliary system. With restricted treatment options at hand, the challenging aspect of early CCA diagnosis leads to a bleak prognosis. Besides the intrinsic characteristics of tumor cells, the generation and progression of CCA are profoundly influenced by the tumor microenvironment, which engages in intricate interactions with cholangiocarcinoma cells. Of notable significance is the role of extracellular vesicles as key carriers in enabling communication between cancer cells and the tumor microenvironment. This review aims to provide a comprehensive overview of current research examining the interplay between extracellular vesicles and the tumor microenvironment in the context of CCA. Specifically, we will emphasize the significant contributions of extracellular vesicles in molding the CCA microenvironment and explore their potential applications in the diagnosis, prognosis assessment, and therapeutic strategies for this aggressive malignancy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Shu, Liu, Shi, Zhao, Huang, Sheng, Yan, Song, Huang, Tang and Zhang.)

Background: Immense attention has been given to the outcome of COVID-19 infection. However, comprehensive studies based on large populational cohort with long-term follow-up are still lacking. This study aimed to investigate the risk of various short-term comorbidities (within one month) and long-term sequelae (above one month) after COVID-19 infection., Methods: In this large prospective cohort study with 14 months follow-up information based on UK biobank, we included 16,776 COVID-19-positive participants and 58,281 COVID-19-negative participants matched for comparison. The risk of each comorbidity and sequela was evaluated by multivariable logistic regression analysis and presented as hazard ratio (HR) and 95% confidence interval (95% CI)., Results: COVID-19-positive individuals had a higher risk of 47 types of comorbidities within one month following COVID-19 infection, especially those who were older, male, overweight/obese, ever-smoked, with more pre-existing comorbidities and hospitalized. About 70.37% of COVID-19 patients with comorbidities had more than one co-occurring comorbidities. Additionally, only 6 high-risk sequelae were observed after one month of COVID-19 infection, and the incidence was relatively low (< 1%)., Conclusion: In addition to long-term sequelae following COVID-19 infection, plenty of comorbidities were observed, especially in patients with older age, male gender, overweight/obese, more pre-existing comorbidities and severe COVID-19, indicating that more attention should be given to these susceptible persons within this period., (© 2023. The Author(s).)

Fluorescent materials with high brightness play a crucial role in the advancement of various technologies such as bioimaging, photonics, and OLEDs. While significant efforts are dedicated to designing new organic dyes with improved performance, enhancing the brightness of existing dyes holds equal importance. In this study, we present a simple supramolecular strategy to develop ultrabright cyanine-based fluorescent materials by addressing long-standing challenges associated with cyanine dyes, including undesired cis-trans photoisomerization and aggregation-caused quenching. Supra-cyanines are obtained by incorporating cyanine moieties in a cyclic peptide-based supramolecular scaffold, and exhibit high fluorescence quantum yields (up to 50 %) in both solution and in the solid state. These findings offer a versatile approach for constructing highly emissive cyanine-based supramolecular materials., (© 2023 Wiley-VCH GmbH.)

Hepatocellular carcinoma (HCC) is one of most common and deadliest malignancies. Celastrol (Cel), a natural product derived from the Tripterygium wilfordii plant, has been extensively researched for its potential effectiveness in fighting cancer. However, its clinical application has been hindered by the unclear mechanism of action. Here, we used chemical proteomics to identify the direct targets of Cel and enhanced its targetability and anti-tumor capacity by developing a Cel-based liposomes in HCC. We demonstrated that Cel selectively targets the voltage-dependent anion channel 2 (VDAC2). Cel directly binds to the cysteine residues of VDAC2, and induces cytochrome C release via dysregulating VDAC2-mediated mitochondrial permeability transition pore (mPTP) function. We further found that Cel induces ROS-mediated ferroptosis and apoptosis in HCC cells. Moreover, coencapsulation of Cel into alkyl glucoside-modified liposomes (AGCL) improved its antitumor efficacy and minimized its side effects. AGCL has been shown to effectively suppress the proliferation of tumor cells. In a xenograft nude mice experiment, AGCL significantly inhibited tumor growth and promoted apoptosis. Our findings reveal that Cel directly targets VDAC2 to induce mitochondria-dependent cell death, while the Cel liposomes enhance its targetability and reduces side effects. Overall, Cel shows promise as a therapeutic agent for HCC., Competing Interests: The authors declare no conflicts of interest. The authors alone are responsible for the content and writing of this article., (© 2023 Shenyang Pharmaceutical University. Published by Elsevier B.V.)

