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Abstract Heat stress exposure in intermittent heat waves and subsequent exposure during war theaters pose a clinical challenge that can lead to multi-organ dysfunction and long-term complications in the elderly. Using an aged mouse model and high-throughput sequencing, this study investigated the molecular dynamics of the liver-brain connection during heat stress exposure. Distinctive gene expression patterns induced by periodic heat stress emerged in both brain and liver tissues. An altered transcriptome profile showed heat stress-induced altered acute phase response pathways, causing neural, hepatic, and systemic inflammation and impaired synaptic plasticity. Results also demonstrated that proinflammatory molecules such as S100B, IL-17, IL-33, and neurological disease signaling pathways were upregulated, while protective pathways like aryl hydrocarbon receptor signaling were downregulated. In parallel, Rantes, IRF7, NOD1/2, TREM1, and hepatic injury signaling pathways were upregulated. Furthermore, current research identified Orosomucoid 2 (ORM2) in the liver as one of the mediators of the liver-brain axis due to heat exposure. In conclusion, the transcriptome profiling in elderly heat-stressed mice revealed a coordinated network of liver-brain axis pathways with increased hepatic ORM2 secretion, possibly due to gut inflammation and dysbiosis. The above secretion of ORM2 may impact the brain through a leaky blood–brain barrier, thus emphasizing intricate multi-organ crosstalk.

AIM: To evaluate the clinical efficacy of small-diameter acellular porcine corneal stroma (SAPS) for the treatment of peripheral corneal ulceration (PCU). METHODS: This retrospective clinical study included 18 patients (18 eyes) with PCU between April 2018 and December 2020. All patients had PCU and underwent lamellar keratoplasty with SAPS. Observation indicators included preoperative and postoperative best-corrected visual acuity (BCVA) and transparency of SAPS. The infection control rate in the surgical eye-lesion area was also calculated. RESULTS: Eighteen patients underwent lamellar keratoplasty with SAPS to treat PCU. None of the patients experienced rejection after 6mo (18/18) and 12mo (16/16) of follow-up. The BCVA (0.47±0.30) at the 6mo follow-up after operation was significantly improved compared with the baseline (0.99±0.80), and the difference was statistically significant (Z=-3.415, P

Mid-high latitude Northern Asia is one of the most vulnerable and sensitive areas to global warming, but relatively less studied previously. We used an ensemble of a regional climate model (RegCM4) projections to assess future changes in surface air temperature, precipitation and Köppen‒Trewartha (K‒T) climate types in Northern Asia under the 1.5–4 °C global warming targets. RegCM4 is driven by five CMIP5 global models over an East Asia domain at a grid spacing of 25 km. Validation of the present day (1986–2005) simulations shows that the ensembles of RegCM4 (ensR) and driving GCMs (ensG) reproduce the major characters of the observed temperature, precipitation and K‒T climate zones reasonably well. Greater and more realistic spatial detail is found in RegCM4 compared to the driving GCMs. A general warming and overall increases in precipitation are projected over the region, with these changes being more pronounced at higher warming levels. The projected warming by ensR shows different spatial patterns, and is in general lower, compared to ensG in most months of the year, while the percentage increases of precipitation are maximum during the cold months. The future changes in K‒T climate zones are characterized by a substantial expansion of Dc (temperature oceanic) and retreat of Ec (sub-arctic continental) over the region, reaching ∼20% under the 4 °C warming level. The most notable change in climate types in ensR is found over Japan (∼60%), followed by Southern Siberia, Mongolia, and the Korean Peninsula (∼40%). The largest change in the K‒T climate types is found when increasing from 2 to 3 °C. The results will help to better assess the impacts of climate change and in implementation of appropriate adaptation measures over the region.

Abstract Non-small cell lung cancer (NSCLC), characterized by low survival rates and a high recurrence rate, is a major cause of cancer-related mortality. Aberrant activation of the PI3K/AKT/mTOR signaling pathway is a common driver of NSCLC. Within this study, the inhibitory activity of (+)-anthrabenzoxocinone ((+)-ABX), an oxygenated anthrabenzoxocinone compound derived from Streptomyces, against NSCLC is demonstrated for the first time both in vitro and in vivo. Mechanistically, it is confirmed that the PI3K/AKT/mTOR signaling pathway is targeted and suppressed by (+)-ABX, resulting in the induction of S and G2/M phase arrest, apoptosis, and autophagy in NSCLC cells. Additionally, the augmentation of intracellular ROS levels by (+)-ABX is revealed, further contributing to the inhibition of the signaling pathway and exerting inhibitory effects on tumor growth. The findings presented in this study suggest that (+)-ABX possesses the potential to serve as a lead compound for the treatment of NSCLC. Graphical abstract

Abstract FBXO32, a member of the F-box protein family, is known to play both oncogenic and tumor-suppressive roles in different cancers. However, the functions and the molecular mechanisms regulated by FBXO32 in lung adenocarcinoma (LUAD) remain unclear. Here, we report that FBXO32 is overexpressed in LUAD compared with normal lung tissues, and high expression of FBXO32 correlates with poor prognosis in LUAD patients. Firstly, we observed with a series of functional experiments that FBXO32 alters the cell cycle and promotes the invasion and metastasis of LUAD cells. We further corroborate our findings using in vivo mouse models of metastasis and confirmed that FBXO32 positively regulates LUAD tumor metastasis. Using a proteomic-based approach combined with computational analyses, we found a positive correlation between FBXO32 and the PI3K/AKT/mTOR pathway, and identified PTEN as a FBXO32 interactor. More important, FBXO32 binds PTEN via its C-terminal substrate binding domain and we also validated PTEN as a bona fide FBXO32 substrate. Finally, we demonstrated that FBXO32 promotes EMT and regulates the cell cycle by targeting PTEN for proteasomal-dependent degradation. In summary, our study highlights the role of FBXO32 in promoting the PI3K/AKT/mTOR pathway via PTEN degradation, thereby fostering lung adenocarcinoma progression.

Abstract Cholangiocarcinoma in patients with Choledochal cysts is rare in childhood; however, it seriously affects the prognosis of the disease. The key to addressing this situation lies in completely removing the extrahepatic cyst. We herein present a case report of a 3-year-old boy with cholangiocarcinoma associated with a choledochal cyst (CDC). Preoperative 3D simulation, based on CT data, played an important role in the treatment of this patient.

Wooden breast barriers the development of broiler industry, and traditional detection methods are time-consuming and inefficient. To investigate the feasibility of the hyperspectral imaging (HSI) technique for the detection of wooden breasts, four different grades of white feather chicken breast were selected and their HSI information of 400~1000 and 1000~2000 nm was collected. After spectral preprocessing and spectral variable selection, partial least squares discriminant (PLS-DA) models and support vector machine (SVM) models were developed based on full wavelength and characteristic spectral variables, as well as their fused HSI data. The results showed that SVM models showed better results than PLS-DA models to discriminate woody grades of chicken breasts. The overall discrimination rates based on the full HSI bands and selected spectral variables in 1000~2000 nm were higher than those of models in 400~1000 nm. Besides, the discrimination models based on fused HSI data of HSI bands and selected spectral variables provided the best results, with the overall discrimination rate of 96.7% for four different woody grades, and the accuracy of the four grades could reach more than 90%. The research results provided technical support for HSI to achieve rapid and non-destructive detection of wooden chicken breasts.

