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Background: Exosomes and other secretory membrane vesicles, collectively referred to as extracellular vesicles (EVs), have garnered increasing attention in research due to their biological characteristics. Notably, studies have shown promising results regarding the role of stem cell-derived extracellular vesicles (SC-EVs) in skin and plastic surgery applications. This study aims to elucidate current trends in SC-EVs within the context of skin and plastic surgery and offer insights for future research directions in advancing this critical field., Methods: A comprehensive search was conducted for relevant studies on SC-EVs in skin and plastic surgery spanning from 2003 to 2023, utilizing the Web of Science database. Subsequently, data analysis was performed using VOSviewer and CiteSpace., Results: A total of 1089 studies were identified, with a noticeable annual increase in publications on SC-EVs' application in skin and plastic surgery. China emerged as the leading contributor to this field, with Shanghai Jiao Tong University being a notable institution. Stem Cell Research & Therapy and the International Journal of Molecular Sciences were the top journals publishing relevant articles. Author Fu Xiaobing from the Chinese People's Liberation Army General Hospital had the highest publication count in this area. Keyword co-occurrence analysis revealed six distinct clusters, with "exosomes" being the most prevalent keyword in recent years. Wound healing and skin rejuvenation emerged as primary research focuses and hotspots in this field., Conclusion: This comprehensive review offers insights into global trends surrounding SC-EVs in skin and plastic surgery. Analysis of journals, institutions, references, and keywords provides valuable guidance for researchers in determining future research directions., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Background: Breast cancer, the most prevalent tumor in women globally, significantly impacts young women, compromising their daily lives and overall well-being. Breast cancer represents a significant public health concern due to its extensive physical and psychological consequences., Material and Methods: Data from the Global Burden of Disease (GBD) were used to assess the global, regional, and national burden of breast cancer in young women aged 20-39 from 1990 to 2021. This analysis focused on trends measured by the estimated annual percentage change (EAPC) and explored the socioeconomic impacts via the sociodemographic index (SDI)., Results: During 1990-2021, the incidence and prevalence of breast cancer among young women increased globally, with annual rates of 0.82 and 0.87%, respectively. The mortality rate and disability-adjusted life years (DALYs) also rose annually by -0.12% and -0.05, respectively. A significant burden shift was observed towards regions with lower SDI, with diet high in red meat, alcohol use, and high fasting plasma glucose identified as prominent risk factors, particularly in lower SDI regions., Conclusion: Our findings underscore breast cancer in young women as an escalating global health challenge, with the burden increasingly shifting towards lower socioeconomic areas. This underscores the necessity for targeted prevention and control strategies for breast cancer, focusing on reducing the identified risk factors and ensuring equitable health resource distribution., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Currently, cell-assisted lipotransfer (CAL) and platelet-rich plasma (PRP) -assisted lipotransfer have been used to overcome the low survival rate of conventional lipotransfer. However, there is still insufficient evidence to determine which technique is the best strategy for autologous fat grafting in breast cosmetic and reconstructive surgery., Objective: The present study aimed to compare the efficacy of traditional fat transplantation, CAL, and PRP-assisted lipotransfer., Methods: A systematic search was conducted in several databases including PUBMED, Web of Science, Cochrane, ClinicalTrials.gov, and EMBASE from January 21, 2024, to identify studies that met the inclusion criteria. Twelve studies were included after a rigorous selection process based on predefined criteria. Statistical analyses were conducted using R Ver. 4.0.5 with the netmeta and dmetar packages, employing a frequentist approach with a random-effects model. A network meta-analysis was performed to compare different fat graft procedures regarding fat survival rate and complication events. The review protocol was prospectively registered in PROSPERO (CRD42024501780)., Results: The results indicate that CAL and PRP-assisted lipotransfer are better than traditional fat grafts in terms of fat survival rate. And there is no significant difference in the incidence of postoperative complications between the CAL group, PRP group, and traditional group., Conclusion: Based on the results of network meta-analysis, it appears that both CAL and PRP-assisted lipotransfer have a higher fat survival rate for autologous fat grafting in breast augmentation and reconstruction. However, the transplantation strategy still needs to be analyzed based on actual conditions in clinical applications., Competing Interests: Declaration of Interest Statement: All authors states 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 by the American Society of Plastic Surgeons.)

"Exercise is the best medicine" is well known, but the optimal dose of physical activity (PA) for males and females across different age groups is still unknown. This study, using data from the four waves of CHARLS, aimed to determine the optimal PA dose that reduces frailty risks among older adults across various age groups and both sexes. We created a frailty index score using 63 health-related variables and used 0.21 as the frailty cut point. Binary logistic regression was used to compare the effect of vigorous, moderate, and light intensity PA under IPAQ criteria on frailty risk. The study found that regardless of whether males or females, the optimal effect of vigorous-intensity PA in reducing the risk of frailty is consistently observed throughout the entire old age career. Moreover, the age groups at which moderate-intensity PA reduces the risk of frailty were from age 70 for males and from age 80 for females. And light-intensity PA had no effect on reducing the risk of frailty. Moderate and vigorous intensity of PA in older adults should be promoted, but guidelines and recommendations must account for optimal associations with PA dose across genders and age groups., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Stroke, a critical health issue in the US, not only has physical repercussions but also potentially affects the health-related quality of life (HRQoL) through neuropsychiatric outcomes like depressive symptoms and suicidal thoughts. This study utilized a nationally representative sample of 1302 US stroke survivors (age ≥ 20) from the US National Health and Nutrition Examination Survey (2005-2018) to assessed relationships between QoL via the CDC HRQOL-4 and evaluated depressive symptoms and suicidal ideation using the Patient Health Questionnaire-9 (PHQ-9). Participants (mean age: 64.4; 56.0 % female) showed that 40.7 % had at least mild depressive symptoms, and 18.8 % exhibited major depressive symptoms. Suicidal ideation was reported by 8.1 %. After sociodemographic and health condition adjustments, mild and major depressive symptoms, along with suicidal ideation, were associated with poorer general health status and more physically and mentally unhealthy days and activity limitation days. A dose-response relationship between PHQ-9 scores and HRQoL outcomes was evident (All P for trend <0.001). Stroke survivors with suicidal ideation also experienced more physically and mentally unhealthy days and activity limitation days. Depressive symptoms and suicidal ideation are associated with reduced HRQoL among US stroke survivors, underscoring the importance of thorough neuropsychiatric evaluations and interventions to bolster stroke survivors' well-being., Competing Interests: Declaration of competing interest The authors have no conflicts to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Physical activity and sedentary behavior, both distinct lifestyle behaviors associated with brain health, have an unclear potential relationship with brain cortical structure. This study aimed to determine the causal link between physical activity, sedentary behavior, and brain cortical structure (cortical surface area and thickness) through Mendelian randomization analysis. The inverse-variance weighted method was primarily utilized, accompanied by sensitivity analyses, to confirm the results' robustness and accuracy. Analysis revealed nominally significant findings, indicating a potential positive influence of physical activity on cortical thickness in the bankssts (β = 0.002 mm, P = 0.043) and the fusiform (β = 0.002 mm, P = 0.018), and a potential negative association of sedentary behavior with cortical surface area in the caudal middle frontal (β = -34.181 mm2, P = 0.038) and the pars opercularis (β = -33.069 mm2, P = 0.002), alongside a nominally positive correlation with the cortical surface area of the inferior parietal (β = 58.332 mm2, P = 0.035). Additionally, a nominally significant negative correlation was observed between sedentary behavior and cortical thickness in the paracentral (β = -0.014 mm, P = 0.042). These findings offer insights into how lifestyle behaviors may influence brain cortical structures, advancing our understanding of their interaction with brain health., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Androgenic alopecia (AGA) is a highly prevalent form of non-scarring alopecia but lacks effective treatments. Stem cell exosomes have similar repair effects to stem cells, suffer from the drawbacks of high cost and low yield yet. Cell-derived nanovesicles acquired through mechanical extrusion exhibit favorable biomimetic properties similar to exosomes, enabling them to efficiently encapsulate substantial quantities of therapeutic proteins. In this study, we observed that JAM-A, an adhesion protein, resulted in a significantly increased the adhesion and resilience of dermal papilla cells to form snap structures against damage caused by dihydrotestosterone and macrophages, thereby facilitating the process of hair regrowth in cases of AGA. Consequently, adipose-derived stem cells were modified to overexpress JAM-A to produce engineered JAM-A overexpressing nanovesicles (JAM-A OE @NV). The incorporation of JAM-A OE @NV into a thermosensitive hydrogel matrix (JAM-A OE @NV Gel) to effectively addresses the limitations associated with the short half-life of JAM-A OE @NV, and resulted in the achievement of a sustained-release profile for JAM-A OE @NV. The physicochemical characteristics of the JAM-A OE @NV Gel were analyzed and assessed for its efficacy in promoting hair regrowth in vivo and vitro. The JAM-A OE @NV Gel, thus, presents a novel therapeutic approach and theoretical framework for promoting the treatment of low cell adhesion diseases similar to AGA., Competing Interests: The authors declare no competing financial interests or personal relationships that could have influenced the work reported in this paper., (© 2024 The Authors.)

