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Pinolenic acid is a polyunsaturated fatty acid present only in Pinus koraiensis Sieb. et Zucc seed oil. In order to solve the structural instability problem of polyunsaturated fatty acids, pinolenic acid of P. koraiensis seed oil was effectively isolated and purified by the integrated strategy of ethyl esterification followed by urea inclusion for the first time. Under the optimal conditions after the Box-Benhnken Design experimental, ethyl pinolenate with high purity 94.95% could be obtained, and the average content of PNAEE can still reach 86.18%. Then ethyl pinolenate was characterized by Gas chromatography-mass spectrometry, Fourier transform infrared, and Nuclear magnetic resonance spectra, results showed that ethyl pinolenate was successfully prepared. In addition, the hypolipidemic activity of ethyl pinolenate had been tested in vivo and showed that ethyl pinolenate had obvious hypolipidemic activity. The new strategy for high purity ethyl pinolenate production from P. koraiensis seed oil possesses great potential in food healthy field in the future., 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 © 2024. Published by Elsevier B.V.)

"Transition" metal-coordinated plant polyphenols are a type of promising antitumor nanodrugs owing to their high biosafety and catalytic therapy potency; however, the major obstacle restricting their clinical application is their poor tumor accumulation. Herein, Fe-doped ZIF-8 was tailored using tannic acid (TA) into a hollow mesoporous nanocarrier for gallic acid (GA) loading. After hyaluronic acid (HA) modification, the developed nanosystem of HFZIF-8/GA@HA was used for the targeted delivery of Fe ions and GA, thereby intratumorally achieving the synthesis of an Fe-GA coordinated complex. The TA-etching strategy facilitated the development of a cavitary structure and abundant coordination sites of ZIF-8, thus ensuring an ideal loading efficacy of GA (23.4 wt%). When HFZIF-8/GA@HA accumulates in the tumor microenvironment (TME), the framework is broken due to the competitive protonation ability of overexpressed protons in the TME. Interestingly, the intratumoral degradation of HFZIF-8/GA@HA provides the opportunity for the in situ "meeting" of GA and Fe ions, and through the coordination of polyhydroxyls assisted by conjugated electrons on the benzene ring, highly stable Fe-GA nanochelates are formed. Significantly, owing to the electron delocalization effect of GA, intratumorally coordinated Fe-GA could efficiently absorb second near-infrared (NIR-II, 1064 nm) laser irradiation and transfer it into thermal energy with a conversion efficiency of 36.7%. The photothermal performance could speed up the Fenton reaction rate of Fe-GA with endogenous H 2 O 2 for generating more hydroxyl radicals, thus realizing thermally enhanced chemodynamic therapy. Overall, our research findings demonstrate that HFZIF-8/GA@HA has potential as a safe and efficient anticancer nanodrug.

Non-small-cell lung cancer (NSCLC) is a highly lethal tumor that often develops resistance to targeted therapy. It is shown that Tank-binding kinase 1 (TBK1) phosphorylates AGO2 at S417 (pS417-AGO2), which promotes NSCLC progression by increasing the formation of microRNA-induced silencing complex (miRISC). High levels of pS417-AGO2 in clinical NSCLC specimens are positively associated with poor prognosis. Interestingly, the treatment with EGFR inhibitor Gefitinib can significantly induce pS417-AGO2, thereby increasing the formation and activity of oncogenic miRISC, which may contribute to NSCLC resistance to Gefitinib. Based on these, two therapeutic strategies is developed. One is jointly to antagonize multiple oncogenic miRNAs highly expressed in NSCLC and use TBK1 inhibitor Amlexanox reducing the formation of oncogenic miRISC. Another approach is to combine Gefitinib with Amlexanox to inhibit the progression of Gefitinib-resistant NSCLC. This findings reveal a novel mechanism of oncogenic miRISC regulation by TBK1-mediated pS417-AGO2 and suggest potential therapeutic approaches for NSCLC., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Objective: This study aims to map evidence from Randomized Controlled Trials (RCTs) and systematic reviews/Meta-analyses concerning the treatment of Diabetic Nephropathy (DN) with Traditional Chinese Medicine (TCM), understand the distribution of evidence in this field, and summarize the efficacy and existing problems of TCM in treating DN. The intention is to provide evidence-based data for TCM in preventing and treating DN and to offer a reference for defining future research directions., Methods: Comprehensive searches of major databases were performed, spanning from January 2016 to May 2023, to include clinical RCTs and systematic reviews/Meta-analyses of TCM in treating DN. The analysis encompasses the publishing trend of clinical studies, the staging of research subjects, TCM syndrome differentiation, study scale, intervention plans, and outcome indicators. Methodological quality of systematic reviews was evaluated using the AMSTAR (Assessment of Multiple Systematic Reviews) checklist, and evidence distribution characteristics were analyzed using a combination of text and charts., Results: A total of 1926 RCTs and 110 systematic reviews/Meta-analyses were included. The majority of studies focused on stage III DN, with Qi-Yin deficiency being the predominant syndrome type, and sample sizes most commonly ranging from 60 to 100. The TCM intervention durations were primarily between 12-24 weeks. Therapeutic measures mainly consisted of Chinese herbal decoctions and patented Chinese medicines, with a substantial focus on clinical efficacy rate, TCM symptomatology, and renal function indicators, while attention to quality of life, dosage of Western medicine, and disease progression was inadequate. Systematic reviews mostly scored between 5 and 8 on the AMSTAR scale, and evidence from 94 studies indicated potential positive effects., Conclusion: DN represents a significant health challenge, particularly for the elderly, with TCM showing promise in symptom alleviation and renal protection. Yet, the field is marred by research inconsistencies and methodological shortcomings. Future investigations should prioritize the development of standardized outcome sets tailored to DN, carefully select evaluation indicators that reflect TCM's unique intervention strategies, and aim to improve the robustness of clinical evidence. Emphasizing TCM's foundational theories while incorporating advanced scientific technologies will be essential for innovating research methodologies and uncovering the mechanisms underlying TCM's efficacy in DN management., 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 Gao, Li, Wang, Zhang, Huang, Fu, Xu, Li, Liu and Zhang.)

Harvesting renewable mechanical energy is envisioned as a promising and sustainable way for power generation. Many recent mechanical energy harvesters are able to produce instantaneous (pulsed) electricity with a high peak voltage of over 100 V. However, directly storing such irregular high-voltage pulse electricity remains a great challenge. The use of extra power management components can boost storage efficiency but increase system complexity. Here utilizing the conducting polymer PEDOT:PSS, high-rate metal-free micro-supercapacitor (MSC) arrays are successfully fabricated for direct high-efficiency storage of high-voltage pulse electricity. Within an area of 2.4 × 3.4 cm 2 on various paper substrates, large-scale MSC arrays (comprising up to 100 cells) can be printed to deliver a working voltage window of 160 V at an ultrahigh scan rate up to 30 V s -1 . The ultrahigh rate capability enables the MSC arrays to quickly capture and efficiently store the high-voltage (≈150 V) pulse electricity produced by a droplet-based electricity generator at a high efficiency of 62%, significantly higher than that (<2%) of the batteries or capacitors demonstrated in the literature. Moreover, the compact and metal-free features make these MSC arrays excellent candidates for sustainable high-performance energy storage in self-charging power systems., (© 2024 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Objective: To review the research progress of the weak state of the lateral wall in intertrochanteric fracture, in order to provide clinical references., Methods: The relevant research literature on the lateral wall of intertrochanteric fracture at home and abroad in recent years was summarized and analyzed in terms of morphology, fracture line in coronal plane, and bone density., Results: Assessment of weak state of the lateral wall is particularly important in the treatment of intertrochanteric fractures. Lateral wall thickness is the main way to assess the weak state of the lateral wall, but there are still problems. Many scholars at home and abroad have studied various aspects such as width, height, and length of the anterior cortex, but there is a lack of a comprehensive assessment method. Coronal fractures affect lateral wall morphology and are difficult to detect on X-ray films, requiring vigilance on the part of the clinician. Further research is needed to clarify the correlation between bone density and the weak state of the lateral wall. The femur lesser trochanter fractures interacts with the latertal wall, and the lesser trochanter fracture exacerbates the weak state. The soft tissue around the lateral wall also affects the weak state, so attention must be paid to protecting the soft tissues during operation., Conclusion: There are more methods for assessing the weak state of the lateral wall, but none of them has formed a unified standard. Most of the current studies assess the weak state from a single perspective and lack a comprehensive assessment of all aspects affecting the lateral wall. Fewer studies have been conducted to assess the residual lateral wall function after a partial fracture of the lateral wall, and further research is needed.

