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Abstract Gastrointestinal cancer is the most common malignancy in humans, often accompanied by poor prognosis. N6-methyladenosine (m6A) modification is widely present in eukaryotic cells as the most abundant RNA modification. It plays a crucial role in RNA splicing and processing, nuclear export, translation, and stability. Human AlkB homolog 5 (ALKBH5) is a type of RNA demethylase exhibiting abnormal expression in various gastrointestinal cancers.It is closely related to the tumorigenesis, proliferation, migration, and other biological functions of gastrointestinal cancer. However, recent studies indicated that the role and mechanism of ALKBH5 in gastrointestinal cancer are complicated and even controversial. Thus, this review summarizes recent advances in elucidating the role of ALKBH5 as a tumor suppressor or promoter in gastrointestinal cancer. It examines the biological functions of ALKBH5 and its potential as a therapeutic target, providing new perspectives and insights for gastrointestinal cancer research.

Abstract A 27-year-old man was admitted to the hospital after a year of marriage due to infertility. During laparoscopic exploratory surgery, the presence of a retrovesical uterus was clearly observed, and the gonadal organs were visible on both sides. However, the testicles or ovaries were not identifiable, nor were the spermatic vessels and fallopian tubes at the joint. Intraoperative bilateral gonad biopsy was performed. Cryopreservation of the right gonadal gland revealed gonadoblastoma and malignant germinoma (asexual tumor/seminoma) with sclerosis and atrophy of testicular tissue. No proliferation of germ cells and sertoli cells was observed in spermatic tubule. The left gonad was diagnosed as a gonadoblastoma. Finally, total hysterectomy and bilateral gonadal tumor organectomy were performed to seal the vaginal stump. Local radiotherapy was administered after surgery. In general, tumors were found on both sides of the gonads, especially gonadoblastoma and malignant germinoma on the right side and gonadoblastoma on the left side.

Abstract Background Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and second leading cause of cancer-related deaths worldwide. The heightened mortality associated with HCC is largely attributed to its propensity for metastasis, which cannot be achieved without remodeling or loss of the basement membrane (BM). Despite advancements in targeted therapies and immunotherapies, resistance and limited efficacy in late-stage HCC underscore the urgent need for better therapeutic options and early diagnostic biomarkers. Our study aimed to address these gaps by investigating and evaluating potential biomarkers to improve survival outcomes and treatment efficacy in patients with HCC. Method In this study, we collected the transcriptome sequencing, clinical, and mutation data of 424 patients with HCC from The Cancer Genome Atlas (TCGA) and 240 from the International Cancer Genome Consortium (ICGC) databases. We then constructed and validated a prognostic model based on metastasis and basement membrane-related genes (MBRGs) using univariate and multivariate Cox regression analyses. Five immune-related algorithms (CIBERSORT, QUANTISEQ, MCP counter, ssGSEA, and TIMER) were then utilized to examine the immune landscape and activity across high- and low-risk groups. We also analyzed Tumor Mutation Burden (TMB) values, Tumor Immune Dysfunction and Exclusion (TIDE) scores, mutation frequency, and immune checkpoint gene expression to evaluate immune treatment sensitivity. We analyzed integrin subunit alpha 3 (ITGA3) expression in HCC by performing single-cell RNA sequencing (scRNA-seq) analysis using the TISCH 2.0 database. Lastly, wound healing and transwell assays were conducted to elucidate the role of ITGA3 in tumor metastasis. Results Patients with HCC were categorized into high- and low-risk groups based on the median values, with higher risk scores indicating worse overall survival. Five immune-related algorithms revealed that the abundance of immune cells, particularly T cells, was greater in the high-risk group than in the low-risk group. The high-risk group also exhibited a higher TMB value, mutation frequency, and immune checkpoint gene expression and a lower tumor TIDE score, suggesting the potential for better immunotherapy outcomes. Additionally, scRNA-seq analysis revealed higher ITGA3 expression in tumor cells compared with normal hepatocytes. Wound healing scratch and transwell cell migration assays revealed that overexpression of the MBRG ITGA3 enhanced migration of HCC HepG2 cells. Conclusion This study established a direct molecular correlation between metastasis and BM, encompassing clinical features, tumor microenvironment, and immune response, thereby offering valuable insights for predicting clinical outcomes and immunotherapy responses in HCC.