Adipose tissue macrophages can promote beige adipose thermogenesis by altering local sympathetic activity. Here, we perform sympathectomy in mice and further eradicate subcutaneous adipose macrophages and discover that these macrophages have a direct beige-promoting function that is independent of sympathetic system. We further identify adipocyte Ets1 as a vital mediator in this process. The anti-inflammatory M2 macrophages suppress Ets1 expression in adipocytes, transcriptionally activate mitochondrial biogenesis, as well as suppress mitochondrial clearance, thereby increasing the mitochondrial numbers and promoting the beiging process. Male adipocyte Ets1 knock-in mice are completely cold intolerant, whereas male mice lacking Ets1 in adipocytes show enhanced energy expenditure and are resistant to metabolic disorders caused by high-fat-diet. Our findings elucidate a direct communication between M2 macrophages and adipocytes, and uncover a function for Ets1 in responding to macrophages and negatively governing mitochondrial content and beige adipocyte formation., (© 2024. The Author(s).)

Compound Chinese medicine (F1) is a traditional prescription in Chinese medicine that is commonly used to treat spleen deficiency diarrhea (SDD). It has demonstrated remarkable effectiveness in clinical practice. However, the precise mechanism by which it exerts its antidiarrheal effect is still unclear. This study aimed at investigating the antidiarrheal efficacy and mechanism of F1 on senna-induced secretory diarrhea (SDD). Senna was utilized to induce the development of a mouse model of senna-induced secretory diarrhea (SDD) in order to observe the rate of diarrhea, diarrhea index, blood biochemistry, and histopathological changes in the small intestine. Additionally, the levels of sodium and hydrogen exchange protein 3 (NHE3) and short-chain fatty acids (SCFAs) were determined using enzyme-linked immunosorbent assay (ELISA). The impact of F1 on the senna-induced SDD mouse models was evaluated by monitoring changes in the gut microbiota through 16S rRNA (V3-V4) sequencing. The results demonstrated that F1, a traditional Chinese medicine, effectively increased the body weight of SDD mice and reduced the incidence of diarrhea and diarrhea index. Additionally, F1 restored liver and kidney function, reduced the infiltration of inflammatory cells in intestinal tissue, and promoted the growth of intestinal villi. Furthermore, F1 was found to enhance the expression of NHE3 and SCFAs. It also increased the abundance of Firmicutes and Lactobacillus species, while decreasing the abundance of Proteobacteria and Shigella., 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 Wang, Li, Yang, Yang, Sun, Duan, Sun, Zhou, He and Dai.)

Polybrominated diphenyl ethers (PBDEs) are widely used brominated flame retardants, they are easily released into environment and causing adverse effects to the ecosystem and human health. This review aims to summarize the research status of PBDEs-induced male reproductive toxicity and its mechanisms at various levels such as molecular/cellular, tissue/organ and individual/population. The Adverse Outcome Pathways (AOPs) diagram showed that PBDEs-induced reactive oxygen species (ROS) production, disruptions of estrogen receptor-α (ERα) and antagonism of androgen receptor (AR) were defined as critical molecular initiating events (MIEs). They caused key events (KEs) at the molecular and cellular levels, including oxidative stress, increased DNA damage, damaging mitochondria, increased glycolipid levels and apoptosis, depletion of ectoplasmic specialization and decreased Leydig cells numbers. These in turn lead to followed KEs at the tissue or organ levels, such as the impaired spermatogenesis, impaired blood-testis barrier and reduced testosterone synthesis and function. As a result, reproductive system-related adverse outcomes (AOs) were reported, such as the decreased sperm quantity or quality, shorten male anogenital distance and cryptorchidism in individual and reduced reproduction of the population. This review assembled information on the mechanisms of male reproductive toxicity induced by PBDEs, and constructed a causal mechanism relationship diagram from different levels using the an AOP framework to provide theoretical basis for ecological risk assessment and environmental management of PBDEs. The AOP framework makes it possible to develop risk management strategies based on toxicity mechanisms and support for development of Integrated Approach to Testing and Assessment (IATA) which are available for regulatory purposes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Unsupervised Domain adaptation (UDA) aims to transfer knowledge from the labeled source domain to the unlabeled target domain. Most existing domain adaptation methods are based on convolutional neural networks (CNNs) to learn cross-domain invariant features. Inspired by the success of transformer architectures and their superiority to CNNs, we propose to combine the transformer with UDA to improve their generalization properties. In this paper, we present a novel model named Trans ferable V ector Q uantization A lignment for Unsupervised Domain Adaptation (TransVQA), which integrates the Transferable transformer-based feature extractor (Trans), vector quantization domain alignment (VQA), and mutual information weighted maximization confusion matrix (MIMC) of intra-class discrimination into a unified domain adaptation framework. First, TransVQA uses the transformer to extract more accurate features in different domains for classification. Second, TransVQA, based on the vector quantization alignment module, uses a two-step alignment method to align the extracted cross-domain features and solve the domain shift problem. The two-step alignment includes global alignment via vector quantization and intra-class local alignment via pseudo-labels. Third, for intra-class feature discrimination problem caused by the fuzzy alignment of different domains, we use the MIMC module to constrain the target domain output and increase the accuracy of pseudo-labels. The experiments on several datasets of domain adaptation show that TransVQA can achieve excellent performance and outperform existing state-of-the-art methods.

