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Abstract Background Ischemia/reperfusion (I/R) is an inevitable pathophysiological process during heart transplantation, and ferroptosis is an important pathogenic mechanism. Unlike other modes of cell death, ferroptosis depends on the accumulation of iron within the cell and the oxidative degradation of polyunsaturated fatty acids. Dysregulation of this pathway has been linked to the progression of multiple pathological conditions, making it an attractive target for therapeutic intervention. Therefore, this study aims to explore the effect of ferroptosis on I/R during heart transplantation. Methods GEO2R was applied to identify differentially expressed genes (DEGs) obtained from GSE50884 data, which was involved in I/R and heart transplantation. And ferroptosis-related DEGs (FRDEGs) were screened by venn diagram with ferroptosis-related genes downloaded from FerDb database. FRDEGs was enriched and analyzed by GO and KEGG, and hub genes related to ferroptosis were screened by Cytoscape software and database STRING. Additionally, considering the relationship between ferroptosis and immunity, CIBERSORTx was to analyze the infiltration of 22 kinds of immune cells in I/R during heart transplantation, and the correlation between each immune cell and the expression of FRDEGs was also discussed. Finally, the mouse model of heart transplantation with I/R was constructed, and the hub genes was verified by RT-qPCR and western blot. Results 12 FRDEGs were identified out of 327 DEGs in GSE50844, which were mainly involved in ferroptosis and other pathways. Three hub genes (SLC7A11, PSAT1, ASNS) were obtained by the degree algorithm of cytohubba plug-in. Immunoinfiltration analysis showed that 16 of 22 immune cells changed, and the immune score of heart transplantation with I/R was higher than that without I/R. In addition, hub genes exhibited significant correlation with Eosinophils, NK cells resting, Dendritic cells resting, NK cells activated and T cells CD4 memory activated. We verified the expression of SLC7A11, PSAT1 and ASNS was higher than that in normal tissues using RT-qPCR and western blot in mouse models of heart transplantation with I/R, companied by ferroptosis aggravated is involved. Conclusions In short, ferroptosis is involved in I/R injury during heart transplantation, which is related to immune cell infiltration. Three hub genes (SLC7A11, PSAT1 and ASNS) identified in this study provide therapeutic targets for ameliorating I/R injury in heart transplantation.

Abstract Reactive oxygen species exacerbate nonalcoholic steatohepatitis (NASH) by oxidizing macromolecules; yet how they promote NASH remains poorly understood. Here, we show that peroxidase activity of global hepatic peroxiredoxin (PRDX) is significantly decreased in NASH, and palmitic acid (PA) binds to PRDX1 and inhibits its peroxidase activity. Using three genetic models, we demonstrate that hepatic PRDX1 protects against NASH in male mice. Mechanistically, PRDX1 suppresses STAT signaling and protects mitochondrial function by scavenging hydrogen peroxide, and mitigating the oxidation of protein tyrosine phosphatases and lipid peroxidation. We further identify rosmarinic acid (RA) as a potent agonist of PRDX1. As revealed by the complex crystal structure, RA binds to PRDX1 and stabilizes its peroxidatic cysteine. RA alleviates NASH through specifically activating PRDX1’s peroxidase activity. Thus, beyond revealing the molecular mechanism underlying PA promoting oxidative stress and NASH, our study suggests that boosting PRDX1’s peroxidase activity is a promising intervention for treating NASH.

Abstract Oxidative stress plays a crucial role in organ aging and related diseases, yet the endogenous regulators involved remain largely unknown. This work highlights the importance of metabolic homeostasis in protecting against oxidative stress in the large intestine. By developing a low-input and user-friendly pipeline for the simultaneous profiling of five distinct cysteine (Cys) states, including free SH, total Cys oxidation (Sto), sulfenic acid (SOH), S-nitrosylation (SNO), and S-glutathionylation (SSG), we shed light on Cys redox modification stoichiometries and signaling with regional resolution in the aging gut of monkeys. Notably, the proteins modified by SOH and SSG were associated primarily with cell adhesion. In contrast, SNO-modified proteins were involved in immunity. Interestingly, we observed that the Sto levels ranged from 0.97% to 99.88%, exhibiting two distinct peaks and increasing with age. Crosstalk analysis revealed numerous age-related metabolites potentially involved in modulating oxidative stress and Cys modifications. Notably, we elucidated the role of fumarate in alleviating intestinal oxidative stress in a dextran sulfate sodium (DSS)-induced colitis mouse model. Our findings showed that fumarate treatment promotes the recovery of several cell types, signaling pathways, and genes involved in oxidative stress regulation. Calorie restriction (CR) is a known strategy for alleviating oxidative stress. Two-month CR intervention led to the recovery of many antioxidative metabolites and reshaped the Cys redoxome. This work decodes the complexities of redoxomics during the gut aging of non-human primates and identifies key metabolic regulators of oxidative stress and redox signaling.