Abstract In machine learning (ML) problems, it is widely believed that more training samples lead to improved predictive accuracy but incur higher computational costs. Consequently, achieving better data efficiency, that is, the trade-off between the size of the training set and the accuracy of the output model, becomes a key problem in ML applications. In this research, we systematically investigate the data efficiency of Univariate Time Series Anomaly Detection (UTS-AD) models. We first experimentally examine the performance of nine popular UTS-AD algorithms as a function of the training sample size on several benchmark datasets. Our findings confirm that most algorithms become more accurate when more training samples are used, whereas the marginal gain for adding more samples gradually decreases. Based on the above observations, we propose a novel framework called FastUTS-AD that achieves improved data efficiency and reduced computational overhead compared to existing UTS-AD models with little loss of accuracy. Specifically, FastUTS-AD is compatible with different UTS-AD models, utilizing a sampling- and scaling law-based heuristic method to automatically determine the number of training samples a UTS-AD model needs to achieve predictive performance close to that when all samples in the training set are used. Comprehensive experimental results show that, for the nine popular UTS-AD algorithms tested, FastUTS-AD reduces the number of training samples and the training time by 91.09–91.49% and 93.49–93.82% on average without significant decreases in accuracy.

Abstract Advancements in clinical treatment are increasingly constrained by the limitations of supervised learning techniques, which depend heavily on large volumes of annotated data. The annotation process is not only costly but also demands substantial time from clinical specialists. Addressing this issue, we introduce the S4MI (Self-Supervision and Semi-Supervision for Medical Imaging) pipeline, a novel approach that leverages advancements in self-supervised and semi-supervised learning. These techniques engage in auxiliary tasks that do not require labeling, thus simplifying the scaling of machine supervision compared to fully-supervised methods. Our study benchmarks these techniques on three distinct medical imaging datasets to evaluate their effectiveness in classification and segmentation tasks. Notably, we observed that self-supervised learning significantly surpassed the performance of supervised methods in the classification of all evaluated datasets. Remarkably, the semi-supervised approach demonstrated superior outcomes in segmentation, outperforming fully-supervised methods while using 50% fewer labels across all datasets. In line with our commitment to contributing to the scientific community, we have made the S4MI code openly accessible, allowing for broader application and further development of these methods. The code can be accessed at https://github.com/pranavsinghps1/S4MI .

Neonicotinoid insecticides (NEOs) have been extensively approved for application in agricultural production both in China and globally. Previous studies indicated that human exposure to NEOs would have adverse health effects. However, studies on occurrences of NEOs in kidney injury patients and their association with nephrotoxicity are limited. This study investigates the potential correlation between exposure to NEOs and kidney injury within a subset (n = 224) of the population residing in South China. Levels of 8 NEOs and 5 metabolites were quantified in blood samples obtained from both the 110 healthy and 114 kidney injury cohorts in South China. We found that target analytes were frequently detected in samples from the healthy and kidney injury cohorts (61%–100 %). Dinotefuran is the predominant NEO in the healthy (42.3 %) and kidney injury cohort (49.6 %). Significantly positive (p

Abstract Plants have evolved diverse defense mechanisms encompassing physical and chemical barriers. Cotton pigment glands are known for containing various defense metabolites, but the precise regulation of gland size to modulate defense compound levels remains enigmatic. Here, it is discovered that the VQ domain‐containing protein JAVL negatively regulates pigment gland size and the biosynthesis of defense compounds, while the MYC2‐like transcription factor GoPGF has the opposite effect. Notably, GoPGF directly activates the expression of JAVL, whereas JAVL suppresses GoPGF transcription, establishing a negative feedback loop that maintains the expression homeostasis between GoPGF and JAVL. Furthermore, it is observed that JAVL negatively regulates jasmonate levels by inhibiting the expression of jasmonate biosynthetic genes and interacting with GoPGF to attenuate its activation effects, thereby maintaining homeostatic regulation of jasmonate levels. The increased expression ratio of GoPGF to JAVL leads to enlarged pigment glands and elevated jasmonates and defense compounds, enhancing insect and pathogen resistance in cotton. These findings unveil a new mechanism for regulating gland size and secondary metabolites biosynthesis, providing innovative strategies for strengthening plant defense.