Although plant-derived cancer therapeutic products possess great promise in clinical translations, they still suffer from quick degradation and low targeting rates. Herein, based on the oxygen vacancy (OV)-immobilization strategy, an OV-enriched biodegradable silicate nanoplatform with atomically dispersed Fe/Mn active species and polyethylene glycol modification was innovated for loading gallic acid (GA) (noted as FMMPG) for intratumoral coordination-enhanced multicatalytic cancer therapy. The OV-enriched FMMPG nanozymes with a narrow band gap (1.74 eV) can be excited by a 650 nm laser to generate reactive oxygen species. Benefiting from the Mn-O bond in response to the tumor microenvironment (TME), the silicate skeleton in FMMPG collapses and completely degrades after 24 h. The degraded metal M (M = Fe, Mn) ions and released GA can in situ produce a stable M-GA nanocomplex at tumor sites. Importantly, the formed M-GA with strong reductive ability can transform H 2 O 2 into the fatal hydroxyl radical, causing serious oxidative damage to the tumor. The released Fe 3+ and Mn 2+ can serve as enhanced contrast agents for magnetic resonance imaging, which can track the chemodynamic and photodynamic therapy processes. The work offers a reasonable strategy for a TME-responsive degradation and intratumoral coordination-enhanced multicatalytic therapy founded on bimetallic silicate nanozymes to achieve desirable tumor theranostic outcomes.

The microRNAs, which are small RNAs of 18-25 nt in length, act as key regulatory factors in posttranscriptional gene expression during plant growth and development. However, little is known about their regulatory roles in response to stressful environments in birch (Betula platyphylla). Here, we characterized and further explored miRNAs from osmotic- and salt-stressed birch. Our analysis revealed a total of 190 microRNA (miRNA) sequences, which were classified into 180 conserved miRNAs and 10 predicted novel miRNAs based on sequence homology. Furthermore, we identified Bp-miR408a under osmotic and salt stress and elucidated its role in osmotic and salt stress responses in birch. Notably, under osmotic and salt stress, Bp-miR408a contributed to osmotic and salt tolerance sensitivity by mediating various physiological changes, such as increases in reactive oxygen species accumulation, osmoregulatory substance contents and Na+ accumulation. Additionally, molecular analysis provided evidence of the in vivo targeting of BpBCP1 (blue copper protein) transcripts by Bp-miR408a. The overexpression of BpBCP1 in birch enhanced osmotic and salt tolerance by increasing the antioxidant enzyme activity, maintaining cellular ion homeostasis and decreasing lipid peroxidation and cell death. Thus, we reveal a Bp-miR408a-BpBCP1 regulatory module that mediates osmotic and salt stress responses in birch., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Microorganisms play an important role in plant growth and development. In particular, endophytic fungi is one of the important kinds of microorganisms and has a mutually beneficial symbiotic relationship with host plants. Endophytic fungi have many substantial benefits to host plants, especially for woody plants, such as accelerating plant growth, enhancing stress resistance, promoting nutrient absorption, resisting pathogens and etc. However, the effects of endophytic fungi on the growth and development of woody plants have not been systematically summarized. In this review, the functions of endophytic fungi for the growth and development of woody plants have been mainly reviewed, including regulating plant growth (e.g., flowering, root elongation, etc.) by producing nutrients and plant hormones, and improving plant disease, insect resistance and heavy metal resistance by producing secondary metabolites. In addition, the diversity of endophytic fungi could improve the ability of woody plants to adapt to adverse environment. The components produced by endophytic fungi have excellent potential for the growth and development of woody plants. This review has systematically discussed the potential regulation mechanism of endophytic fungi regulating the growth and development of woody plants, it would be of great significance for the development and utilization of endophytic fungi resource from woody plants for the protection of forest resources.

Background: Lateral wall fractures represent crucial risk factors for postoperative internal fixation failure in intertrochanteric femoral fractures. However, no consensus exists on the type of lateral wall fracture requiring interventional management. This study aimed to investigate the effect of residual lateral wall volume on the postoperative stability of intertrochanteric femur fractures with associated lateral wall fractures, providing valuable reference for the clinical management of the lateral wall., Methods: Eleven bone defect models of intertrochanteric femur fractures with varying residual lateral wall volumes were constructed using finite element analysis. These models were fixed with proximal femoral nail antirotation (PFNA). Simulations of von Mises stress and displacement distribution of the PFNA and femur during normal walking were conducted. Statistical analysis was performed to assess the correlation between volume and the maximum von Mises stresses and displacements of the PFNA and femur., Results: In all 11 models, the maximum von Mises stress and displacement of the helical blade, intramedullary nail, and femur occurred at the same locations. As residual lateral wall volume increased, the maximum von Mises stress and displacement of the helical blade, intramedullary nail, and maximum femoral displacement gradually decreased. However, the overall trend of the maximum femoral von Mises stress gradually decreased. At 70% retention of the residual lateral wall volume, there was a more pronounced change in the value of the maximum stress change of the helical blade and the intramedullary nail. Statistical analysis, including the Shapiro-Wilk test and Pearson correlation analysis, demonstrated a significant negative correlation between volume and the maximum von Mises stress and displacement of the helical blade, intramedullary nail, and femur. Linear regression analysis further confirmed this significant negative correlation., Conclusion: Finite element analysis of the residual lateral wall revealed a significant correlation between volume and the postoperative stability of intertrochanteric femur fractures. A volume of 70% may serve as the threshold for stabilizing the residual lateral wall. Volume emerges as a novel index for evaluating the strength of the residual lateral walls., (© 2024. The Author(s).)

Biodegradable silicate nanoconstructs have aroused tremendous interest in cancer therapeutics due to their variable framework composition and versatile functions. Nevertheless, low intratumoral retention still limits their practical application. In this study, oxygen vacancy (OV)-enriched bimetallic silicate nanozymes with Fe-Ca dual active sites via modification of oxidized sodium alginate and gallic acid (GA) loading (OFeCa SA -V@GA) were developed for targeted aggregation-potentiated therapy. The band gap of silica markedly decreased from 2.76 to 1.81 eV by codoping of Fe 3+ and Ca 2+ , enabling its excitation by a 650 nm laser to generate reactive oxygen species. The OV that occurred in the hydrothermal synthetic stage of OFeCa SA -V@GA can anchor the metal ions to form an atomic phase, offering a massive fabrication method of single-atom nanozymes. Density functional theory results reveal that the Ca sites can promote the adsorption of H 2 O 2, and Fe sites can accelerate the dissociation of H 2 O 2 , thereby realizing a synergetic catalytic effect. More importantly, the targeted delivery of metal ions can induce a morphological transformation at tumor sites, leading to high retention (the highest retention rate is 36.3%) of theranostic components in tumor cells. Thus, this finding may offer an ingenious protocol for designing and engineering highly efficient and long-retention nanodrugs.