In order to obtain a high lift-drag ratio, hypersonic vehicles usually fly with a certain angle of attack. As a potential means to delay hypersonic boundary layer transition at 0° angle of attack, it is not clear how wavy wall affect the deve-lopment of instability waves with angles of attack. In order to study the influence of wavy wall on the development of instability waves in hypersonic boundary layer at small angle of attack, the stability of boundary layer was studied by adopting high-speed infrared camera and high-frequency pressure sensor (PCB) in Mach 6 Ludwieg tube wind tunnel. The development of instability waves along different azimuths and flow directions was analyzed. The experimental results show that the instability waves leading transition at 1° angle of attack are the second-mode waves. Under the condition of 1° angle of attack, the wavy wall has no delay effect on transition at 45° azimuth angle, but has a promotion effect at 90°, 135° and 180° azimuth angles.

Abstract Background Guillain–Barré syndrome (GBS), a post-infectious, immune-mediated, acute demyelinating disease of the peripheral nerves and nerve roots, represents the most prevalent and severe acute paralyzing neuropathy. Purinergic P2X7 receptors (P2X7R) play a crucial role in central nervous system inflammation. However, little is known about their role in the immune-inflammatory response within the peripheral nervous system. Methods Initially, we assessed the expression of purinergic P2X7R in the peripheral blood of patients with GBS using flow cytometry and qRT-PCR. Next, we explored the expression of P2 X7R in CD4+ T cells, CD8+ T cells, and macrophages within the sciatic nerves and spleens of rats using immunofluorescence labeling and flow cytometry. The P2X7R antagonist brilliant blue G (BBG) was employed to examine its therapeutic impact on rats with experimental autoimmune neuritis (EAN) induced by immunization with the P0180 − 199 peptide. We analyzed CD4+ T cell differentiation in splenic mononuclear cells using flow cytometry, assessed Th17 cell differentiation in the sciatic nerve through immunofluorescence staining, and examined the expression of pro-inflammatory cytokine mRNA using RT-PCR. Additionally, we performed protein blotting to assess the expression of P2X7R and NLRP3-related inflammatory proteins within the sciatic nerve. Lastly, we utilized flow cytometry and immunofluorescence labeling to examine the expression of NLRP3 on CD4+ T cells in rats with EAN. Results P2X7R expression was elevated not only in the peripheral blood of patients with GBS but also in rats with EAN. In rats with EAN, inhibiting P2X7R with BBG alleviated neurological symptoms, reduced demyelination, decreased inflammatory cell infiltration of the peripheral nerves, and improved nerve conduction. BBG also limited the production of pro-inflammatory molecules, down-regulated the expression of P2X7R and NLRP3, and suppressed the differentiation of Th1 and Th17 cells, thus protecting against EAN. These effects collectively contribute to modifying the inflammatory environment and enhancing outcomes in EAN rats. Conclusions Suppression of P2X7R relieved EAN manifestation by regulating CD4+ T cell differentiation and NLRP3 inflammasome activation. This finding underscores the potential significance of P2X7R as a target for anti-inflammatory treatments, advancing research and management of GBS.

Abstract Background Severe aplastic anemia (SAA) is a syndrome of bone marrow failure which is life-threatening. Recent studies have demonstrated that CD4 + T cell subsets, including T regulatory (Treg) and T helper 17 (Th17) cells, play a pivotal role in the pathogenesis of SAA. Formononetin (FMN) is a natural compound extracted from the traditional Chinese medicine Huangqi, which has the ability to regulate the imbalance of Treg/Th17 cells in some inflammatory diseases. Nevertheless, the therapeutic effect of FMN in SAA has yet to be definitively established. Therefore, the objective of this research was to investigate the effect of FMN on SAA and elucidate its underlying mechanism. Methods In vivo experiments, the mice were divided into the following five groups: control, model, low-dose FMN, high-dose FMN, and positive control cyclosporine A group. The immune-mediated bone marrow failure (BMF) mouse model was established by the total body X-ray radiation and lymphocyte infusion. After 10 days of continuous administration of FMN, the numbers of Treg/Th17 cells in the bone marrow and spleen were assessed by flow cytometry. The protein expressions of PI3K/Akt pathway in the bone marrow and spleen was assessed by immunohistochemistry and western blotting. In vitro, the impact of FMN on the differentiation of naive CD4 + T cells into Treg cells was investigated by flow cytometry and ELISA. Results In comparison with the control group, the model group showed a reduction in bone marrow nucleated cells, a significant decrease in peripheral blood cells, and an altered CD8 + /CD4 + T cell ratio. These findings indicate the successful establishment of a mouse model of immune-mediated BMF. After FMN treatment, there were the increased levels of red blood cells and hemoglobin. In addition, FMN mitigated the bone marrow destruction and restored the CD8 + /CD4 + T cell ratio. Furthermore, in comparison with the control group, the model group showed the decreased levels of Treg cells and the increased levels of Th17 cells. After FMN treatment, there was a significantly increased number of Treg cells and a decreased number of Th17 cells. Additionally, FMN remarkably down-regulated the expression levels of PI3K and Akt proteins in immune-mediated BMF mice. Conclusions FMN alleviates immune-mediated BMF by modulating the balance of Treg/Th17 cells through the PI3K/Akt signaling pathway.

Natural gas is easily soluble in oil-based muds (OBM), leading to complex flow behavior in wellbores, especially in horizontal wells. In this study, a new transient flow model considering wellbore-formation coupling and gas solubility on flow behavior is developed to simulate gas kicks during horizontal drilling with OBM. Furthermore, the effect of gas solubility on parameters such as bottom-hole pressure (BHP), gas void fraction and mixture velocity in the flow behavior is analyzed. Finally, several critical factors affecting flow behavior are investigated and compared to gas kicks in water-based muds (WBM) where the effect of solubility is neglected. The results show that the invading gas exists as dissolved gas in the OBM and as free gas in the WBM. Before the gas escapes from the OBM, the pit gain is zero and there is barely any change in the BHP, annulus return flow rate and mixture velocity, which means that detecting gas kicks through these warning signs can be challenging until they get very close to the surface and develop rapidly. However, in WBM drilling, these parameters change quickly with the increasing gas kick time. Additionally, for both cases, the longer the horizontal length and the greater reservoir permeability, the greater the decrease in BHP, and the shorter the time for gas to migrate from the bottom-hole to the wellhead. A larger flow rate contributes to a greater initial BHP and a lesser BHP reduction. This research is of value in characterizing gas kick behavior and identifying novel ways for early gas kick detection during horizontal drilling with OBM.