Background: Liver fibrosis caused by chronic liver injury, eventually develops into liver cirrhosis and hepatocellular carcinoma. Currently, there are no effective drugs to relieve liver fibrosis due to the lack of molecular pathogenesis characteristics. Former research demonstrates that the hepatic immune microenvironment plays a key role in the pathogenesis of liver fibrosis, thus macrophages are important immune cells in the liver. Our previous study has found that IDO1 plays an important role in the liver immune microenvironment. CRG is a gallic acid tannin found in medicinal plants of many ethnicities that protects against inflammation, tumors and chronic liver disease. However, the mechanism of by which CRG mediates the interaction of IDO1 with macrophages during hepatic immune maturation is not clear., Purpose: To investigate the regulatory mechanism of CRG in liver fibrosis and the intrinsic relationship between IDO1 and macrophage differentiation., Methods: Zebrafish, RAW264.7 cells and mice were used in the study. IDO1 overexpression and knockdown cell lines were constructed using lentiviral techniques., Results: We discovered that CRG remarkably reduced the AST and ALT serum levels. Histological examination revealed that CRG ameliorates CCL4-induced liver fibrosis and depressed the expression of α-SMA, Lamimin, Collagen-Ι and fibronectin. Besides, we found that CRG promoted increased MerTK expression on partly macrophages. Interestingly, in vitro, we found that CRG suppressed IDO1 expression and regulated macrophage differentiation by upregulating CD86, CD80 and iNOS, while downregulating CD206, CD163, IL-4 and IL-10 expression. Additionally, we found that CRG could inhibit hepatic stellate cell activation by direct or indirect action., Conclusion: Our findings suggest that CRG alleviates liver fibrosis by mediating IDO1-mediated M2 macrophage repolarization., Competing Interests: Declaration of Competing Interest All authors report no conflict of interest., (Copyright © 2023. Published by Elsevier GmbH.)

Hepatocellular carcinoma (HCC) is a common malignancy affecting many people worldwide. Baicalin is a flavonoid extracted from the dried root of Scutellaria baicalensis Georgi. It can effectively inhibit the occurrence and development of HCC. Nonetheless, the mechanism through which Baicalin inhibits HCC growth and metastasis remain unknown. This work discovered that Baicalin inhibited HCC cell proliferation, invasion, metastasis while inducing cell cycle arrest at the G0/G1 phase and apoptosis. In vivo HCC xenograft results indicated that Baicalin inhibited HCC growth. Western blotting analysis indicated that Baicalin suppressed the expressions of ROCK1, p-GSK-3β, and β-catenin, whereas it up-regulated the expressions of GSK-3β and p-β-catenin. Baicalin also reduced the expressions of Bcl-2, C-myc, Cyclin D1, MMP-9, and VEGFA, while increasing the expression of Bax. Molecular docking revealed that Baicalin docked in the binding site of the ROCK1 agonist, with a binding energy of -9 kcal/mol between the two. In addition, lentivirus-mediated suppression of ROCK1 expression improved the inhibitory effect of Baicalin on the proliferation, invasion, and metastasis of HCC and the expression of proteins associated with ROCK1/GSK-3β/β-catenin signaling pathway. Moreover, restoring ROCK1 expression decreased the anti-HCC efficacy of Baicalin. These findings suggest that Baicalin may decrease HCC proliferation and metastasis by suppressing ROCK1/GSK-3β/β-catenin signaling., (© 2023 John Wiley & Sons Ltd.)

Anatomical and functional heterogeneous substantia nigra (SN) has been extensively studied in humans and animals like rhesus monkeys given its crucial role in modulating a broad range of behaviors. Increasingly important cross-species research of SN may require connectionally homogeneous and homologous subregions of SN as objective and stable starting points from which the evolutionary characteristics of brain could be inspected. However, existing atlases of SN were all inaccurate mappings as a cross-species connectome atlas due to inadequate homology constraint during their constructions, and arbitrary paired use of these atlases might cause unreliable findings. In this study, a reliable blind-source cross-species parcellation of SN was developed based on the following rationale: striatonigrostriatal circuits form major structure of nigral connectivity; different nigral components have unique striatonigrostriatal connectivity; and inter-species corresponding human and macaque nigral components have similar striatonigrostriatal connectivity. Specifically, all voxels in human and macaque SN were grouped together and then classified based on inter-species identically characterized striatonigrostriatal connectivity attributes. Our results delineated a pars compacta-pars reticulate-like parcellation and further demonstrated its reliability by illustrating best-matched whole-brain structural and functional connectivity profiles of inter-species corresponding nigral subregions. Detailed inter-species and inter-regional differences in multi-aspect connectivities of these nigral subregions were inspected. It is expected that this cross-species connectome atlas of SN can offer biologically reliable cornerstones and important information to facilitate future cross-species research., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

To date, reliable biomarkers remain unclear that could link functional connectivity to patients' symptoms for detecting and predicting the process from normal aging to Alzheimer's disease (AD) in elderly people with specific genotypes. To address this, individual-specific functional connectivity is constructed for elderly participants with/without APOE ε4 allele. Then, we utilize recursive feature selection-based machine learning to reveal individual brain-behavior relationships and to predict the symptom transition in different genotypes. Our findings reveal that compared with conventional atlas-based functional connectivity, individual-specific functional connectivity exhibits higher classification and prediction performance from normal aging to AD in both APOE ε4 groups, while no significant performance is detected when the data of two genotyping groups are combined. Furthermore, individual-specific between-network connectivity constitutes a major contributor to assessing cognitive symptoms. This study highlights the essential role of individual variation in cortical functional anatomy and the integration of brain and behavior in predicting individualized symptoms., (© 2023. The Author(s).)