Multivariate time series anomaly detection is a crucial data mining technique with a wide range of applications in areas such as IT applications. Currently, the majority of anomaly detection methods for time series data rely on unsupervised approaches due to the rarity of anomaly labels. However, in real-world scenarios, obtaining a limited number of anomaly labels is feasible and affordable. Effective usage of these labels can offer valuable insights into the temporal characteristics of anomalies and play a pivotal role in guiding anomaly detection efforts. To improve the performance of multivariate time series anomaly detection, we proposed a novel deep learning model named EDD (Encoder-Decoder-Discriminator) that leverages limited anomaly samples. The EDD model innovatively integrates a graph attention network with long short term memory (LSTM) to extract spatial and temporal features from multivariate time series data. This integrated approach enables the model to capture complex patterns and dependencies within the data. Additionally, the model skillfully maps series data into a latent space, utilizing a carefully crafted loss function to cluster normal data tightly in the latent space while dispersing abnormal data randomly. This innovative design results in distinct probability distributions for normal and abnormal data in the latent space, enabling precise identification of anomalous data. To evaluate the performance of our EDD model, we conducted extensive experimental validation across three diverse datasets. The results demonstrate the significant superiority of our model in multivariate time series anomaly detection. Specifically, the average F1-Score of our model outperformed the second-best method by 2.7% and 73.4% in both evaluation approaches, respectively, highlighting its superior detection capabilities. These findings validate the effectiveness of our proposed EDD model in leveraging limited anomaly samples for accurate and robust anomaly detection in multivariate time series data.

ABSTRACT Chronic obstructive pulmonary disease (COPD) is one of the primary causes of mortality and morbidity worldwide. The gut microbiome, particularly the bacteriome, has been demonstrated to contribute to the progression of COPD. However, the influence of gut virome on the pathogenesis of COPD is rarely studied. Recent advances in viral metagenomics have enabled the rapid discovery of its remarkable role in COPD. In this study, deep metagenomics sequencing of fecal virus-like particles and bacterial 16S rRNA sequencing was performed on 92 subjects from China to characterize alterations of the gut virome in COPD. Lower richness and diversity of the gut virome were observed in the COPD subjects compared with the healthy individuals. Sixty-four viral species, including Clostridium phage, Myoviridae sp., and Synechococcus phage, showed positive relationships with pulmonary ventilation functions and had markedly declined population in COPD subjects. Multiple viral functions, mainly involved in bacterial susceptibility and the interaction between bacteriophages and bacterial hosts, were significantly declined in COPD. In addition, COPD was characterized by weakened viral-bacterial interactions compared with those in the healthy cohort. The gut virome showed diagnostic performance with an area under the curve (AUC) of 88.7%, which indicates the potential diagnostic value of the gut virome for COPD. These results suggest that gut virome may play an important role in the development of COPD. The information can provide a reference for the future investigation of diagnosis, treatment, and in-depth mechanism research of COPD.IMPORTANCEPrevious studies showed that the bacteriome plays an important role in the progression of chronic obstructive pulmonary disease (COPD). However, little is known about the involvement of the gut virome in COPD. Our study explored the disease-specific virome signatures of patients with COPD. We found the diversity and compositions altered of the gut virome in COPD subjects compared with healthy individuals, especially those viral species positively correlated with pulmonary ventilation functions. Additionally, the declined bacterial susceptibility, the interaction between bacteriophages and bacterial hosts, and the weakened viral-bacterial interactions in COPD were observed. The findings also suggested the potential diagnostic value of the gut virome for COPD. The results highlight the significance of gut virome in COPD. The novel strategies for gut virome rectifications may help to restore the balance of gut microecology and represent promising therapeutics for COPD.

Bioelectrochemical systems (BES) have emerged as a dual-function technology for treating wastewater and recovering energy. A vital element of BES is the rapid formation and maintenance of electroactive biofilms (EABs). Previous attempts to accelerate EAB formation and improve electroactivities focused on enhancing the bacterial adhesion process while neglecting the rate-limiting step of the bacterial transport process. Here, we introduce membrane filtration into BES, establishing a dynamic membrane filtration system that enhances overall performance. We observed that optimal membrane flux considerably reduced the startup time for EAB formation. Specifically, EABs established under a 25 L m−2 h−1 flux (EAB25 LMH) had a formation time of 43.8 ± 1.3 h, notably faster than the 51.4 ± 1.6 h in the static state (EAB0 LMH). Additionally, EAB25 LMH exhibited a significant increase in maximum current density, approximately 2.2 times higher than EAB0 LMH. Pearson correlation analysis indicated a positive relationship between current densities and biomass quantities and an inverse correlation with startup time. Microbial analysis revealed two critical findings: (i) variations in maximum current densities across different filtration conditions were associated with redox-active substances and biomass accumulation, and (ii) the incorporation of a filtration process in EAB formation enhanced the proportion of viable cells and encouraged a more diverse range of electroactive bacteria. Moreover, the novel electroactive membrane demonstrated sustained current production and effective solid-liquid separation during prolonged operation, indicating its potential as a viable alternative in membrane-based systems. This approach not only provides a new operational model for BES but also holds promise for expanding its application in future wastewater treatment solutions.