Abstract Sugar Will Eventually be Exported Transporter (SWEET) proteins are highly conserved in various organisms and play crucial roles in sugar transport processes. However, SWEET proteins in peanuts, an essential leguminous crop worldwide, remain lacking in systematic characterization. Here, we identified 94 SWEET genes encoding the conservative MtN3/saliva domains in three peanut species, including 47 in Arachis hypogea, 23 in Arachis duranensis, and 24 in Arachis ipaensis. We observed significant variations in the exon-intron structure of these genes, while the motifs and domain structures remained highly conserved. Phylogenetic analysis enabled us to categorize the predicted 286 SWEET proteins from eleven species into seven distinct groups. Whole genome duplication/segment duplication and tandem duplication were the primary mechanisms contributing to the expansion of the total number of SWEET genes. In addition, an investigation of cis-elements in the potential promoter regions and expression profiles across 22 samples uncovered the diverse expression patterns of AhSWEET genes in peanuts. AhSWEET24, with the highest expression level in seeds from A. hypogaea Tifrunner, was observed to be localized on both the plasma membrane and endoplasmic reticulum membrane. Moreover, qRT-PCR results suggested that twelve seed-expressed AhSWEET genes were important in the regulation of seed development across four different peanut varieties. Together, our results provide a foundational basis for future investigations into the functions of SWEET genes in peanuts, especially in the process of seed development.

Abstract Due to the long-term low survival rates of gastric adenocarcinoma (GAC) patients, the occurrence and prognosis of second primary malignancies (SPMs) are often underreported and overlooked as a significant concern.To date, only a few studies have addressed this issue in the context of GAC. These studies, however, are limited by their small patient cohorts and lack of substantial, meaningful findings. Our study aims to fill this gap by investigating the incidence, risk factors, and prognostic significance of SPMs among GAC survivors. Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, we analysed data from patients diagnosed with GAC between 2000 and 2020. The study employs the standardized incidence ratio (SIR) to assess the relative risk of SPMs, competing risk regression to identify risk factors for SPM development after GAC, and Kaplan-Meier and COX regression analyses for survival outcomes. Out of 44,041 GAC patients analyzed, 2,032 (4.3%) developed SPMs, with a median latency period of 36 months. The incidence of SPMs was significantly higher in GAC patients (SIR 1.36, 95% CI 1.32-1.4, EAR 53.57) compared to the general population. Key factors including older age, sex, tumor grade, summary stage, and history of surgical and radiation therapy were related to the higher risk of developing SPMs following GAC. Interestingly, GAC patients without SPMs exhibited poorer overall survival compared to those with SPMs. Age, summary stage, and surgical history were identified as independent prognostic factors for GAC patients with SPMs. This comprehensive analysis underscores the necessity of vigilant monitoring and tailored follow-up for SPMs in GAC survivors, highlighting the study's contribution to enhancing GAC survivors care strategies.

Abstract Patients treated with RET protein tyrosine kinase inhibitors (TKIs) selpercatinib or pralsetinib develop RET TKI resistance by secondary RET mutations or alterative oncogenes, of which alterative oncogenes pose a greater challenge for disease management because of multiple potential mechanisms and the unclear tolerability of drug combinations. A patient with metastatic medullary thyroid carcinoma (MTC) harboring a RET activation loop D898_E901del mutation was treated with selpercatinib. Molecular alterations were monitored with tissue biopsies and cfDNA during the treatment. The selpercatinib-responsive MTC progressed with an acquired ETV6::NTRK3 fusion, which was controlled by selpercatinib plus the NTRK inhibitor larotrectinib. Subsequently, tumor progressed with an acquired EML4::ALK fusion. Combination of selpercatinib with the dual NTRK/ALK inhibitor entrectinib reduced the tumor burden, which was followed by appearance of NTRK3 solvent-front G623R mutation. Preclinical experiments validated selpercatinib plus larotrectinib or entrectinib inhibited RET/NTRK3 dependent cells, whereas selpercatinib plus entrectinib was necessary to inhibit cells with RET/NTRK3/ALK triple alterations or a mixture of cell population carrying these genetic alterations. Thus, RET-altered MTC adapted to selpercatinib and larotrectinib with acquisition of ETV6::NTRK3 and EML4::ALK oncogenes can be managed by combination of selpercatinib and entrectinib providing proof-of-concept of urgency of incorporating molecular profiling in real-time and personalized N-of-1 care transcending one-size-fits-all approach.

Over the past decades, there has been ongoing effort to develop complex biomimetic tissue engineering strategies for in vitro cultivation and maintenance of organoids. The defined hydrogels can create organoid models for various organs by changing their properties and various active molecules. An increasing number of researches has been done on the application of hydrogels in organoids, and a large number of articles have been published on the topic. Although there have been existing reviews describing the application of hydrogels in the field of organoids, there is still a lack of comprehensive studies summarizing and analyzing the overall research trends in this field. The citation can be used as an indicator of the scientific influence of an article in its field. This study aims to evaluate the application of hydrogels in organoids through bibliometric analysis, and to predict the hotspots and developing trends in this field.

Sustained and intense inflammation is the pathological basis for intervertebral disc degeneration (IVDD). Effective antagonism or reduction of local inflammatory factors may help regulate the IVDD microenvironment and reshape the extracellular matrix of the disc. This study reports an immunomodulatory hydrogel microsphere system combining cell membrane-coated mimic technology and surface chemical modification methods by grafting neutrophil membrane-coated polylactic-glycolic acid copolymer nanoparticles loaded with transforming growth factor-beta 1 (TGF-β1) (T-NNPs) onto the surface of methacrylic acid gelatin anhydride microspheres (GM) via amide bonds. The nanoparticle-microsphere complex (GM@T-NNPs) sustained the long-term release of T-NNPs with excellent cell-like functions, effectively bound to pro-inflammatory cytokines, and improved the release kinetics of TGF-β1, maintaining a 36 day-acting release. GM@T-NNPs significantly inhibited lipopolysaccharide-induced inflammation in nucleus pulposus cells in vitro, downregulated the expression of inflammatory factors and matrix metalloproteinase, and upregulated the expression of collagen-II and aggrecan. GM@T-NNPs effectively restored intervertebral disc height and significantly improved the structure and biomechanical function of the nucleus pulposus in a rat IVDD model. The integration of biomimetic technology and nano-drug delivery systems expands the application of biomimetic cell membrane-coated materials and provides a new treatment strategy for IVDD.

Fat content is an important trait in pig production. Adipose tissue and muscle are important sites for fat deposition and affect production efficiency and quality. To regulate the fat content in these tissues, we need to understand the mechanisms behind fat deposition. Laiwu pigs, a Chinese indigenous breed, have significantly higher fat content in both adipose tissue and muscle than commercial breeds such as Duroc. In this study, we analyzed the transcriptomes in adipose tissue and muscle of 21-d-old Laiwu and Duroc piglets. Results showed that there were 828 and 671 differentially expressed genes (DEG) in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), respectively. Functional enrichment analysis showed that these DEG were enriched in metabolic pathways, especially carbohydrate and lipid metabolism. Additionally, in the longissimus muscle (LM) and psoas muscle (PM), 312 and 335 DEG were identified, demonstrating enrichment in the cell cycle and metabolic pathways. The protein–protein interaction (PPI) networks of these DEG were analyzed and potential hub genes were identified, such as FBP1 and SCD in adipose tissues and RRM2 and GADL1 in muscles. Meanwhile, results showed that there were common DEG between adipose tissue and muscle, such as LDHB, THRSP, and DGAT2. These findings showed that there are significant differences in the transcriptomes of the adipose tissue and muscle between Laiwu and Duroc piglets (P