Phenylalanine, as an essential aromatic amino acid, is not only needed for protein and vital molecules such as neurotransmitter and hormone synthesis but also a substrate for the biosynthesis of phenylpropanoids and various bioactive compounds. The metabolism of phenylalanine is dynamic and transitory, which would otherwise inhibit cell growth. Therefore, it is challenging and imperative to monitor intracellular phenylalanine bioavailability in real time, which has great significance for evaluating the effectiveness of introducing pathway-specific genetic modifications to enhance phenylalanine generation. In this study, we proposed a live-cell biomonitoring system to assess phenylalanine bioavailability in real time in cyanobacteria based on codon degeneracy and species-specific usage bias. The biomonitoring system was generated through genetic modification of phenylalanine codons in the chloramphenicol antibiotic resistance gene to wholly preferred and rare codons, in combination with an orthogonal constitutive promoter Trc to express these genes. Cyanobacterial cells equipped with a preferred codon-based gene showed a significant growth advantage over those with rare codons under antibiotic pressure, while the delayed growth caused by rare codon-based genes could be rescued by supplementing phenylalanine in the cultivation medium. Increasing intracellular phenylalanine bioavailability could promote rare codon-based gene containing cell growth to a similar level as wild-type strains harboring preferred codon-based gene, providing a live-cell visualized screening method to relatively define phenylalanine content from either random mutation libraries or pathway-specific engineering cyanobacterial chassis before conducting labor-intensive quantitative measurements., 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 B.V. All rights reserved.)

An oleanolic acid (OA) surface molecularly imprinted polymer silylated porous composite aerogels (OA-MIP@Si-PC-aerogels) adsorbent material was successfully prepared and characterized. The material not only has a great selectivity for the target molecule OA but also has other noteworthy qualities including high stability, excellent repeatability, and a sizable adsorption capacity. via cellulose and sodium alginate as the main materials, the carrier Si-PC-aerogels were made through ionic cross-linking, chemical cross-linking, and silylation procedures. By adopting a surface molecular imprinting approach on Si-PC-aerogels, OA-MIP@Si-PC-aerogels were effectively created utilizing OA as the template molecule and MAA as the functional monomer. Due to the presence of a specific imprinted layer on the aerogel surface, the adsorption capacity of OA-MIP@Si-PC-aerogels for OA could reach 66.20 mg g -1 . OA-MIP@Si-PC-aerogels could achieve a 68.86% yield of OA from the extracts of lingonberry (Vaccinium Vitis-Idaea L.). The adsorption capacity remained at 90% after five consecutive adsorption-desorption cycles. HepG2 cells were exposed to OA that was effectively enriched with OA-MIP@Si-PC-aerogels in lingonberry (Vaccinium Vitis-Idaea L.) fruit homogenates. This OA significantly inhibited the growth of HepG2 cells in vitro. It further demonstrated that OA-MIP@Si-PC-aerogels could efficiently target OA enrichment and separation with good recovery., 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 B.V. All rights reserved.)

Glycine-rich RNA-binding proteins (GRPs) have been implicated in the responses of plants to environmental stresses, but the function of GRP genes involved in salt stress and the underlying mechanism remain unclear. In this study, we identified BpGRP1 (glycine-rich RNA-binding protein), a Betula platyphylla gene that is induced under salt stress. The physiological and molecular responses to salt tolerance were investigated in both BpGRP1-overexpressing and suppressed conditions. BpGRF3 (growth-regulating factor 3) was identified as a regulatory factor upstream of BpGRP1. We demonstrated that overexpression of BpGRF3 significantly increased the salt tolerance of birch, whereas the grf3-1 mutant exhibited the opposite effect. Further analysis revealed that BpGRF3 and its interaction partner, BpSHMT, function upstream of BpGRP1. We demonstrated that BpmiR396c, as an upstream regulator of BpGRF3, could negatively regulate salt tolerance in birch. Furthermore, we uncovered evidence showing that the BpmiR396c/BpGRF3 regulatory module functions in mediating the salt response by regulating the associated physiological pathways. Our results indicate that BpmiR396c regulates the expression of BpGRF3, which plays a role in salt tolerance by targeting BpGRP1., (© 2023 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Due to their atomically dispersed active centers, single-atom nanozymes (SAzymes) have unparalleled advantages in cancer catalytic therapy. Here, loaded with chlorin e6 (Ce6), a hydrothermally mass-produced bimetallic silicate-based nanoplatforms with atomically dispersed manganese/gadolinium (Mn/Gd) dual sites and oxygen vacancies (OVs) (PMn SA GMSNs-V@Ce6) is constructed for tumor glutathione (GSH)-triggered chemodynamic therapy (CDT) and O 2 -alleviated photodynamic therapy. The band gaps of silica are significantly reduced from 2.78 to 1.88 eV by doping with metal ions, which enables it to be excited by a 650 nm laser to produce electron-hole pairs, thereby facilitating the generation of reactive oxygen species. The Gd sites can modulate the local electrons of the atom-catalyzed Mn sites, which contribute to the generation of superoxide and hydroxyl radicals ( • OH). Tumor GSH-triggered Mn 2+ release can convert endogenous H 2 O 2 to • OH and realize GSH-depletion-enhanced CDT. Significantly, the hydrothermally generated OVs can not only capture Mn and Gd atoms to form atomic sites but also can elongate and weaken the O-O bonds of H 2 O 2 , thereby improving the efficacy of Fenton reactions. The degraded Mn 2+ /Gd 3+ ions can be used as tumor-specific magnetic resonance imaging contrast agents. All the experimental results demonstrate the great potential of PMn SA GMSNs-V@Ce6 as cancer theranostic agent., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Aluminium (Al) toxicity decreases crop production in acid soils in general, but many crops have evolved complex mechanisms to resist it. However, our current understanding of how plants cope with Al stress and perform Al resistance is still at the initial stage. In this study, the citrate transporter CcMATE35 was identified to be involved in Al stress response. The release of citrate was increased substantially in CcMATE35 over-expression (OE) lines under Al stress, indicating enhanced Al resistance. It was demonstrated that transcription factor CcNFYB3 regulated the expression of CcMATE35, promoting the release of citrate from roots to increase Al resistance in pigeon pea. We also found that a Long noncoding RNA Targeting Citrate Synthase (CcLTCS) is involved in Al resistance in pigeon pea. Compared with controls, overexpression of CcLTCS elevated the expression level of the Citrate Synthase gene (CcCS), leading to increases in root citrate level and citrate release, which forms another module to regulate Al resistance in pigeon pea. Simultaneous overexpression of CcNFYB3 and CcLTCS further increased Al resistance. Taken together, these findings suggest that the two modules, CcNFYB3-CcMATE35 and CcLTCS-CcCS, jointly regulate the efflux and synthesis of citrate and may play an important role in enhancing the resistance of pigeon pea under Al stress., (© 2023 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

As a multifunctional hormone-like molecule, melatonin exhibits a pleiotropic role in plant salt stress tolerance. While actin cytoskeleton is essential to plant tolerance to salt stress, it is unclear if and how actin cytoskeleton participates in the melatonin-mediated alleviation of plant salt stress. Here, we report that melatonin alleviates salt stress damage in pigeon pea by activating a kinase-like protein, which interacts with an actin-depolymerizing factor. Cajanus cajan Actin-Depolymerizing Factor 9 (CcADF9) has the function of severing actin filaments and is highly expressed under salt stress. The CcADF9 overexpression lines (CcADF9-OE) showed a reduction of transgenic root length and an increased sensitivity to salt stress. By using CcADF9 as a bait to screen an Y2H library, we identified actin depolymerizing factor-related phosphokinase 1 (ARP1), a novel protein kinase that interacts with CcADF9. CcARP1, induced by melatonin, promotes salt resistance of pigeon pea through phosphorylating CcADF9, inhibiting its severing activity. The CcARP1 overexpression lines (CcARP1-OE) displayed an increased transgenic root length and resistance to salt stress, whereas CcARP1 RNA interference lines (CcARP1-RNAi) presented the opposite phenotype. Altogether, our findings reveal that melatonin-induced CcARP1 maintains F-actin dynamics balance by phosphorylating CcADF9, thereby promoting root growth and enhancing salt tolerance., (© 2023 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Targeted separation of active phytochemicals is urgently needed in the natural medicine field. In this paper, due to the natural porosity and high biocompatibility of cellulose, a nanocellulose membrane combined with surface molecular imprinting was successfully prepared; the efficient nanocellulose-based molecular imprinted membrane (NC-MIM) provided good adsorption for the targeted separation of phytochemicals such as 10-deacetylbaccatin III (10-DAB), an essential intermediate in the synthesis of the anticancer drug paclitaxel. Through a series of characterization and adsorption experiments, the adsorption mechanism of NC-MIM was determined. At pH 8.0 and temperatures of 20 °C-40 °C, the maximum capacity of NC-MIM for adsorption of 10-DAB reached 66.90 mg g - 1 , and the content of 10-DAB was dramatically increased 17.5-fold after adsorption. The specific adsorption results showed that NC-MIM had excellent capacity for targeted separation of 10-DAB from among taxane structural analogues. Even after ten cycles, NC-MIM demonstrated a remarkable adsorption capacity of 86.43%, thereby indicating exceptional selectivity and stability. The successful implementation of NC-MIM for green, safe, and efficient enrichment of phytochemicals from plants provides a promising new approach and valuable insights into its practical application., 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. Published by Elsevier B.V.)