Abstract Yu-Ping-Feng-San (YPF) is a famous classical Chinese medicine formula known for its ability to boost immunity. YPF has been applied to enhance the immune status of tumor patients in clinical practice. However, there is still a lack of research on its immune regulatory effects and mechanisms in the tumor microenvironment. This study was designed to investigate the effects and mechanism of YPF on improving the immune suppression state of hepatocellular carcinoma (HCC) microenvironment. In an orthotopic mouse model of HCC, YPF improved the immune microenvironment of HCC immunosuppression, enhanced the maturation of dendritic cells (DCs), promoted the release of IL-12, and decreased the presence of JAK2, p-JAK2, STAT3, and p-STAT3 proteins in both tumor tissue and paracancerous tissues. YPF also could promote the maturation and reduce the activation of JAK2, p-JAK2, STAT3, and p-STAT3 proteins of mouse bone marrow-derived DCs induced by culture medium or tumor supernatant in vitro. Transient transfection of siRNA-STAT3 with DCs resulted in an increase in its maturation and its secretion of IL-12. On the whole, these combined effects of YPF served to ameliorate the HCC immune suppression microenvironment, which conducive to immune cells play the role of immune surveillance and killing liver cancer cells. The mechanisms of these combined effects were, at least in part, related to its inhibition of the activated JAK2-STAT3 signaling pathway in DCs within the HCC microenvironment.

Abstract Background There are growing global concerns about informal waste pickers and their health issues. This cross-sectional study drew on the structural violence theory to examine the mental health situation of informal waste pickers in Hong Kong and identified the determinants of depression and anxiety in them ranging from individual to societal and governmental levels. Method The data from the largest territory-wide study of informal waste pickers in 2023 was analysed. Descriptive statistics and logistic regressions were used to investigate the association between mental health and socioeconomic variables, including demographic background, governmental measures against informal waste pickers, other negative experiences related to safety and public discrimination, and supportive resources. The symptoms of depression and anxiety were assessed using the Patient Health Questionnaire (PHQ) and General Anxiety Disorder (GAD). Results The results showed that physical strain/illness and chronic illness caused by long-term scavenging works (for depression adjusted OR 3.33, 95% CI [1.75, 6.31]; for anxiety adjusted OR 5.01, 95% CI [2.45, 10.24]), recycling or personal property stolen (for depression adjusted OR 2.04, 95% CI [1.23, 3.36]; for anxiety adjusted OR 2.72, 95% CI [1.62, 4.56]), being treated rudely by citizens (for depression adjusted OR 2.16, 95% CI [1.32, 3.55]); for anxiety (adjusted OR 2.85, 95% CI [1.74, 4.67]) are the critical risk factors of informal waste pickers’ mental health. While higher intention to continue scavenging work if financial conditions permit is the critical protective factor for depression (adjusted OR 0.46, 95% CI [0.24, 0.88]) and anxiety (adjusted OR 0.43, 95% CI [0.22, 0.86]), compared to lower intention to continue scavenging work if financial conditions permit in the multivariate model. Conclusions This study discloses the close relationship between informal waste pickers’ long-term physical strain/illness and mental health and identifies the governmental measures, other negative experiences related to safety issues and public discrimination as risk factors for informal waste pickers’ mental health. Providing outreach, tailored medical services, increasing the unit price of recycling, developing specific recycling zones and establishing membership-based organisations help alleviate the challenges of precarious employment and enhance the well-being of the informal waste pickers.

Abstract Adoptive cell transfer (ACT) using neoantigen-specific T cells is an effective immunotherapeutic strategy. However, the difficult isolation of neoantigen-specific T cells limits the clinical application of ACT. Here, we propose a method to prepare neoantigen-reactive T cells (NRT) for ACT following immunization with a tumor lysate-loaded dendritic cell (DC) vaccine. We show that the DC vaccine not only induces a neoantigen-reactive immune response in lung cancer-bearing mice in vivo, but also facilitate NRT cell preparation in vitro. Adoptive transfer of the NRTs as combinatorial therapy into DC vaccine-immunized, LL/2 tumor-bearing mice allows infiltration of the infused NRTs, as well as the enrichment of neoantigen reactive, non-ACT/NRT T cells into the tumor microenvironment with the function of these neoantigen-reactive T-cell receptors validated in vitro. In summary, we propose a method for preparing NRTs that increases ACT efficacy and paves the way to the design of personalized immunotherapies.

Abstract Background Spine grape (Vitis davidii) is a promising source of high-quality anthocyanins, with vast potential for application in food, pharmaceutical, and cosmetic industries. However, their availability is limited by resource constraints. Plant cell culture has emerged as a valuable approach for anthocyanin production and serves as an ideal model to investigate the regulation of anthocyanin biosynthesis. Elicitors are employed to achieve targeted enhancement of anthocyanin biosynthesis. The present study investigated the impact of 5-aminolevulinic acid (ALA) as an elicitor on the accumulation of anthocyanins and flavonoids during spine grape callus growth. Specifically, we examined the effects of ALA on anthocyanin and its component accumulation in callus, and biosynthetic anthocyanin gene expression. Results ALA at 25 µg/L increased the biomass of spine grape callus. ALA induction enhanced the levels of flavonoids, anthocyanins and proanthocyanidins in callus, with maximum values reaching 911.11 mg/100 g DW, 604.60 mg/100 g DW, and 5357.00 mg/100 g DW, respectively, after callus culture for 45 days. Notably, those levels were 1.47-, 1.93- and 1.83-fold higher than controls. ALA induction modulated the flavonoid profile, and among 97 differential flavonoid metabolites differing from controls, 77 were upregulated and 20 were downregulated. Six kinds of anthocyanins, namely cyanidin (8), delphinidin (6), peonidin (5), malvidin (4), petunidin (3) and pelargonidin (3), were detected in callus, with peonidin most abundant. Compared with controls, anthocyanin components were increased in ALA-treated callus. The key genes PAL1, PAL2, PAL4, CHI, CHS3, F3’H, F3H, FLS, DFR, UFGT, MYBA1, LDOX, OMT3, GT1 and ACT involved in anthocyanin biosynthesis were upregulated following ALA treatment, resulting in anthocyanin accumulation. Conclusion This study revealed a novel mode of ALA-mediated promotion of plant anthocyanin biosynthesis and accumulation at the cellular level, and a strategy for enhancing anthocyanin content in spine grape callus. The findings advance commercial-scale production of anthocyanins via spine grape callus culture. we also explored the accumulation patterns of flavonoids and anthocyanins under ALA treatment. Augmentation of anthocyanins coincided with elevated expression levels of most genes involved in anthocyanin biosynthesis within spine grape callus following ALA treatment.