With the surge in cyber attacks, there is a pressing need for more robust network intrusion detection systems (IDSs). These IDSs perform at their best when they can monitor all the traffic coursing through the network, especially within a software-defined network (SDN). In an SDN configuration, the control plane and data plane operate independently, facilitating dynamic control over network flows. Typically, an IDS application resides in the control plane, or a centrally located network IDS transmits security reports to the controller. However, the controller, equipped with various control applications, may encounter challenges when analyzing substantial data, especially in the face of high traffic volumes. To enhance the processing power, detection rates, and alleviate the controller’s burden, deploying multiple instances of IDS across the data plane is recommended. While deploying IDS on individual switches within the data plane undoubtedly enhances detection rates, the associated costs of installing one at each switch raise concerns. To address this challenge, this paper proposes the deployment of IDS chains across the data plane to boost detection rates while preventing controller overload. The controller directs incoming traffic through alternative paths, incorporating IDS chains; however, potential delays from retransmitting traffic through an IDS chain could extend the journey to the destination. To address these delays and optimize flow distribution, our study proposes a method to balance flow assignments to specific IDS chains with minimal delay. Our approach is validated through comprehensive testing and evaluation using a test bed and trace-based simulation, demonstrating its effectiveness in reducing delays and hop counts across various traffic scenarios.

Abstract Background The blood-based biomarkers are approaching the clinical practice of Alzheimer’s disease (AD). Chronic kidney disease (CKD) has a potential confounding effect on peripheral protein levels. It is essential to characterize the impact of renal function on AD markers. Methods Plasma phospho-tau181 (P-tau181), and neurofilament light (NfL) were assayed via the Simoa HD-X platform in 1189 dementia-free participants from the Shanghai Aging Study (SAS). The estimated glomerular filter rate (eGFR) was calculated. The association between renal function and blood NfL, P-tau181 was analyzed. An analysis of interactions between various demographic and comorbid factors and eGFR was conducted. Results The eGFR levels were negatively associated with plasma concentrations of NfL and P-tau181 (B = − 0.19, 95% CI − 0.224 to − 0.156, P

Abstract The shotgun proteomic analysis is currently the most promising single-cell protein sequencing technology, however its identification level of ~1000 proteins per cell is still insufficient for practical applications. Here, we develop a pick-up single-cell proteomic analysis (PiSPA) workflow to achieve a deep identification capable of quantifying up to 3000 protein groups in a mammalian cell using the label-free quantitative method. The PiSPA workflow is specially established for single-cell samples mainly based on a nanoliter-scale microfluidic liquid handling robot, capable of achieving single-cell capture, pretreatment and injection under the pick-up operation strategy. Using this customized workflow with remarkable improvement in protein identification, 2449–3500, 2278–3257 and 1621–2904 protein groups are quantified in single A549 cells (n = 37), HeLa cells (n = 44) and U2OS cells (n = 27) under the DIA (MBR) mode, respectively. Benefiting from the flexible cell picking-up ability, we study HeLa cell migration at the single cell proteome level, demonstrating the potential in practical biological research from single-cell insight.

Abstract Background The need for radiotherapy among the elderly rises with increasing life expectancy and a corresponding increase of elderly cancer patients. Radiation-induced skin injury is one of the most frequent adverse effects in radiotherapy patients, severely limiting their life quality. Re-epithelialization and collagen deposition have essential roles in the recovery of skin injuries induced by high doses of ionizing radiation. At the same time, radiation-induced senescent cells accumulate in irradiated tissues. However, the effects and mechanisms of senescent cells on re-epithelialization and collagen deposition in radiation-induced skin injury have not been fully elucidated. Results Here, we identified a role for a population of senescent cells expressing p16 in promoting re-epithelialization and collagen deposition in radiation-induced skin injury. Targeted ablation of p16+ senescent cells or treatment with Senolytics resulted in the disruption of collagen structure and the retardation of epidermal coverage. By analyzing a publicly available single-cell sequencing dataset, we identified fibroblasts as a major contributor to the promotion of re-epithelialization and collagen deposition in senescent cells. Notably, our analysis of publicly available transcriptome sequencing data highlighted IL-33 as a key senescence-associated secretory phenotype produced by senescent fibroblasts. Neutralizing IL-33 significantly impedes the healing process. Finally, we found that the effect of IL-33 was partly due to the modulation of macrophage polarization. Conclusions In conclusion, our data suggested that senescent fibroblasts accumulated in radiation-induced skin injury sites participated in wound healing mainly by secreting IL-33. This secretion regulated the local immune microenvironment and macrophage polarization, thus emphasizing the importance of precise regulation of senescent cells in a phased manner. Graphical Abstract

Abstract Objectives Tumor spread through air spaces (STAS) is associated with poor prognosis and impacts surgical options. We aimed to develop a user-friendly model based on 2-[18F] FDG PET/CT to predict STAS in stage I lung adenocarcinoma (LAC). Materials and methods A total of 466 stage I LAC patients who underwent 2-[18F] FDG PET/CT examination and resection surgery were retrospectively enrolled. They were split into a training cohort (n = 232, 20.3% STAS-positive), a validation cohort (n = 122, 27.0% STAS-positive), and a test cohort (n = 112, 29.5% STAS-positive) according to chronological order. Some commonly used clinical data, visualized CT features, and SUVmax were analyzed to identify independent predictors of STAS. A prediction model was built using the independent predictors and validated using the three chronologically separated cohorts. Model performance was assessed using ROC curves and calculations of AUC. Results The differences in age (P = 0.009), lesion density subtype (P

Abstract Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) still present a huge threaten to women’s health, especially the local advanced patients. Hence, developing more effectiveness prognostic signatures is urgently needed. This study constructed and verified a robust RNA-binding proteins (RBPs) related signature through a series of bioinformatics methods and explored the biological function of hub RBP in vitro experiments. As a result, the 10 RBPs signature was successfully established and could act as an independent prognostic biomarker in CESC patients, which displayed the highest sensitivity and specificity in prognosis prediction compared with other clinicopathological parameters. The risk model also presented good performance in risk stratification among CESC patients. Besides, a nomogram was constructed based on pathological stage and the risk signature and exhibited satisfactory accuracy in prognosis prediction. Functional enrichment indicated that the risk signature mainly participated in immune-related pathways and cancer-related pathways, and the infiltration level of immune cells and immune checkpoints showed a significantly higher degree in low-risk patients compared with high-risk patients. Notably, the 10 RBPs signature act as a novel biomarker in immunotherapy and chemotherapy response. In addition, PRPF40B was selected as hub RBP and its transcription and translation levels were obviously increased in CESC tissues, as well as Hela and Siha cells. Knockdown of PRPF40B inhibits the proliferation, migration and invasion of Hela and Siha cells in vitro. In conclusion, our research provides a noticeable strategy in prognostic prediction among CESC patients, which may illuminate the prospect of CESC patients’ clinical outcome.