This was a prospective, randomized, double-blind, single-center placebo-controlled trial to assess the efficacy and safety of melatonin as an add-on treatment for infantile epileptic spasms syndrome (IESS). Participants aged 3 months to 2 years with a primary diagnosis of IESS were recruited and assigned to two groups in a 1:1 ratio. Both treatment groups received a combination of adrenocorticotrophic hormone (ACTH) and magnesium sulfate (MgSO 4 ) for 2 weeks, and the treatment group also received melatonin (3 mg) between 20:00 and 21:00 daily, 0.5-1 h before bedtime. The study's primary endpoint was the average reduction rate in spasm frequency assessed by seizure diaries. Secondary endpoints included assessment of the response rate, EEG hypsarrhythmia (Kramer score), and psychomotor development (Denver Developmental Screening Test, DDST). Sleep quality was assessed by using the Brief Infant Sleep Questionnaire (BISQ), the Infant Sleep Assessment Scale (ISAS), and actigraphy. Safety parameters were also evaluated. Statistical analyses were conducted on intention-to-treat and per-protocol populations. The trial is registered at Clinicaltrials.gov (ChiCTR2000036208). Out of 119 screened patients, 70 were randomized and 66 completed treatments. In the intention-to-treat population, there were no significant differences in the average percentage reduction of spasm frequency (median [interquartile range, IQR: Q3-Q1], 100% [46.7%] vs. 66.7% [55.3%], p = .288), the 3-day response rate (51.4% vs. 37.1%, p = .229), the 28-day response rate (42.9% vs. 28.6%, p = .212), EEG Kramer scores (2 [3.5] vs. 2 [3], p = .853), or DDST comprehensive months (5 [2.5] vs. 6 [6], p = .239) between the melatonin (n = 35) and placebo (n = 35) groups. However, caregivers reported improved sleep quality after melatonin treatment, with 85.7% reporting regular sleep compared to 42.9% with placebo (42.9%, p < .001). The melatonin group had lower ISAS scores in 4-11-month-old patients compared to the placebo (mean ± SD, 29.3 ± 4.4 vs. 35.2 ± 5.9, p < .001). Moreover, the median (IQR) value of sleep-onset latency was shortened by 6.0 (24.5) min after melatonin treatment, while that in the placebo group was extended by 3.0 (22.0) min (p = .030). The serum melatonin (6:00 h) level (pg/mL) of the children in the melatonin group after treatment was significantly higher than in the placebo group (median [IQR], 84.8 [142] vs. 17.5 [37.6], p < .001). No adverse effects related to melatonin were observed in the study, and there were no significant differences in adverse effects between the melatonin and placebo groups. Although not statistically significant, the results of this randomized clinical trial proved that melatonin supplementation, as an add-on treatment, can improve spasm control rate in the treatment of IESS. For IESS children treated with ACTH, the addition of melatonin was found to improve sleep quality, shorten sleep onset latency, and increase blood melatonin levels. Moreover, it was observed to be a safe treatment option., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The surface coatings of cereal plants are dominated by waxy β-diketones crucial for drought resistance and, therefore, grain yield. Here, barley (Hordeum vulgare) wax analyses reveal β-diketone and associated 2-alkanol ester profiles suggesting a common C 16 3-ketoacid precursor. Isotope analysis further shows that the major (C 31 ) diketone is synthesized from two plastidial C 16 acyl units. Previous studies identified a gene cluster encoding enzymes responsible for β-diketone formation in barley, but left their biochemical functions unknown. Various assays now characterize one of these enzymes as a thioesterase producing long-chain (mainly C 16 ) 3-ketoacids, and another one as a polyketide synthase (PKS) condensing the 3-ketoacids with long-chain (mainly C 16 ) acyl-CoAs into β-diketones. The two enzymes are localized to the plastids and Endoplasmic Reticulum (ER), respectively, implying substrate transfer between these two sub-cellular compartments. Overall, our findings define a two-step pathway involving an unprecedented PKS reaction leading directly to the β-diketone products., (© 2023. The Author(s).)

Background: Non-healing wounds are an intractable problem of major clinical relevance. Evidence has shown that dermal papilla cells (DPCs) may regulate the wound-healing process by secreting extracellular vesicles (EVs). However, low isolation efficiency and restricted cell viability hinder the applications of DPC-EVs in wound healing. In this study, we aimed to develop novel 3D-DPC spheroids (tdDPCs) based on self-feeder 3D culture and to evaluate the roles of tdDPC-EVs in stimulating angiogenesis and skin wound healing., Methods: To address the current limitations of DPC-EVs, we previously developed a self-feeder 3D culture method to construct tdDPCs. DPCs and tdDPCs were identified using immunofluorescence staining and flow cytometry. Subsequently, we extracted EVs from the cells and compared the effects of DPC-EVs and tdDPC-EVs on human umbilical vein endothelial cells (HUVECs) in vitro using immunofluorescence staining, a scratch-wound assay and a Transwell assay. We simultaneously established a murine model of full-thickness skin injury and evaluated the effects of DPC-EVs and tdDPC-EVs on wound-healing efficiency in vivo using laser Doppler, as well as hematoxylin and eosin, Masson, CD31 and α-SMA staining. To elucidate the underlying mechanism, we conducted RNA sequencing (RNA-seq) of tdDPC-EV- and phosphate-buffered saline-treated HUVECs. To validate the RNA-seq data, we constructed knockdown and overexpression vectors of Krüppel-like factor 4 (KLF4). Western blotting, a scratch-wound assay, a Transwell assay and a tubule-formation test were performed to detect the protein expression, cell migration and lumen-formation ability of KLF4 and vascular endothelial growth factor A (VEGFA) in HUVECs incubated with tdDPC-EVs after KLF4 knockdown or overexpression. Dual-luciferase reporter gene assays were conducted to verify the activation effect of KLF4 on VEGFA., Results: We successfully cultured tdDPCs and extracted EVs from DPCs and tdDPCs. The tdDPC-EVs significantly promoted the proliferation, lumen formation and migration of HUVECs. Unlike DPC-EVs, tdDPC-EVs exhibited significant advantages in terms of promoting angiogenesis, accelerating wound healing and enhancing wound-healing efficiency both in vitro and in vivo . Bioinformatics analysis and further functional experiments verified that the tdDPC-EV-regulated KLF4/VEGFA axis is pivotal in accelerating wound healing., Conclusions: 3D cultivation can be utilized as an innovative optimization strategy to effectively develop DPC-derived EVs for the treatment of skin wounds. tdDPC-EVs significantly enhance wound healing via KLF4/VEGFA-driven angiogenesis., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press.)

Syntheses of highly functionalized 4-alkylated 1,4-dihydropyridines (1,4-DHPs) from cyclic ethers and enaminones via iron(II)-mediated oxidative free radical cascade C(sp 3 )-H bond functionalization/C(sp 3 )-O bond cleavage/cyclization reaction have been first developed. This novel synthetic strategy offers an alternative method for the construction of 1,4-DHPs by using esters as the C4 sources, as well as expands the application of ethers in heterocycle synthesis.

An Fe-mediated four-component reaction of enaminones, anhydrides and tetrahydrofuran through a cascade [1 + 2 + 3]-cyclization/esterification process is presented. This protocol provides a new and effective method to construct 4-alkylated 1,4-dihydropyridines with an ester fragment. Cyclic ether is employed as the C4 source of 1,4-dihydropyridines for the first time.

Background: Circulating tumor cells (CTCs), an indispensable liquid biopsy classifier, can provide extra information for the diagnosis and prognosis of hepatocellular carcinoma (HCC)., Methods: We systematically analyzed the peripheral blood of preoperative HCC patients (n = 270) for CTC number, Ki67 index reflecting the proliferative CTC percentage (PCP), and CTC clusters correlated with the characteristics of malignant HCC tumors., Results: Driver gene mutations were found with high levels of consistency between CTCs and primary tumors (n = 73). CTC number and PCP were associated with tumor size, microvascular invasion (MVI), presence or absence of multiple tumors, and thrombosis significantly. CTC number and PCP robustly separated patients with and without relapse, with a sensitivity of 88.89%/81.48% and a specificity of 72.73%/94.81% in the training set (n = 104) and corresponding values of 80.00%/86.67% and 78.38%/89.19% in the validation set (n = 52), showing a better performance than that associated with the alpha-fetoprotein (AFP) level. CTC number, PCP, CTC clusters, and MVI were independent significant risk factors for HCC recurrence (P = 0.0375, P < 0.0001, P = 0.0017, and P = 0.0157). A nomogram model based on these risk factors showed a considerable prediction ability for HCC recurrence (area under the curve = 0.947). PCP (training: log-rank P < 0.0001; hazard ratio [HR] 30.13, 95% confidence interval [CI] = 11.12-81.62; validation: log-rank P < 0.0001; HR 25.73, 95% CI = 5.28-106.60) and CTC clusters (training: log-rank P < 0.0001; HR 17.34, 95% CI = 7.46-40.30; validation: log-rank P < 0.0001; HR 9.92, 95% CI = 2.55-38.58) were more significantly correlated with worse recurrence-free survival than CTC number (training: log-rank P < 0.0001; HR 14.93, 95% CI = 4.48-49.78; validation: log-rank P = 0.0007; HR 9.03, 95% CI = 2.53-32.24)., Conclusion: PCP and CTC clusters may predict HCC recurrence and improve the performance of the serum biomarker AFP., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

An inexpensive and efficient aminoguanidine-catalyzed reductive cyclization of o -phenylenediamines with CO 2 in the presence of triethoxysilane is described. Various functionalized benzimidazoles, benzoxazole, and benzothiazole were synthesized in high yields. Mechanistic studies indicate that formic acid as a cocatalyst promotes the cyclization reaction.