Abstract Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting tens of millions of people globally. The causal relationship between metabolites and AD pathology has not yet been formally indicated, and the mediating mechanism by which metabolites affect AD has not yet been explored. This study aimed to determine the genetic relationship between metabolites and AD and to determine the pathways through which amino acid metabolites affect AD. Meta-analysis integrates the results of multiple GWAS analyses using METAL software. Using bidirectional two-sample Mendelian randomization (MR), we analyzed the causal relationships between metabolites and AD. The principal MR test of causal effects was conducted using inverse-variance weighted regression, and we used reverse MR analysis to exclude reverse causality. We also performed the MR-PRESSO test to detect and correct for possible pleiotropic effects, and used the Cochran Q test to assess heterogeneity. Two-step MR was utilized to analyze the mediating factors between amino acid metabolites and the onset of AD. The correlation between mediating factors (inflammatory protein S100A12) and immune cell infiltration was analyzed using the edgeR and GSVA software packages. Using single-cell sequencing data from skin tissues of patients with AD, we studied the regulatory role of the S100A12 gene in immune cells. Multiple drug databases and macromolecular docking were used to search for S100A12-targeting drugs. Bidirectional two-sample MR analyses indicated that twenty-two metabolites and one inflammatory protein (S100A12) were significantly associated with AD pathogenesis. S100A12 is a mediator of amino acid metabolites (N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine) that are genetically associated with AD. S100A12 was positively correlated with the infiltration of multiple immune cell types in lesional AD skin. The amino acid metabolites N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine influence AD pathogenesis by mediating S100A12 expression.

BackgroundElevated plasma homocysteine (Hcy) has been reported as a risk factor for cognitive impairment in the general population. However, there are conflicting results regarding the relationship between Hcy and cognitive impairment across various cognitive domains in Parkinson’s disease (PD).ObjectiveThis study aims to explore the association between plasma Hcy levels, cognitive impairment, and dysfunction in various cognitive domains among PD patients with and without mild cognitive impairment (MCI).MethodsA total of 101 PD patients underwent plasma Hcy measurement, comprising 50 PD-MCI patients and 51 patients with normal cognition (PD-NC). A battery of neuropsychological tests was administered to assess different cognitive domains. Adjusted generalized linear models were used to assess the correlations between Hcy levels and cognitive functions.ResultsAs anticipated, PD-MCI patients demonstrated a significant decline in cognitive function across all five cognitive domains (memory, executive function, attention/working memory, language, and visuospatial function). Elevated plasma Hcy levels (≥ 10 μmol/L) were associated with a higher odds of PD-MCI, even within the normal range of Hcy levels (< 15 μmol/L). After adjusting for confounding factors, a negative correlation was observed between plasma Hcy levels and the performance on specific cognitive tests evaluating executive functions in PD, such as the Stroop Color-Word Test-C (β = −1.123, 95% CI = −1.845 ∼−0.401, p = 0.0023).ConclusionThis study underscores a significant link between plasma Hcy levels and PD-MCI, particularly concerning executive dysfunction, even within the normal range of Hcy levels (< 15 μmol/L).

Hepatocellular carcinoma (HCC) is still one of the leading causes of tumor-related deaths. Accumulating evidence indicates that immunogenic cell death (ICD) could occur in tumor cells. However, ICD-related studies are limited in HCC. This study collected HCC RNA sequencing data from the Cancer Genome Atlas, International Cancer Genome Consortium, and Gene Expression Omnibus databases. R software was used to analyze the expression of ICD in HCC and to screen essential genes with prognostic value. qRT-PCR and WB determined the mRNA and protein expressions of hub gene. Cell viability assay, Clonal formation assay, and Live/dead staining assay were employed to determine the gene functions. After cross-analysis of differentially expressed genes (DEGs) and ICD-related genes (ICDRGs), 7 differentially expressed ICDRGs were identified in HCC. Of them, HSP90AA1, with the most excellent prognostic value in HCC, was selected, whose expression was also validated in public cohorts, cell lines, and clinical tissue samples. High HSP90AA1 expression indicated an inferior prognosis of HCC, and HSP90AA1 knockdown significantly suppressed cell viability and chemotherapy resistance of HCC. ICD-related gene HSP90AA1 was an unfavorable factor for HCC, and high HSP90AA1 expression contributed to tumor cell survival and chemotherapy resistance.

Abstract Furcate cord insertion refers to the separation of umbilical vessels before reaching the placenta, where the branching vessels normally attach at the edge of the placental parenchyma or near the placental membranes. This is an extremely rare abnormal umbilical cord insertion. This paper reported a case of a furcate cord insertion, where the rupture of exposed umbilical vessels led to intrauterine fetal death at full term. Through literature review, we analyzed the prenatal ultrasound characteristics and pregnancy outcomes of furcate cord insertions, with the aim to improve detection rates and reduce the risk of adverse pregnancy outcomes.

