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Abstract Epigenetic reprogramming plays a critical role in cancer progression of cancer, and N6-methyladenosine (m6A) is the most common RNA modification in eukaryotes. The purpose of this study was to explore the related modification mode of m6A regulator construction and evaluate the invasion and migration of thyroid cancer. Our results showed that m6A levels were significantly increased in papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) samples, which may have been induced by the down-regulation of demethylase fat mass and obesity-associated gene (FTO). Moreover, FTO inhibited PTC and ATC invasion and metastasis through the epithelial-to-mesenchymal transition (EMT) pathway in vivo and in vitro. Mechanistically, an m6A-mRNA epitranscriptomic microarray showed that Cadherin 12 (CDH12) is the key target gene mediated by FTO in an m6A-dependent manner. CDH12 promotes invasion and metastasis through the EMT pathway in thyroid cancer, both in vivo and in vitro. Furthermore, we found that insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is an important m6A reading protein, that regulates the stability of CDH12 mRNA and mediates EMT progression, thereby promoting the invasion and metastasis of PTC and ATC. Thus, FTO, IGF2BP2 and CDH12 may be effective therapeutic targets for PTC and ATC with significant invasion or distant metastasis. Schematic summary of FTO-IGF2BP2 axis in modulation of CDH12 mRNA m6A and upregulation of CDH12 expression in the invasion and metastasis of thyroid carcinoma.

Abstract The primary reason for high mortality rates among cancer patients is metastasis, where tumor cells migrate through the bloodstream from the original site to other parts of the body. Recent advancements in technology have significantly enhanced our comprehension of the mechanisms behind the bloodborne spread of circulating tumor cells (CTCs). One critical process, DNA methylation, regulates gene expression and chromosome stability, thus maintaining dynamic equilibrium in the body. Global hypomethylation and locus-specific hypermethylation are examples of changes in DNA methylation patterns that are pivotal to carcinogenesis. This comprehensive review first provides an overview of the various processes that contribute to the formation of CTCs, including epithelial-mesenchymal transition (EMT), immune surveillance, and colonization. We then conduct an in-depth analysis of how modifications in DNA methylation within CTCs impact each of these critical stages during CTC dissemination. Furthermore, we explored potential clinical implications of changes in DNA methylation in CTCs for patients with cancer. By understanding these epigenetic modifications, we can gain insights into the metastatic process and identify new biomarkers for early detection, prognosis, and targeted therapies. This review aims to bridge the gap between basic research and clinical application, highlighting the significance of DNA methylation in the context of cancer metastasis and offering new avenues for improving patient outcomes.

ABSTRACT: Notoginseng Radix et Rhizoma (Sanqi in Chinese) is a precious traditional Chinese herbal medicine. It has the effect of dispersing blood stasis and stopping bleeding, reducing swelling and fixing pain. However, it tends to contaminate with harmful fungi during storage, which may make it much less effective. In order to understand the fungal contamination of Notoginseng Radix et Rhizoma and master its composition of the exogenous fungi. The surface fungi of Notoginseng Radix et Rhizoma samples collected from six Chinese provinces and districts were investigated by using dilution plate method. Detection of aflatoxins by UPLC-MS/MS. The results showed that Penicillium citrinum was dominantly isolated from Notoginseng Radix et Rhizoma samples from No.1 to No.4. Aspergillus flavus, which produces aflatoxin, was dominantly isolated from Notoginseng Radix et Rhizoma samples from No.5 and No.6. In addition, kinds of mycotoxin were assayed which were produced by three of those identified A. flavus. All three fungi strains produced aflatoxin B1 (AFB1) and one strain HBSQ1-5 additionally produced other three kinds of mycotoxin, AFB2, AFG1 and AFG2. It is the results implied that it will be very important to take serious cautions when using Notoginseng Radix et Rhizoma. As well as, understanding the composition of the exogenous fungi of Notoginseng Radix et Rhizoma and the strains of toxin-producing fungi, which can play an important role in guiding the storage of Notoginseng Radix et Rhizoma..

Abstract Background Knee osteoarthritis (KOA) characterized by degeneration of knee cartilage and subsequent bone hyperplasia is a prevalent joint condition primarily affecting aging adults. The pathophysiology of KOA remains poorly understood, as it involves complex mechanisms that result in the same outcome. Consequently, researchers are interested in studying KOA and require appropriate animal models for basic research. Chinese herbal compounds, which consist of multiple herbs with diverse pharmacological properties, possess characteristics such as multicomponent, multipathway, and multitarget effects. The potential benefits in the treatment of KOA continue to attract attention. Purpose This study aims to provide a comprehensive overview of the advantages, limitations, and specific considerations in selecting different species and methods for KOA animal models. This will help researchers make informed decisions when choosing an animal model. Methods Online academic databases (e.g., PubMed, Google Scholar, Web of Science, and CNKI) were searched using the search terms “knee osteoarthritis,” “animal models,” “traditional Chinese medicine,” and their combinations, primarily including KOA studies published from 2010 to 2023. Results Based on literature retrieval, this review provides a comprehensive overview of the methods of establishing KOA animal models; introduces the current status of advantages and disadvantages of various animal models, including mice, rats, rabbits, dogs, and sheep/goats; and presents the current status of methods used to establish KOA animal models. Conclusion This study provides a review of the animal models used in recent KOA research, discusses the common modeling methods, and emphasizes the role of traditional Chinese medicine compounds in the treatment of KOA.

Abstract Neoantigens derived from somatic mutations in Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), the most frequently mutated oncogene, represent promising targets for cancer immunotherapy. Recent research highlights the potential role of human leukocyte antigen (HLA) allele A*11:01 in presenting these altered KRAS variants to the immune system. In this study, we successfully generate and identify murine T-cell receptors (TCRs) that specifically recognize KRAS8–16 G12V from three predicted high affinity peptides. By determining the structure of the tumor-specific 4TCR2 bound to KRASG12V-HLA-A*11:01, we conduct structure-based design to create and evaluate TCR variants with markedly enhanced affinity, up to 15.8-fold. This high-affinity TCR mutant, which involved only two amino acid substitutions, display minimal conformational alterations while maintaining a high degree of specificity for the KRASG12V peptide. Our research unveils the molecular mechanisms governing TCR recognition towards KRASG12V neoantigen and yields a range of affinity-enhanced TCR mutants with significant potential for immunotherapy strategies targeting tumors harboring the KRASG12V mutation.

Abstract Ferroptosis, a therapeutic strategy for tumours, is a regulated cell death characterised by the increased accumulation of iron-dependent lipid peroxides (LPO). Tumour-associated long non-coding RNAs (lncRNAs), when combined with traditional anti-cancer medicines or radiotherapy, can improve efficacy and decrease mortality in cancer. Investigating the role of ferroptosis-related lncRNAs may help strategise new therapeutic options for breast cancer (BC). Herein, we briefly discuss the genes and pathways of ferroptosis involved in iron and reactive oxygen species (ROS) metabolism, including the XC −/GSH/GPX4 system, ACSL4/LPCAT3/15-LOX and FSP1/CoQ10/NAD(P)H pathways, and investigate the correlation between ferroptosis and LncRNA in BC to determine possible biomarkers related to ferroptosis.