Using benzylamines as the C4 source of 1,4-dihydropyridines (1,4-DHPs), a Cu-catalyzed oxidative [1+2+1+2] cascade cyclization for the synthesis of 1,4-DHPs was firstly developed. A broad range of easily available N,N-dimethyl enaminones and benzylamines are employed smoothly to provide a diverse range of 1,4-DHPs with high efficiency. This method is performed by a one-pot cascade C(sp 3 )-H bond functionalization/C(sp 3 )-N cleavage/cyclization strategy to form simultaneously two C(sp 3 )-C(sp 2 ) bonds, two C(sp 2 )-N bonds, and a 1,4-DHP ring., (© 2023 Wiley-VCH GmbH.)

Although estrogen is predominantly related to the maintenance of reproductive functioning in females, it mediates various physiological effects in nearly all tissues, especially the central nervous system. Clinical trials have revealed that estrogen, especially 17β-estradiol, can attenuate cerebral damage caused by an ischemic stroke. One mechanism underlying this effect of 17β-estradiol is by modulating the responses of immune cells, indicating its utility as a novel therapeutic strategy for ischemic stroke. The present review summarizes the effect of sex on ischemic stroke progression, the role of estrogen as an immunomodulator in immune reactions, and the potential clinical value of estrogen replacement therapy. The data presented here will help better understand the immunomodulatory function of estrogen and may provide a basis for its novel therapeutic use in ischemic stroke., 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 Zhong, Sun, Lu and Xu.)

Chronic kidney disease (CKD) is a disease with decreased, irreversible renal function. Pruritus is the most common skin symptom in patients with CKD, especially in end-stage renal disease. The underlying molecular and neural mechanism of CKD-associated pruritus (CKD-aP) remains obscure. Our data show that the level of allantoin increases in the serum of CKD-aP and CKD model mice. Allantoin could induce scratching behavior in mice and active DRG neurons. The calcium influx and action potential reduced significantly in DRG neurons of MrgprD KO or TRPV1 KO mice. U73122, an antagonist of phospholipase C, could also block calcium influx in DRG neurons induced by allantoin. Thus, our results concluded that allantoin plays an important role in CKD-aP, mediated by MrgprD and TrpV1, in CKD patients., (© 2023 Wiley Periodicals LLC.)

Background: Symbiotic bacteria affect physiology and ecology of insect hosts. The Sitobion miscanthi L type symbiont (SMLS) is a recently discovered and widely distributed secondary symbiont in the grain aphid Sitobion miscanthi Takahashi in China., Results: In this study, SMLS-infected (SI) and SMLS-uninfected (SU) aphid strains were obtained from field population. The artificially SMLS-re-infected (SRI) strain was established by injecting SU aphids with the SI strain hemolymph containing SMLS. The SRI and SU strains had identical genetic backgrounds and similar microbial community structures. Compared with the SU strain, adult longevity, survival rate, and fecundity were significantly greater in the SRI strain (biological fitness of 1.48). Moreover, the SRI strain spent more time ingesting phloem than the SU strain. A comparative transcriptome analysis indicated that reproduction- and longevity-related genes were more highly expressed in the SRI strain than in the SU strain., Conclusion: The findings indicated that the infection with SMLS enhanced the Sitobion miscanthi fitness and feeding behavior. The beneficial effect of the SMLS on hosts could explain why it frequently infects the field populations in the grain aphid Sitobion miscanthi Takahashi in China. © 2022 Society of Chemical Industry., (© 2022 Society of Chemical Industry.)

Objective. Patient-dependent seizure detection based on intracranial electroencephalography (iEEG) has made significant progress. However, due to the difference in the locations and number of iEEG electrodes used for each patient, patient-independent seizure detection based on iEEG has not been carried out. Additionally, current seizure detection algorithms based on deep learning have outperformed traditional machine learning algorithms in many performance metrics. However, they still have shortcomings of large memory footprints and slow inference speed. Approach. To solve the above problems of the current study, we propose a novel lightweight convolutional neural network model combining the Convolutional Block Attention Module (CBAM). Its performance for patient-independent seizure detection is evaluated on two long-term continuous iEEG datasets: SWEC-ETHZ and TJU-HH. Finally, we reproduce four other patient-independent methods to compare with our method and calculate the memory footprints and inference speed for all methods. Main results. Our method achieves 83.81% sensitivity (SEN) and 85.4% specificity (SPE) on the SWEC-ETHZ dataset and 86.63% SEN and 92.21% SPE on the TJU-HH dataset. In particular, it takes only 11 ms to infer 10 min iEEG (128 channels), and its memory footprint is only 22 kB. Compared to baseline methods, our method not only achieves better patient-independent seizure detection performance but also has a smaller memory footprint and faster inference speed. Significance. To our knowledge, this is the first iEEG-based patient-independent seizure detection study. This facilitates the application of seizure detection algorithms to the future clinic., (© 2023 IOP Publishing Ltd.)

Background: Emerging evidence indicates that myristoylated alanine-rich C kinase substrate like 1 (MARCKSL1) is involved in the progression of esophageal squamous cell carcinoma (ESCC). However, the underpinning mechanism is unclear. Here, we investigated the mechanisms involving MARCKSL1 in ESCC progression., Methods: CCK8, Transwell and wound-healing assays were employed to test the effect of MARCKSL1 on proliferation, invasion and migration in vitro. Next, transcriptome profiling was conducted through RNA sequencing to reveal the underlying mechanism of MARCKSL1 in ESCC progression, which was subsequently verified by western blot and qPCR analysis. Moreover, immunofluorescence and gelatin degradation assays were performed to reveal the ability of MARCKSL1 to mediate invadopodia formation and extracellular matrix (ECM) degradation. Finally, the correlation between MARCKSL1 and the clinicopathological features of ESCC patients was assessed based on TCGA database analysis and immunohistochemistry staining of tissue microarrays., Results: Knockdown of MARCKSL1 markedly attenuated the cell motility capacity of ESCC cells in vitro, while MARCKSL1 overexpression had the opposite effect. Transcriptomic analysis showed that MARCKSL1 mediated the mobility and migration of ESCC cells. In addition, overexpression of MARCKSL1 increased the colocalization of F-actin and cortactin at the frontier edge of migrating cells and ECM degradation. Furthermore, in ESCC patients, the mRNA level of MARCKSL1 in esophageal carcinomas (n = 182) was found to be notably higher than that in adjacent esophageal epithelia (n = 286) and the expression levels of MARCKSL1 in the tumor tissues (n = 811) were significantly increased compared to those in noncancerous esophageal tissues (n = 442) with a large sample size. Higher expression of MARCKSL1 was positively correlated with lymph node metastasis and associated with worse survival rates of patients with ESCC., Conclusion: MARCKSL1 promotes cell migration and invasion by interacting with F-actin and cortactin to regulate invadopodia formation and ECM degeneration. High MARCKSL1 expression is positively correlated with poor prognosis in ESCC patients with lymph node metastasis., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: To observe the characteristics of suction loss in small-incision lenticule extraction (SMILE) and analyze the factors affecting the stability of the suction ring, classify and grade suction loss, and determine the principles for its prevention and control., Methods: This study enrolled patients who underwent SMILE between June 2014 and June 2017. The relationship between the stability of the suction ring and suction loss was ascertained using surgical records and video recordings. The suction loss was classified and graded according to its characteristics and relationship with eye or head movement. The effect of target intervention on suction loss was observed., Results: Suction loss can be divided into sudden and progressive types. According to the severity, the latter was divided into three grades (grade 1A or 1B, 2 and 3). Of the 1200 eyes (608 patients), two (0.17%) had sudden suction loss, and 132 (11%) had progressive suction loss. The superior part, inferior part, and other parts accounted for 63.4%, 19.3%, and 17.3% of progressive suction loss, respectively. The proportion of grades 1A, 1B, 2, and 3 suction loss was 53%, 34%, 12%, and 1%, respectively. The location of the threatened suction loss was opposite to the direction of the patient's head movement. After the intraoperative intervention, grades 1 and 2 did not develop into "actual" suction loss., Conclusions: Progressive suction loss was the most frequently observed suction loss during SMILE procedure. Grading suction loss can elucidate its underlying mechanism, which can guide targeted intervention measures to effectively control and reduce suction loss-induced damage, and further improve the safety and efficacy of SMILE., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Esophageal squamous cell carcinoma (ESCC) is one of the fatal malignancies worldwide. It has an increased propensity to metastasize via lymphogenous routes in an early stage. The prognosis of patients with lymph node metastases (LNM) is often worse than that of patients without metastases. Although several factors have been found to influence metastasis, the mechanisms of preference for specific metastatic routes remain poorly understood. Herein, we provide evidence that the intrinsic hypersensitivity of tumor cells to ferroptosis may proactively drive lymphatic metastasis. Serum autoantibodies associated with LNM of early ESCC were screened using a whole-proteome protein array containing 19 394 human recombinant proteins, and an anti-BACH1 autoantibody was first identified. Pan-cancer analysis of ferroptosis-related genes with preferential lymphatic metastasis and preferential hematogenous metastasis based on The Cancer Genome Atlas data was performed. Only BACH1 showed significant overexpression in tumors with preferential lymphatic metastasis, whereas it was downregulated in most tumors with preferential nonlymphatic metastasis. In addition, it was found that the serum levels of autoantibodies against BACH1 were elevated in early-stage patients with LNM. Interestingly, BACH1 overexpression and ferroptosis induction promoted LNM but inhibited hematogenous metastasis in mouse models. Transcriptomic and lipidomic analyses found that BACH1 repressed SCD1-mediated biosynthesis of monounsaturated fatty acids, especially oleic acid (OA). OA significantly attenuated the ferroptotic phenotypes and reversed the metastatic properties of BACH1-overexpressing cells. OA addition significantly rescued the ferroptotic phenotypes and reversed the metastatic properties of BACH1-overexpressing cells. Importantly, the concentration gradient of OA between primary lesions and the lymph resulted in the chemoattraction of tumor cells to promote invasion, thus facilitating lymphatic metastasis. BACH1-induced ferroptosis drives lymphatic metastasis via the BACH1-SCD1-OA axis. More importantly, this study confirms that ferroptosis is a double-edged sword in tumorigenesis and tumor progression. The clinical application of ferroptosis-associated agents requires a great caution., (© 2023. The Author(s).)