Somatic hypermutation (SHM), initiated by activation-induced cytidine deaminase (AID), generates mutations in the antibody-coding sequence to allow affinity maturation. Why these mutations intrinsically focus on the three nonconsecutive complementarity-determining regions (CDRs) remains enigmatic. Here, we found that predisposition mutagenesis depends on the single-strand (ss) DNA substrate flexibility determined by the mesoscale sequence surrounding AID deaminase motifs. Mesoscale DNA sequences containing flexible pyrimidine-pyrimidine bases bind effectively to the positively charged surface patches of AID, resulting in preferential deamination activities. The CDR hypermutability is mimicable in in vitro deaminase assays and is evolutionarily conserved among species using SHM as a major diversification strategy. We demonstrated that mesoscale sequence alterations tune the in vivo mutability and promote mutations in an otherwise cold region in mice. Our results show a non-coding role of antibody-coding sequence in directing hypermutation, paving the way for the synthetic design of humanized animal models for optimal antibody discovery and explaining the AID mutagenesis pattern in lymphoma., Competing Interests: Declaration of interests Shanghai Institute of Biochemistry and Cell Biology and Shanghai Jiao Tong University School of Medicine have filed a patent application based on the findings in this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Potential miRNA-disease associations (MDA) play an important role in the discovery of complex human disease etiology. Therefore, MDA prediction is an attractive research topic in the field of biomedical machine learning. Recently, several models have been proposed for this task, but their performance limited by over-reliance on relevant network information with noisy graph structure connections. However, the application of self-supervised graph structure learning to MDA tasks remains unexplored. Our study is the first to use multi-view self-supervised contrastive learning (MSGCL) for MDA prediction. Specifically, we generated a learner view without association labels of miRNAs and diseases as input, and utilized the known association network to generate an anchor view that provides guiding signals for the learner view. The graph structure was optimized by designing a contrastive loss to maximize the consistency between the anchor and learner views. Our model is similar to a pre-trained model that continuously optimizes upstream tasks for high-quality association graph topology, thereby enhancing the latent representation of association predictions. The experimental results show that our proposed method outperforms state-of-the-art methods by 2.79$\%$ and 3.20$\%$ in area under the receiver operating characteristic curve (AUC) and area under the precision/recall curve (AUPR), respectively., (© Crown copyright 2023.)

With the recent development of deep learning, the regression, classification, and segmentation tasks of Computer-Aided Diagnosis (CAD) using Non-Contrast head Computed Tomography (NCCT) for spontaneous IntraCerebral Hematoma (ICH) have become popular in the field of emergency medicine. However, a few challenges such as time-consuming of ICH volume manual evaluation, excessive cost demanding patient-level predictions, and the requirement for high performance in both accuracy and interpretability remain. This paper proposes a multi-task framework consisting of upstream and downstream components to overcome these challenges. In the upstream, a weight-shared module is trained as a robust feature extractor that captures global features by performing multi-tasks (regression and classification). In the downstream, two heads are used for two different tasks (regression and classification). The final experimental results show that the multi-task framework has better performance than single-task framework. And it also reflects its good interpretability in the heatmap generated by Gradient-weighted Class Activation Mapping (Grad-CAM), which is a widely used model interpretation method, and will be presented in subsequent sections., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gong, Dai, Wang, Zheng, Shi, Yu, Chen, Huang and Wang.)