Non-small cell lung cancer (NSCLC) is one of the most devastating cancers with a high incidence and mortality rates of all cancers. Locally advanced or metastatic NSCLC patients can benefit from platinum-based chemotherapy and targeted therapy drugs. Nevertheless, primary or acquired drug resistance will result in ineffective treatment, leading to tumor progression. The detailed mechanism underlying drug resistance to NSCLC are complicated and result from various factor. Among them, long noncoding RNAs (lncRNAs) have been found to be critically involved in NSCLC development and play a vital role in mediating therapy resistance. In this review, we attempt to systematically summarize the mechanisms underlying the lncRNA-mediated resistance to chemotherapy agents and targeted therapy drugs against lung cancer., Competing Interests: 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., (© 2023 The Authors. Published by Elsevier Ltd.)

Overcoming CD8 + T cell exhaustion is critical in cancer immunotherapy. Recently, an intratumor stem/progenitor-like CD8 + T cell (T prog cell) population that mediates the persistence of antitumor responses has been defined, which can further develop into a terminally differentiated CD8 + T cell (T term cell) subpopulation with potent cytotoxic functions. T prog cells are the main responders to immune checkpoint blockade therapies, yet how extrinsic signals via transcription factors control T prog cell generation and persistence in tumors is unclear. Here, we found that BCL6 inhibits tumor-specific T term cell generation from T prog cell downstream of TCF1. We show that Bcl6 deficiency reduced the persistence of T prog cells, without affecting their generation, thus abrogating long-term tumor control. High-level BCL6 expression was observed in tumor-specific T cells in draining lymph nodes (LNs) and was associated with T cell exhaustion. This was observed in TOX + TCF1 + T prog cells in both LNs and tumors. BCL6 expression in CD8 + T cells was up-regulated by TGF-β-SMAD2 signaling but down-regulated by the IL-2-STAT5 pathway. Mechanistically, BCL6 transcriptionally repressed the expression of T term cell-associated genes and induced those of T prog cell-related genes, in a manner antagonistic to BLIMP1. Prdm1 deficiency also promoted the T prog cell program and greatly improved the efficacy of anti-PD-1 therapy. Thus, we identified the TGF-β-BCL6 and IL-2-BLIMP1 antagonistic pathways in regulation of antitumor CD8 + T cells, which may benefit the development of long-lasting and effective cancer immunotherapy.

Lingonberry are underutilised due to the lack of evaluating active compounds in different parts. In this study, the phytochemical profiles, antioxidant and antiproliferative activities of lingonberry's fruits, leaves and stems from different regions of China were compared. Ninety-five bioactive compounds were rapidly identified using a molecular network based on UPLC-Q-Exactive Orbitrap mass spectrometry. The UPLC-QqQ-MS/MS method combined with principal component analysis (PCA) quantified 18 bioactive components in 6 classes. The highest content of arbutin (15 mg/100 g DW) was found in leaves of Huzhong (P6). Ursolic acid and cyanidin-3- O -galactoside were highest in fruits of Tahe (P4) (4.5 mg/100 g DW and 3.2 mg/100 g DW, respectively). Antioxidant activities determined by DPPH, ABTS + and FRAP methods were significantly correlated with total phenolic content (TPC), total flavonoid content (TFC) and total anthocyanin content (TAC). The results indicate that the strongest antioxidant activity and antiproliferative efficacy are observed in the fruits of Tahe (P4) and leaves of Huzhong (P6), respectively. Our results provide valuable insights into lingonberry's comprehensive development and utilization., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Lung squamous cell carcinoma (LUSC) remains a leading cause of cancer-related deaths with few therapeutic strategies. Immune checkpoint inhibitors (ICIs) have demonstrated promising efficacy in patients with LUSC. However, ICIs could also lead to a unique spectrum of immune-related adverse events (irAEs), which dampen the clinical outcome. In-depth characterization of the immune hallmarks of antitumor responses and irAEs remains an unmet need to maximize ICI-treatment benefits of patients., Methods: We performed single-cell RNA sequencing (scRNA-seq) on pre-ICI and on-ICI treatment tumor biopsies. We used bulk RNA-seq data of matched pretreatment/on-treatment tumors and irAE affected organs to validate observations from scRNA-seq analysis. Two independent patient cohorts were collected to determine circulating tumor necrosis factor (TNF) protein expression levels., Results: We found that increased proportions of a macrophage subcluster with highly expressed secreted phosphoprotein 1 (SPP1) and two tumor cell subclusters in irAE patients, whereas proportions of two cytotoxic CD8+ T cell subclusters were higher in patients with partial response (PR). TNF signaling pathway was conversely associated with treatment efficacy and irAE development in most macrophage and tumor cell subclusters. Cell-cell communications for TNF ligand-receptor pairs between macrophage/T cells and tumor cells were also bidirectionally remodeled in responders versus non-responders and irAE versus non-irAE patients. Bulk RNA-seq analysis on matched pretreatment/on-treatment tumors and irAE affected organs revealed remarkably enhanced macrophage abundance and TNF signaling pathway in on-treatment tumors and organs developed irAEs. Furthermore, we observed significantly increased circulating TNF protein in plasma or serum of irAE patients but not ICI responders, based on analysis of two independent LUSC patient cohorts and one published ICI patient cohort., Conclusions: Our data depicts specific reprogramming of macrophage, T cells and tumor cells associated with ICI response and irAEs, elucidates divergent roles of TNF signaling in antitumor immunity and irAEs, and highlights the significance of TNF expression in irAE development in the LUSC setting., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In this article, thermosensitive molecularly imprinted polymer and composite aerogel were combined for the first time to create an intelligent temperature-responsive aerogel reactor to effectively enrich ursolic acid (UA). Because aerogel carrier had a higher specific surface area and higher porosity compared to other carriers, the ursolic acid molecularly imprinted intelligent temperature responsive aerogel reactor (ITR&AR(G570)&UA-MIP) demonstrated a higher adsorption capacity for UA. More notably, ITR&AR(G570)&UA-MIP have the extraordinary capacity to spontaneously adsorb-desorb target molecule UA by regulating the reaction temperature. The ratio of the target molecule UA to the functional monomer and crosslinker in the grafting process and external influences had a major impact on how ITR&AR(G570)&UA-MIP were prepared overall. When the molar ratio of UA to 4-VP was 1:8, the weight ratio between ITR&AR(G570)&UA-MIP and EGDMA/DVB was 1:2:10, the reaction temperature was 60 °C, and the ambient pH = 6, the material showed the best adsorption capacity, reaching a peak of about 70 mg g -1 . After researching the appropriate synthesis conditions, ITR&AR(G570)&UA-MIP were applied to lingonberry (Vaccinium Vitis-Idaea L.) berry extracts in this work. The outcomes show that this technique provides a new, intelligent, temperature-controlled adsorption material for the solid-phase extraction of triterpenoid acids in natural products, with good specific adsorption performance for the target molecule UA., 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 B.V. All rights reserved.)