Sulfoxaflor belongs to a new class of insecticides that is effective against many sap-feeding pests. In this study on Sitobion miscanthi (Takahashi) (i.e., the predominant wheat pest), a highly sulfoxaflor-resistant (SulR) population was obtained from a field. Its resistance to the other seven insecticides and its biological fitness were analyzed using a leaf-dip method and a two-sex life table approach, respectively. Compared with the relatively susceptible (SS) population, the SulR population was highly resistant to sulfoxaflor, with a relative insecticide resistance ratio (RR) of 199.8 and was moderately resistant to beta-cypermethrin (RR = 14.5) and bifenthrin (RR = 42.1) but exhibited low resistance to chlorpyrifos (RR = 5.7). Additionally, the SulR population had a relative fitness of 0.73, with a significantly prolonged developmental period as well as a lower survival rate and poorer reproductive performance than the SS population. In conclusion, our results suggest that S . miscanthi populations that are highly resistant to sulfoxaflor exist in the field. The possibility that insects may develop multi-resistance between sulfoxaflor and pyrethroids is a concern. Furthermore, the high sulfoxaflor resistance of S . miscanthi was accompanied by a considerable fitness cost. The study data may be useful for improving the rational use of insecticides and for exploring novel insecticide resistance mechanisms.

Infiltration by adipose tissue macrophages (ATMs) and subsequent metabolic inflammation are the key causes of obesity-induced insulin resistance and metabolic disorders. In this study, we analyzed the potential protective effect of tangeretin, a key flavonoid found extensively in citrus peels, against diet-induced metabolic inflammation. Daily gavages of tangeretin at 20 mg/kg protected the mice from high fat diet (HFD) feeding-induced insulin resistance, ATMs activation, and M1 macrophage polarization. Interestingly, in vitro assays using bone marrow-derived macrophages (BMDMs) showed that tangeretin had only a minimal effect on macrophage polarization. Assays of central carbon metabolism (CCM) in adipose tissue showed that tangeretin treatment rerouted the carbon metabolism and caused lactate accumulation in the microenvironment. Co-culture assays further suggested that tangeretin enhanced M2 polarization of BMDMs when adipocytes were present, whereas blocking the lactate uptake in macrophages reversed the effect of tangeretin on polarization. Taken together, these findings indicated that tangeretin provided indirect protection from diet-induced ATMs activation by reprogramming glucose metabolism and promoting lactate accumulation that subsequently promoted macrophage M2 polarization and reduced inflammation., Competing Interests: Declaration of competing interest None, (Copyright © 2022 Elsevier Inc. All rights reserved.)

Automatic seizure detection algorithms are necessary for patients with refractory epilepsy. Many excellent algorithms have achieved good results in seizure detection. Still, most of them are based on discontinuous intracranial electroencephalogram (iEEG) and ignore the impact of different channels on detection. This study aimed to evaluate the proposed algorithm using continuous, long-term iEEG to show its applicability in clinical routine. In this study, we introduced the ability of the transformer network to calculate the attention between the channels of input signals into seizure detection. We proposed an end-to-end model that included convolution and transformer layers. The model did not need feature engineering or format transformation of the original multi-channel time series. Through evaluation on two datasets, we demonstrated experimentally that the transformer layer could improve the performance of the seizure detection algorithm. For the SWEC-ETHZ iEEG dataset, we achieved 97.5% event-based sensitivity, 0.06/h FDR, and 13.7 s latency. For the TJU-HH iEEG dataset, we achieved 98.1% event-based sensitivity, 0.22/h FDR, and 9.9 s latency. In addition, statistics showed that the model allocated more attention to the channels close to the seizure onset zone within 20 s after the seizure onset, which improved the explainability of the model. This paper provides a new method to improve the performance and explainability of automatic seizure detection.