Low-light images captured at night often suffer from improper exposure, color distortion, and noise, which degrades the image quality and have a negative influence on subsequent applications. Many existing deep learning-based methods enhance low-light images through spatial domain, which may sacrifice the original image information. In this paper, we put forward a deep learning network for enhancing low-light images based on wavelet transform. We utilize the wavelet transform to divide the image into various frequency scales and then analyze the frequency characteristics of different low-light images in the wavelet domain. The proposed network comprises a low-frequency restoration subnet and high-frequency reconstruction subnet that uses an optimal coefficient of wavelet decomposition to construct a frequency pyramid. Furthermore, we utilized different attention mechanisms to extract frequency information from different images, gradually restoring the brightness information and details of low-light images. Additionally, we utilized a self-constructed multi-scale exposure low-light image dataset for training. Numerous experiments on publicly accessible datasets and our established dataset show that the proposed approach quantitatively and qualitatively surpasses state-of-the-art approaches, particularly for real and complex low-light scenarios. Furthermore, our method produces better visual effects than others and performs well in real-time and real-word downstream vision tasks.

Abstract We used 10 × genomics single‐cell transcriptome sequencing technology to reveal the tumor immune microenvironment characteristics of small cell lung cancer (SCLC) in a patient with malignant pleural effusion (MPE). A total of 8008 high‐quality cells were finally obtained for subsequent bioinformatic analysis, which were divided into 10 cell clusters further identified as B cells, T cells, myeloid cells, NK cells, and cancer cells. Such SCLC related genes as NOTCH1, MYC, TSC22D1, SOX4, BLNK, YBX3, VIM, CD8A, CD8B, and KLF6 were expressed in different degrees during differentiation of T and B cells. Different ligands and receptors between T, B and tumor cells almost interact through MHC II, IL‐16, galectin, and APP signaling pathway.

Cervical cancer is a leading cause of cancer-related mortality in females worldwide, necessitating urgent solutions for effective treatment. Paclitaxel (PTX), a natural diterpene alkaloid compound, has the ability to inhibit mitosis and induce programmed apoptosis in tumor cells. However, its toxicity and drug resistance limit its efficacy in certain cervical cancer patients. β-elemene (β-ELE) can reverse multidrug resistance by inhibiting ATP-binding cassette transporters, thereby enhancing chemotherapy drug retention. Therefore, we propose a combination therapy using PTX/β-ELE to improve chemotherapy sensitivity. To enhance targeted drug delivery, we developed M1-macrophage-membrane-coated nanoparticles (M1@PLGA/PTX/β-ELE) for co-delivery of PTX&β-ELE. Through both in vitro and in vivo cervical cancer models, we demonstrated that M1@PLGA/PTX/β-ELE effectively suppressed tumor progression and polarization of tumor-associated macrophages. Furthermore, H&E staining confirmed the high therapeutic biosafety of M1@PLGA/PTX/β-ELE as there was no significant damage observed in major organs throughout the entire therapeutic process. Overall, this study presents a targeted biomimetic nanoplatform and combinatorial strategy that synergistically enhances chemosensitivity in malignant tumors.

ObjectivesYolk sac tumors (YSTs) are rare and highly malignant ovarian malignancies that have a very poor prognosis. The aim of this study is to delineate the ultrasound and clinicopathological features of female pelvic YSTs to better understand the disease.MethodsThis study was a retrospective analysis of the clinicopathological and ultrasound imaging data from 16 YST patients who received treatment at our hospital between January 2012 and August 2023. Then, the ultrasound imaging characteristics were compared with pathological findings.ResultsAmong the 16 patients, various degrees of serum AFP increase were observed, and CA125 levels increased in 58.33% (7 out of 12) of patients. Thirteen patients (81.25%) had tumors located in ovary, two patients (12.5%) had tumors located in the sacrococcygeal region, and one patient (6.25%) had tumors located in the mesentery. Pathologically, nine patients presented with simple yolk sac tumors and seven with mixed germ cell tumors. According to the ultrasound manifestations, YST lesions can be classified into three types. (1) the cystic type, was diagnosed in two patients who presented with a large cystic mass with regular morphology and clear boundary and dense liquid within the cyst; and (2) the cystic-solid mixed type, was diagnosed in 4 patients. On 2D ultrasound, the lesions showed a cystic-solid mixed echo, and color Doppler showed a rich blood flow signal in the solid region and cystic separation. made up of four cases. (3) In ten patients with the solid type, 2D ultrasound showed solid uniform echoes with clear boundaries. The “fissure sign” was observed in the lesion. Color Doppler displayed rich blood flow in the solid part, and PW showed low to moderate resistance index of artery (RI:0.21–0.63). On contrast-enhanced ultrasound (CEUS), rapid and high enhancement in the solid part and cystic separation was observed in 2 patients.ConclusionsCombining ultrasound features with clinical information and tumor markers provides reliable clues for the diagnosis of YST. The application of two-dimensional ultrasound and CEUS combined with patient tumor marker levels can provide a robust reference for determining the necessity of fertility-preserving surgery and postoperative chemotherapy, which can improve clinical decision-making and patient consultation.