Abstract Dapagliflozin (DAPA) demonstrates promise in the management of diabetic mellitus (DM) and cardiomyopathy. Trimethylamine N-oxide (TMAO) is synthesized by the gut microbiota through the metabolic conversion of choline and phosphatidylcholine. Ferroptosis may offer novel therapeutic avenues for the management of diabetes and myocardial ischemia–reperfusion injury (IRI). However, the precise mechanism underlying ferroptosis in cardiomyocytes and the specific role of TMAO generated by gut microbiota in the therapeutic approach for DM and myocardial IRI utilizing DAPA need to be further explored. Nine male SD rats with specific pathogen-free (SPF) status were randomly divided equally into the normal group, the DM + IRI (DIR) group, and the DAPA group. The diversity of the gut microbiota was analyzed using 16S rRNA gene sequencing. Additionally, the Wekell technique was employed to measure the levels of TMAO in the three groups. Application of network pharmacology to search for intersection targets of DAPA, DIR, and ferroptosis, and RT-PCR experimental verification. Ultimately, the overlapping targets that were acquired were subjected to molecular docking analysis with TMAO. The changes of Bacteroidetes and Firmicutes in the gut microbiota of DIR rats were most significantly affected by DAPA. Escherichia-Shigella and Prevotella_9 within the phylum Bacteroidetes could be identified as the primary effects of DAPA on DIR. Compared with the normal group, the TMAO content in the DIR group was significantly increased, while the TMAO content in the DAPA group was decreased compared to the DIR group. For the network pharmacology analysis, DAPA and DIR generated 43 intersecting target genes, and then further intersected with ferroptosis-related genes, resulting in 11 overlapping target genes. The mRNA expression of ALB, HMOX1, PPARG, CBS, LCN2, and PPARA decreased in the DIR group through reverse transcription polymerase chain reaction (RT-PCR) validation, while the opposite trend was observed in the DAPA group. The docking score between TMAO and DPP4 was − 5.44, and the MM-GBSA result of − 22.02 kcal/mol. It epitomizes the finest docking performance among all the target genes with the lowest score. DAPA could reduce the levels of metabolite TMAO produced by gut microbiota, thereby regulating related target genes to decrease ferroptosis in DIR cardiomyocytes.

Rheumatic immune disorders are a group of conditions that affect the immune system, leading to various clinical symptoms. These diseases can cause pain, reduce the quality of life, and increase the risk of death in severe cases. Diagnosis and treatment are very complex due to the different types of disease and individual differences and the unknown pathogenesis of the disease. Further research is necessary to provide new clues for disease treatment. Organoid technology that makes up for the shortcomings of animal model species differences can better simulate disease onset mechanisms than animal models. It can be used as a screening platform for new therapeutic targets, as well as personalized settings based on patient-derived organoids, promising as an effective tool for the study of rheumatic immune diseases. Therefore, the article summarizes studies related to organoids and their application in rheumatic immune diseases. It also provides an outlook on the potential of organoids in this field and discusses the challenges that need to be addressed, putting new ideas for future research on these diseases.

Sepsis is a dysregulated immune response to infection that comes with multiple organ dysfunction and high mortality. The management of sepsis relies heavily on early recognition and diagnosis, but current diagnostic methods have limitations in timeliness, sensitivity, and discriminability. This study aims to discover novel biomarkers for sepsis diagnosis. Four datasets from different regions were analyzed using weighted gene co-expression network analysis (WGCNA), and genes with high Gene Significance values across these datasets were overlapped. Finally, two genes, CD177 and ANXA3, were identified. ANXA3 was validated as a potential sepsis biomarker by checking multiple datasets and Receiver Operating Characteristic (ROC) Curve Analysis. Of note, ANXA3 could distinguish not only between adult and child sepsis patients and healthy controls, but also between septic shock and cardiogenic shock. Moreover, a murine sepsis model was established and the results showed that the transcription of ANXA3 in peripheral blood of septic mice was significantly higher than that of healthy controls, while Escherichia coli infection alone did not significantly increase the transcription level of this gene. Subsequent studies of sepsis in mice revealed that the predictive effect of Anxa3 on sepsis could be observed as early as 6 h post-modeling. Interestingly, ANXA3 expression was predominantly up-regulated in myeloid cells, up-regulated in spleen, down-regulated in lung, and not detected in liver after sepsis modeling. Taken together, this study provides a way for the discovery of biomarkers and finds that ANXA3 may be a novel diagnostic biomarker for sepsis.

Abstract Long non‐coding RNAs (lncRNAs) can crucially regulate activation and transformation of cancer‐associated fibroblasts (CAFs) but have not been systematically investigated at single cell resolution. Here, by utilizing integrated single‐cell sequencing datasets, we screened the aberrantly expressed lncRNAs in CAFs, which are the major component of tumor microenvironment. Our findings revealed a consistent CAF‐specific downregulation of Maternally Expressed Gene 3 (MEG3) expression and increased MEG3+ proportion at the pan‐cancer level, which may be attributed to m6A‐related post‐transcriptional modifications. Through activation trajectory analysis of the major CAF subtypes, it was determined that elevated MEG3 expression in CAFs leads to an increase in PDGFRA expression. This, in turn, promotes CAF activation and transformation into an MEG3+ adipogenic CAF (MACAF) subtype, which is more sensitive to Dasatinib. MACAF‐related cell–cell interactions highlighted that MACAF could enhance the epithelial‐mesenchymal transition process in tumor cells via the TGF‐β pathway, promoting tumor cell migration and possibly contributing to tumor progression and invasiveness. Notably, patients with higher MACAF scores experience unfavorable prognoses and poor response rates to checkpoint inhibitor‐based immunotherapy, suggesting a correlation between MACAF and immunosuppressive microenvironment shaping. Our findings provide novel insights of the MEG3 in CAF activation and highlight the potential value of the MACAF score for therapeutic strategies design involving Dasatinib and immunotherapy.