Currently, there is an urgent need to develop functional nanomaterials for highly effective environmental remediation. However, the long-term effect of remedial materials upon their injection into contaminated aquifer has frequently been overlooked. Here, the remediation of Cr(VI) contaminated aquifer by reduced graphene oxide (rGO) supported nanoscale zero-valent iron (nZVI@rGO) was investigated from a long-term perspective. The performances of nZVI@rGO samples with different rGO loadings in the removal of aqueous Cr(VI) were evaluated in batch experiments. The electron transfer properties different nZVI@rGO samples were investigated by measuring their corrosive potentials using the steady-state Tafel polarization curves. The results show that the electron transfer efficiency between Cr(VI) and nZVI@rGO is enhanced owing to the large reactive conjugated structure of rGO. Besides, the surface passivation of nZVI is effectively retarded due to the uniform accommodation of Cr(III) precipitates on rGO. The structure and composition of nZVI@rGO before and after Cr(VI) removal were analyzed by scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The characterization results revealed that most Cr(VI) ions (∼90%) will be reduced to Cr(III) precipitates on nZVI@rGO as the passivation product. Accordingly, Cr(VI) ions tend to react more readily at less blocked regions on the surface of rGO, and a layer-by-layer passivation model on nZVI@rGO surface is proposed. Our results provide new insights into the mechanism underlying the long-term remediation of Cr(VI) contaminated aquifer using nZVI@rGO, which helps design new materials and approaches for practical in-situ remediation engineering., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cuticular waxes cover the aerial surfaces of land plants and protect them from various environmental stresses. Alkanes are major wax components and contribute to plant drought tolerance, but the biosynthesis and regulation of alkanes remain largely unknown in wheat (Triticum aestivum L.). Here, we identified and functionally characterized a key alkane biosynthesis gene ECERIFERUM1-6A (TaCER1-6A) from wheat. The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated knockout mutation in TaCER1-6A greatly reduced the contents of C27, C29, C31, and C33 alkanes in wheat leaves, while TaCER1-6A overexpression significantly increased the contents of these alkanes in wheat leaves, suggesting that TaCER1-6A is specifically involved in the biosynthesis of C27, C29, C31, and C33 alkanes on wheat leaf surfaces. TaCER1-6A knockout lines exhibited increased cuticle permeability and reduced drought tolerance, whereas TaCER1-6A overexpression lines displayed reduced cuticle permeability and enhanced drought tolerance. TaCER1-6A was highly expressed in flag leaf blades and seedling leaf blades and could respond to abiotic stresses and abscisic acid. TaCER1-6A was located in the endoplasmic reticulum, which is the subcellular compartment responsible for wax biosynthesis. A total of three haplotypes (HapI/II/III) of TaCER1-6A were identified in 43 wheat accessions, and HapI was the dominant haplotype (95%) in these wheat varieties. Additionally, we identified two R2R3-MYB transcription factors TaMYB96-2D and TaMYB96-5D that bound directly to the conserved motif CAACCA in promoters of the cuticular wax biosynthesis genes TaCER1-6A, TaCER1-1A, and fatty acyl-CoA reductase4. Collectively, these results suggest that TaCER1-6A is required for C27, C29, C31, and C33 alkanes biosynthesis and improves drought tolerance in wheat., (© American Society of Plant Biologists 2022. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

A transition-metal-free method for the construction of 3-substituted or 3,4-disubstituted quinolines from readily available N , N -dimethyl enaminones and o -aminobenzyl alcohols is reported. The direct oxidative cyclocondensation reaction tolerates broad functional groups, allowing the efficient synthesis of various quinolines in moderate to excellent yields. The reaction involves a C (sp 3 )-O bond cleavage and a C=N bind and a C=C bond formation during the oxidative cyclization process, and the mechanism was proposed., 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 Rao, Chai, Zhou, Liu, Sun and Yu.)

Esophageal squamous cell carcinoma (ESCC) is one of the most fatal malignancies worldwide. Recently, our group identified purine-rich element binding protein alpha (PURα), a single-stranded DNA/RNA-binding protein, to be significantly associated with the progression of ESCC. Additional immunofluorescence staining demonstrated that PURα forms cytoplasmic stress granules to suppress mRNA translation initiation. The expression level of cytoplasmic PURα in ESCC tumor tissues was significantly higher than that in adjacent epithelia and correlated with a worse patient survival rate by immunohistochemistry. Functionally, PURα strongly preferred to bind to UG-/U-rich motifs and mRNA 3´UTR by CLIP-seq analysis. Moreover, PURα knockout significantly increased the protein level of insulin-like growth factor binding protein 3 (IGFBP3). In addition, it was further demonstrated that PURα-interacting proteins are remarkably associated with translation initiation factors and ribosome-related proteins and that PURα regulates protein expression by interacting with translation initiation factors, such as PABPC1, eIF3B and eIF3F, in an RNA-independent manner, while the interaction with ribosome-related proteins is significantly dependent on RNA. Specifically, PURα was shown to interact with the mRNA 3´UTR of IGFBP3 and inhibit its expression by suppressing mRNA translation initiation. Together, this study identifies cytoplasmic PURα as a modulator of IGFBP3, which could be a promising therapeutic target for ESCC treatment., (© 2022. The Author(s).)

Spinal cord injury (SCI) is a devastating trauma characterized by serious neuroinflammation and permanent neurological dysfunction. However, the molecular mechanism of SCI remains unclear, and few effective medical therapies are available at present. In this study, multiple bioinformatics methods were used to screen out novel targets for SCI, and the mechanism of these candidates during the progression of neuroinflammation as well as the therapeutic effects were both verified in a rat model of traumatic SCI. As a result, CASP4, IGSF6 and IL1R1 were identified as the potential diagnostic and therapeutic targets for SCI by computational analysis, which were enriched in NF-κB and IL6-JAK-STATA3 signaling pathways. In the injured spinal cord, these three signatures were up-regulated and closely correlated with NLRP3 inflammasome formation and gasdermin D (GSDMD) -induced pyroptosis. Intrathecal injection of inhibitors of IL1R1 or CASP4 improved the functional recovery of SCI rats and decreased the expression of these targets and inflammasome component proteins, such as NLRP3 and GSDMD. This treatment also inhibited the pp65 activation into the nucleus and apoptosis progression. In conclusion, our findings of the three targets shed new light on the pathogenesis of SCI, and the use of immunosuppressive agents targeting these proteins exerted anti-inflammatory effects against spinal cord inflammation by inhibiting NF-kB and NLRP3 inflammasome activation, thus blocking GSDMD -induced pyroptosis and immune activation., 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 handling editor declared a shared parent affiliation with the authors at the time of review., (Copyright © 2022 Wang, Ma, Zhang, Hua, Wang, Wang, Han, Li, Wu, Sun, Yang and Lu.)

Both tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and nicotine can be metabolized by cytochrome P450 2A13 (CYP2A13). Previous studies have shown that nicotine has a potential inhibitory effect on the toxicity of NNK. However, due to the lack of CYP2A13 activity in conventional lung cell lines, there had been no systematic in vitro investigation for the key target organ, the lung. Here, BEAS-2B cells stably expressing CYP2A13 (B-2A13 cells) were constructed to investigate the effects of nicotine on the cytotoxicity and genotoxicity of NNK. The results showed more sensitivity for NNK-induced cytotoxicity in B-2A13 cells than in BEAS-2B and B-vector cells. NNK significantly induced DNA damage, cell cycle arrest, and chromosomal damage in B-2A13 cells, but had no significant effect on BEAS-2B cells and the vector control cells. The combination of different concentration gradient of nicotine without cytotoxic effects and a single concentration of NNK reduced or even counteracted the cytotoxicity and multi-dimensional genotoxicity in a dose-dependent manner. In conclusion, CYP2A13 caused the cytotoxicity and genotoxicity of NNK in BEAS-2B cells, and the addition of nicotine could inhibit the toxicity of NNK.