Abstract Shock wave/boundary layer interaction (SWBLI) continues to pose a significant challenge in the field of aerospace engineering. This paper aims to address this issue by proposing a novel approach for predicting aerodynamic coefficients and heat transfer in viscous supersonic and hypersonic flows using a high-order flux reconstruction technique. Currently, finite volume methods are extensively employed for the computation of skin aerodynamic coefficients and heat transfer. Nevertheless, these numerical methods exhibit considerable susceptibility to a range of factors, including the inviscid flux function and the computational mesh. The application of high-order flux reconstruction techniques offers promising potential in alleviating these challenges. In contrast to other high-order methods, the flux reconstruction is combined with the lattice Boltzmann flux solver in this study. The current method evaluates the common inviscid flux at the cell interface by locally reconstructing the lattice Boltzmann equation solution from macroscopic flow variables at solution points. Consequently, this framework performs a positivity-preserving, entropy-based adaptive filtering method for shock capturing. The present approach is validated by simulating the double Mach reflection, and then simulating some typical viscous problems. The results demonstrate that the current method accurately predicts aerodynamic coefficients and heat transfer, providing valuable insights into the application of high-order methods for shock wave/boundary layer interaction.

Foundation settlement is a common problem in civil engineering. In the case of un-even settlement, it can lead to structural deformation and damage, which seriously affects the safety and reliability of the project. Therefore, the influence of adjusting the stiffness of the foundation on un-even settlement was analyzed through finite element analysis to effectively solve un-even settlement. By simulating the settlement of soil under different foundation stiffness and load conditions, the influence of foundation stiffness adjustment on soil deformation and settlement distribution was analyzed, and its impact on structural safety was evaluated. These studies confirmed that thickened layers could effectively solve the un-even settlement. Within the range of 0.2 to 1.0 meters, the difference in thickness was the greatest. The adjustment of differential settlement by layer thickness was phased and decreased with increasing thickness. Adjusting the stiffness of the foundation could effectively solve un-even settlement, reduce differences in soil settlement, and improve the overall stability and safety of the structure. These results have important guiding significance for the design of foundation and the solution of un-even settlement problems in engineering practice and provide certain reference and basis for further research.

With the annual promotion of the international “dual carbon” goals, countries attach great importance to the development and innovation of clean energy. The United States, Japan, and China have all created many policies for the research and market development of photovoltaic energy. This article incorporates market dynamic regulation capability into a two-dimensional system of government subsidy policies and photovoltaic revenue, constructs a three-dimensional dynamic nonlinear model based on market dynamic regulation capability, government subsidies, and enterprise revenue, and numerically simulates and analyzes the impact of parameter and initial value changes in the equation on enterprise revenue. The market dynamic regulation capability is obtained from Chaotic attractors and dynamic evolution graphs of the nonlinear evolution between government subsidies and corporate profits in different scenarios. Research has shown that: (1) Rapidly improving the dynamic regulation ability of the market cannot continuously increase the revenue of the photovoltaic industry; (2) The changes in market dynamics affect the dependence of enterprises on government subsidies; (3) The demand for government subsidies by enterprises gradually decreases with the increase of their own profits.

In this work, for nonlinear multi-agent systems, we mainly study distributed double-integrator finite-time and fixed-time containment control with undirected heterogeneous networks. At the first, two controllers to realize finite-time containment and two controllers to achieve fixed-time containment were designed. Second, we design appropriate finite-time and fixed-time containment protocols to ensure followers can move to geometric region formed by leaders, and settling time can be estimated. We can obtain that the calculation of convergence time of finite-time containment control is associated to the initial state. And the settling time of the fixed-time containment control is related to the parameters. Finally, correctness of the theory is verified by mathematical simulation experiments.

The Ludwieg tube wind tunnel serves as a crucial testing ground for fundamental studies of hypersonic aerodynamics. However, the quick-opening valve-started hypersonic Ludwieg tube wind tunnel has been affected by the quick-opening valve for a long time, resulting in different types of flow disturbance modes. The double-throat aerodynamic configuration can effectively eliminate the disturbance source of the upstream components of the quick-opening valve-started hypersonic Ludwieg tube wind tunnel, but it will lead to a significant reduction in the effective running time of the wind tunnel. In order to solve this problem, the unsteady numerical simulation was used to study the start-up characteristics of the hypersonic Ludwieg tube wind tunnel with double-throat aerodynamic configuration. Then, a fusion design was carried out for the first nozzle expansion section and the stable section. The effects of different combinations of expansion angles and stable sections on the start-up time and flow field quality of the wind tunnel were studied. The results show that the effective running time of the hypersonic Ludwieg tube wind tunnel with double-throat aerodynamic configuration can be increased by nearly 20% by using the combined design of reducing the expansion angle, and the static flow field quality in the downstream experimental section is almost unaffected, which effectively improves the experimental ability of the wind tunnel. At the same time, compared with the larger expansion angle combination, the smaller expansion angle design can reduce the total pressure loss by about 10%.

With the growing number of user-side resources connected to the distribution system, an occasional imbalance between the distribution side and the user side arises, making short-term power load forecasting technology crucial for addressing this issue. To strengthen the capability of load multi-feature extraction and improve the accuracy of electric load forecasting, we have constructed a novel BILSTM-SimAM network model. First, the entirely non-recursive Variational Mode Decomposition (VMD) signal processing technique is applied to decompose the raw data into Intrinsic Mode Functions (IMF) with significant regularity. This effectively reduces noise in the load sequence and preserves high-frequency data features, making the data more suitable for subsequent feature extraction. Second, a convolutional neural network (CNN) mode incorporates Dropout function to prevent model overfitting, this improves recognition accuracy and accelerates convergence. Finally, the model combines a Bidirectional Long Short-Term Memory (BILSTM) network with a simple parameter-free attention mechanism (SimAM). This combination allows for the extraction of multi-feature from the load data while emphasizing the feature information of key historical time points, further enhancing the model's prediction accuracy. The results indicate that the R2 of the BILSTM-SimAM algorithm model reaches 97.8%, surpassing mainstream models such as Transformer, MLP, and Prophet by 2.0%, 2.7%, and 3.6%, respectively. Additionally, the remaining error metrics also show a reduction, confirming the validity and feasibility of the method proposed.

In response to the issues of relatively low image contrast, blurry boundaries of infrared small targets, and various environmental noise interferences in thermal imaging systems, resulting in reduced target recognition rates and tracking effectiveness. This paper proposes an infrared target image recognition algorithm based on fuzzy comprehensive assessment. Built upon infrared image sequences captured by an on-board thermal imager, the algorithm employs grayscale processing, neighborhood mean filtering, and second-order difference method to filter and enhance the infrared target images. This process improves the quality of infrared target images and enhances the contrast between targets and backgrounds. The algorithm utilizes the maximum interclass variance method for segmenting the infrared target images, combining it with the Canny operator to extract target edges, thereby obtaining clearer details of the infrared target edges. Finally, based on the extracted target feature information, the algorithm calculates the confidence of each marked region, establishes the membership function of target likelihood, employs a comprehensive weighted approach to construct the target confidence function, and compares the confidence of marked regions with that of the template image to achieve precise target recognition. Experimental validation against theoretical methods and comparisons with other approaches demonstrate the effectiveness and feasibility of the proposed method, providing theoretical support for reliable target tracking in electro-optical imaging systems.