Human health is at risk from pulmonary hypertension (PH), characterized by decreased pulmonary vascular resistance and constriction of the pulmonary vessels, resulting in right heart failure and dysfunction. Thus, preventing PH and monitoring its progression before treating it is vital. Wogonin, derived from the leaves of Scutellaria baicalensis Georgi, exhibits remarkable pharmacological activity. In this study, we examined the effectiveness of wogonin in mitigating the progression of PH in mice using right heart catheterization and hematoxylin-eosin (HE) staining. As an alternative to minimize the possibility of harming small animals, we present a scientifically effective feature selection method (BSCDWOA-KELM) that will allow us to develop a novel simpler noninvasive prediction method for wogonin in treating PH. In this method, we use the proposed enhanced whale optimizer (SCDWOA) in conjunction with the kernel extreme learning machine (KELM). Initially, we let SCDWOA perform global optimization experiments on the IEEE CEC2014 benchmark function set to verify its core advantages. Lastly, 12 public and PH datasets are examined for feature selection experiments using BSCDWOA-KELM. As shown in the experimental results for global optimization, the proposed SCDWOA has better convergence performance. Meanwhile, the proposed binary SCDWOA (BSCDWOA) significantly improves the ability of KELM to classify data. By utilizing the BSCDWOA-KELM, key indicators such as the Red blood cell (RBC), the Haemoglobin (HGB), the Lymphocyte percentage (LYM%), the Hematocrit (HCT), and the Red blood cell distribution width-size distribution (RDW-SD) can be efficiently screened in the Pulmonary hypertension dataset, and one of its most essential points is its accuracy of greater than 0.98. Consequently, the BSCDWOA-KELM introduced in this study can be used to predict wogonin therapy for treating pulmonary hypertension in a simple and noninvasive manner., 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 Ltd. All rights reserved.)

Cisplatin is an important platinum drug in cancer chemotherapy in clinical practice. It is well established that the main target of cisplatin is nuclear DNA. However, recent studies have demonstrated that platinum drugs may act on some important functional proteins in the human body. E-cadherin is a newly discovered glycoprotein that has been regarded as an important sign of the occurrence and development of some tumors. This study examines the interactions between cisplatin and E-cadherin by fluorescence spectrometry and atomic force microscopy (AFM). The fluorescence spectrometry results indicated that cisplatin can efficiently quench the fluorescence of E-cadherin. The calculated binding constant K b was 3.20 × 10 6 (25 ℃), 1.36 × 10 6 (31 ℃), and 8.22 × 10 5 L mol -1 (37 ℃). These results reveal that the fluorescence quenching effect of cisplatin on E-cadherin is static quenching. The obtained thermodynamic parameters ΔH < 0, ΔS < 0, and ΔG < 0, indicate that the binding of cisplatin on E-cadherin is a spontaneous process dominated by hydrogen bonds and Van der Waals forces. The AFM results revealed that E-cadherins are interlaced with each other to form a spherical-chain structure. The addition of cisplatin can significantly disrupt the interlaced structure of the E-cadherin molecules., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Second near-infrared (NIR-II, 1000-1700 nm) photon-mediated fluorescence imaging has attracted extensive interest in the field of bioimaging. However, NIR-II fluorescent nanoprobes competent for plant imaging have been rarely developed. Herein, lanthanide-doped nanoparticle (LDNP) optimal core-shell structure and ultrabright NIR-II emission were developed for "lighting" plants. The Ce 3+ -doped active shell coated on the NaErF 4 :Tm core enables dual-mode red upconversion (UC) and NIR-II downconversion (DC) emission of LDNPs upon 980 nm laser excitation. Under the optimized doping content, the intensities of red UC and NIR-II DC emission were respectively boosted by 5- and 19-fold those of the core nanoparticles, which endowed LDNPs with ideal NIR-II emissive capabilities for optical imaging of plants. Significantly, the NIR-II fluorescent signal affords much higher signal-to-noise rate than the red UC. LDNPs were modified with polyethyleneimine to enable outstanding hydrophilicty and facilitate their uptake by plants. Arabidopsis thaliana and Nicotiana benthamiana were chosen as plant models for NIR-II imaging studies. The toxic effect of LDNPs after being transported into Brassica rapa chinensis was systematically studied on mice. The NIR-II imaging strategy offers a promising method for studying the uptake and transport of nanoparticles in plants.

MYB transcription factor (TF) is one of the largest superfamilies that play a vital role in multiple plant biological processes. However, the MYB family has not been comprehensively identified and functionally verified in Cajanus cajan, which is the sixth most important legume crop. Here, 170 CcR2R3-MYBs were identified and divided into 43 functional subgroups. Segmental and tandem duplications and alternative splicing events were found and promoted the expansion of the CcR2R3-MYB gene family. Functional prediction results showed that CcR2R3-MYBs were mainly involved in secondary metabolism, cell fate and identity, developmental processes, and responses to abiotic stress. Cis-acting element analysis of promoters revealed that stress response elements were widespread in the above four functional branches, further suggesting CcR2R3-MYBs were extensively involved in abiotic stress response. The transcriptome data and qRT-PCR results indicated that most of the CcR2R3-MYB genes responded to various stresses, of which the expression of CcMYB107 was significantly induced by drought stress. Overexpression of CcMYB107 enhanced antioxidant enzyme activity and increased proline and lignin accumulation, thus improving the drought resistance of C. cajan. Furthermore, Overexpression of CcMYB107 up-regulated the expression of stress-related genes and lignin biosynthesis genes after drought stress. Our findings established a strong foundation for the investigation of biological function of CcR2R3-MYB TFs in C. cajan., (© 2023 Scandinavian Plant Physiology Society.)

A novel endophytic fungus producing beta-glucosidase was isolated and characterized from pigeon pea (Cajanus cajan [L.] Millsp.), which has excellent properties in converting ginsenoside Rb1 to ginsenoside Rd in Panax notoginseng. According to the 16S rDNA gene sequence, the G11-7 strain was identified as Fusarium proliferatum, and the accession number KY303906 was confirmed in GenBank. The G11-7 immobilized spores, in which the activity of beta-glucosidase could reach 0.95 U/mL, were co-cultured with P. notoginseng plant material to obtain a continuous beta-glucosidase supply for the biotransformation of ginsenoside Rb1 to Rd. Under the liquid-solid ratio (20:1), initial pH (6.0), and temperature (30 °C) constituents, the maximum ginsenoside Rd yield was obtained as 9.15 ± 0.65 mg/g, which was 3.67-fold higher than that without fungal spore co-culture (2.49 ± 0.98 mg/g). Furthermore, immobilized G11-7 spores showed significant beta-glucosidase producing ability which could be recovered and reused for 6 cycles. Overall, these results suggested that immobilized G11-7 offered a promising and effective approach to enhance the production of ginsenoside Rd for possible nutraceutical and pharmaceutical uses., (© 2022. Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i.)