Phosphorus (P) deficiency significantly affects crop productivity, especially legume crops. Therefore, it is important to understand the P-acquisition strategies of different leguminous crops. In this study, we undertook a pot experiment with 11 legume crops (soybean, faba bean, pea, cowpea, common bean, lentil, adzuki bean, chickpea, grass pea, red kidney bean and common vetch) to investigate P-acquisition strategies related to root morphology, organic acid and acid phosphatase exudations, and arbuscular mycorrhizal fungi (AMF) colonisation under low (4.4 mg/kg) and optimal (40 mg/kg) P conditions. The results revealed that P deficiency significantly decreased biomass and P accumulation, root length (10.5%), and root surface area (7.9%), increased organic acid exudation (80.2%) and acid phosphatase activity (16.8%), and did not affect root diameter or root AMF colonisation rate. Principal component analysis revealed a positive correlation between organic acid exudation and acid phosphatase activity, while root length and root surface area negatively correlated with organic acid exudation, acid phosphatase activity and root AMF colonisation rate. P accumulation positively correlated with root length, surface area, and diameter but negatively correlated with organic acid exudation, acid phosphatase activity, and AMF colonisation rate. These findings confirmed the following: (1) legume crops use a P-mobilisation strategy related to organic acid exudation and acid phosphatase activity to acquire P under low soil P conditions; (2) organic acid exudation coincided with acid phosphatase activity to mobilise soil inorganic and organic P, improving P accumulation; (3) a trade-off exists between the P-scavenging strategy related to root morphology traits and mobilisation strategy.

Cell secretion repairs tissue damage and restores homeostasis throughout adult life. The extracellular heat shock protein-90alpha (eHsp90α) has been reported as an exosome cargo and a potential driver of wound healing. However, neither the mechanism of secretion nor the genetic evidence for eHsp90α in wound healing has been substantiated. Herein, we show that tissue injury causes massive deposition of eHsp90α in tissues and secretion of eHsp90α by cells. Sequential centrifugations of conditioned medium from relevant cell lines revealed the relative distributions of eHsp90α in microvesicle, exosome and trypsin-sensitive supernatant fractions to be approximately 95%, respectively. Establishing the cell-number-to-interstitial-fluid-volume (CIF) ratio for the microenvironment of human tissues as 1 × 109 cells: 1 mL interstitial fluid enabled us to predict the corresponding tissue concentrations of eHsp90α in these fractions as 3.74 μg/mL, 5.61 μg/mL and 178 μg/mL. Remarkably, the 178 μg/mL eHsp90α matches the previously reported 100–300 μg/mL of recombinant eHsp90α whose topical application promotes maximum wound healing in animal models. More importantly, we demonstrate that two parallel secretory autophagy-regulating gene families, the autophagy-regulating (AR) genes and the Golgi reassembly-stacking protein (GRASP) genes work together to mediate the secretion of the physiological concentration of eHsp90α to promote wound healing. Thus, utilization of the CIF ratio-based extrapolation method may enable investigators to rapidly predict biomarker targets from cell-conditioned-medium data.