Abstract This work develops a new robust multi‐objective model predictive control (MoMPC) strategy for constrained non‐linear systems with bounded disturbances. The multiple objectives are always contradictory, and the presence of disturbances may result in the violation of state constraints and instability of the controlled system. Firstly, the conflict between multiple objectives is reconciled by minimizing the distance of the cost function vector to the vector of independently minimised objectives obtained by solving a set of steady‐state optimisation problems. Then the contractive state set, which takes into account the effect of disturbances on system states, is constructed to guarantee the robust satisfaction of state constraints. Finally, a stability constraint updated online by solving an auxiliary optimization problem is established to ensure the robust stability of the system under MoMPC. An isothermal chemical reactor system is employed to verify the effectiveness of the controller proposed here.

Nasal drug delivery efficiency is highly dependent on the position in which the drug is deposited in the nasal cavity. However, no reliable method is currently available to assess its impact on delivery performance. In this study, a biomimetic nasal model based on three-dimensional (3D) reconstruction and three-dimensional printing (3DP) technology was developed for visualizing the deposition of drug powders in the nasal cavity. The results showed significant differences in cavity area and volume and powder distribution in the anterior part of the biomimetic nasal model of Chinese males and females. The nasal cavity model was modified with dimethicone and validated to be suitable for the deposition test. The experimental device produced the most satisfactory results with five spray times. Furthermore, particle sizes and spray angles were found to significantly affect the experimental device's performance and alter drug distribution, respectively. Additionally, mometasone furoate (MF) nasal spray (NS) distribution patterns were investigated in a goat nasal cavity model and three male goat noses, confirming the in vitro and in vivo correlation. In conclusion, the developed human nasal structure biomimetic device has the potential to be a valuable tool for assessing nasal drug delivery system deposition and distribution.

[INLINE:1] Neurotrophic keratopathy is a persistent defect of the corneal epithelium, with or without stromal ulceration, due to corneal nerve deficiency caused by a variety of etiologies. The treatment options for neurotrophic keratopathy are limited. In this study, an ophthalmic solution was constructed from a chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor (CTH-mNGF). Its effectiveness was evaluated in corneal denervation (CD) mice and patients with neurotrophic keratopathy. In the preclinical setting, CTH-mNGF was assessed in a murine corneal denervation model. CTH-mNGF was transparent, thermosensitive, and ensured sustained release of mNGF for over 20 hours on the ocular surface, maintaining the local mNGF concentration around 1300 pg/mL in vivo. Corneal denervation mice treated with CTH-mNGF for 10 days showed a significant increase in corneal nerve area and total corneal nerve length compared with non-treated and CTH treated mice. A subsequent clinical trial of CTH-mNGF was conducted in patients with stage 2 or 3 neurotrophic keratopathy. Patients received topical CTH-mNGF twice daily for 8 weeks. Fluorescein sodium images, Schirmer’s test, intraocular pressure, Cochet-Bonnet corneal perception test, and best corrected visual acuity were evaluated. In total, six patients (total of seven eyes) diagnosed with neurotrophic keratopathy were enrolled. After 8 weeks of CTH-mNGF treatment, all participants showed a decreased area of corneal epithelial defect, as stained by fluorescence. Overall, six out of seven eyes had fluorescence staining scores < 5. Moreover, best corrected visual acuity, intraocular pressure, Schirmer’s test and Cochet-Bonnet corneal perception test results showed no significant improvement. An increase in corneal nerve density was observed by in vivo confocal microscopy after 8 weeks of CTH-mNGF treatment in three out of seven eyes. This study demonstrates that CTH-mNGF is transparent, thermosensitive, and has sustained-release properties. Its effectiveness in healing corneal epithelial defects in all eyes with neurotrophic keratopathy suggests CTH-mNGF has promising application prospects in the treatment of neurotrophic keratopathy, being convenient and cost effective.

Marigold (Tagetes erecta L., African marigold) is a widely grown ornamental plant and a main source of the carotenoid lutein for the industrial production of pharmaceuticals, food coloring, and feed additives. To gain a deeper understanding of the genetic mechanism of lutein in marigold, a chromosome-scale assembly of the marigold (T. erecta V-01) genome was completed based on Illumina, PacBio, and Hi-C reads. The 707.21-Mb assembled genome consisted of 35 834 annotated protein-coding genes, with 97.7% genomic integrity. We anchored 87.8% of the contigs (covering 621.20 Mb) to 12 pseudochromosomes, bringing the scaffold N50 length to 54.15 Mb. Phylogenetic analysis showed that marigold was closely related to the Asteraceae species bitter vine (Mikania micrantha) and sunflower (Helianthus annuus), all three of which originated in the Americas. Marigold diverged from the sunflower clade 23.57 million years ago (MYA) and from M. micrantha 19.59 MYA. Marigold has undergone three whole-genome duplication events, as well as a recent whole-genome duplication event (WGD-2) common to H. annuus and M. micrantha. Marigold gene families were significantly less expanded than those of M. micrantha or H. annuus, and the marigold genome contained significantly fewer interspersed repeats, which might account for its smaller genome. In addition, a range of candidate genes involved in the lutein biosynthetic pathway were identified. The high-quality reference genome obtained in this study provided a valuable genomic resource for studying the evolution of the Asteraceae family and for improving marigold breeding strategies.

Abstract Background The efficacy of systemic therapy regimens, such as immune checkpoint inhibitors and tyrosine kinase inhibitors (IO‐TKI) and targeted therapy, for metastatic clear cell renal cell carcinoma (ccRCC) remains unpredictable due to the lack of effective biomarkers. Neutrophil extracellular trap (NET) plays an important role in promoting ccRCC. This study explores the NET predictive value of the efficacy in metastatic ccRCC. Methods In this retrospective study, patients with metastatic ccRCC who received targeted drugs and IO‐TKI were included. Immunofluorescence staining was utilized to quantify the levels of tissue NETs through cell counts of H3Cit(+) and MPO(+) cells. Results A total of 183 patients with metastatic ccRCC were enrolled, including 150 patients who received TKIs and 33 patients who received IO‐TKI. The levels of NETs in tumor tissue were significantly higher than in para‐tumor tissue (p

Abstract Lung cancer is the leading cause of cancer-related death. Lysosomes are key degradative compartments that maintain protein homeostasis. In current study, we aimed to construct a lysosomes-related genes signature to predict the overall survival (OS) of patients with Lung Adenocarcinoma (LUAD). Differentially expressed lysosomes-related genes (DELYs) were analyzed using The Cancer Genome Atlas (TCGA-LUAD cohort) database. The prognostic risk signature was identified by Least Absolute Shrinkage and Selection Operator (LASSO)-penalized Cox proportional hazards regression and multivariate Cox analysis. The predictive performance of the signature was assessed by Kaplan–Meier curves and Time-dependent receiver operating characteristic (ROC) curves. Gene set variant analysis (GSVA) was performed to explore the potential molecular biological function and signaling pathways. ESTIMATE and single sample gene set enrichment analysis (ssGSEA) were applied to estimate the difference of tumor microenvironment (TME) between the different risk subtypes. An eight prognostic genes (ACAP3, ATP8B3, BTK, CAV2, CDK5R1, GRIA1, PCSK9, and PLA2G3) signature was identified and divided patients into high-risk and low-risk groups. The prognostic signature was an independent prognostic factor for OS (HR > 1, p