Background: Stroke is the second leading cause of death worldwide and has a significantly high recurrence rate. We aimed to identify risk factors for stroke recurrence and develop an interpretable machine learning model to predict 30-day readmissions after stroke., Methods: Stroke patients deposited in electronic health records (EHRs) in Xuzhou Medical University Hospital between February 1, 2021, and November 30, 2021, were included in the study, and deceased patients were excluded. We extracted 74 features from EHRs, and the top 20 features (chi-2 value) were used to build machine learning models. 80% of the patients were used for pre-training. Subsequently, a 20% holdout dataset was used for verification. The Shapley Additive exPlanations (SHAP) method was used to explore the interpretability of the model., Results: The cohort included 6,558 patients, of whom the mean (SD) age was 65 (11) years, 3,926 were males (59.86 %), and 132 (2.01 %) were readmitted within 30 days. The area under the receiver operating characteristic curve (AUROC) for the optimized model was 0.80 (95 % CI 0.68-0.80). We used the SHAP method to identify the top 10 risk factors (i.e., severe carotid artery stenosis, weak, homocysteine, glycosylated hemoglobin, sex, lymphocyte percentage, neutrophilic granulocyte percentage, urine glucose, fresh cerebral infarction, and red blood cell count). The AUROC of a model with the 10 features was 0.80 (95 % CI 0.69-0.80) and was not significantly different from that of the model with 20 risk factors., Conclusions: Our methods not only showed good performance in predicting 30-day readmissions after stroke but also revealed risk factors that provided valuable insights for treatments., 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 B.V. All rights reserved.)

In cancer, persistent antigens drive CD8+ T cell differentiation into exhausted progenitor (Texprog) and terminally exhausted (Texterm) cells. However, how the extrinsic and intrinsic regulatory mechanisms cooperate during this process still remains not well understood. Here, we found that STAT3 signaling plays essential roles in promoting intratumor Texterm cell development by enhancing their effector functions and survival, which results in better tumor control. In tumor microenvironments, STAT3 is predominantly activated by IL-10 and IL-21, but not IL-6. Besides, STAT3 also plays critical roles in the development and function of terminally differentiated effector CD8+ T cells in acute infection. Mechanistically, STAT3 transcriptionally promotes the expression of effector function-related genes, while it suppresses those expressed by the progenitor Tex subset. Moreover, STAT3 functions in collaboration with BATF and IRF4 to mediate chromatin activation at the effector gene loci. Thus, we have elucidated the roles of STAT3 signaling in terminally differentiated CD8+ T cell development, especially in cancer, which benefits the development of more effective immunotherapies against tumors., (© 2023 Sun et al.)

Flavonoids are important secondary metabolites in the plant growth and development process. As a medicinal plant, pigeon pea is rich in secondary metabolites. As a flavonoid, there are few studies on the regulation mechanism of naringenin in plant stress resistance. In our study, we found that naringenin can increase the pigeon pea's ability to tolerate salt and influence the changes that occur in flavonoids including naringenin, genistein and biochanin A. We analyzed the transcriptome data after 1 mM naringenin treatment, and identified a total of 13083 differentially expressed genes. By analyzing the metabolic pathways of these differentially expressed genes, we found that these differentially expressed genes were enriched in the metabolic pathways of phenylpropanoid biosynthesis, starch and sucrose metabolism and so on. We focused on the analysis of flavonoid biosynthesis related pathways. Among them, the expression levels of enzyme genes CcIFS, CcCHI and CcCHS in the flavonoid biosynthesis pathway had considerably higher expression levels. By counting the number of transcription factors and the binding sites on the promoter of the enzyme gene, we screened the transcription factors CcMYB62 and CcbHLH35 related to flavonoid metabolism. Among them, CcMYB62 has a higher expression level than the others. The hairy root transgene showed that CcMYB62 could induce the upregulation of CcCHI, and promote the accumulation of naringenin, genistein and biochanin A. Our study revealed the molecular mechanism of naringenin regulating flavonoid biosynthesis under salt stress in pigeon pea, and provided an idea for the role of flavonoids in plant resistance to abiotic stresses., 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. Published by Elsevier Masson SAS.)

Cell plasticity and neuroendocrine differentiation in prostate and lung adenocarcinomas are one of the major reasons for therapeutic resistance to targeted therapy. Whether and how metabolic changes contribute to this adenocarcinoma-to-neuroendocrine cell fate transition remains largely unclear. Here we show that neuroendocrine prostate or lung cancer cells possess mostly fragmented mitochondria with low membrane potential and rely on glycolysis for energy metabolism. We further show an important role of the cell fate determinant Numb in mitochondrial quality control via binding to Parkin and facilitating Parkin-mediated mitophagy. Deficiency in the Numb/Parkin pathway in prostate or lung adenocarcinomas causes a metabolic reprogramming featured with a significant increase in production of lactate acid, which subsequently leads to an upregulation of histone lactylation and transcription of neuroendocrine-associated genes. Collectively, the Numb/Parkin-directed mitochondrial fitness is a key metabolic switch and a promising therapeutic target on cancer cell plasticity through the regulation of histone lactylation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Obesity has become a worldwide burden and is associated with severe medical complications. Geraniin is a polyphenolic compound that has a wide range of bioactive properties. There is also evidence to support its pharmacological effects on improving lipid accumulation and obesity. This research investigates the effect of geraniin on lipid accumulation in adipocytes and the underlying mechanism. Mature adipocytes were differentiated from immature 3T3-L1 cells. Oil Red O staining and a triglyceride content determination were conducted to evaluate the intracellular lipid accumulation. Molecular docking studies were performed to determine the interaction between geraniin and the key proteins. Western blotting was used to detect the expression of lipogenic enzymes and transcription factors. Geraniin dose-dependently inhibited lipid accumulation in adipocytes by reducing the expression of fatty acid synthase and increasing the phosphorylation level of acetyl-coenzyme A carboxylase. Moreover, geraniin promoted the phosphorylation of AMP-activated protein kinase (AMPK) and further reduced the expression of lipogenic transcription factors (peroxisome proliferator-activated receptor gamma and CCAAT/enhancer binding protein alpha). The expression of the calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) was increased by the geraniin administration. The molecular docking study demonstrated that geraniin can interact with CaMKK2, which is an upstream kinase of AMPK. A selective CaMKK2 inhibitor reversed the suppressive effect of geraniin on lipogenesis. Geraniin targeted CaMKK2 to inhibit lipid accumulation in 3T3-L1 adipocytes by suppressing lipogenesis, and this supports its potential as a candidate natural anti-obesity drug., 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 B.V. All rights reserved.)

In this study, ethylenediaminetetraacetic acid (EDTA) disodium was first chosen as catalyst to convert psoralenoside (PO) to psoralen (PSO) for increasing the extraction yield of PSO. An efficient continuous system for synchronous transformation and extraction of PSO from fig leaves applying microwave-assisted EDTA disodium (MAE-EDTA) was developed. The optimal MAE-EDTA condition was obtained: EDTA disodium concentration of 0.07 mol·L -1 , ethanol volume fraction of 56%, extraction time of 16 min, and extraction temperature of 70 °C by single factor experiments and response surface method (RSM). Under the optimal condition, the yield of PSO reached 27.24 mg·g -1 . Compared with microwave-assisted ethanol extraction (MAE) and reflux extraction (RE), the yield of PSO by MAE-EDTA is 2.03-fold higher than RE and 1.70-fold higher than MAE. Therefore, MAE-EDTA is an efficient method for extracting PSO from fig leaves, and it might provide references for the extraction of PSO from other medicinal plants.

The chestnut shell is usually discarded as agricultural waste and the random deposition of it can cause environmental problems. In this study, monodisperse crystalline Ag nanoparticles (AgNPs) were synthesized by a hydrothermal approach, in which the chestnut shell extract served as both reducing agent and stabilizer. The synthesized Ag nanoparticles were characterized by ultraviolet-visible (UV) spectrophotometry, transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD) measurements. The TEM, XRD and XPS results revealed that the synthesized product was spherical Ag nanoparticles with a face-centered cubic crystal structure. The antimicrobial activity test indicated that the Ag nanoparticles modified by the chestnut shell extract had an obvious inhibitory effect on Escherichia coli , Staphylococcus aureus and Candida albicans . The measured MIC and MBC of functionalized chestnut-shell-extract AgNPs against E. coli , S. aureus and C. albicans is relatively low, which indicated that the present functionalized chestnut-shell-extract AgNPs are an efficient antimicrobial agent.