Widespread public opinion of food safety (POFS) has exacerbated consumer concerns about food safety and health, then driving consumers to purchase green food. However, the mechanisms at play in such concerns to consumer behaviour towards green food consumption have not explored, especially in the environment of social media. To fill up this gap, this research adopted a sequential two-stage mixed-methods approach to identify and examine the effects and mechanisms of public opinion of food safety on consumers' green food purchase intentions. In the initial qualitative research phase, the public comments on the microblogging platform was analyzed and we identified four top hot topics: public opinion of food safety, insecurity, green label trust (GLT) and green food purchase intentions (GFPI) based on text mining. In the quantitative phase of the survey-based research, we introduced the protection motivation theory and the hyper-attention cognitive model to construct a conceptual model. Based on this conceptual model, we conducted an empirical test with 1087 online questionnaires. The result showed that POFS had a significant positive effect on consumers' GFPI; consumer insecurity mediated the relationship between POFS and GFPI, and GLT played a moderating role between them. This study illustrates a psychological mechanism by which public opinion of food safety motivates consumers to switch to green food and provides new insights into green food consumption behaviour. It is an essential reference for encouraging green food consumption and promoting sustainability in the food industry.

This research reports a case of histological transformation from non-small cell lung cancer (NSCLC) to transformed small cell lung cancer (T-SCLC) in a patient undergoing EGFR-tyrosine kinase inhibitors (TKIs). The aggressive characteristics of the tumor diverged significantly from those commonly associated with lung adenocarcinomas, leading to further histological analysis. The subsequent histological examination confirmed the transformation to SCLC, consistent with established mechanisms of acquired resistance in NSCLC. Given the limited therapeutic options, the patient was administered a serplulimab-based immunochemotherapy regimen, achieving a progression-free survival (PFS) of 6 months post-transformation. The study underscores the potential of PD-1 inhibitors, particularly serplulimab, in the treatment landscape for T-SCLC and highlights the need for future comprehensive research.

Abstract. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a well-established oncogenic long non-coding RNA, the higher expression of which is strongly correlated with cancer events such as tumorigenesis, progression, metastasis, drug resistance, and treatment outcome in solid cancers. Recently, a series of studies has highlighted its potential role in hematological malignancies in terms of these events. Similar to solid cancers, MALAT1 can regulate various target genes via sponging and epigenetic mechanisms, but the miRNAs sponged by MALAT1 differ from those identified in solid cancers. In this review, we systematically describe the role and underlying mechanisms of MALAT1 in multiple types of hematological malignancies, including regulation of cell proliferation, metastasis, stress response, and glycolysis. Clinically, MALAT1 expression is related to poor treatment outcome and drug resistance, therefore exhibiting potential prognostic value in multiple myeloma, lymphoma, and leukemia. Finally, we discuss the evaluation of MALAT1 as a novel therapeutic target against cancer in preclinical studies.

Abstract Background Dystrophinopathies are the most common X-linked inherited muscle diseases, and the disease-causing gene is DMD. Exonic duplications are a common type of pathogenic variants in the DMD gene, however, 5’ end exonic duplications containing exon 1 are less common. When assessing the pathogenicity of exonic duplications in the DMD gene, consideration must be given to their impact on the reading frame. Traditional molecular methods, such as multiplex ligation-dependent probe amplification (MLPA) and next-generation sequencing (NGS), are commonly used in clinics. However, they cannot discriminate the precise physical locations of breakpoints and structural features of genomic rearrangement. Long-read sequencing (LRS) can effectively overcome this limitation. Results We used LRS technology to perform whole genome sequencing on three families and analyze the structural variations of the DMD gene, which involves the duplications of exon 1 and/or exon 2. Two distinct variant types encompassing exon 1 in the DMD Dp427m isoform and/or Dp427c isoform are identified, which have been infrequently reported previously. In pedigree 1, the male individuals harboring duplication variant of consecutive exons 1–2 in the DMD canonical transcript (Dp427m) and exon 1 in the Dp427c transcript are normal, indicating the variant is likely benign. In pedigree 3, the patient carries complex SVs involving exon 1 of the DMD Dp427c transcript showing an obvious phenotype. The locations of the breakpoints and the characteristics of structural variants (SVs) are identified by LRS, enabling the classification of the variants' pathogenicity. Conclusions Our research sheds light on the complexity of DMD variants encompassing Dp427c/Dp427m promoter regions and emphasizes the importance of cautious interpretation when assessing the pathogenicity of DMD 5' end exonic duplications, particularly in carrier screening scenarios without an affected proband.