Introduction: Infantile spasms (IS) is a type of severe epileptic encephalopathy that occurs in infancy and early childhood. IS is characterised clinically by epileptic spasms, often accompanied by sleep disorder and abnormal circadian rhythm. The endogenous circadian rhythm disorder, in turn, can make spasms worse. Melatonin has also been found to have anticonvulsant and neuroprotective properties by adjusting the circadian rhythm. However, there are lack of relevant studies on controlling IS by using melatonin. This study aims to analyse the therapeutic effect of melatonin supplementation for the treatment of IS., Methods and Analysis: This is a triple-blinded (trial participant, outcome assessor and the data analyst), prospective, randomised controlled trial to be conducted in the Department of Paediatrics, The First Medical Center of Chinese PLA General Hospital, Beijing, China from November 2020. Patients (n=70) aged 3 months to 2 years with IS will be recruited in this study after receiving written consent from their parents or guardians. Patients will be randomly divided into two equal groups and treated with a combination of adrenocorticotropic hormone, magnesium sulfate and either melatonin or placebo. Clinical data from the patients in the two groups before and after the treatment will be collected and compared. The primary outcome will be assessed 2 weeks later by seizure diaries and reported as the average reduced rate of spasms frequency. Secondary outcomes include the response rate (the rate of spasms-free), electroencephalogram hypsarrhythmia assessment and the psychomotor development assessment (Denver Developmental Screening Test). Sleep quality and safety will also be assessed., Ethics and Dissemination: The protocol for this study was approved by the Ethics Committee of Chinese PLA General Hospital (reference number S2020-337-01) and was reported according to the Standard Protocol Items: Recommendations for Interventional Trials statement. Findings of this research will be disseminated through national and international meetings, conferences and peer-reviewed journals., Trial Registration Number: ChiCTR2000036208., Competing Interests: Competing interests: By partnership agreement, Timage Natural Bioengineering (Beijing, China) donated all melatonin study preparations. Dr Tianming Li is responsible for the formulation of the placebo and melatonin preparation; however, neither Dr Tianming Li, nor Timage Natural Bioengineering had any input into other aspects of study design, and will have no involvement in analysis or interpretation of results. The authors declare no conflict of interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Detection of mild cognitive impairment (MCI) is essential to screen high risk of Alzheimer's disease (AD). However, subtle changes during MCI make it challenging to classify in machine learning. The previous pathological analysis pointed out that the hippocampus is the critical hub for the white matter (WM) network of MCI. Damage to the white matter pathways around the hippocampus is the main cause of memory decline in MCI. Therefore, it is vital to biologically extract features from the WM network driven by hippocampus-related regions to improve classification performance., Methods: Our study proposes a method for feature extraction of the whole-brain WM network. First, 42 MCI and 54 normal control (NC) subjects were recruited using diffusion tensor imaging (DTI), resting-state functional magnetic resonance imaging (rs-fMRI), and T1-weighted (T1w) imaging. Second, mean diffusivity (MD) and fractional anisotropy (FA) were calculated from DTI, and the whole-brain WM networks were obtained. Third, regions of interest (ROIs) with significant functional connectivity to the hippocampus were selected for feature extraction, and the hippocampus (HIP)-related WM networks were obtained. Furthermore, the rank sum test with Bonferroni correction was used to retain significantly different connectivity between MCI and NC, and significant HIP-related WM networks were obtained. Finally, the classification performances of these three WM networks were compared to select the optimal feature and classifier., Results: (1) For the features, the whole-brain WM network, HIP-related WM network, and significant HIP-related WM network are significantly improved in turn. Also, the accuracy of MD networks as features is better than FA. (2) For the classification algorithm, the support vector machine (SVM) classifier with radial basis function, taking the significant HIP-related WM network in MD as a feature, has the optimal classification performance (accuracy = 89.4%, AUC = 0.954). (3) For the pathologic mechanism, the hippocampus and thalamus are crucial hubs of the WM network for MCI., Conclusion: Feature extraction from the WM network driven by hippocampus-related regions provides an effective method for the early diagnosis of AD., 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 Zhou, Si, Chao, Chen, Lin, Li, Zhang, Sun, Ming and Li.)

Currently, imaging, fecal immunochemical tests (FITs) and serum carcinoembryonic antigen (CEA) tests are not adequate for the early detection and evaluation of metastasis and recurrence in colorectal cancer (CRC). To comprehensively identify and validate more accurate noninvasive biomarkers in urine, we implement a staged discovery-verification-validation pipeline in 657 urine and 993 tissue samples from healthy controls and CRC patients with a distinct metastatic risk. The generated diagnostic signature combined with the FIT test reveals a significantly increased sensitivity (+21.2% in the training set, +43.7% in the validation set) compared to FIT alone. Moreover, the generated metastatic signature for risk stratification correctly predicts over 50% of CEA-negative metastatic patients. The tissue validation shows that elevated urinary protein biomarkers reflect their alterations in tissue. Here, we show promising urinary protein signatures and provide potential interventional targets to reliably detect CRC, although further multi-center external validation is needed to generalize the findings., (© 2022. The Author(s).)

Spinal cord injury (SCI) results from various pathogenic factors that destroy the normal structure and function of the spinal cord, subsequently causing sensory, motor, and autonomic nerve dysfunction. SCI is one of the most common causes of disability and death globally. It leads to severe physical and mental injury to patients and causes a substantial economic burden on families and the society. The pathological changes and underlying mechanisms within SCI involve oxidative stress, apoptosis, inflammation, etc. As a traditional therapy, acupuncture has a positive effect promoting the recovery of SCI. Acupuncture-induced neuroprotection includes several mechanisms such as reducing oxidative stress, inhibiting the inflammatory response and neuronal apoptosis, alleviating glial scar formation, promoting neural stem cell differentiation, and improving microcirculation within the injured area. Therefore, the recent studies exploring the mechanism of acupuncture therapy in SCI will help provide a theoretical basis for applying acupuncture and seeking a better treatment target and acupuncture approach for SCI patients., 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 Jiang, Sun and Chen.)

Exercise preconditioning has attracted extensive attention to induce endogenous neuroprotection and has become the hotspot in neurotherapy. The training exercise is given multiple times before cerebral ischemia, effectively inducing ischemic tolerance and alleviating secondary brain damage post-stroke. Compared with other preconditioning methods, the main advantages of exercise include easy clinical operation and being readily accepted by patients. However, the specific mechanism behind exercise preconditioning to ameliorate brain injury is complex. It involves multi-pathway and multi-target regulation, including regulation of inflammatory response, oxidative stress, apoptosis inhibition, and neurogenesis promotion. The current review summarizes the recent studies on the mechanism of neuroprotection induced by exercise, providing the theoretical basis of applying exercise therapy to prevent and treat ischemic stroke. In addition, we highlight the various limitations and future challenges of translational medicine from fundamental study to clinical application., 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 Zhu, Sun, Hu and Pan.)

The pancreatic ductal adenocarcinoma (PDAC) microenvironment contains dense desmoplastic stroma dominated by cancer-associated fibroblasts (CAFs) and is crucial to cancer development and progression. Several studies have revealed that thrombospondin 2 (THBS2) is a valuable serological-marker in PDAC. However, the detailed mechanism of the cancer-stroma interactome remains unclear. Here we showed that elevated THBS2 expression in PDAC was predominantly restricted to stroma and correlated with tumor progression and poor prognosis by quantitative proteomics and immunohistochemistry analyses. RNA in situ hybridization confirmed that CAFs but not neoplastic cells expressed THBS2 in precancerous lesions and its levels gradually increased with disease progression in genetically engineered mouse models. Mechanistically, cancer cell-secreted TGF-β1 activated CAFs to induce THBS2 expression via the p-Smad2/3 pathway. Consequently, CAF-derived THBS2 bound to the membrane receptors integrin α v β 3 /CD36 and activated the MAPK pathway in PDAC cells to promote tumor growth and adhesion in vitro and in vivo. Inhibition of integrin α v β 3 , CD36, MEK and JNK rescued THBS2-induced malignant phenotypes. In conclusion, the TGF-β1-THBS2-integrin α v β 3 /CD36-MAPK cascade forms a complex feedback circuit to mediate reciprocal interactions of pancreatic cancer cells-CAFs. THBS2 may act as a novel therapeutic-target to block the cancer-stroma communication., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The crude polysaccharides (NLCEP) were extracted from Notarchus leachii freeri eggs strings by the saltextractionmethod. The extraction conditions were optimized using the single-factorexperimentmethod and response surface method (RSM). The results showed that the maximum extraction yield of NLCEP was obtained under the following conditions: NaCl solution concentration of 2.96 %, raw material to liquid ratio of 1: 40 g/mL, extraction time of 2 h and extraction temperature of 69 °C. A new novel pure polysaccharide fraction named as NLCEPs-1 was fractionated from NLCEP by using DEAE-Cellulose 52 and Sephadex G-100. Its structure and immunomodulatory and antioxidant activities were analyzed. The results exhibited that the molecular weight of NLCEPs-1 was 31.4 kDa and it was composed of rhamnose, glucose, galactose, xylose and arabinose in the molar percentage of 11.128: 63.770: 5.439: 6.585: 13.077. The backbone of NLCEPs-1 was mainly consisted of → )4-α-d-Glcp (1→, →6)-α-d-Glcp (1→, →1)-β-d-Galp and β-d-Galp-(1→. NLCEPs-1 exhibited the strong antioxidant activity in scavenging ability of various free radicals and immunomodulatory activity by the enhancement of the pinocytic capacity, nitric oxide (NO) and cytokines., (Copyright © 2021. Published by Elsevier Inc.)