Purpose: We aimed to explore the clinicodemographic characteristics and prognosis of grey zone squamous cell cancer (GZSCC) located in the overlapping or ambiguous area of oral cavity and oropharynx and to identify valuable factors that would improve its differential diagnosis and prognosis., Methods: Information of GZSCC patients in the Surveillance, Epidemiology, and End Results (SEER) database were compared to patients with oral cavity (OCSCC) and oropharyngeal (OPSCC) squamous cell carcinomas with corresponding HPV status, respectively. Kaplan-Meier method with log-rank test and multivariate Cox regression analysis were applied to assess associations between clinical characteristics and overall survival (OS). A predictive model integrating age, gender, marital status, HPV status and staging variables was conducted to classify GZSCC patients into three risk groups and verified internally by tenfold cross validation., Results: A total of 3318 GZSCC, 10792 OPSCC and 6656 OCSCC patients were identified. HPV-positive GZSCC patients had the best 5-year OS as HPV-positive OPSCC (81% vs. 82%). However, the 5-year OS of HPV-negative/unknown GZSCC (43%/42%) were the worst among all groups, indicating that HPV status and the overlapping nature of tumors were valuable prognostic predictors in GZSCC patients. Compared with the strategy of dividing GZSCC into two groups by HPV status, the predictive model integrating more variables could additionally identify a unique high-risk GZSCC group with the lowest OS rate., Conclusions: GZSCC patients had distinct clinical characteristics and prognosis compared with OPSCC and OCSCC, integrating HPV status and other clinical factors could help distinguish GZSCC and predict their prognosis., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Alcoholic liver disease (ALD) is associated with hepatic inflammatory activation and iron overload. The receptor for advanced glycation end products (RAGE) is an important metabolic mediator during the development of ALD. The aim of this study was to determine the effect of RAGE on iron homeostasis in ALD. We found increased circulating transferrin, hepcidin and ferritin in ALD patients and positively correlated with RAGE level. RAGE knockout (RAGE -/- ) and wild-type mice were subjected to chronic alcoholic feeding for 6 weeks to induce ALD, and RAGE inhibitor, iron chelator or lipid peroxidation inhibitor were administered. We showed that chronic alcohol administration triggered hepatic steatosis, inflammation, and oxidative stress, which were eliminated by deficiency or inhibition of RAGE. Surprisingly, pathways of hepatic iron metabolism were significantly altered, including increased iron uptake (Tf/TfR) and storage (Ferritin), as well as decreased iron export (FPN1/Hepcidin). In vitro experiments confirmed that RAGE had different effects on the mechanism of iron metabolism of hepatocytes and macrophages respectively. In conclusion, our data revealed preclinical evidence for RAGE inhibition as an effective intervention for alleviating alcohol-induced liver injury., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Although recent guidelines recommend endoscopic resection of rectal neuroendocrine tumors (NET) ≤10 mm, there is no consensus on which endoscopic modality should be performed. We aimed to compare the safety and efficacy of modified cap-assisted endoscopic mucosal resection (mEMR-C) and endoscopic submucosal dissection (ESD) methods for the treatment of rectal NET ≤10 mm., Methods: A randomized noninferiority trial comparing mEMR-C and ESD was conducted. The primary outcome was the histological complete resection rate; the secondary outcomes included en bloc resection rate, operation time, complications, and so on. Subgroup analyses and follow-up were also performed., Results: Ninety patients were enrolled, and 79 patients with pathologically confirmed rectal NET were finally analyzed, including 38 cases of mEMR-C and 41 cases of ESD. Histological complete resection rate was 97.4% in the mEMR-C group and 92.7% in the ESD group. The noninferiority of mEMR-C compared with that of ESD was confirmed because the absolute difference was 4.7% (2-sided 90% confidence interval, -3.3% to 12.2%; P = 0.616). En bloc resection and successful removal of rectal NET were achieved in all patients. Advantages of mEMR-C over ESD included shorter operation time (8.89 ± 4.58 vs 24.8 ± 9.14 minutes, P < 0.05) and lower hospitalization cost ($2,233.76 ± $717.70 vs $2,987.27 ± $871.81, P < 0.05). Postoperative complications were recorded in 4 patients who received mEMR-C and 2 patients in the ESD group (11.5% vs 4.9%, P = 0.509), which were all well managed using endoscopy. Similar findings were observed when subgroup analysis was performed., Discussion: mEMR-C is noninferior to ESD with a similar complete resection rate. In addition, mEMR-C had shorter procedure duration time and lower hospitalization costs., Trial Registration: ClinicalTrials.gov Identifier: NCT03982264., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Adhesion G protein-coupled receptors are elusive in terms of their structural information and ligands. Here, we solved the cryogenic-electron microscopy (cryo-EM) structure of apo-ADGRG2, an essential membrane receptor for maintaining male fertility, in complex with a G s trimer. Whereas the formations of two kinks were determinants of the active state, identification of a potential ligand-binding pocket in ADGRG2 facilitated the screening and identification of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate and deoxycorticosterone as potential ligands of ADGRG2. The cryo-EM structures of DHEA-ADGRG2-G s provided interaction details for DHEA within the seven transmembrane domains of ADGRG2. Collectively, our data provide a structural basis for the activation and signaling of ADGRG2, as well as characterization of steroid hormones as ADGRG2 ligands, which might be used as useful tools for further functional studies of the orphan ADGRG2., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Breast cancer is the most common cause of cancer death in women. Early screening and treatment can effectively improve the success rate of treatment. Ultrasound imaging technology, as the preferred modality for breast cancer screening, provides an essential reference for early diagnosis. Existing computer-aided ultrasound imaging diagnostic techniques mainly rely on the selected key frames for breast cancer lesion diagnosis. In this paper, we first collected and annotated a dataset of ultrasound video sequences of 268 cases of breast lesions. Moreover, we propose a contrastive learning-guided multi-meta attention network (CLMAN) by combining a deformed feature extraction module and a multi-meta attention module to address breast lesion diagnosis in ultrasound sequence. The proposed feature extraction module can autonomously acquire key information of the feature map in the spatial dimension, whereas the designed multi-meta attention module is dedicated to effective information aggregation in the temporal dimension. In addition, we utilize a contrast learning strategy to alleviate the problem of high imaging variability within ultrasound lesion videos. The experimental results on our collected dataset show that our CLMAN significantly outperforms existing advanced methods for video classification., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huang, Lin, Huang, Wang, Chan and Wang.)