Increasing evidence demonstrates that mammals have different reactions to hypoxia with varied oxygen dynamic patterns. It takes ∼24 h for tri-gas incubator to achieve steady cell hypoxia, which fails to recapitulate ultrafast oxygen dynamics of intestinal ischemia/reperfusion (IR) injury. Inspired from the structure of native intestinal villi, we engineered an intestinal organoid chip embedded with engineered artificial microvessels based on co-axial microfluidic technology by using pH-responsive ZIF-8/sodium alginate scaffold. The chip was featured on: (i) eight times the oxygen exchange efficiency compared with the conventional device, tri-gas incubator, (ii) implantation of intestinal organoid reproducing all types of intestinal epithelial cells, and (iii) bio-responsiveness to hypoxia and reoxygenation (HR) by presenting metabolism disorder, inflammatory reaction, and cell apoptosis. Strikingly, it was found for the first time that Olfactomedin 4 (Olfm4) was the most significantly down-regulated gene under a rapid HR condition by sequencing the RNA from the organoids. Mechanistically, OLFM4 played protective functions on HR-induced cell inflammation and tissue damage by inhibiting the NF-kappa B signaling activation, thus it could be used as a therapeutic target. Altogether, this study overcomes the issue of mismatched oxygen dynamics between in vitro and in vivo, and sets an example of next-generation multisystem-interactive organoid chip for finding precise therapeutic targets of IR injury.

IntroductionFine needle aspiration (FNA) biopsy is a widely accepted method for diagnosing thyroid nodules. However, the influence of maximum diameter (MD) of ACR TIRADS 5 (TR5) thyroid nodules on the FNA outcomes remains debated. This study examined the influence of MD on the FNA outcomes and investigated the optimal MD threshold for FNA in TR5 nodules.MethodsWe conducted a retrospective analysis of 280 TR5 thyroid nodules from 226 patients who underwent FNA from January to June 2022 in our department. Probably malignant (PM) group was defined as Bethesda V in cytopathology with confirmed BRAF V600E mutation or Bethesda VI, the other cytopathology outcomes were defined as probably benign (PB) group. We examined factors influencing malignant cytopathology outcomes and determined the optimal MD threshold for FNA in TR5 nodules using logistic regression and restricted cubic spline (RCS) analysis.ResultsAmong these nodules, 58.2% (163/280) had PM outcomes. The PM group had a significantly larger MD than the PB group [6.5mm (range 5.0-8.4) vs. 5.3mm (range 4.0-7.0), p < 0.001]. In multivariate logistic regression fully adjusted for confounders, MD was significantly associated with PM outcomes [odds ratio 1.16, 95%CI 1.05-1.31; p = 0.042]. The highest quartile of MD had a greater likelihood of PM outcomes compared to the lowest quartile [odds ratio 4.71, 95% CI 1.97-11.69, p = 0.001]. The RCS analysis identified 6.2 mm as the optimal MD threshold for FNA in TR5 nodules.ConclusionMD significantly affects the probability of malignant outcomes in FNA of TR5 thyroid nodules. A MD threshold of ≥6.2mm is suggested for FNA in these nodules.

Competence development is essential for bacterial transformation since it enables bacteria to take up free DNA from the surrounding environment. The regulation of teichoic acid biosynthesis is tightly controlled during pneumococcal competence; however, the mechanism governing this regulation and its impact on transformation remains poorly understood. We demonstrated that a defect in lipoteichoic acid ligase (TacL)-mediated lipoteichoic acids (LTAs) biosynthesis was associated with impaired pneumococcal transformation. Using a fragment of tacL regulatory probe as bait in a DNA pulldown assay, we successfully identified several regulatory proteins, including ComE. Electrophoretic mobility shift assays revealed that phosphomimetic ComE, but not wild-type ComE, exhibited specific binding to the probe. DNase I footprinting assays revealed the specific binding sequences encompassing around 30 base pairs located 31 base pairs upstream from the start codon of tacL. Expression of tacL was found to be upregulated in the ΔcomE strain, and the addition of exogenous competence-stimulating peptide repressed the tacL transcription in the wild-type strain but not the ΔcomE mutant, indicating that ComE exerted a negative regulatory effect on the transcription of tacL. Mutation in the JH2 region of tacL upstream regulatory sequence led to increased LTAs abundance and displayed higher transformation efficiency. Collectively, our work identified the regulatory mechanisms that control LTAs biosynthesis during competence and thereby unveiled a repression mechanism underlying pneumococcal transformation.

Chronic inflammation can delay wound healing, eventually leading to tissue necrosis and even cancer. Developing real-time intelligent inflammation monitoring and treatment to achieve effective wound management is important to promote wound healing. In this study, a smart multifunctional hydrogel (Hydrogel@Au NCs&DG) was proposed to monitor and treat the wound inflammation. It was prepared by mixing 3-carboxy-phenylboronic acid modified chitosan (CS-cPBA), β-glycerophosphate (β-GP), albumin-protected gold nanoclusters (BSA-Au NCs), and dipotassium glycyrrhizinate (DG) about 10 s. In this hydrogel, CS-cPBA and β-GP are crosslinked together by boric acid ester bond and hydrogen bond to form the main hydrogel network, endowing the hydrogel with self-healing and injectable properties to adapt irregular wounds. Importantly, the as-prepared hydrogel with good biocompatibility and excellent adhesion property could directly determine the H2O2 to monitor the wound microenvironment by visible fluorescence change of BSA-Au NCs and then guide the frequency of dressing change to eliminate inflammation. The results demonstrated that the as-prepared smart hydrogel could be expected to serve as an intelligent wound dressing to promote inflammation-infected wound healing.

Background: Extracellular high mobility group box 1 (HMGB1) is a key mediator in driving allergic airway inflammation and contributes to asthma. Yet, mechanism of HMGB1 secretion in asthma is poorly defined. Pulmonary metabolic dysfunction is recently recognized as a driver of respiratory pathology. However, the altered metabolic signatures and the roles of metabolic to allergic airway inflammation remain unclear. Methods: Male C57BL/6 J mice were sensitized and challenged with toluene diisocyanate (TDI) to generate a chemically induced asthma model. Pulmonary untargeted metabolomics was employed. According to results, mice were orally administered allopurinol, a xanthine oxidase (XO) inhibitor. Human bronchial epithelial cells (16HBE) were stimulated by TDI-human serum albumin (HSA). Results: We identified the purine metabolism was the most enriched pathway in TDI-exposed lungs, corresponding to the increase of xanthine and uric acid, products of purine degradation mediated by XO. Inhibition of XO by allopurinol ameliorates TDI-induced oxidative stress and DNA damage, mixed granulocytic airway inflammation and Th1, Th2 and Th17 immunology as well as HMGB1 acetylation and secretion. Mechanistically, HMGB1 acetylation was caused by decreased activation of the NAD+-sirtuin 1 (SIRT1) axis triggered by hyperactivation of the DNA damage sensor poly (ADP-ribose)-polymerase 1 (PARP-1). This was rescued by allopurinol, PARP-1 inhibitor or supplementation with NAD+ precursor in a SIRT1-dependent manner. Meanwhile, allopurinol attenuated Nrf2 defect due to SIRT1 inactivation to help ROS scavenge. Conclusions: We demonstrated a novel regulation of HMGB1 acetylation and secretion by purine metabolism that is critical for asthma onset. Allopurinol may have therapeutic potential in patients with asthma.