Abstract The existing conventional treatments for breast cancer, including immune checkpoint blockade, exhibit limited effects in some cancers, particularly triple-negative breast cancer. Epigenetic alterations, specifically DNMT and HDAC alterations, are implicated in breast cancer pathogenesis. We demonstrated that DNMTs and HDACs are overexpressed and positively correlated in breast cancer. The combination of DNMT and HDAC inhibitors has shown synergistic antitumour effects, and our previously designed dual DNMT and HDAC inhibitor (termed DNMT/HDACi) 15a potently inhibits breast cancer cell proliferation, migration, and invasion and induces apoptosis in vitro and in vivo. Mechanistically, 15a induces a viral mimicry response by promoting the expression of endogenous retroviral elements in breast cancer cells, thus increasing the intracellular level of double-stranded RNA to activate the RIG-I–MAVS pathway. This in turn promotes the production of interferons and chemokines and augments the expression of interferon-stimulated genes and PD-L1. The combination of 15a and an anti-PD-L1 antibody had an additive effect in vivo. These findings indicate that this DNMT/HDACi has immunomodulatory functions and enhances the effectiveness of immune checkpoint blockade therapy. A novel dual DNMT and HDAC inhibitor induces viral mimicry, which induces the accumulation of dsRNA to activate tumoral IFN signalling and cytokine production to enhance the immune response in breast cancer.

Abstract Asparagine, an important amino acid in mammals, is produced in several organs and is widely used for the production of other nutrients such as glucose, proteins, lipids, and nucleotides. Asparagine has also been reported to play a vital role in the development of cancer cells. Although several types of cancer cells can synthesise asparagine alone, their synthesis levels are insufficient to meet their requirements. These cells must rely on the supply of exogenous asparagine, which is why asparagine is considered a semi-essential amino acid. Therefore, nutritional inhibition by targeting asparagine is often considered as an anti-cancer strategy and has shown success in the treatment of leukaemia. However, asparagine limitation alone does not achieve an ideal therapeutic effect because of stress responses that upregulate asparagine synthase (ASNS) to meet the requirements for asparagine in cancer cells. Various cancer cells initiate different reprogramming processes in response to the deficiency of asparagine. Therefore, it is necessary to comprehensively understand the asparagine metabolism in cancers. This review primarily discusses the physiological role of asparagine and the current progress in the field of cancer research.

Alterations in the tumor microenvironment are closely associated with the metabolic phenotype of tumor cells. Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor growth and metastasis. Existing studies have suggested that lactate produced by tumor cells can activate CAFs, yet the precise underlying mechanisms remain largely unexplored. In this study, we initially identified that lactate derived from lung cancer cells can promote nuclear translocation of NUSAP1, subsequently leading to the recruitment of the transcriptional complex JUNB-FRA1-FRA2 near the DESMIN promoter and facilitating DESMIN transcriptional activation, thereby promoting CAFs' activation. Moreover, DESMIN-positive CAFs, in turn, secrete IL-8, which recruits TAMs or promotes M2 polarization of macrophages, further contributing to the alterations in the tumor microenvironment and facilitating lung cancer progression. Furthermore, we observed that the use of IL-8 receptor antagonists, SB225002, or Navarixin, significantly reduced TAM infiltration and enhanced the therapeutic efficacy of anti-PD-1 or anti-PD-L1 treatment. This finding indicates that inhibiting IL-8R activity can attenuate the impact of CAFs on the tumor microenvironment, thus restraining the progression of lung cancer.

Hematopoietic cell kinase (Hck), a non-receptor tyrosine kinase belonging to the Src kinase family, is intricately linked to the pathogenesis of numerous human diseases, with a particularly pronounced association with cancer. Hck not only directly impacts the proliferation, migration, and apoptosis of cancer cells but also interacts with JAK/STAT, MEK/ERK, PI3K/AKT, CXCL12/CXCR4, and other pathways. Hck also influences the tumor microenvironment to facilitate the onset and progression of cancer. This paper delves into the functional role and regulatory mechanisms of Hck in various solid tumors. Additionally, it explores the implications of Hck in hematological malignancies. The review culminates with a summary of the current research status of Hck inhibitors, the majority of which are in the pre-clinical phase of investigation. Notably, these inhibitors are predominantly utilized in the therapeutic management of leukemia, with their combinatorial potential indicating promising avenues for future research. In conclusion, this review underscores the significance of the mechanism of Hck in solid tumors. This insight is crucial for comprehending the current research trends regarding Hck: targeted therapy against Hck shows great promise in both diagnosis and treatment of malignant tumors. Further investigation into the role of Hck in cancer, coupled with the development of specific inhibitors, has the potential to revolutionize approaches to cancer treatment.

Citri Reticulatae Pericarpium(CRP) and Polygalae Radix (PR) are traditional Chinese medicinal herbs and dietary supplements, and they are commonly included in most prescriptions. Fungal contamination in CRP and PR has long been a concern for the public. Thus, in this study, the fungal diversity and abundance in CRP and PR were investigated via high-throughput sequencing technology. Analysis was conducted to determine the differences in dominant fungal microbiomes between mouldy and nonmouldy samples, and the correlation between the total number of fungi and fungal diversity in medicinal herbs at different altitudes and latitudes with other research was explored. Results show the fungal contamination of all 12 samples. At the phylum level, Ascomycota prevailed the most in CRP and PR with relative abundances of 56.96%–99.26% and 23.28%–76.06%, respectively. The dominant genera in CRP comprised Xeromyces (2.57%–53.21%), Aspergillus (0.18%–23.04%), Cystofilobasidium (0.032%–28.03) and Xerochrysium (0.31%–34.41%). The dominant genera in PR included Wallemia (0.27%–56.20%), Aspergillus (2.03%–48.06%), Xeromyces (0.20%–48.28%) and Xerochrysium (0.093%–43.95%). Two potential toxigenic fungi were detected: Alternaria alternata and Aspergillus versicolor. In addition, combined with the results of previous studies, the findings reveal the possible relation of diversity and abundance of fungal species to altitude and latitude: As the altitude and latitude decrease, the diversity and abundance of fungal species may increase. In conclusion, for the first time, this study focused on altitude and latitude as indicators and integrated multiple research findings to explore the correlation between the total amount and diversity of fungal species in the two edible herbs. Results reveal the fungal contamination of the surfaces of CRP and PR and provide a theoretical basis for the prevention and control of their fungal contamination.

National parks play a crucial role in global biodiversity preservation, with China’s Giant Panda National Park (GPNP) serving as a key stronghold for protecting unique flora and fauna endemic to diverse mountainous regions. This study focused on unraveling the dynamics of diversity within local giant panda populations and their sympatric species in the Ya’an section of the GPNP. Five specific local population patches (LPPs) were selected as subjects, utilizing data from the 4th National Giant Panda Survey. Through identification, classification, and analysis of observed species within each LPP, α and β diversity patterns were revealed, leading to actionable recommendations. A comprehensive record of 34 species spanning 5 orders and 16 families was documented. Notably, 8 species were under the first-class of the National Key Protected Wildlife List in China, and the IUCN Red List has identified 3 species – Rhinopithecus roxellana, Moschus berezovskii, and Ailurus styani – as endangered, showing its high biodiversity and conservation significance. While α-diversity assessment highlighted the DaxianglingA2 (DXLA2) with the highest Shannon-Wiener and Simpson’s indices, the QionglaishanA3 (QLSA3) exhibited greater species richness. However, these differences lacked statistical significance (P > 0.05). The Jaccard similarity coefficient indicated a stronger turnover process compared to nestedness. The dominance of turnover in total β-diversity accentuated the importance of encompassing all five LPPs in conservation strategies. The study underscored the imperative of conservation management for each LPP, with a focus on enhancing habitat connectivity between disparate small LPPs to prevent species extinction by fostering species exchange and gene flow. This pioneering research shed light on spatial utilization patterns and diversity drivers for local giant panda populations and their sympatric species within the GPNP. It provides valuable references to appraise conservation strategy effectiveness and offers scientific backing to optimize biodiversity conservation and management within national parks and protected areas.