As Unmanned Aerial Vehicle (UAV) technology advances, UAVs have attracted widespread attention across military and civilian fields due to their low cost and flexibility. In unknown environments, UAVs can significantly reduce the risk of casualties and improve the safety and covertness when performing missions. Reinforcement Learning allows agents to learn optimal policies through trials in the environment, enabling UAVs to respond autonomously according to the real-time conditions. Due to the limitation of the observation range of UAV sensors, UAV target search missions face the challenge of partial observation. Based on this, Partially Observable Deep Q-Network (PODQN), which is a DQN-based algorithm is proposed. The PODQN algorithm utilizes the Gated Recurrent Unit (GRU) to remember the past observation information. It integrates the target network and decomposes the action value for better evaluation. In addition, the artificial potential field is introduced to solve the potential collision problem. The simulation environment for UAV target search is constructed through the custom Markov Decision Process. By comparing the PODQN algorithm with random strategy, DQN, Double DQN, Dueling DQN, VDN, QMIX, it is demonstrated that the proposed PODQN algorithm has the best performance under different agent configurations.

Andrographis paniculata is mainly used to treat skin inflammations, wounds, and infections. In this study, Andrographis Herba, the aerial part of the plant, was proven to increase the viability of UVB-damaged HaCat cells and reduce reactive oxygen species levels. The chemical composition of Andrographis Herba extract (AHE) was analyzed using UPLC-Q-TOF-MS, and diterpene lactones were identified as its primary constituents. Then, the fraction of diterpene lactones was prepared and exhibited similar effects to AHE. AHE, its diterpene lactones component, and its representative constituent andrographolide all decreased the expression of IL-1β, IL-6, and CDKN1A. Furthermore, the protective effects of AHE and its active ingredients on UVB-damaged epidermal stem cells were investigated. Notably, the combined treatment with andrographolide and collagen XVII enhanced the viability of UVB-damaged epidermal stem cells, increased the expression of stemness markers integrin β1 and p63, and decreased the expression of the differentiation marker keratin 10. This combination demonstrated significant synergy in maintaining skin homeostasis, which provides evidences for the development of skin-protective products.

Cancer remains a significant global challenge, with escalating incidence rates and a substantial burden on healthcare systems worldwide. Herein, we present an in-depth exploration of the intricate interplay between cancer cell death pathways and tumor immunity within the tumor microenvironment (TME). We begin by elucidating the epidemiological landscape of cancer, highlighting its pervasive impact on premature mortality and the pronounced burden in regions such as Asia and Africa. Our analysis centers on the pivotal concept of immunogenic cell death (ICD), whereby cancer cells succumbing to specific stimuli undergo a transformation that elicits robust anti-tumor immune responses. We scrutinize the mechanisms underpinning ICD induction, emphasizing the release of damage-associated molecular patterns (DAMPs) and tumor-associated antigens (TAAs) as key triggers for dendritic cell (DC) activation and subsequent T cell priming. Moreover, we explore the contributions of non-apoptotic RCD pathways, including necroptosis, ferroptosis, and pyroptosis, to tumor immunity within the TME. Emerging evidence suggests that these alternative cell death modalities possess immunogenic properties and can synergize with conventional treatments to bolster anti-tumor immune responses. Furthermore, we discuss the therapeutic implications of targeting the TME for cancer treatment, highlighting strategies to harness immunogenic cell death and manipulate non-apoptotic cell death pathways for therapeutic benefit. By elucidating the intricate crosstalk between cancer cell death and immune modulation within the TME, this review aims to pave the way for the development of novel cancer therapies that exploit the interplay between cell death mechanisms and tumor immunity and overcome Challenges in the Development and implementation of Novel Therapies.

Time Domain Coding Metasurface (TDCM) is an emerging technology enabling dynamic modulation of electromagnetic waves. In response to the control characteristics of this technology, this paper presents a radar jamming method based on TDCM intrapulse and interpulse coding optimization. First, optimization models are established in fast and slow time domains. By optimizing intrapulse and interpulse phase coding, the energy redistribution of targets is achieved, thereby generating deceptive interference on the range-Doppler two-dimensional plot. Subsequently, a genetic algorithm is employed to solve this discrete optimization problem. Furthermore, this paper analyzes the effect of various modulation factors on interference effectiveness in terms of TDCM coding strategies, providing guidance for achieving optimal strategies for deceptive interference.

Oomycete pathogens secrete numerous crinkling and necrosis proteins (CRNs) to manipulate plant immunity and promote infection. However, the functional mechanism of CRN effectors is still poorly understood. Previous research has shown that the Phytophthora sojae effector PsCRN108 binds to the promoter of HSP90s and inhibits their expression, resulting in impaired plant immunity. In this study, we found that in addition to HSP90, PsCRN108 also suppressed other Heat Shock Protein (HSP) family genes, including HSP40. Interestingly, PsCRN108 inhibited the expression of NbHSP40 through its promoter, but did not directly bind to its promoter. Instead, PsCRN108 interacted with NbCAMTA2, a negative regulator of plant immunity. NbCAMTA2 was a negative regulator of NbHSP40 expression, and PsCRN108 could promote such inhibition activity of NbCAMTA2. Our results elucidated the multiple roles of PsCRN108 in the suppression of plant immunity and revealed a new mechanism by which the CRN effector hijacked transcription factors to affect immunity. [Graphic: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Pharmacological perturbation studies based on protein-level signatures are fundamental for drug discovery. In the present study, we used a mass spectrometry (MS)-based proteomic platform to profile the whole proteome of the breast cancer MCF7 cell line under stress induced by 78 bioactive compounds. The integrated analysis of perturbed signal abundance revealed the connectivity between phenotypic behaviors and molecular features in cancer cells. Our data showed functional relevance in exploring the novel pharmacological activity of phenolic xanthohumol, as well as the noncanonical targets of clinically approved tamoxifen, lovastatin, and their derivatives. Furthermore, the rational design of synergistic inhibition using a combination of histone methyltransferase and topoisomerase was identified based on their complementary drug fingerprints. This study provides rich resources for the proteomic landscape of drug responses for precision therapeutic medicine.