Background: Hematological indices assist in predicting clinical outcomes., Objectives: To explore changes of hematological indices on oropharynx squamous cell carcinoma (OPSCC) patients received radiotherapy and their association with survival., Material and Methods: The white blood cell count (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), hemoglobin (Hb), platelet (Plt), albumin (Alb), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) at baseline, 1-, 3-, 6- and 12-months follow-up were retrospectively collected. The trajectory of indices was described. A linear model with random effects was to describe indices' changing rate and trend. Univariable Cox analysis was to assess the correlation between indices and survival., Results: Of the 85 patients, WBC and ALC dropped during acute phase and gradually recovered, while NLR and PLR increased during acute phase and subsequently declined (all p  < .01). Higher absolute value of nutritional indices (Alb and Hb) was associated with better prognosis ( p  < .05). In contrast, patients with higher absolute value or upward trend of inflammatory indices (ANC, Plt, NLR and PLR) had worse survival ( p  < .05)., Conclusions and Significance: The short- and long-term changes of indices differed in OPSCC patients received radiotherapy, and absolute values and dynamic changes of indices had the potential to be prognostic factors.

Knowledge of the spatial-temporal variations of soil organic carbon (SOC) quantity and quality and its microbial regulation mechanisms is essential for long-term SOC sequestration in agroecosystems; nevertheless, this information is lacking in the process of walnut plantations. Here, we used the modified Walkley-Black method, phospholipid fatty acid analysis, and micro-plate enzyme technique to analyze the evolution of SOC stocks and quality/lability as well as microbial communities and enzyme activities at different soil depths in walnut plantations with a chronosequence of 0-, 7-, 14-, and 21-years in the Eastern Taihang Mountains, China. The results indicated that long-term walnut plantations (14-and 21-years) enhanced SOC stocks, improved SOC quality/lability (as indicated by the lability index), and promoted microbial growth and activities (i.e., hydrolase and oxidase activities) in the 0-40 cm soil layers. Besides, these above-mentioned SOC-and microbial-related indices (except for oxidase activities) decreased with increasing soil depths, while oxidase activities were higher in deeper soils (40-60 cm) than in other soils (0-40 cm). The partial least squares path model also revealed that walnut plantation ages and soil depths had positive and negative effects on microbial attributes (e.g., enzyme activities, fungal and bacterial communities), respectively. Meanwhile, the SOC stocks were closely related to the fungal community; meanwhile, the bacterial community affected SOC quality/liability by regulating enzyme activities. Comprehensively, long-term walnut plantations were conducive to increasing SOC stocks and quality through altering microbial communities and activities in the East Taihang Mountains in Hebei, China., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Luan, Liu, Huang, Qiao, Chen, Guo, Zhang, Guo, Zhang and Qi.)