Abstract PARP inhibitors and HDAC inhibitors have been approved for the clinical treatment of malignancies, but acquired resistance of or limited effects on solid tumors with a single agent remain as challenges. Bioinformatics analyses and a combination of experiments had demonstrated the synergistic effects of PARP and HDAC inhibitors in triple-negative breast cancer. A series of novel dual PARP and HDAC inhibitors were rationally designed and synthesized, and these molecules exhibited high enzyme inhibition activity with excellent antitumor effects in vitro and in vivo. Mechanistically, dual PARP and HDAC inhibitors induced BRCAness to restore synthetic lethality and promoted cytosolic DNA accumulation, which further activates the cGAS–STING pathway and produces proinflammatory chemokines through type I IFN-mediated JAK–STAT pathway. Moreover, these inhibitors promoted neoantigen generation, upregulated antigen presentation genes and PD-L1, and enhanced antitumor immunity when combined with immune checkpoint blockade therapy. These results indicated that novel dual PARP and HDAC inhibitors have antitumor immunomodulatory functions in triple-negative breast cancer. Novel dual PARP and HDAC inhibitors induce BRCAness to restore synthetic lethality, activating tumoral IFN signaling via the cGAS–STING pathway and inducing cytokine production, promoting neoantigen generation and presentation to enhance the immune response.

Abstract Background The role of Serum uric acid (SUA) in acute myocardial infarction (AMI) was controversial, which might be influenced by the renal clearance function of the patients. The present study aimed to explore the association between serum uric acid to serum creatinine ratio (SUA/Scr), reflecting a net production of SUA, and the in-hospital outcomes of elderly patients with AMI. Methods In this retrospective study, a total of 330 elderly AMI patients (≥ 75 years) were enrolled. Data of SUA and Scr on admission were collected to calculate SUA/Scr ratio. Logistic regression analysis and receiver-operating curves were performed to assess the association between SUA/Scr ratio and in-hospital major adverse cardiovascular events (MACEs) and all-cause death. Results Among the 330 patients, 68 patients had MACEs and 44 patients died. Patients with MACEs or died had lower SUA/Scr values compared with those without MACEs or survival (P

Summary: The activation and specialization of regulatory T cells (Tregs) are crucial for maintaining immune self-tolerance; however, the regulation of these processes by histone modifications is not fully understood. Here, we show that T cell-specific deletion of the lysine methyltransferase MLL1 results in a spontaneous lymphocyte proliferation phenotype in aged mice without disturbing the development of conventional T cells and Tregs. Treg-specific MLL1 ablation leads to a systemic autoimmune disease associated with Treg dysfunction. Moreover, RNA sequencing demonstrates that the induction of multiple genes involved in Treg activation, functional specialization, and tissue immigration is defective in MLL1-deficient Tregs. This dysregulation is associated with defects in H3K4 trimethylation at these genes’ transcription start sites. Finally, using a T-bet fate-mapping mouse system, we determine that MLL1 is required to establish stable Th1-type Tregs. Thus, MLL1 is essential in optimal Treg function by providing a coordinated chromatin context for activation and specialization.

Environmental exposures during pregnancy have been associated with adverse obstetric outcomes. However, limited and inconsistent evidence exists regarding the association between air temperature exposure and the risk of preeclampsia (PE). This study aimed to evaluate the correlation between ambient temperature exposure during pregnancy and PE risk, as well as identify the specific time window of temperature exposure that increases PE risk. A population-based cohort study was conducted from January 2012 to April 2022 in Guangzhou, China. Pregnant women were recruited in early pregnancy and followed until delivery. A total of 3,314 PE patients and 114,201 normal pregnancies were included. Ambient temperature exposures at different gestational weeks were recorded for each participant. Logistic regression models were used to evaluate the correlation between ambient temperature exposure and PE risk. Stratified analyses were conducted based on maternal age and pre-pregnancy BMI. Distributed lag models were employed to identify the time window of temperature exposure related to PE. Exposure to extreme high temperature (aOR = 1.24, 95 % CI 1.12–1.38) and moderate high temperature (aOR = 1.22, 95 % CI 1.10–1.35) during early pregnancy was associated with an increased risk of PE. Furthermore, women with higher pre-pregnancy BMI had a higher risk of developing PE when exposed to high temperature during early pregnancy compared to normal-weight women. The time window of temperature exposure related to PE was identified as pregnancy weeks 1 to 8. This study provides evidence for the association of high temperature exposure during early pregnancy with the risk of PE, as well as identifies the specific time window of temperature exposure related to PE. These findings have implications for developing potential strategies to protect pregnant women, particularly those with higher pre-pregnancy BMI, from the adverse effects of extreme temperatures during early pregnancy.

Regeneration and repair are prerequisites for maintaining effective function of skeletal muscle under high energy demands, and myogenic differentiation is one of the key steps in the regeneration and repair process. A striking feature of the process of myogenic differentiation is the alteration of mitochondria in number and function. Mitochondrial dysfunction can activate a number of transcriptional, translational and post-translational programmes and pathways to maintain cellular homeostasis under different types and degrees of stress, either through its own signaling or through constant signaling interactions with the nucleus and cytoplasm, a process known as the mitochondrial stress responses (MSRs). It is now believed that mitochondrial dysfunction is closely associated with a variety of muscle diseases caused by reduced levels of myogenic differentiation, suggesting the possibility that MSRs are involved in messaging during myogenic differentiation. Also, MSRs may be involved in myogenesis by promoting bioenergetic remodeling and assisting myoblast survival during myogenic differentiation. In this review, we will take MSRs as an entry point to explore its concrete regulatory mechanisms during myogenic differentiation, with a perspective to provide a theoretical basis for the treatment and repair of related muscle diseases.

ABSTRACTGram-negative bacteria have a thin peptidoglycan layer between the cytoplasmic and outer membranes protecting the cell from osmotic challenges. Hydrolases of this structure are needed to cleave bonds to allow the newly synthesized peptidoglycan strands to be inserted by synthases. These enzymes need to be tightly regulated and their activities coordinated to prevent cell lysis. To better understand this process in Escherichia coli, we probed the genetic interactions of mrcA (encodes PBP1A) and mrcB (encodes PBP1B) with genes encoding peptidoglycan amidases and endopeptidases in envelope stress conditions. Our extensive genetic interaction network analysis revealed relatively few combinations of hydrolase gene deletions with reduced fitness in the absence of PBP1A or PBP1B, showing that none of the amidases or endopeptidases is strictly required for the functioning of one of the class A PBPs. This illustrates the robustness of the peptidoglycan growth mechanism. However, we discovered that the fitness of ∆mrcB cells is significantly reduced under high salt stress and in vitro activity assays suggest that this phenotype is caused by a reduced peptidoglycan synthesis activity of PBP1A at high salt concentration.IMPORTANCEEscherichia coli and many other bacteria have a surprisingly high number of peptidoglycan hydrolases. These enzymes function in concert with synthases to facilitate the expansion of the peptidoglycan sacculus under a range of growth and stress conditions. The synthases PBP1A and PBP1B both contribute to peptidoglycan expansion during cell division and growth. Our genetic interaction analysis revealed that these two penicillin-binding proteins (PBPs) do not need specific amidases, endopeptidases, or lytic transglycosylases for function. We show that PBP1A and PBP1B do not work equally well when cells encounter high salt stress and demonstrate that PBP1A alone cannot provide sufficient PG synthesis activity under this condition. These results show how the two class A PBPs and peptidoglycan hydrolases govern cell envelope integrity in E. coli in response to environmental challenges and particularly highlight the importance of PBP1B in maintaining cell fitness under high salt conditions.