The traditional organic and inorganic solvents used for polysaccharide extraction generally have long extraction time, large solvent consumption, low extraction efficiency and certain pollution problems, and the exploration of new safe solvents has become a hot issue in polysaccharide extraction. As an emerging green solvent, low eutectic solvent (DES) has a variety of solvent characteristics that traditional organic solvents do not possess, and has been widely used in the field of plant polysaccharide extraction in recent years. In this paper, the composition, main properties, synthesis method and important factors affecting the properties of DES are reviewed, and the progress of the application of DES in the extraction of plant polysaccharides such as tea polysaccharides, herbal polysaccharides and peel pectin are summarized.Compared with traditional water and acid-base extraction, the extraction conditions of DES are relatively mild and the energy consumption is lower. The extracted plant polysaccharides have higher extraction rate and purity, and the biological activity and biocompleteness of polysaccharides are better. The limitations and potentials of DES in plant polysaccharide extraction are further elaborated, aiming to provide ideas and theoretical references for the research related to the extraction of plant polysaccharides by DES.

Abstract Background Previously we reported that inhibition of GPR17 prevents amyloid β 1–42 (Aβ1-42)-induced cognitive impairment in mice. However, the role of GPR17 on cognition is still largely unknown. Methods Herein, we used a mouse model of cognitive impairment induced by lipopolysaccharide (LPS) to further investigate the role of GPR17 in cognition and its potential mechanism. The mice were pretreated with GPR17 shRNA lentivirus and cangrelor by microinjection into the dentate gyrus (DG) region of the hippocampus. After 21 days, LPS (0.25 mg/kg, i.p.) was administered for 7 days. Animal behavioral tests as well as pathological and biochemical assays were performed to evaluate the cognitive function in mice. Results LPS exposure resulted in a significant increase in GPR17 expression at both protein and mRNA levels in the hippocampus. Gene reduction and pharmacological blockade of GPR17 improved cognitive impairment in both the Morris water maze and novel object recognition tests. Knockdown and inhibition of GPR17 inhibited Aβ production, decreased the expression of NF-κB p65, increased CREB phosphorylation and elevated BDNF expression, suppressed the accumulation of pro-inflammatory cytokines, inhibited Glial cells (microglia and astrocytes) activation, and increased Bcl-2, PSD-95, and SYN expression, reduced Bax expression as well as decreased caspase-3 activity and TUNEL-positive cells in the hippocampus of LPS-treated mice. Notably, knockdown and inhibition of GPR17 not only provided protective effects against cholinergic dysfunction but also facilitated the regulation of oxidative stress. In addition, cangrelor pretreatment can effectively inhibit the expression of inflammatory cytokines by suppressing NF-κB/CREB/BDNF signaling in BV-2 cells stimulated by LPS. However, activation of hippocampal GPR17 with MDL-29951 induced cognitive impairment in normal mice. Conclusions These observations indicate that GPR17 may possess a neuroprotective effect against LPS-induced cognition deficits, and neuroinflammation by modulation of NF-κB/CREB/BDNF signaling in mice, indicating that GPR17 may be a promising new target for the prevention and treatment of AD.

To screen strains with high production of cold-active lipase and optimize enzyme production conditions, as well as to provide production information for the industrial development of lipase, a cold-active lipase producing strain was screened from soil samples in Mohe County, Heilongjiang Province, and identified as Serratia plymuthica by morphological identification, physiological and biochemical experiments and molecular biology. The effects of different factors such as temperature, pH, loading volume, inoculum, carbon source, nitrogen source, metal ion and inducer on the enzyme production of the strain were investigated by single-factor experiments, as well as the optimization of the addition of olive oil, peptone and loading volume by Plackett-Burman experiment, hill climbing test and response surface design. The results showed that the optimal enzyme production conditions were 20 ℃, pH7.5, loading volume 42 mL, inoculum 0.5%, 20 g/L maltose, 14 g/L peptone, 0.5 g/L MgSO4·7H2O and 46 mL/L olive oil. The lipase activity under this optimized condition was 98.05 U/mL, which was 5.85 times higher than that before optimization. The results of enzymatic properties showed that the optimum temperature of this lipase was 30 ℃, which was a low temperature lipase, and the optimum reaction pH was 7. Mg2+ could obviously promote the enzyme activity. The organic solvents methanol and ethanol obviously inhibited the enzyme activity, while n-hexane could obviously promote the enzyme activity. The conclusion can provide some theoretical basis and methodological guidance for the development and utilization of microbial resources and industrial production of low-temperature lipase.