Background: Liver fibrosis is a major disease that threatens people's health around the world. However, there is a lack of effective treatment to completely reverse liver fibrosis. Liver transplantation is currently the only curative option for patients with advanced cirrhosis. Ferroptosis is a newly discovered type of cell death and plays an important role in the process of liver fibrosis, but the specific mechanism needs to be clarified., Hypothesis/purpose: To explore the regulatory mechanism of isoliquiritigenin (ISL) in the process of liver fibrosis and the relationship between Cav-1 and ferroptosis., Methods: In this research, zebrafish, HSC-T6 cells, and mice were used as the research object. Different ROS probes to visually detect the content and distribution of ROS in live zebrafish and cells. Lentivirus and siRNA-mediated transfection techniques were used for the construction of Cav-1 overexpression and knockdown cell lines to verify the important role of Cav-1 in vitro., Results: Generally, we first elucidated that ISL relieved liver fibrosis by inducing hepatic stellate cells (HSCs) ferroptosis through repressing GPX4 expression and increasing the expression of TFR and DMT1, thus producing a large number of ROS, we also found that Cav-1 exerted its anti-hepatic fibrosis effect by promoting HSCs ferroptosis., Conclusion: Our results have shown that Cav-1-mediated HSCs ferroptosis is necessary for ISL to play an anti-fibrotic effect in vitro and in vivo., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Cholangiocarcinoma (CCA) is a type of highly malignant tumor originating from bile ducts. The prognosis of CCA is poor and the treatment options are limited. The biomarker study of CCA has made little progresses in recent years because of the difficulty to obtain CCA specimens. SOX9 is an important regulator of cholangiocyte proliferation and differentiation. We performed mRNA sequencing of CCA, retrieved TCGA data, and detected SOX9 expression in a large CCA cohort. With WNT3A stimulation, SOX9 expression and transcription was elevated by TCF7. Moreover, SOX9 was substantially up-regulated in CCA tissues and was identified as a prognostic biomarker of CCA. With mRNA sequencing and in vitro/vivo validation, we demonstrated that SOX9 enhanced the transcription and expression of FGF7 and FGFR2. FGF7 was significantly up-regulated in the bile and serum of CCA patients, and may promote CCA proliferation by activating FGFR2 in an autocrine pathway. co-expression of FGF7 and FGFR2 was a more sensitive marker for poor prognosis. SOX9-induced overexpression of FGF7 and FGFR2 was the key reason of SOX9-involved pemigatinib resistance. In conclusion, SOX9 and FGF7 were prognostic biomarkers of CCA. WNT3A-TCF7-SOX9 axis could induce pemigatinib resistance in two independent pathways: (1)SOX9 directly promotes FGFR2 transcription and expression; (2)SOX9 elevates FGF7 expression, which could be secreted from CCA cells and activates FGFR2 phosphorylation in an autocrine pathway., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Fluorescence correlation spectroscopy (FCS) investigates the temporal relationship of fluctuating fluorescence signals reflecting underlying molecular processes occurring in a solution sample or a single live cell. This review article introduces the principles of two basic and most used FCS techniques: fluorescence auto-correlation spectroscopy (FACS) and fluorescence cross-correlation spectroscopy (FCCS). Combined, FACS and FCCS techniques can quantitatively analyze multiple properties of molecule or nanoparticle samples, including molar concentration, diffusion coefficient and hydrodynamic radius, homo- or hetero-interaction, fluorescence brightness, etc . Not surprisingly, FCS techniques have long been used to investigate molecular mechanisms of biomolecular phase separation, first in the lipid bilayer and more recently in cell cytosol and nucleoplasm. The latter applications are especially exciting since a whole new class of membraneless cellular organelles have been discovered, which are proposed to be results of biomolecule liquid-liquid phase separation (LLPS). LLPS research can benefit significantly from the multifunctionality and single-molecule sensitivity of a variety of FCS techniques, particularly for live-cell studies. This review illustrates how FACS and FCCS techniques can be used to investigate multiple aspects of the molecular mechanisms of LLPS, and summarizes FCS applications to LLPS research in vivo and in vitro ., Competing Interests: Zhulou Wang, Huizhi Zhang, Lin Jian, Bo Ding, Keying Huang, Wolun Zhang, Qian Xiao and Shaohui Huang declare that they have no conflict of interest., (© The Author(s) 2022.)

Background: There are no data comparing a regular diet with a restricted diet after endoscopic polypectomy in patients with colorectal polyps. The current guidelines also did not provide the detailed information of dietary patterns after polypectomy. In this study, we aimed to evaluate the safety and efficacy of different diets on post-polypectomy outcomes., Methods: A total of 302 patients with colorectal polyps who underwent polypectomy were prospectively enrolled between March 2019 and December 2019 in Nanfang Hospital (Guangzhou, China). Enrolled patients were then randomly assigned to a regular diet group or a restricted diet group after polypectomy. The study is a non-inferior design and the primary end point was the post-operative adverse events (AE) rate. Secondary end points included length of stay (LOS) and hospitalization cost., Results: Among all the included patients, 148 patients received a restricted diet and 154 patients received a regular diet after polypectomy. A total of 376 polyps were removed, with 183 polyps in the restricted diet group and 193 polyps in the regular diet group. Shorter LOS (4.0 ± 1.4 vs 4.8 ± 1.7, P  < 0.001) and lower hospitalization costs (7,701.63 ± 2,579.07 vs 8,656.05 ± 3,138.53, P  = 0.001) were observed in the regular diet group. In particular, there was no significant difference in 3-day AE rates between the restricted diet and the regular diet group (1.35% [2/148] vs 2.60% [4/154], P  = 0.685). Subgroup analysis looking at the number of polyps removed in each patient and different treatment modalities also showed similar findings., Conclusion: Regular diet should be recommended after polypectomy for polyps <20 mm as it can shorten LOS and save hospitalization costs., (© The Author(s) 2022. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-sen University.)