Tuberculosis (TB) continues to be a major global health burden and kills over a million people annually. New immunization strategies are required for the development of an efficacious TB vaccine that can potentially induce sterilizing immunity. In this study, we first confirmed that a live vaccine strain of Mycobacterium smegmatis, previously designated as IKEPLUS, conferred a higher survival benefit than the Bacillus Calmette-Guerin (BCG) in a murine model of intravenous Mycobacterium tuberculosis (Mtb) infection. We have shown that there was a significant increase in the expression of the Rv0282 gene, which is encoded in the esx-3 locus, which played an important role in iron uptake when IKEPLUS was grown in both low zinc and iron-containing Sauton medium. We then confirmed using in vitro assays of biofilm formation that zinc plays a vital role in the growth and formation of M. smegmatis biofilms. IKEPLUS grown in low zinc media led to the better protection of mice after intravenous challenge with a very high dosage of Mtb. We also showed that various variants of IKEPLUS induced apoptotic cell-death of infected macrophages at a higher rate than wild-type M. smegmatis. We next attempted to determine if zinc containing ribosomal proteins such as rpmb2 could contribute to protective efficacy against Mtb infection. Since BCG has an established role in anti-mycobacterial efficacy, we boosted BCG vaccinated mice with rmpb2, but this did not lead to an increment in the protection mediated by BCG.

ObjectiveBenign Brenner tumor (BBT) is a rare ovarian tumor, and there are few discrete reports about its manifestation in an ultrasound. This study sought to investigate the two-dimensional (2D) and contrast-enhanced ultrasound (CEUS) features of this entity.MethodsThis is a retrospective single-center study. The clinical manifestations, laboratory examination, and ultrasound data of 25 female patients with BBT were confirmed by pathology when they underwent 2D and/or CEUS examination at Ningbo First Hospital from January 2012 to June 2023. The ultrasound findings of the patients were analyzed using the terminology of the International Organization for the Analysis of Ovarian Tumor and were read by two senior sonographers who reached an agreement.ResultsAmong the all 25 patients, most of them were unilateral, and only one patient was bilateral. Thus, 26 lesions were found: 44.0% (11/25) were in the left and 52.0% (13/25) were in the right. Moreover, 53.84% (14/26) were solid lesions, 15.38% (4/26) were mixed lesions, and 26.92% (7/26) were cystic lesions. Among the solid-type patients, 42.85% (6/14) of the cases were with calcification. Upon laboratory examination, 12.0% (3/25) of the patients had high carbohydrate antigen 125 (CA-125) level, and 19.04% (4/21) of the patients had an elevated carbohydrate antigen724 (CA-724) level in the serum tumor markers. In the hormone test, 14.28% (3/21) were found to have a high postmenopausal estrogen level and 14.28%(3/21) were found to have a high level of follicle-stimulating hormone (FSH). One patient with complex manifestations and three with solid manifestations were examined by CEUS to observe the microcirculation perfusion of the tumor. One with solid and cystic separation was rapidly hyperenhanced and cleared, and the filling subsided faster than the uterus. The postoperative pathological diagnosis was benign Brenner tumor with mucinous cystadenoma. The other three cases were solid adnexal lesions, which showed isoenhancement on CEUS and disappeared slowly, synchronizing with the uterus. The CEUS results were considered as benign tumors and confirmed by pathology.ConclusionsBBT can show ovarian cystic, mixed cystic and solid type, and solid echo in 2D ultrasound. Unilateral ovarian fibrosis with punctate calcification is an important feature of BBT in 2D ultrasound. However, for solid adnexal masses and mixed cystic and solid masses with unclear diagnosis, if CEUS shows isoenhancement or hyperenhancement, the possibility of BBT cannot be excluded.

Proton radiotherapy may be a compelling technical option for the treatment of breast cancer due to its unique physical property known as the “Bragg peak.” This feature offers distinct advantages, promising superior dose conformity within the tumor area and reduced radiation exposure to surrounding healthy tissues, enhancing the potential for better treatment outcomes. However, proton therapy is accompanied by inherent challenges, primarily higher costs and limited accessibility when compared to well-developed photon irradiation. Thus, in clinical practice, it is important for radiation oncologists to carefully select patients before recommendation of proton therapy to ensure the transformation of dosimetric benefits into tangible clinical benefits. Yet, the optimal indications for proton therapy in breast cancer patients remain uncertain. While there is no widely recognized methodology for patient selection, numerous attempts have been made in this direction. In this review, we intended to present an inspiring summarization and discussion about the current practices and exploration on the approaches of this treatment decision-making process in terms of treatment-related side-effects, tumor control, and cost-efficiency, including the normal tissue complication probability (NTCP) model, the tumor control probability (TCP) model, genomic biomarkers, cost-effectiveness analyses (CEAs), and so on. Additionally, we conducted an evaluation of the eligibility criteria in ongoing randomized controlled trials and analyzed their reference value in patient selection. We evaluated the pros and cons of various potential patient selection approaches and proposed possible directions for further optimization and exploration. In summary, while proton therapy holds significant promise in breast cancer treatment, its integration into clinical practice calls for a thoughtful, evidence-driven strategy. By continuously refining the patient selection criteria, we can harness the full potential of proton radiotherapy while ensuring maximum benefit for breast cancer patients.