ABSTRACTIt is urgently needed to evaluate the necessity and benefits of booster vaccination against the coronavirus 2 of the severe acute respiratory syndrome (SARS-CoV-2) Omicron to facilitate clinical decision-making for 2019 coronavirus disease (COVID-19) convalescents. We conducted a multicenter, prospective clinical trial (registration number: ChiCTR2100045810) in the first patients with COVID-19 from 28 January 2020 to 20 February 2020 to assess the long-term durability of neutralizing antibodies against live Omicron BA.5 and further assess the efficiency and safety of CoronaVac in the convalescent group. A total of 96 COVID-19 convalescents were enrolled in this study. Neutralizing antibody titers in convalescents were significantly reduced in 9–10 months. A dose-refreshing vaccination in 28 convalescents with an antibody titer below 96 significantly induced neutralizing antibodies against live Omicron by 4.84-fold. Meanwhile, the abundance of naive T cells increased dramatically, and TEMRA and TEM cells gradually decreased after vaccination. Activation-induced cell death and apoptosis-related genes were significantly elevated after vaccination in all T-cell subtypes. One-dose booster vaccination was effective in inducing a robust antibody response against SARS-CoV-2 Omicron in COVID-19 convalescents with low antibody titers. However, vaccine-mediated T-cell consumption and regeneration patterns may be detrimental to the antiviral response.IMPORTANCEThe globally dominant coronavirus 2 of the severe acute respiratory syndrome (SARS-CoV-2) Omicron variant raises the possibility of repeat infections among 2019 coronavirus disease (COVID-19) convalescents with low neutralizing antibody titers. The importance of this multicenter study lies in its evaluation of the long-term durability of neutralizing antibodies in COVID-19 convalescents and the efficacy of a booster vaccination against the live Omicron. The findings suggest that a one-dose booster vaccination is effective in inducing a robust antibody response against SARS-CoV-2 Omicron in convalescents with low antibody titers. However, the study also highlights the potential detrimental effects on the antiviral response due to vaccine-mediated T-cell consumption and regeneration patterns. These results are crucial for facilitating clinical decision-making for COVID-19 convalescents and informing public health policies regarding booster vaccinations.

Purpose: To study the role of mitochondrial metabolism and obtain novel biomarkers in immunotherapy for non-small cell lung cancer (NSCLC). Methods: We collected the 188 genes involved in mitochondrial metabolism(MMGs) from the MSIGDB project and then quantified the activity of mitochondrial metabolism. All the NSCLC patients were divided into C1 and C2 clusters based on the 26 prognosis-related MMGs. The differences in biology, differential immune microenvironment, chronic hypoxia and prognosis between C1 and C2 patients were also analyzed. In addition, we validated the results of bioinformatics analysis in lung cancer tissues and cell lines. Results: Patients in the C2 cluster had a higher level of mitochondrial metabolism. Patients in the C2 cluster responded better to immunotherapy and had a lower level of T-cell exclusion. The markers of T-cell failure were upregulated in the C1 patients. Hypoxia can lead to a high percentage of C1 patients. ADH1C might be involved in mitochondrial metabolism and immunotherapy response, which can be affected by hypoxia, making it an underlying biomarker. The expression levels of ADH1C in BEAS-2B, H1299, A549 and H460 cells were detected, revealing that ADH1C is upregulated in lung cancer cells. We observed that patients with low ADH1C expression had a longer survival time. The enzyme activities of HK, PK, LDH and SDH were significantly reduced in H1299 and H460 cells with ADH1C knockdown, along with more ROS. Furthermore, the expression levels of PD-L1 and HHLA2 in tumor tissues were analyzed, which found that ADH1C was significantly positively correlated with the expression of PD-L1 and HHLA2. Conclusions: In summary, our study comprehensively explored the molecules involved in mitochondrial metabolism and their role in immunotherapy and T lymphocyte failure.

To ensure efficient and convenient operation and maintenance of Hainan operation and maintenance system for geoscience observarory network, the project is based on B/S architecture, using Django, Uwsgi, Virtualenv and Python and other technical means to design and implement a set of Hainan geophysical station network operation and maintenance auxiliary system. The platform system has the characteristics of high efficiency, convenience and easy operation, and can realize one-click parallel transmission of backed up data from server to mobile hard disk or computer, it can realize one-click quick access to service software and hardware conditions and database status. In addition, one-click backup of important database data through page visualization operation can avoid repetitive operation, and one-click output of monthly report of Excel tables with parameters such as server and database can be realized. Through the auxiliary work of this platform system, it is helpful to improve the work efficiency of operation and maintenance of Hainan geophysical station network, reduce the burden of operation and maintenance, and provide data integrity, continuity, safety and security work.

In this study, to improve the fatigue strength of the LDED (laser-directed energy deposition) 316L stainless steel, an in situ ultrasonic rolling technology is developed to assist the laser-directed energy deposition process (LDED-UR). The microstructural characteristics and fatigue behavior are comprehensively discussed. The results show that the average size of pores of the LDED-UR alloy is about 10.2 μm, which is much smaller than that of the LDED alloy (34.1 μm). Meanwhile, the density of the LDED alloy is also enhanced from 98.26% to 99.27% via the in situ ultrasonic rolling. With the application of the in situ ultrasonic rolling, the grains are transformed into fully equiaxed grains, and their average grain size is greatly reduced from 84.56 μm to 26.93 μm. The fatigue limit of the LDED-UR alloy is increased by 29% from 210 MPa (LDED alloy) to 270 MPa, which can be ascribed to the decreased porosity and the fine grains. In particular, the crack initiation site of the LDED alloy is located at the surfaces, while it is nucleated from the sub-surface for the LDED-UR alloy. This is mainly attributed to the compression residual stress induced by the in situ ultrasonic rolling. This research offers a valuable understanding of the failure mechanisms in additively manufactured metals, guiding the development of effective strategies to improve their fatigue threshold under severe operating conditions.

Joint photographic experts group (JPEG) images are widely used on the Internet due to their ability to maintain good picture quality while requiring less storage space.Reversible data hiding (RDH) techniques for JPEG images enable the hiding and extraction of secret information while allowing for lossless restoration of the original image.RDH is of great significance in file management and image authentication.However, many existing RDH methods result in a significant increase in the storage space of the encoded image after embedding secret information.For methods based on discrete cosine transform (DCT) coefficient embedding, the key issue that affects the performance of reversible information hiding in JPEG images is how to select the frequency band position.A reversible information hiding method for JPEG images was proposed, based on optimal DCT frequency embedding.The entropy decoded JPEG image was divided into 8×8 non-overlapping DCT blocks.The average texture complexity of each DCT block was calculated and ordered in ascending order.Then the alternating current (AC) in adjacent DCT blocks was paired pairwise.By satisfying the capacity of the information to be embedded, the optimal AC coefficient frequency position set was obtained from the distortion cost function of the AC coefficient frequency.The secret information was embedded according to the designed two-dimensional histogram mapping strategy.Experimental results demonstrate that the proposed method can reduce the expansion of the loaded image file’s storage size compared to existing methods, while maintaining good visual quality of the cover image.