Neuroblastoma (NB) is a malignant tumor in young children that originates from the neural crest of the sympathetic nervous system. Generally, NB occurs in the adrenal glands, but it can also affect the nerve tissues of the neck, chest, abdomen, and pelvis. Understanding the pathophysiology of NB and developing novel therapeutic approaches are critical. Noncoding RNAs (ncRNAs) are associated with crucial aspects of pathology, metastasis and drug resistance in NB. Here, we summarized the pretranscriptional, transcriptional and posttranscriptional regulatory mechanisms of ncRNAs involved in NB, especially focusing on regulatory pathways. Furthermore, ncRNAs with the potential to serve as biomarkers for risk stratification, drug resistance and therapeutic targets are also discussed, highlighting the clinical application of ncRNAs in NB., (© 2022. The Author(s).)

The flow stress behavior and corrosive properties of Al-7Si alloy were studied by thermal compression test, electrochemical test, and electron probe microanalysis. The influences of temperatures, strain rates, strains, and morphology of Si particles on stress-strain curves of Al-7Si alloy were analyzed. The peak stress of unmodified-Al-7Si alloy is higher than that of Sr-modified-Al-7Si alloy at the same deformation conditions, and the phenomenon is obviously relevant to the distribution and morphology of Si particles. The morphology of Si particles of unmodified-undeformed-Al-7Si alloy is a typical thick layer, and that of unmodified-deformed-Al-7Si alloy is broken into relatively small particles and the distribution is relatively even in homogeneous deformation zone II. The distribution of Si particles in Sr-modified-deformed-Al-7Si alloy is obviously more even than undeformed alloy. The effect of a small deformation of 20% on the distribution and morphology of Si particles is obviously smaller than that of a large deformation of 50%. The electrochemical self-corrosion potential of Sr-modified-Al-7Si alloy is higher than that of unmodified-Al-7Si alloy, and it proves that the distribution and morphology of Si particles have a certain influence on the corrosive properties of Al-7Si alloy. That is, the even fine Si particles are more conducive to improving the corrosive properties of Al-7Si alloy.

The intrinsically disordered C-terminal domain (CTD) of protein 4.1G is able to specifically bind a 26-residue intrinsically disordered region of NuMA, forming a dynamic fuzzy complex. As one of a few cases of extremely fuzzy interactions between two intrinsically disordered proteins/regions (IDPs/IDRs) without induced folding, the principle of the binding is unknown. Here, we combined experimental and computational methods to explore the detailed mechanism of the interaction between 4.1G-CTD and NuMA. MD simulations suggest that the kinetic hub states in the structure ensemble of 4.1G-CTD are favorable in the fuzzy complex. The feature of these hub states is that the binding 'hot spot' motifs βA and βB exhibit β strand propensities and are well packed to each other. The binding between 4.1G-CTD and NuMA is disrupted at low pH, which changes the intramolecular packing of 4.1G-CTD and weakens the packing between βA and βB motifs. Low pH conditions also lead to increased hydrodynamic radius and acceleration of backbone dynamics of 4.1G-CTD. All these results underscore the importance of tertiary structural arrangements and overall compactness of 4.1G-CTD in its binding to NuMA, i.e. the compact disordered state of 4.1G-CTD is crucial for binding. Different from the short linear motifs (SLiMs) that are often found to mediate IDP interactions, 4.1G-CTD functions as an intrinsically disordered domain (IDD), which is a functional and structural unit similar to conventional protein domains. This work sheds light on the molecular recognition mechanism of IDPs/IDRs and expands the conventional structure-function paradigm in protein biochemistry., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background & Aims: Acute liver failure (ALF) is a condition with high mortality and morbidity, characterized by glutathione depletion, oxidative stress, and mitochondrial dysfunction. Ferroptosis may be involved in ALF. Indeed, emerging studies have shown that ferroptosis plays a significant role in ALF. However, the mechanism of ferroptosis in hepatocytes during ALF remains unknown., Methods: Hepatic-specific transforming growth factor β receptor 1 knockout (TGFβr1 Δhep-CKO ) mice and nuclear factor erythroid 2-related factor 2 knockout (Nrf2 -/- ) mice were generated and subjected to ALF. Electron microscopy was used to detect mitochondrial and other cell substructure changes during ALF., Results: In this study, we noticed that lipopolysaccharide (LPS)/D-galactosamine (D-GalN) induced caspases-mediated apoptosis as current research reported, we also found lipid peroxidation, reactive oxygen species accumulation, and glutathione, co-enzyme Q10 system inhibition mediated ferroptosis during LPS/D-GalN-induced ALF. Rescue studies have shown that ferrostatin-1 (Fer-1) and deferoxamine mesylate (DFOM), the inhibitor of ferroptosis, could alleviate LPS/D-GalN-induced ALF. In addition, we noticed that TGFβ1 was increased during ALF, while ALF was relieved in TGFβr1 Δhep-CKO mice. We also noticed that liver TGFβr1 deficiency alleviated LPS/D-GalN-induced apoptosis and ferroptosis by affecting the phosphorylation of glycogen synthase kinase 3β and Nrf2, a key antioxidant factor, by up-regulating the levels of glutathione peroxidase 4 (GPX4), glutamine antiporter xCT (XCT), dihydroorotate dehydrogenase (DHODH), and ferroptosis suppressor protein 1 (FSP1), and down-regulating transferrin receptor (TFR), prostaglandin-endoperoxide synthase (Ptgs2), chaC glutathione specific gamma-glutamylcyclotransferase 1 (CHAC1), and cytochrome P450 reductase (POR) expression. The further supplemental experiment showed that ferroptosis was aggravated significantly in Nrf2 -/- mice compared with its wild-type controls and reversed by ferrostatin-1., Conclusions: This study shows that TGFβr1 plays a critical role in mediating LPS/D-GalN-induced ALF by promoting apoptosis and ferroptosis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