IntroductionThe goal of this study is to explore the pharmacological potential of the amyloid-reducing vasodilator fasudil, a selective Ras homolog (Rho)-associated kinases (ROCK) inhibitor, in the P301S tau transgenic mouse model (Line PS19) of neurodegenerative tauopathy and Alzheimer's disease (AD).MethodsWe used LC-MS/MS, ELISA and bioinformatic approaches to investigate the effect of treatment with fasudil on the brain proteomic profile in PS19 tau transgenic mice. We also explored the efficacy of fasudil in reducing tau phosphorylation, and the potential beneficial and/or toxic effects of its administration in mice.ResultsProteomic profiling of mice brains exposed to fasudil revealed the activation of the mitochondrial tricarboxylic acid (TCA) cycle and blood-brain barrier (BBB) gap junction metabolic pathways. We also observed a significant negative correlation between the brain levels of phosphorylated tau (pTau) at residue 396 and both fasudil and its metabolite hydroxyfasudil.ConclusionsOur results provide evidence on the activation of proteins and pathways related to mitochondria and BBB functions by fasudil treatment and support its further development and therapeutic potential for AD.

Background: Epithelial cell adhesion molecule (EpCAM), a well-established marker for circulating tumor cells, plays a crucial role in the complex process of cancer metastasis. The primary objective of this investigation is to study EpCAM expression in pan-cancer and elucidate its significance in the context of kidney renal clear cell carcinoma (KIRC). Methods: Data obtained from the public database was harnessed for the comprehensive assessment of the EpCAM expression levels and prognostic and clinicopathological correlations in thirty-three types of cancer. EpCAM was validated in our own KIRC sequencing and immunohistochemical cohorts. Subsequently, an in-depth exploration was conducted to scrutinize the interrelationship between EpCAM and various facets, including immune cells, immune checkpoints, and chemotherapy drugs. We employed Cox regression analysis to identify prognostic immunomodulators associated with EpCAM, which were subsequently utilized in the development of a prognostic model. The model was validated in our own clinical cohort and public datasets, and compared with 137 published models. The role of EpCAM in KIRC was explored by biological function experiments in vitro. Results: While EpCAM exhibited pronounced overexpression across a wide spectrum of cancer types, a notable reduction was observed in KIRC tissues. As grade increased, EpCAM expression decreased. EpCAM expression decreased in patients without metastasis. EpCAM mRNA and protein levels were used as independent, favorable prognostic factors in patients with KIRC in our own cohort. The expression of EpCAM exhibited strong associations with immune-related pathways, demonstrating an inverse correlation with the majority of immune cell types. Immune checkpoint inhibitors exert better therapeutic effects on patients with low EpCAM expression. In addition, EpCAM can be used as a drug resistance indicator and guide the clinical medication of patients with KIRC. A robust model, which had good predictive accuracy and applicability, showed significant superiority over other models. Importantly, EpCAM played the dual roles of promoting proliferation and resisting metastasis in KIRC. Conclusion: In the context of KIRC, EpCAM assumes a surprising dual role, where it not only facilitates cell proliferation but also exerts resistance against the metastatic process. EpCAM serves as a standalone prognostic marker for patients with KIRC, and related models can also effectively predict prognosis. These discoveries offer novel perspectives on the functional significance of EpCAM in the context of KIRC.

Land use transition (LUT) impacts regional land use and the ecological environment. To reveal LUT and its ecological effects in karst mountain areas (KMA) of Southwest China, this paper first constructs a correlation model between LUT and ecological restoration in the region and carries out an example verification in the typical KMA, the Huajiang Canyon. The study demonstrates that: (1) LUT has occurred in KMA of Southwest China, mainly, the area of sloping cropland has decreased, and the forest land has increased. Land use patterns have shifted from traditional farming to modernized economic and fruit forestry; (2) The driving forces of LUT in KMA of Southwest China can be summarized into three factors: socio-economic, natural, and policy, among which natural factors are the basic conditions of LUT, socio-economic factors play a decisive role in the process of LUT, and policy factors provide policy guarantee for LUT; (3) LUT in KMA of Southwest China has curbed land degradation, promoted ecosystem restoration, and made a certain contribution making China greener, which is conducive to achieving the goal of sustainable development. This paper explores the characteristics of LUT and its driving forces in KMA of Southwest China from the coupling analysis of LUT and ecosystem, reveals the effects of LUT in KMA of Southwest China, and provides some theoretical references for the balance between high-quality development and ecological protection in KMA of Southwest China from the perspective of LUT.