Purpose – Privacy scholars appear to struggle in conceptualizing blockchain from a privacy perspective: is it a privacy-enhancing mechanism like differential privacy, a privacy-intruding tool like third-party cookies or a technology orthogonal to the issue of privacy? Blockchain does not seem to neatly fit into any of these buckets that we traditionally use to gauge the privacy implications of information technologies. In this article, the authors argue that blockchain transcends the extant conceptualization of privacy because it modifies the nature of data flow upon which the modern concept of privacy is based. Design/methodology/approach – The authors introduce a conceptualization of blockchain as a new mechanism for data management. Then, following this conceptualization, the authors present a functional review of blockchain, summarizing the features it provides for the data it manages. This review sets up the discussion of how blockchain redefines data flow by separating the power of collection, access and query of data to different entities. After illustrating how this change regrounds privacy concerns in a blockchain system, the authors conclude with a discussion of the recommendations for future privacy research on blockchain. Findings – The authors demonstrate that blockchain, by design, separates three core data-centric operations that are assumed to be inextricably linked in the canonical conceptualization of privacy: the collection, access and query of data. Collection means to capture and then store the data; access means to modify or augment the data and query means the ability to test or verify certain properties of the data (e.g. whether a bank account has a zero balance). Traditionally, any entities that collect data can evidently read, modify or query the same data as they wish. With blockchain, however, an entity that stores the data may not be able to modify the data, yet an entity that cannot even read the data may be able to verify certain properties of the data. Originality/value – Privacy scholars appear to struggle in conceptualizing blockchain from a privacy perspective: is it a privacy-enhancing mechanism like differential privacy, a privacy-intruding tool like third-party cookies or a technology orthogonal to the issue of privacy? In this article, the authors aim to respond to this important question.

BackgroundPredicting flap viability benefits patients by reducing complications and guides flap design by reducing donor areas. Due to varying anatomy, obtaining individual vascular information preoperatively is fundamental for designing safe flaps. Although indocyanine green angiography (ICGA) is a conventional tool in intraoperative assessment and postoperative monitoring, it is rare in preoperative prediction.MethodsICGA was performed on 20 male BALB/c mice under five wavelengths (900/1,000/1,100, /1,250/1,450 nm) to assess vascular resolution after ICG perfusion. A “mirrored-L” flap model with three angiosomes was established on another 20 male BALB/c mice, randomly divided into two equal groups. In Group A, a midline between angiosomes II and III was used as a border. In Group B, the points of the minimized choke vessel caliber marked according to the ICG signal at 1,450 nm wavelength (ICG1450) were connected. Necrotic area calculations, pathohistological testing, and statistical analysis were performed.ResultsThe vascular structure was clearly observed at 1,450 nm wavelength, while the 900 to 1,100 nm failed to depict vessel morphology. Necrosis was beyond the borderline in 60% of Group A. Conversely, 100% of Group B had necrosis distal to the borderline. The number of choke vessels between angiosomes II and III was positively correlated with the necrotic area (%). The pathohistological findings supported the gross observation and analysis.ConclusionICG1450 can delineate the vessel structure in vivo and predict the viability of pedicled skin flaps using the choke vessel as the border between angiosomes.

Preterm birth represents a multifaceted syndrome with intricacies still present in our comprehension of its etiology. In the context of a semi-allograft, the prosperity from implantation to pregnancy to delivery hinges on the establishment of a favorable maternal-fetal immune microenvironment and a successful trilogy of immune activation, immune tolerance and then immune activation transitions. The occurrence of spontaneous preterm birth could be related to abnormalities within the immune trilogy, stemming from deviation in maternal and fetal immunity. These immune deviations, characterized by insufficient immune tolerance and early immune activation, ultimately culminated in an unsustainable pregnancy. In this review, we accentuated the role of both innate and adaptive immune reason in promoting spontaneous preterm birth, reviewed the risk of preterm birth from vaginal microbiome mediated by immune changes and the potential of vaginal microbiomes and metabolites as a new predictive marker, and discuss the changes in the role of progesterone and its interaction with immune cells in a preterm birth population. Our objective was to contribute to the growing body of knowledge in the field, shedding light on the immunologic reason of spontaneous preterm birth and effective biomarkers for early prediction, providing a roadmap for forthcoming investigations.

Abstract γδ T cells are evolutionarily conserved T lymphocytes that manifest unique antitumor efficacy independent of tumor mutation burden (TMB) and conventional human leukocyte antigen (HLA) recognition. However, the dynamic changes in their T cell receptor (TCR) repertoire during cancer progression and treatment courses remain unclear. Here, a comprehensive characterization of γδTCR repertoires are performed in thyroid cancers with divergent differentiation states through cross‐sectional studies. The findings revealed a significant correlation between the differentiation states and TCR repertoire diversity. Notably, highly expanded clones are prominently enriched in γδ T cell compartment of dedifferentiated patients. Moreover, by longitudinal investigations of the γδ T cell response to various antitumor therapies, it is found that the emergence and expansion of the Vδ2neg subset may be potentially associated with favorable clinical outcomes after post‐radiotherapeutic immunotherapy. These findings are further validated at single‐cell resolution in both advanced thyroid cancer patients and a murine model, underlining the importance of further investigations into the role of γδTCR in cancer immunity and therapeutic strategies.

Hydrogen can serve as an abundant, green, low-carbon, and widely applicable secondary energy source, holding significant importance in building a clean, low-carbon, secure, and efficient energy system and achieving carbon peak and carbon neutrality goals. In the research of hydrogen fuel cells, thermal management, particularly cooling methods, plays a crucial role in the operation of the battery units. This paper primarily focuses on cooling methods in thermal management, using factors such as arrangement, cooling medium, and environmental temperature as variables to establish a simulation model for the thermal behavior of cylindrical hydrogen fuel cells and conduct a parametric study. The research findings indicate that enveloping the battery with a cooling medium can enhance heat dissipation by 19 %. Arranging the hydrogen fuel cell units in a symmetrical rectangular pattern yields excellent heat dissipation results. The battery's maximum temperature increases with the rise in environmental temperature, with every 5 K increase in environmental temperature resulting in a 1.01 % rise in the battery's maximum temperature.