Abstract Hydroxylated isoprenoid GDGTs (OH‐GDGTs) have emerged as a novel tool for reconstructing sea surface temperatures. However, when using marine OH‐GDGT calibration in lacustrine settings, it leads to a significant overestimation of temperatures, emphasizing the necessity for a thorough examination of OH‐GDGTs in lakes. Here, we investigated OH‐GDGT distributions in surface sediments from 65 lakes in West China and compiled published Asian lake and global marine OH‐GDGT data sets. Among all GDGT‐based indices, RI‐OH showed the strongest correlation with temperature across Asian lakes. The RI‐OH value was higher in lakes than in marine sediments, likely due to differences in the composition of Group 1.1a thaumarchaeotal species between the two settings. The first RI‐OH temperature calibration for lakes was developed and it addressed the issue of temperature overestimation when applied to both water column and sediment core, highlighting the potential of OH‐GDGTs as a new terrestrial paleothermometer.

Brooks are significant ecological sources and migration channels of material flow as well as energy flow in urban–rural fringes. Despite their significance, the absence of monitoring data poses challenges in assessing brook pollution risk. Taking Muli Brook as an example, a spatiotemporal variability of water quality was revealed through sample collection and water chemistry analysis. We reveal spatiotemporal variability of pollution and then developed an Exposure Index (EPI), verifying its substitution effect in assessing brook pollution risk. Our findings demonstrate a downward trend in pollution from 2020 to 2022, with exceptions in dissolved oxygen (DO) and pH. Notably, more severe pollution is observed during spring and summer, influenced by seasonal production activities and extreme weather events. Despite the diminishing disparity near urban areas, the cumulative influence of upstream pollutants outweighs that of surrounding human activities. Stronger associations between pollution risks and water area EPI were observed, compared to those of construction land and farm land. In conclusion, EPI emerges as a valuable tool for assessing brook pollution risks in urban–rural fringes, offering precise insights into brook habitat characteristics, especially in the absence of consistent monitoring data.

Background Ferroptosis plays an important role in enhancing the efficacy of anti-programmed cell death 1 (PD-1) immunotherapy; however, the molecular mechanisms by which tumor ferroptosis sensitizes melanoma and lung cancer to anti-PD-1 immunotherapy have not been elucidated.Methods Cytotoxicity assays, colony formation assays, flow cytometry and animal experiments were used to evaluate the effects of mefloquine (Mef) on survival and ferroptosis in melanoma and lung cancer. RNA sequencing, Real-time quantitative PCR (qRT-PCR), western blotting, chromatin immunoprecipitation-qPCR and flow cytometry were used to determine the molecular mechanisms by which Mef regulates lysophosphatidylcholine acyltransferase 3 (LPCAT3). The relationship between LPCAT3 and the efficacy of anti-PD-1 immunotherapy was verified via a clinical database and single-cell RNA sequencing (ScRNA-Seq).Results In this study, we discovered that Mef induces ferroptosis. Furthermore, treatment with Mef in combination with T-cell-derived interferon-γ (IFN-γ) enhanced tumor ferroptosis and sensitized melanoma and lung cancer cells to anti-PD-1 immunotherapy. Mechanistically, Mef upregulated the expression of LPCAT3, a key gene involved in lipid peroxidation, by activating IFN-γ-induced STAT1-IRF1 signaling, and knocking down LPCAT3 impaired the induction of ferroptosis by Mef+IFN-γ. Clinically, analysis of the transcriptome and single-cell sequencing results in patients with melanoma showed that LPCAT3 expression was significantly lower in patients with melanoma than in control individuals, and LPCAT3 expression was positively correlated with the efficacy of anti-PD-1 immunotherapy.Conclusions In conclusion, our study demonstrated a novel mechanism by which LPCAT3 is regulated, and demonstrated that Mef is a highly promising new target that can be utilized to enhance the efficacy of anti-PD-1 immunotherapy.

Mitochondrial transfer RNA mutation is one of the most important causes of hereditary hearing loss in humans. Mitochondrial transfer RNASer (UCN) gene is another hot spot for mutations associated with non-syndromic hearing loss, besides the 12S ribosomal RNA gene. In this study, we assessed the clinical phenotype and the molecular characteristics of two Chinese families with non-syndromic hearing loss. Mutational analysis revealed that 7445A > G and 7510T > C mutations in the mitochondrial transfer RNASer (UCN) gene were the molecular etiology of Family 1 and Family 2, respectively. However, the clinical and genetic characteristics of the two families carrying the above mutations in the transfer RNASer (UCN) gene exhibited a variable expression of hearing loss and an incomplete penetrance. Sequencing analysis of the complete mitochondrial genome showed the presence of transfer RNATrp 5568A > G and NADH-ubiquinone oxidoreductase chain 4 11696G > A mutations in Family 1. The mitochondrial haplotype analysis showed that the two families belonged to Asian D4 and M80′D haplotypes, respectively, and no pathogenic variations were found in the nuclear genes. To our knowledge, our study is the first to report 7445A > G and 7510T > C mutations in the mitochondrial transfer RNASer (UCN) gene, in multi-generation non-syndromic hearing loss pedigrees from China. Our study suggests that 5568A > G and 11696G > A mutations may enhance the penetrance of hearing loss in Chinese Family 1, while mitochondrial haplotypes and known nuclear genes may not be modifiers for the phenotypic expression of 7445A > G and 7510T > C mutations in these Chinese families.

Abstract Background The establishment of a robust gut microbiota in piglets during their early developmental stage holds the potential for long-term advantageous effects. However, the optimal timeframe for introducing probiotics to achieve this outcome remains uncertain. Results In the context of this investigation, we conducted a longitudinal assessment of the fecal microbiota of 63 piglets at three distinct pre-weaning time points. Simultaneously, we gathered vaginal and fecal samples from 23 sows. Employing 16S rRNA gene and metagenomic sequencing methodologies, we conducted a comprehensive analysis of the fluctuation patterns in microbial composition, functional capacity, interaction networks, and colonization resistance within the gut microbiota of piglets. As the piglets progressed in age, discernible modifications in intestinal microbial diversity, composition, and function were observed. A source-tracking analysis unveiled the pivotal role of fecal and vaginal microbiota derived from sows in populating the gut microbiota of neonatal piglets. By D21, the microbial interaction network displayed a more concise and efficient configuration, accompanied by enhanced colonization resistance relative to the other two time points. Moreover, we identified three strains of Ruminococcus sp. at D10 as potential candidates for improving piglets' weight gain during the weaning phase. Conclusions The findings of this study propose that D10 represents the most opportune juncture for the introduction of external probiotic interventions during the early stages of piglet development. This investigation augments our comprehension of the microbiota dynamics in early-life of piglets and offers valuable insights for guiding forthcoming probiotic interventions.