Sorafenib and lenvatinib are approved first-line targeted therapies for advanced liver cancer, but most patients develop acquired resistance. Herein, we found that sorafenib induced extensive acetylation changes towards a more energetic metabolic phenotype. Metabolic adaptation was mediated via acetylation of the Lys-491 (K491) residue of phosphoenolpyruvate carboxykinase isoform 2 (PCK2) (PCK2-K491) and Lys-473 (K473) residue of PCK1 (PCK1-K473) by the lysine acetyltransferase 8 (KAT8), resulting in isoenzyme transition from cytoplasmic PCK1 to mitochondrial PCK2. KAT8-catalyzed PCK2 acetylation at K491 impeded lysosomal degradation to increase the level of PCK2 in resistant cells. PCK2 inhibition in sorafenib-resistant cells significantly reversed drug resistance in vitro and in vivo. High levels of PCK2 predicted a shorter progression-free survival time in patients who received sorafenib treatment. Therefore, acetylation-induced isoenzyme transition from PCK1 to PCK2 contributes to resistance to systemic therapeutic drugs in liver cancer. PCK2 may be an emerging target for delaying tumor recurrence., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective . By detecting abnormal white matter changes, diffusion magnetic resonance imaging (MRI) contributes to the detection of juvenile myoclonic epilepsy (JME). In addition, deep learning has greatly improved the detection performance of various brain disorders. However, there is almost no previous study effectively detecting JME by a deep learning approach with diffusion MRI. Approach . In this study, the white matter structural connectivity was generated by tracking the white matter fibers in detail based on Q-ball imaging and neurite orientation dispersion and density imaging. Four advanced deep convolutional neural networks (CNNs) were deployed by using the transfer learning approach, in which the transfer rate searching strategy was proposed to achieve the best detection performance. Main results . Our results showed: (a) Compared to normal control, the white matter' neurite density of JME was significantly decreased. The most significantly abnormal fiber tracts between the two groups were found to be cortico-cortical connection tracts. (b) The proposed transfer rate searching approach contributed to find each CNN's best performance, in which the best JME detection accuracy of 92.2% was achieved by using the Inception&#95;resnet&#95;v2 network with a 16% transfer rate. Significance . The results revealed: (a) Through detection of the abnormal white matter changes, the white matter structural connectivity can be used as a useful biomarker for detecting JME, which helps to characterize the pathophysiology of epilepsy. (b) The proposed transfer rate, as a new hyperparameter, promotes the CNNs transfer learning performance in detecting JME., (© 2021 IOP Publishing Ltd.)

The electroencephalography (EEG) microstate has recently emerged as a new whole-brain mapping tool for studying the temporal dynamics of the human brain. Meanwhile, the neuromodulation effect of external stimulation on the human brain is of increasing interest to neuroscientists. Acupuncture, which originated in ancient China, is recognized as an external neuromodulation method with therapeutic effects. Effective acupuncture could elicit the deqi effect, which is a combination of multiple sensations. However, whether the EEG microstate could be used to reveal the neuromodulation effect of acupuncture with deqi remains largely unclear. In this study, multichannel EEG data were recorded from 16 healthy subjects during acupuncture manipulation, as well as during pre- and post-manipulation tactile controls and pre- and post-acupuncture rest controls. As the basic acupuncture unit for regulating the central nervous system, the Hegu acupoint was used in this study, and each subject's acupuncture deqi behavior scores were collected. To reveal the neuroimaging evidence of acupuncture with deqi , EEG microstate analysis was conducted to obtain the microstate maps and microstate parameters for different conditions. Furthermore, Pearson's correlation was analyzed to investigate the correlation relationship between microstate parameters and deqi behavioral scores. Results showed that: (1) compared with tactile controls, acupuncture manipulation caused significantly increased deqi behavioral scores. (2) Acupuncture manipulation significantly increased the duration, occurrence, and contribution parameters of microstate C, whereas it decreased those parameters of microstate D. (3) Microstate C's duration parameter showed a significantly positive correlation with acupuncture deqi behavior scores. (4) Acupuncture manipulation significantly increased the transition probabilities with microstate C as node, whereas it reduced the transition probabilities with microstate D as node. (5) Microstate B→C's transition probability also showed a significantly positive correlation with acupuncture deqi behavior scores. Taken together, the temporal dynamic feature of EEG microstate could be used as objective neuroimaging evidence to reveal the neuromodulation effect of acupuncture with deqi ., 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 © 2021 Si, Han, Zhang, Zhang, Sun, Yu and Ming.)

Colorectal cancers (CRCs) are characterized by diffuse infiltration of tumor cells into the regional lymph nodes and metastasis to distant organs, and its highly invasive nature contributes to disease recurrence and poor outcomes. The molecular mechanisms underlying CRC cell invasion remain incompletely understood. Here, we identified the upregulation of DNA damage repair-related protein RAD23B in CRC cells and tissues and showed that it associates with coronin 1C or coronin 3 (CORO1C) to facilitate invasion. We found that knockdown of RAD23B expression significantly inhibited the proliferation, invasion, and migration abilities of CRC cells both in vitro and in vivo, and suppressed the talin1/2/integrin/FAK/RhoA/Rac1/CORO1C signaling pathways. Interestingly, RAD23B interacted and co-localized with CORO1C, and CORO1C aggregated toward the margin of cancer cells in both CRC cells and tissues when RAD23B overexpressed. Mechanistically, overexpression of RAD23B and/or CORO1C further increased invadopodia formation and matrix degradation in SW480 and HCT8 CRC cells. Conversely, silencing of RAD23B expression suppressed tumorigenesis and liver metastasis in xenotransplant murine models. Furthermore, we found that RAD23B was significantly overexpressed in tumor tissues (n = 720) compared to adjacent non-tumor tissues (n = 694) of patients with CRC. Finally, we identified a strong correlation between higher levels of cytoplasmic expression of RAD23B, and poor prognosis and liver metastasis in CRC patients. Taken together, our data highlight a novel RAD23B-CORO1C signaling axis in CRC cell invasion and metastasis that may be of clinical significance., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Vagus nerve stimulation (VNS) has been demonstrated to be safe and effective for patients with refractory epilepsy, but there are few reports on the use of VNS for postencephalitic epilepsy (PEE). This retrospective study aimed to evaluate the efficacy of VNS for refractory PEE., Methods: We retrospectively studied 20 patients with refractory PEE who underwent VNS between August 2017 and October 2019 in Chinese PLA General Hospital and Beijing Children's Hospital. VNS efficacy was evaluated based on seizure reduction, effective rate (percentage of cases with seizure reduction ≥ 50%), McHugh classification, modified Early Childhood Epilepsy Severity Scale (E-Chess) score, and Grand Total EEG (GTE) score. The follow-up time points were 3, 6, and 12 months after VNS. Pre- and postoperative data were compared and analyzed., Results: The median [interquartile range (IQR)] seizure reduction rates at 3, 6, and 12 months after VNS were 23.72% (0, 55%), 46.61% (0, 79.04%), and 67.99% (0, 93.78%), respectively. The effective rates were 30% at 3 months, 45% at 6 months, and 70% at 12 months. E-chess scores before the operation and at 3, 6, and 12 months after the operation were 10 (10, 10.75), 9 (9, 10), 9 (9, 9.75), and 9 (8.25, 9) ( P < 0.05), respectively. GTE scores before surgery and at 12 months after the operation were 11 (9, 13) and 9 (7, 11) ( P < 0.05), respectively. The mean intensity of VNS current was 1.76 ± 0.39 (range: 1.0-2.5) mA. No intraoperative complications or severe post-operative adverse effects were reported., Conclusions: Our study shows that VNS can reduce the frequency and severity of seizure in patients with refractory PEE. VNS has a good application prospect in patients with refractory PEE., 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 © 2021 Sun, Chen, Fang, Wan, Shi, Wang, Li, Wang, Cui, Xu, Ling, Zou and Yang.)