Despite remarkable efficacy, targeted treatments often yield a subpopulation of residual tumor cells in part due to non-genetic adaptions. Previous mechanistic understanding on the emergence of these drug-tolerant persisters (DTPs) has been limited to epigenetic and transcriptional reprogramming. Here, by comprehensively interrogating therapy-induced early dynamic protein changes in diverse oncogene-addicted non-small cell lung cancer models, we identified adaptive MCL1 increase as a new and universal mechanism to confer apoptotic evasion and DTP formation. In detail, acute MAPK signaling disruption in the presence of genotype-based tyrosine kinase inhibitors (TKIs) prompted mitochondrial accumulation of pro-apoptotic BH3-only protein BIM, which sequestered MCL1 away from MULE-mediated degradation. A small-molecule combination screen uncovered that PI3K-mTOR pathway blockade prohibited MCL1 upregulation. Biochemical and immunocytochemical evidence indicated that mTOR complex 2 (mTORC2) bound and phosphorylated MCL1, facilitating its interaction with BIM. As a result, short-term polytherapy combining antineoplastic TKIs with PI3K, mTOR or MCL1 inhibitors sufficed to prevent DTP development and promote cancer eradication. Collectively, these findings support that upfront and transient targeting of BIM-dependent, mTORC2-regulated adaptive MCL1 preservation holds enormous promise to improve the therapeutic index of molecular targeted agents., (© 2022. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Introduction: Pulmonary embolism (PE) is a cardiopulmonary condition that can be fatal. PE can lead to sudden cardiovascular collapse and is potentially life-threatening, necessitating risk classification to modify therapy following the diagnosis of PE. We collected clinical characteristics, routine blood data, and arterial blood gas analysis data from all 139 patients., Methods: Combining these data, this paper proposes a PE risk stratified prediction framework based on machine learning technology. An improved algorithm is proposed by adding sobol sequence and black hole mechanism to the cuckoo search algorithm (CS), called SBCS. Based on the coupling of the enhanced algorithm and the kernel extreme learning machine (KELM), a prediction framework is also proposed., Results: To confirm the overall performance of SBCS, we run benchmark function experiments in this work. The results demonstrate that SBCS has great convergence accuracy and speed. Then, tests based on seven open data sets are carried out in this study to verify the performance of SBCS on the feature selection problem. To further demonstrate the usefulness and applicability of the SBCS-KELM framework, this paper conducts aided diagnosis experiments on PE data collected from the hospital., Discussion: The experiment findings show that the indicators chosen, such as syncope, systolic blood pressure (SBP), oxygen saturation (SaO2%), white blood cell (WBC), neutrophil percentage (NEUT%), and others, are crucial for the feature selection approach presented in this study to assess the severity of PE. The classification results reveal that the prediction model's accuracy is 99.26% and its sensitivity is 98.57%. It is expected to become a new and accurate method to distinguish the severity of PE., 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 Su, Han, Fu, Zhao, Yu, Heidari, Zhang, Shou, Wu, Chen and Chen.)

Introduction: Pulmonary embolism (PE) is a common thrombotic disease and potentially deadly cardiovascular disorder. The ratio of clinical misdiagnosis and missed diagnosis of PE is very large because patients with PE are asymptomatic or non-specific., Methods: Using the clinical data from the First Affiliated Hospital of Wenzhou Medical University (Wenzhou, China), we proposed a swarm intelligence algorithm-based kernel extreme learning machine model (SSACS-KELM) to recognize and discriminate the severity of the PE by patient's basic information and serum biomarkers. First, an enhanced method (SSACS) is presented by combining the salp swarm algorithm (SSA) with the cuckoo search (CS). Then, the SSACS algorithm is introduced into the KELM classifier to propose the SSACS-KELM model to improve the accuracy and stability of the traditional classifier., Results: In the experiments, the benchmark optimization performance of SSACS is confirmed by comparing SSACS with five original classical methods and five high-performance improved algorithms through benchmark function experiments. Then, the overall adaptability and accuracy of the SSACS-KELM model are tested using eight public data sets. Further, to highlight the superiority of SSACS-KELM on PE datasets, this paper conducts comparison experiments with other classical classifiers, swarm intelligence algorithms, and feature selection approaches., Discussion: The experimental results show that high D-dimer concentration, hypoalbuminemia, and other indicators are important for the diagnosis of PE. The classification results showed that the accuracy of the prediction model was 99.33%. It is expected to be a new and accurate method to distinguish the severity of PE., 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 Su, Shou, Fu, Zhao, Heidari, Han, Wu, Chen and Chen.)

ZIF-8, as an important photoresponsive metal-organic framework (MOF), holds great promise in the field of cancer theranostics owing to its versatile physiochemical properties. However, its photocatalytic anticancer application is still restricted because of the wide bandgap and specific response to ultraviolet light. Herein, we developed lanthanide-doped nanoparticles (LDNPs) coated with Fe/Mn bimetal-doped ZIF-8 (LDNPs@Fe/Mn-ZIF-8) for second near-infrared (NIR-II) imaging-guided synergistic photodynamic/chemodynamic therapy (PDT/CDT). The LDNPs were synthesized by encapsulating an optimal Yb 3+ /Ce 3+ -doped active shell on the NaErF 4 :Tm core to achieve dual-mode red upconversion (UC) and NIR-II downconversion (DC) emission upon NIR laser irradiation. At the optimal doping concentration, the UC and DC NIR-II emission intensities of LDNPs were increased 30.2- and 13.2-fold above those of core nanoparticles, which endowed LDNPs@Fe/Mn-ZIF-8 with an outstanding capability to carry out UC-mediated PDT and NIR-II optical imaging. In addition, the dual doping of Fe 2+ /Mn 2+ markedly decreased the bandgap of the ZIF-8 photosensitizer from 5.1 to 1.7 eV, expanding the excitation threshold of ZIF-8 to the visible light region (∼650 nm), which enabled Fe/Mn-ZIF-8 to be efficiently excited by UC photons to achieve photocatalytic-driven PDT. Furthermore, Fe 2+ /Mn 2+ ions could be responsively released in the tumor microenvironment through degradation of Fe/Mn-ZIF-8, thereby producing hydroxyl radicals (·OH) by Fenton/Fenton-like reactions to realize CDT. Meanwhile, the degradation of Fe/Mn-ZIF-8 endowed the nanosystems with tumor self-enhanced NIR-II imaging function, providing precise guidance for CDT/PDT.