Spatial and temporal variations of nutrients and COD in the coastal waters of Yancheng coastal areas were studied based on three seasonal cruises during 2018. Both the organic pollution appraisal index (Q) and the eutrophication index method (E) were used to evaluate the eutrophication of the seawater. The results showed that the spatial-temporal distribution of E and Q were similar in the study area and showed a greater sequence of spring than that of autumn, which is greater than that of summer in the seasonal variation, decreasing gradually away from the shore. The seasonal variation of environmental factors was significant.The clusters analysis showed that the environmental factors could be divided into two groups:the abandoned yellow river and radial sand ridges. The input of rivers entering the sea in Yancheng had a strong influence on the distribution of pollutants,while the hydrodynamic conditions also affected the distribution of environmental factors.The temporal and spatial distribution of the eutrophication index were regulated to a large extent by the runoff.

Background and objective Immune checkpoint inhibitors (ICIs) therapy lacks viable biomarkers for response and prognosis prediction. This study aimed to investigate the correlation of peripheral blood laboratory test results combined with lymphocyte subset ratios to the response and prognosis of immunotherapy in advanced lung cancer. Methods Advanced lung cancer patients admitted to West China Hospital, Sichuan University from May 2021 to July 2023 were prospectively enrolled in this study. Clinical data and peripheral blood were collected before and after treatment and lymphocyte subset ratios were analyzed by flow cytometry. Logistic regression was used to identify factors correlated to ICIs treatment efficacy. Cox modeling was applied to explore the prognostic factors. Results Logistic regression showed that the baseline level of transcription factor T cell factor 1 (TCF1)+CD8+ T cell ratio and peripheral white blood cell (WBC) count, lymphocyte percentage, cytokeratin 19 fragment (CYFRA21-1) after 1 cycle of ICIs treatment were the potential predictors for ICIs response (P

Abstract Background With remarkable success and few side effects, induction chemoimmunotherapy has been used to improve the prognosis of patients with resectable or potentially resectable non-small cell lung cancer (NSCLC), even in stage III disease. However, for patients who are medically inoperable, unresectable or refuse surgery after induction chemoimmunotherapy, it is unclear whether patients should be treated with concurrent chemoradiotherapy (cCRT) or radiotherapy (RT) alone considering patient safety and tolerability. This study aimed to determine whether cCRT is safe and superior to RT alone after chemoimmunotherapy for stage III NSCLC. Methods Patients diagnosed with stage III NSCLC who received chemoimmunotherapy followed by cCRT/RT alone without surgery at Tianjin Cancer Hospital between November 2018 to December 2021 were retrospectively collected. Patients were divided into two groups: induction chemoimmunotherapy followed by cCRT (cCRT cohort) or RT alone (RT alone cohort). Kaplan-Meier method was used to estimate survival. Univariate and multivariate Cox regression models were adopted to estimate risk factors for PFS. Results Sixty-five patients were included, with 44 (67.7%) received RT alone and 21 (32.3%) received cCRT. Patients in the cCRT group had significantly prolonged PFS (HR = 0.155, p = 0.004), LPFS (HR = 0.225, p = 0.029) and DMFS (HR = 0.028, p = 0.006) than those in the RT alone group. Albeit nonsignificant, a trend toward improved OS (HR = 0.030, p = 0.069) was also observed in the cCRT group. The multivariate analysis further confirmed that cCRT (HR = 0.141, p = 0.008) was the independent factor for promoting a favorable PFS. Treatment-related adverse events were similar between groups (p > 0.05). Patients with consolidation immunotherapy exhibited a trend of improved PFS (HR = 0.398, p = 0.274) and numerically better OS (HR = 0.018, p = 0.209) compared with those without. Conclusions For patients with unresectable stage III NSCLC, cCRT following chemoimmunotherapy appears to be safe and may prolong survival compared with radiotherapy alone. Further investigations on the combination of chemoimmunotherapy and CRT are warranted.

Abstract Aged livers have shown aggravated liver ischemia and reperfusion (IR) injury. Timely efferocytosis of apoptotic cells is a key mechanism for avoiding excessive inflammation and tissue injury. Here, we investigated the alteration of efferocytosis by aged macrophages and its role in regulating macrophage STING (stimulator of interferon genes) signaling and liver IR injury. Aged and young mice were subjected to liver partial IR model. Liver injury and inflammation were measured. Efferocytosis by aged macrophages and the underlying regulatory mechanism were analyzed as well. Aged macrophages exhibited impaired efferocytosis with decreased MerTK (c-mer proto-oncogene tyrosine kinase) activation, which was reversed by treatment of the MerTK CRISPR activation plasmid. Increased MerTK cleavage by ADAM17 (a disintegrin and metalloproteinase 17) due to enhanced ROS (reactive oxygen species) levels contributed to defective efferocytosis by aged macrophages. MerTK activation by suppressing ADAM17 or ROS improved aged macrophage efferocytosis, leading to reduced inflammatory liver injury. Moreover, increased apoptotic hepatocytes, DNA accumulation, and macrophage STING activation were observed in aged ischemic livers. Improvement in efferocytosis by aged macrophages via MerTK activation suppressed STING activation and inflammatory liver injury. Our study demonstrates that aging suppresses MerTK- mediated macrophage efferocytosis to promote macrophage STING activation and inflammatory liver IR injury, suggesting a new mechanism and potential therapy to promote inflammation resolution and efferocytosis in aged livers.

In this paper, we propose a contact-free wheat moisture monitoring system, termed Wi-Wheat+, to address the several limitations of the existing grain moisture detection technologies, such as time-consuming process, expensive equipment, low accuracy, and difficulty in real-time monitoring. The proposed system is based on Commodity WiFi and is easy to deploy. Leveraging WiFi CSI data, this paper proposes a feature extraction method based on multi-scale and multi-channel entropy. The feasibility and stability of the system are validated through experiments in both Line-Of-Sight (LOS) and Non-Line-Of-Sight (NLOS) scenarios, where ten types of wheat moisture content are tested using multi-class Support Vector Machine (SVM). Compared with the Wi-Wheat system proposed in our prior work, Wi-Wheat+ ​has higher efficiency, requiring only a simple training process, and can sense more wheat moisture content levels.

In the early stage, N4-acetylcytidine (ac4C) was regarded as a conservative nucleoside present on tRNA and rRNA. Recently, studies have shown that ac4C also exists in human and yeast mRNA. N-Acetyltransferase-like protein 10 (NAT10) is the first enzyme to be found to catalyze ac4C production in eukaryotic RNA and has acetyltransferase activity and RNA-binding activity. Here, we first describe the structure and cellular localization of NAT10. Then, we conclude the active roles of NAT10 as the ac4C “writer” in mRNA stability and translation efficiency, oocyte maturation, bone remodeling, and fatty acid metabolism. With respect to disease, we focused on the promoting functions of NAT10 in proliferation, metastasis, and apoptosis in multiple tumors. The immune regulatory role of NAT10 in systemic lupus erythematosus and the maintenance role of NAT10 in virus RNA stability and replication in influenza A virus are also introduced. This review identifies NAT10 as a potential target for diagnosis, therapy, and prognosis in clinical application.