With the rise of deep learning, using deep learning to segment lesions and assist in diagnosis has become an effective means to promote clinical medical analysis. However, the partial volume effect of organ tissues leads to unclear and blurred edges of ROI in medical images, making it challenging to achieve high-accuracy segmentation of lesions or organs. In this paper, we assume that the distance map obtained by performing distance transformation on the ROI edge can be used as a weight map to make the network pay more attention to the learning of the ROI edge region. To this end, we design a novel framework to flexibly embed the distance map into the two-stage network to improve left atrium MRI segmentation performance. Furthermore, a series of distance map generation methods are proposed and studied to reasonably explore how to express the weight of assisting network learning. We conduct thorough experiments to verify the effectiveness of the proposed segmentation framework, and experimental results demonstrate that our hypothesis is feasible.

Decision-making related to nitrogen (N) fertilization is a crucial step in agronomic practices because of its direct interactions with agronomic productivity and environmental risk. Here, we hypothesized that soil apparent N balance could be used as an indicator to determine the thresholds of N input through analyzing the responses of the yield and N loss to N balance. Based on the observations from 951 field experiments conducted in rice (Oryza sativa L.) cropping systems of China, we established the relationships between N balance and ammonia (NH 3 ) volatilization, yield increase ratio, and N application rate, respectively. Dramatical increase of NH 3 volatilizations and stagnant increase of the rice yields were observed when the N surplus exceeded certain levels. Using a piecewise regression method, the seasonal upper limits of N surplus were determined as 44.3 and 90.9 kg N ha -1 under straw-return and straw-removal scenarios, respectively, derived from the responses of NH 3 volatilization, and were determined as 53.0-74.9 and 97.9-112.0 kg N ha -1 under straw-return and straw-removal scenarios, respectively, derived from the maximum-yield consideration. Based on the upper limits of N surplus, the thresholds of N application rate suggested to be applied in single, middle-MLYR, middle-SW, early, and late rice types ranged 179.0-214.9 kg N ha -1 in order to restrict the NH 3 volatilization, and ranged 193.3-249.8 kg N ha -1 in order to achieve the maximum yields. If rice straw was returned to fields, on average, the thresholds of N application rate could be theoretically decreased by 17.5 kg N ha -1 . This study provides a robust reference for restricting the N surplus and the synthetic fertilizer N input in rice fields, which will guide yield goals and environmental protection., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Biliary tract cancers (BTCs), including cholangiocarcinoma (CCA) and gallbladder cancer (GC), are malignancies originating from the biliary tract with poor prognosis. In the early stage of BTCs, surgery is the only choice for cure. Unfortunately, most patients with BTC are diagnosed at an advanced stage and lose the opportunity for surgery. For many advanced solid tumors, antiangiogenic therapy has achieved encouraging results. While most clinical studies on antiangiogenic therapy in advanced BTCs have shown an excellent disease control rate (DCR), the improvement in overall survival (OS) is controversial. Understanding how the relevant signaling molecules influence the angiogenic response and the functional interaction is necessary for the formulation of new treatment regimens and the selection of enrolled patients. In this review, we aim to summarize and discuss the latest advances in antiangeogenesis for BTCs, mainly focusing on the molecular mechanism of angiogenesis in BTCs and the therapeutic effects from clinical trials. Furthermore, the horizon of antiangiogenesis for BTCs is highlighted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer ZL declared a shared affiliation, with no collaboration, with TC to the handling editor at the time of review., (Copyright © 2021 Wang, Chen, Li, Mu, Liu, Shi, Liu, Zhao, Lian, Huang, Pan and Zhang.)