Castanea mollissima BL. is an outstanding species that represents a valuable woody food resource due to consumers' salient beliefs in the health benefits of chestnut consumption. Besides chestnut kernel, the discarded shells of chestnut were highlighted as remarkable sources of functional ingredients with promising applications in food, nutraceutical, pharmaceutical and industrial raw materials, mainly as natural antioxidants and effective prebiotics. Phytochemical studies reported not only antioxidant and antimicrobial activities, but also anti-inflammatory, anticancer, hypolipidemic, hypoglycemic and neuroprotective activities. This review aims to summarize the botanical characteristics, nutritional compositions, biological activities and comprehensive utilization of the whole C. mollissima, emphasizing the value of sustainable use in the recovery of bioactive compounds and their potential applications in food and other industries. It will provide a reference for the further development of C. mollissima in the field of multi-functional food and will inspiring investigations on the comprehensive utilization of chestnut and their by-products., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Melatonin improves plant resistance to multiple stresses by participating in the biosynthesis of metabolites. Flavonoids are an important family of plant secondary metabolites and are widely recognized to be involved in resistance; however, the crosstalk between melatonin and flavonoid is largely unknown. We found that the resistance of pigeon pea (Cajanus cajan) to salt, drought, and heat stresses were significantly enhanced by pre-treatment with melatonin. Combined transcriptome and LC-ESI-MS/MS metabolomics analyses showed that melatonin significantly induced the enrichment of flavonoids and mediated the reprogramming of biosynthetic pathway genes. The highest fold-increase in expression in response to melatonin treatment was observed for the CcF3´H family, which encodes an enzyme that catalyses the biosynthesis of luteolin, and the transcription factor CcPCL1 directly bonded to the CcF3´H-5 promoter to enhance its expression. In addition, salt stress also induced the expression of CcPCL1 and CcF3´H-5, and their overexpression in transgenic plants greatly enhanced salt tolerance by promoting the biosynthesis of luteolin. Overall, our results indicated that pre-treatment of pigeon pea with melatonin promoted luteolin biosynthesis through the CcPCL1 and CcF3´H-5 pathways, resulting in salt tolerance. Our study shows that melatonin enhances plant tolerance to multiple stresses by mediating flavonoid biosynthesis, providing new avenues for studying the crosstalk between melatonin and flavonoids., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: An increasing number of lung ground-glass nodules (GGNs) have been detected ever since low-dose computer tomography started growing in popularity. Three-dimensional (3D) reconstruction technology plays a critical role in lung resection, especially in segmentectomy. In this study, we explore the role of 3D reconstruction in thoracoscopic complex segmentectomy of lower lung lobe., Methods: A total of 97 patients who underwent complex segmentectomy of lower lung lobe from January 2021 to March 2022 were retrospectively analyzed. We divided these patients into a 3D group ( n  = 42) and a routine group ( n  = 55) based on preoperative 3D reconstruction or without this procedure. The demographics of patients and GGNs were collected and perioperative outcomes were compared between the two groups., Results: All of the baseline characteristics between the groups were comparable (all P  > 0.05). There was no 30-day postoperative mortality and conversion in the two groups. The operation time of the 3D group was significantly shorter than that of the routine group (111.4 ± 20.8 min vs. 127.1 ± 32.3 min, P  = 0.007). The number of stapler reloads during surgery in the 3D group was less than that in the routine group (9.0 ± 2.2 vs. 10.4 ± 2.6, P  = 0.009). The rate of air leakage on postoperative days 1-3 was lower in the 3D group (11.9% vs. 30.9%, P  = 0.027). In addition, the resection margins of all patients in the 3D group were adequate, while four patients in the routine group had inadequate resection margins, although there was no statistically significant difference ( P  = 0.131). Intraoperative blood loss, postoperative drainage, postoperative hospital stay, pneumonia/atelectasis, and hemoptysis were similar between the two groups., Conclusions: For performing complex segmentectomy of the lower lung lobe, the procedure of 3D reconstruction may shorten the operation time, decrease the number of stapler reloads, prevent postoperative air leakage, and guarantee a safe surgical margin. Therefore, 3D reconstruction is recommended for complex segmentectomy of the lower lung lobe., 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., (© 2022 Wang, Wang, Zhang, Yin, Fu, Cao and Zhao.)

Biomimetic nanozyme with natural enzyme-like activities has drawn extensive attention in cancer therapy, while its application was hindered by the limited catalytic efficacy in the complicated tumor microenvironment (TME). Herein, a hybrid biomimetic nanozyme combines polydopamine-decorated CuO with a natural enzyme of glucose oxidase (GOD), among which CuO is endowed with a high loading rate (47.1%) of GOD due to the elaborately designed hollow mesoporous structure that is constructed to maximize the cascade catalytic efficacy. In the TME, CuO could catalyze endogenous H 2 O 2 into O 2 for relieving tumor hypoxia and improving the catalytic efficacy of GOD. Whereafter, the amplified glucose oxidation induces starvation therapy, and the generated H 2 O 2 and H + enhance the catalytic activity of CuO. Significantly, the tumor-specific chemodynamic therapy (CDT) could be realized when CuO degraded into Cu 2+ in acidic and reductive TME. Furthermore, the photothermal therapy with high photothermal conversion efficiency (30.2%) is achieved under NIR-II laser (1064 nm) excitation, which could reinforce the generation of reactive oxygen species (•OH and •O 2 - ). The TME initiates the biochemical reaction cycle of CuO, O 2 , and GOD, which couples with an NIR-II-induced thermal effect to realize O 2 -promoted starvation and photothermal-chemodynamic combined therapy. This hybrid biomimetic nanozyme enlightens the further development of nanozymes in multimodal cancer therapy.

Objective: Alzheimer's disease (AD) is a socially significant neurodegenerative disorder among the elderly worldwide. An increasing number of studies have revealed that as a non-pharmacological intervention, exercise can prevent and treat AD. However, information regarding the research status of this field remains minimal. Therefore, this study aimed to analyze trends and topics in exercise and AD research by using a bibliometric method., Methods: We systematically searched the Web of Science Core Collection for published papers on exercise and AD. The retrieved data regarding institutions, journals, countries, authors, journal distribution, and keywords were analyzed using CiteSpace software. Meanwhile, the co-occurrence of keywords was constructed., Results: A total of 1,104 papers were ultimately included in accordance with our specified inclusion criteria. The data showed that the number of published papers on exercise and AD is increasing each year, with papers published in 64 countries/regions and 396 academic journals. The Journal of Alzheimer's Disease published the most papers (73 publications). Journals are concentrated in the fields of neuroscience and geriatrics gerontology. The University of Kansas and the United States are the major institution and country, respectively. The cited keywords show that oxidative stress, amyloid beta, and physical exercise are the research hotspots in recent years. After analysis, the neuroprotective effect of exercise was identified as the development trend in this field., Conclusions: Based on a bibliometric analysis, the number of publications on exercise and AD has been increasing rapidly, especially in the past 10 years. "Amyloid beta," "oxidative stress," and "exercise program" trigger the most interest among researchers in this field. The study of exercise program and mechanism of exercise in AD is still the focus of future research., 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 Chen, Fu, Song, Zhong and Guo.)

The present study was designed to evaluate the chemical extraction, chemical composition, and antioxidant and antibacterial properties of the total flavonoids in Willow Buds (TFW). We investigated the optimal extraction of TFW using response surface methodology (RSM). Chemical compounds were analyzed using Q-Orbitrap LC-MS/MS. The DPPH radical scavenging capacity, hydroxy radical inhibitory ability, and superoxide anion radical inhibitory ability were explored to determine the antioxidant properties of flavonoid extractions. The antibacterial effect was assessed via minimal inhibitory concentration. The results demonstrated that the optimal extraction conditions were an ethanol concentration of 50%, a time of 35 min, and a liquid/material ratio of 70:1 mL/g. Under these conditions, the yield of TFW was 7.57%. Eight flavonoids, a phenolic glycoside, and an alkaloid were enriched in the Willow Buds. The TFW exhibited significant antioxidant activity, with IC 50 values of 0.18-0.24 mg/mL and antimicrobial activity against Escherichia coli , Salmonella enterica , Staphylococcus aureus , and Streptococcus pneumoniae . TFW may be explored as potential and natural compounds in food and pharmacological applications.

To fabricate a novel stimuli-responsive system enabling controlled drug release and synergistic therapy, yolk-shell shaped bismuth sulfide modified with Au nanoparticles (Au-Bi 2 S 3 ) was prepared. The Au-Bi 2 S 3 nanomaterial with heterojunction structure exhibited excellent photothermal conversion efficiency and considerable free radicals yield under laser irradiation. The drug delivery capacity was confirmed by co-loading Berberine hydrochloride (BBR) and a phase change material 1-tetradecanol (PCM), which could be responsible for NIR light induced thermal controlled drug release. In vitro investigation demonstrated that Au-Bi 2 S 3 has cell selectivity, and with the assistance of the properties of Au-Bi 2 S 3 , the loaded drug could give full play to their cancer cell inhibition ability. Our work highlights the great potential of this nanoplatform which could deliver and control Berberine hydrochloride release as well as realize the synergistic anti-tumor strategy of photothermal therapy, photodynamic therapy and chemotherapy for tumor therapy., (© 2022 IOP Publishing Ltd.)