Summary: Insects have an effective innate immune system to protect themselves against fungal invasion. Metarhizium employs a toxin-based strategy using a nonribosomal peptide called destruxin A (DA) to counteract the host immune response. However, the mechanism by which DA inhibits insect immunity is still unclear. Here, we identified 48 DA-binding proteins in silkworm hemolymph, with the binding affinity (KD) ranging from 2 to 420 μM. Among these proteins, hemocytin, an important immune factor, was determined to be the strongest DA-binding protein. DA binds to hemocytin and regulates its conformation in a multisite manner. Furthermore, DA exerts a significant inhibitory effect on hemocytin-mediated hemocyte aggregation. By disrupting the interaction between hemocytin, actin A3, and gelsolin, DA prevents the transformation of granules into vesicles in hemocytes. These vesicles are responsible for storing, maturing, and exocytosing hemocytin. Therefore, hemocytin secretion is reduced, and the formation of structures that promote aggregation in outer hemocytes is inhibited.

Introduction Perioperative rehabilitation (PORT) has shown a positive effect on patients undergoing cardiac surgery. However, there are minimal data on the impact of short-term PORT in cardiac surgery, which is associated with higher postoperative morbidity and mortality. The trial will assess the efficacy of short-term PORT in reducing in-hospital mortality, postoperative pulmonary complications and length of stay, compared with the usual care in cardiac surgical patients.Methods and analysis This is a single-centre prospective, randomised, open, controlled trial with a 1:1 ratio. Consecutive 800 adult patients undergoing elective valve surgery will be randomised to either usual care or in-hospital short-term PORT that consists of education, inspiratory muscle training, active cycle of breathing techniques and early mobilisation. The primary outcome of this study will be a composite of in-hospital all-cause mortality, incidence of postoperative pulmonary complications and the ratio of postoperative hospitalisation >7 days.Ethics and dissemination The PORT study was granted by the Medical Research Ethics Committee of Guangdong Provincial People’s Hospital in August 2018. Findings will be disseminated to patients, clinicians and commissioning groups through peer-reviewed publication.Trial registration number NCT03709511.

Thymus-originated tTregs and in vitro induced iTregs are subsets of regulatory T cells. While they share the capacity of immune suppression, their stabilities are different, with iTregs losing their phenotype upon stimulation or under inflammatory milieu. Epigenetic differences, particularly methylation state of Foxp3 CNS2 region, provide an explanation for this shift. Whether additional regulations, including cellular signaling, could directly lead phenotypical instability requires further analysis. Here, we show that upon TCR (T cell receptor) triggering, SOCE (store-operated calcium entry) and NFAT (nuclear factor of activated T cells) nuclear translocation are blunted in tTregs, yet fully operational in iTregs, similar to Tconvs. On the other hand, tTregs show minimal changes in their chromatin accessibility upon activation, in contrast to iTregs that demonstrate an activated chromatin state with highly accessible T cell activation and inflammation related genes. Assisted by several cofactors, NFAT driven by strong SOCE signaling in iTregs preferentially binds to primed-opened T helper (TH) genes, resulting in their activation normally observed only in Tconv activation, ultimately leads to instability. Conversely, suppression of SOCE in iTregs can partially rescue their phenotype. Thus, our study adds two new layers, cellular signaling and chromatin accessibility, of understanding in Treg stability, and may provide a path for better clinical applications of Treg cell therapy.

Background: Fibroblast growth factor 1 (FGF1) is extensively amplified in many tumors and accelerates tumor invasion and metastasis. However, the role and precise molecular mechanism by which FGF1 participates in thyroid cancer (TC) are still unclear. Methods: Quantitative real-time polymerase chain reaction- and western blotting were used to detect the mRNA and protein levels of FGF1, high mobility group A (HMGA1), epithelial-to-mesenchymal transition (EMT)-related factors, and FGF receptors in both TC tissues and cell lines. Immunohistochemistry was conducted to examine the expression of FGF1 and HMGA1. Immunofluorescence staining was used to detect the coexpression of FGF1 and HMGA1. Transwell and wound healing assays were conducted to evaluate the effects of FGF1 on the capacity of invasion and migration in cells. Results: FGF1 was upregulated in papillary thyroid carcinoma (PTC) tissues and cell lines and was relatively higher in PTC tissues with cervical lymph node metastasis. Furthermore, FGF1 promotes invasion and metastasis through the EMT pathway. Mechanistically, FGF1 promotes EMT through intracellular function independent of FGF receptors. Interestingly, we demonstrated that FGF1 could upregulate HMGA1 in TC cells, and the correlation of FGF1 and HMGA1 was positive in PTC tissues. FGF1 and HMGA1 had obvious colocalization in the nucleus. We further revealed that FGF1 promotes the invasion and migration of TC cells through the upregulation of HMGA1. Conclusion: Intracellular FGF1 could promote invasion and migration in TC by mediating the expression of HMGA1 independent of FGF receptors, and FGF1 may be an effective therapeutic target in TC.

Immune checkpoint blockade (ICB) therapies, that is, using monoclonal antibodies to reinvigorate tumor-reactive, antigen-specific T cells from the inhibitory effects of CTLA-4, PD-1 and PD-L1 immune checkpoints, have revolutionized the therapeutic landscape of modern oncology. However, only a subset of patients can benefit from the ICB therapy. Biomarkers associated with ICB response, resistance and prognosis have been subjected to intensive research in the past decade. Early studies focused on the analysis of tumor specimens and their residing microenvironment. However, biopsies can be challenging to obtain in clinical practice, and do not reflect the dynamic changes of immunological parameters during the ICB therapy. Recent studies have investigated profiles of antigen-specific T cells derived from the peripheral compartment using multi-omics approaches. By tracking the clonotype and diversity of tumor-reactive T cell receptor repertoire, these studies collectively establish that de novo priming of antigen-specific T cells in peripheral blood occurs throughout the course of ICB, whereas preexisting T cells prior to ICB are exhausted to various degrees. Here, we review what is known about ICB-induced T cell phenotypic and functional changes in cancer patients both within the tumor microenvironment and in the peripheral compartment. A better understanding of parameters influencing the response to ICBs will provide rationales for developing novel diagnostics and combinatorial therapeutic strategies to maximize the clinical efficacies of ICB therapies.

Abstract Background Triple‐negative breast cancer (TNBC), a heterogeneous subtype of breast cancer (BC), had poor prognosis. Endoplasmic reticulum (ER) stress was responsible for cellular processes and played a crucial role in the cell function. ER stress is a complex and dynamic process that can induce abnormal apoptosis and death. However, the underlying mechanism of ER stress involved in TNBC is not well defined. Methods We identified ubiquitin‐specific protease 19 (USP19) as a TNBC negative regulator for further investigation. The effects of USP19 on BC proliferation were assessed in vitro using proliferation test and cell‐cycle assays, while the effects in vivo were examined using a mouse tumorigenicity model. Through in vitro flow cytometric analyses and in vivo TUNEL assays, cell apoptosis was assessed. Proteomics was used to examine the proteins that interact with USP19. Results Multiple in vitro and in vivo tests showed that USP19 decreases TNBC cell growth while increasing apoptosis. Then, we demonstrated that USP19 interacts with deubiquitinates and subsequently stabilises family molecular chaperone regulator 6 (BAG6). BAG6 can boost B‐cell lymphoma 2 (BCL2) ubiquitination and degradation, thereby raising ER calcium (Ca2+) levels and causing ER stress. We also found that the N6‐methyladenosine (m6A) “writer” methyltransferase‐like 14 (METTL14) increased global m6A modification. Conclusions Our study reveals that USP19 elevates the intracellular Ca2+ concentration to alter ER stress via regulation of BAG6 and BCL2 stability and may be a viable therapeutic target for TNBC therapy.

Inflammatory bowel disease is a relapsing inflammatory disease seriously endanger human health. Wedelolactone (WED) is a major active ingredient from Eclipta prostrata (L.) L. and has shown anti-inflammatory effects. However, the mechanism of WED in treating inflammatory colitis remains unknown. We aimed to investigate the mechanisms of WED in treating ulcerative colitis through lipidomic study. Sixty male C57BL/6 mice were exposed to DSS to induce acute colitis. Disease progression was judged by the disease activity index (DAI) and pathological changes of colon tissue. An ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) method was performed for colon and plasma lipidomics analyses. Differential metabolites in the three groups were distinguished by univariate and multivariate analysis. WED exerted anti-inflammatory effects representing by body weight and DAI score. Three metabolites were identified in plasma and 20 in colon. According to pathway analysis, the effects of WED on colitis were associated with seven pathways. The glycerophospholipid metabolism and ether lipid metabolism were the primary pathways. The findings provide important insight of the mechanism of WED in treating DSS induced colitis through lipidomic perspective.

Warming and eutrophication are universal threats to bay ecosystems. However, the response of zooplankton varies due to diverse environmental settings and species composition. As a long and narrow semi-enclosed bay with low salinity (18–27) in the East China Sea, Xiangshan Bay (XSB) is jointly affected by global warming and the thermal drainage, which makes it an appropriate region for ascertaining the response of zooplankton to warming under low-salinity background. We examined the long-term changes in the abundance, biomass and dominant species of large mesozooplankton (LMZ; >505 μm) over four decades in XSB, and found downward trends in the annual abundance and biomass, and the biomass peak shifting from summer to spring since 2010. In addition, the relative abundance of cold-temperate species decreased, while that of warm-temperate/warm-water species and small-sized zooplankton increased. The decreased LMZ abundance and biomass in XSB were supposed to be related to low gelatinization compared with the other semi-enclosed bays in China, Jiaozhou Bay (JZB) in the Yellow Sea and Daya Bay (DYB) in the South China Sea, where the LMZ biomass and abundance increased or fluctuated mainly linked to the increase in gelatinous zooplankton. Salinity, temperature, and nutrient concentration are important factors affecting gelatinization. By comparing the background salinity and magnitudes of temperature and nutrient increases among the three bays, we speculated that the lower salinity (XSB: 18–27, JZB: 30–32, DYB: 30–34) influenced by freshwater input of the Changjiang River might be a potential factor causing the low gelatinization in XSB, as the similar upward trends in both nutrient concentration and temperature were observed in the three bays. This study suggests that miniaturization with low gelatinization and a decrease in cold-temperate species were the main responses of zooplankton to warming in the low-salinity bay in the East China Sea, which may lead to a specific pelagic ecosystem evolution.

Abstract A communication channel should be built to transmit information from one place to another. Imaging is 2 or higher dimensional information communication. Conventionally, an imaging channel comprises a lens with free space at its both sides, whose transfer function is usually known and hence the response of the imaging channel can be well defined. Replacing the lens with a thin scattering medium, the image can still be extracted from the detected optical field, suggesting that the scattering medium retains or reconstructs not only energy but also information transmission channels. Aided by deep learning, we find that unlike the lens system, there are different channels in a scattering medium: the same scattering medium can construct different channels to match the manners of source coding. Moreover, it is found that without a valid channel, the convolution law for a spatial shift-invariant system (the output is the convolution of the point spread function and the input object) is broken, and in this scenario, information cannot be transmitted onto the detection plane. Therefore, valid channels are essential to transmit information through even a spatial shift-invariant system. These findings may intrigue new adventures in imaging through scattering media and reevaluation of the known spatial shift-invariance in various areas.

Abstract Long non-coding RNAs (lncRNAs) have been found to play essential roles in the cell proliferation, fission and differentiation, involving various processes in humans. Recently, there is more and more interest in exploring the relationship between lncRNAs and tumors. Many latest evidences revealed that LINC00467, an oncogenic lncRNA, is highly expressed in lung cancer, gastric cancer, colorectal cancer, hepatocellular carcinoma, breast cancer, glioblastoma, head and neck squamous cell carcinoma, osteosarcoma, and other malignant tumors. Besides, LINC00467 expression was linked with proliferation, migration, invasion and apoptosis via the regulation of target genes and multiple potential pathways. We reviewed the existing data on the expression, downstream targets, molecular mechanisms, functions, relevant signaling pathways, and clinical implications of LINC00467 in various cancers. LINC00467 may serve as a novel biomarker or therapeutic target for the diagnosis and prognosis of various human tumors.

Summary: Foxp3 is the master transcription factor for regulatory T cells (Tregs). Alternative splicing of human Foxp3 results in the expression of two isoforms: the full length and an exon 2-deleted protein. Here, AlphaFold2 predictions and in vitro experiments demonstrate that the N-terminal domain of Foxp3 inhibits DNA binding by moving toward the C terminus and that this movement is mediated by exon 2. Consequently, we find that Foxp3Δ2-bearing thymus-derived Tregs (tTregs) in the peripheral lymphoid organ are less sensitive to T cell receptor (TCR) stimulation due to the enhanced binding of Foxp3Δ2 to the Batf promoter and are hyporesponsive to interleukin-2 (IL-2). In contrast, among RORγt+ peripherally induced Tregs (pTregs) in the large intestine, Foxp3Δ2 pTregs express many more RORγt-related genes, conferring a competitive advantage. Together, our results reveal that alternative splicing of exon 2 generates an active form of Foxp3, which plays a differential role in regulating tTreg and pTreg homeostasis.

Post-translational modifications (PTMs) are crucial mechanisms that underlie the intricacies of biological systems and disease mechanisms. This review focuses on the latest advancements in the design of heterobifunctional small molecules that hijack PTM machineries for target-specific modifications in living systems. A key innovation in this field is the development of proteolysis-targeting chimeras (PROTACs), which promote the ubiquitination of target proteins for proteasomal degradation. The past decade has seen several adaptations of the PROTAC concept to facilitate targeted (de)phosphorylation and acetylation. Protein fusion tags have been particularly vital in these proof-of-concept studies, aiding in the investigation of the functional roles of post-translationally modified proteins linked to diseases. This overview delves into protein-tagging strategies that enable the targeted modulation of ubiquitination, phosphorylation, and acetylation, emphasizing the synergies and challenges of integrating heterobifunctional molecules with protein tags in PTM research. Despite significant progress, many PTMs remain to be explored, and protein tag-assisted PTM-inducing chimeras will continue to play an important role in understanding the fundamental roles of protein PTMs and in exploring the therapeutic potential of manipulating protein modifications, particularly for targets not yet addressed by existing drugs.

Abstract Triple-negative breast cancer (TNBC), an aggressive histological subtype of breast cancer, exhibits a high risk of early recurrence rate and a poor prognosis, and it is primarily associated with the abundance of cancer stem cells (CSCs). At present, the strategies for effectively eradicating or inhibiting TNBC CSCs are still limited, which makes the development of novel drugs with anti-CSCs function be of great value for the treatment of TNBC, especially the refractory TNBC. In this study, we found that the small-molecule tyrosine kinase inhibitor DCC-2036 suppressed TNBC stem cells by inhibiting the tyrosine kinase AXL and the transcription factor KLF5. DCC-2036 downregulated the expression of KLF5 by decreasing the protein stability of KLF5 via the AXL-Akt-GSK3β signal axis, and in turn, the downregulation of KLF5 further reduced the expression of AXL via binding to its promotor (−171 to −162 bp). In addition, p-AXL/AXL levels were positively correlated with KLF5 expression in human TNBC specimens. These findings indicated that DCC-2036 is able to suppress the CSCs in TNBC by targeting the AXL-KLF5 positive feedback loop. Moreover, our findings indicated that DCC-2036 increased the sensitivity of TNBC chemotherapy. Therefore, this study proposes a potential drug candidate and several targets for the treatment of refractory TNBC.

Abstract Background The development of diabetes vascular calcification (VC) is tightly associated with the inhibition of vascular smooth muscle cell (VSMC) autophagy. Previously, our team found that miR-32-5p (miR-32) promotes macrophage activation, and miR-32 is expressed at higher level in the plasma of patients with coronary calcification. However, whether miR-32 mediates the function of macrophages in type 2 diabetes (T2D) VC is still unclear. Methods Wild-type (WT) and miR-32−/− mice were used in this study. qRT-PCR and western blotting were used to analyze gene expression. Flow cytometry was used to analyze the influence of glucose concentration on macrophage polarization. Nanoparticle tracking analysis (NTA), transmission electron microscopy, and confocal microscopy were used to identify macrophage extracellular vehicles (EVs). Immunofluorescence, in situ hybridization (ISH), immunohistochemistry, and alizarin red staining were used to analyze the influence of macrophage EVs on autophagy and calcification of the aorta of miR-32−/− mice. A luciferase assay was used to analyze the effect of miR-32 on myocyte enhancer factor 2D (Mef2d) expression. Co-IP combined with mass spectrometry (MS) and transcriptome sequencing was used to analyze the signalling pathway by which Mef2d acts in VSMC autophagy. Results We found that high glucose conditions upregulate miR-32 expression in macrophages and their EVs. Importantly, macrophages and their EVs promote VSMC osteogenic differentiation and upregulate miR-32 expression in VSMCs. Moreover, miR-32 mimics transfection promoted osteogenic differentiation and inhibited autophagy in VSMCs. In vitro and in vivo experiments showed that Mef2d is the key target gene of miR-32 that inhibits VSMC autophagy. Furthermore, MS and transcriptome sequencing found that cGMP-PKG is an important signalling pathway by which Mef2d regulates VSMC autophagy. In addition, after T2D miR-32−/− mice were injected with macrophage EVs via the caudal vein, miR-32 was detected in aortic VSMCs of miR-32−/− mice. Moreover, autophagy was significantly inhibited, and calcification was significantly enhanced in aorta cells. Conclusions These results reveal that EVs are the key pathway by which macrophages promote T2D VC, and that EVs miR-32 is a key cause of autophagy inhibition in VSMCs.

Mildew is recognized as one of the most critical causes of the damages in food storage. Due to the complex operation and high cost, many advanced detection instruments cannot be widely deployed, while the detection of grain mildew are mostly carried out manually (i.e., inspection by experts) nowadays with very low efficiency. To address this problem, we present a non-destructive, non-intrusive, and low-cost mildew detection system for stored wheat implemented with off-the-shelf WiFi devices, which represents a new application of the Internet of Things (IoT) for smart agriculture. In this paper, we introduce the impact of wheat mildew in stored food, and demonstrate that it is viable to utilize WiFi Channel State Information (CSI) amplitude for detection of mildew in stored wheat. Next, we propose the MiFi system, which comprises sensing of WiFi CSI data, data preprocessing, a radial basis function (RBF) neural network-based detection model, and mildew detection. We conduct extensive experiments to validate the performance of the proposed MiFi system using real grain samples. The results show that MiFi achieves an average detection accuracy of over 90% in both line-of-sight (LOS) and non-line-of-sign (NLOS) scenarios, as well as a comparable detection performance as manual detection by an expert.

Three-dimensional (3D) human pose tracking has recently attracted more and more attention in the computer vision field. Real-time pose tracking is highly useful in various domains such as video surveillance, somatosensory games, and human-computer interaction. However, vision-based pose tracking techniques usually raise privacy concerns, making human pose tracking without vision data usage an important problem. Thus, we propose using Radio Frequency Identification (RFID) as a pose tracking technique via a low-cost wearable sensing device. Although our prior work illustrated how deep learning could transfer RFID data into real-time human poses, generalization for different subjects remains challenging. This paper proposes a subject-adaptive technique to address this generalization problem. In the proposed system, termed Cycle-Pose, we leverage a cross-skeleton learning structure to improve the adaptability of the deep learning model to different human skeletons. Moreover, our novel cycle kinematic network is proposed for unpaired RFID and labeled pose data from different subjects. The Cycle-Pose system is implemented and evaluated by comparing its prototype with a traditional RFID pose tracking system. The experimental results demonstrate that Cycle-Pose can achieve lower estimation error and better subject generalization than the traditional system.

Background People living with HIV (PLWH) have a worse prognosis than the general population. Locally advanced or metastatic bladder cancer (BCa) in PLWH has gradually been increasing in recent years. Immune checkpoint inhibitors can improve antitumor activity in the general population, but relevant data in PLWH are unknown. We thus evaluated the efficacy and safety of tislelizumab in PLWH with locally advanced or metastatic BCa. Methods This retrospective study included 24 patients with locally advanced or metastatic BCa, both HIV positive or negative who underwent tislelizumab treatment (200 mg i.v. every 3 weeks, Q3W) from the multi-centers between December 2019 and March 2022. Demographic details, clinical data, and cancer status were collected. The overall survival (OS), progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), and treatment-related adverse events (TRAEs) were recorded and evaluated. Results A total of 24 individuals were chosen for this study, 10 had HIV and the other 14 did not. The median OS in the HIV-negative group was 62.3 (95% CI, 52.6 to 72.2) was no longer than that of the PLWH group 41.9 (95% CI, 32.9 to 51.0) weeks (HR .7, [95% CI, .17 to 3.30], P = .70). Furthermore, the median PFS in the HIV-negative group was 50.0 (95% CI, 36.2 to 63.9) was also no longer than that of the PLWH group 35.9 (95% CI, 25.5 to 46.3) (HR, 1.34, [95% CI, .38 to 4.69], P = .63). Of 24 patients, treatment-related adverse events, grade 3 or 4 occurred in 2 in the PLWH group and 3 in the HIV-negative group. Conclusion This retrospective multi-center study suggested that tislelizumab may provide encouraging antitumor activity and could be generally well tolerated. In this retrospective analysis of patients with locally advanced or metastatic BCa, it seems that PLWH may have similar overall and progression-free survival compared to HIV-negative cases.