Abstract Whether and how shared intentionality (SI) influences the establishment of a novel interpersonal communication system is poorly understood. To investigate this issue, we designed a coordinating symbolic communication game (CSCG) and applied behavioral, functional near-infrared spectroscopy (fNIRS)-based hyperscanning, and hyper-transcranial alternating current stimulation (hyper-tACS) methods. Here we show that SI is a strong contributor to communicative accuracy. Moreover, SI, communicative accuracy, and interpersonal neural synchronization (INS) in the right superior temporal gyrus (rSTG) are higher when dyads successfully establish a novel communication system. Furthermore, the SI influences communicative accuracy by increasing INS. Additionally, using time series and long short-term memory neural network analyses, we find that the INS can predict communicative accuracy at the early formation stage of the communication system. Importantly, the INS partially mediates the relationship between the SI and the communicative accuracy only at the formation stage of the communication system. In contrast, when the communication system is established, SI and INS no longer contribute to communicative accuracy. Finally, the hyper-tACS experiment confirms that INS has a causal effect on communicative accuracy. These findings suggest a behavioral and neural mechanism, subserved by the SI and INS, that underlies the establishment of a novel interpersonal communication system.

Objective: To investigate the oral health status of older patients with ischemic stroke and analyze the influencing factors, providing valuable insights for developing effective oral health management strategies tailored for this population. Methods: A cross-sectional survey was conducted from January to June 2022, selecting 350 older patients with ischemic stroke from two tertiary hospitals in Chongqing. The Barthel Index (BI), Eating Assessment Tool (EAT-10), and Oral Health Assessment Tool (OHAT) were used to assess patients’ self-care ability, swallowing function, and oral health status, respectively. A self-designed questionnaire was used to collect demographic information, disease-related information, and oral health behaviors of the patients. Binary logistic regression analysis was performed to analyze related influencing factors. Results: A total of 346 older patients with ischemic stroke were included, with 199 males and 147 females. The median total score of OHAT was 5 (total score range 0–16). Dental decay (91.7%, 278/303) and poor oral hygiene (92.2%, 319/346) were the main oral health problems in this population. Binary logistic regression analysis showed that sex, hyperlipidemia, stroke severity, stroke events, oral health behaviors, and care dependency were influencing factors for the oral health of this population (P

Abstract Background Propofol is a drug with potential anticancer effect. This study aimed to explore the effect of propofol on chemosensitivity of cervical cancer cells to paclitaxel. Methods HeLa and CaSki cells were selected for drug experiments. Cell viability was evaluated via CCK‐8 assay, and the combination index (CI) was calculated by CompuSyn software. A clinically relevant concentration and IC30 of propofol were selected in combination with 5 nM paclitaxel. BrdU incorporation, transwell, and flow cytometry assays were utilized to evaluate cell proliferation, migration, invasion, and apoptosis. The expression of β‐tubulin, stathmin 1, and GAPDH proteins was evaluated by Western blot. The stathmin 1 cDNA plasmid was used to establish stathmin 1‐overexpressing CaSki cells. Results At clinically relevant concentrations (0–80 μM), propofol did not affect cancer cell viability, but high concentrations (100–800 μM) reduced cell viability. The CI values of propofol with IC30 (200 μM in HeLa; 400 μM in CaSki) combined with 5 nM paclitaxel were

Abstract Background Duchenne muscular dystrophy (DMD) is a rare hereditary muscular disease. The role of eosinophils in DMD has not been clarified. This study aims to evaluate the association between peripheral blood eosinophil count and severity and prognosis of DMD. Methods A retrospective cohort study was performed for 145 DMD patients between January 2012 and December 2020. Clinical data of 150 healthy children were collected as a control group. Logistic regression and Cox regression analyses were used to explore the influences of eosinophil count on DMD severity and prognosis. Results Eosinophil count in DMD group was lower than the control group (Z = 2.163, P = 0.031). It was negatively correlated with Vignos scale score, Spearman correlation coefficient was p = 0.245, P = 0.040 (at admission), p = 0.137, P = 0.032 (at follow-up); was a protective factor for high Vignos scale score at admission [odds ratio (OR) = 0.038, 95%CI: 0.002–0.752, P = 0.032] and follow-up (OR = 0.033,95%CI: 0.001–0.121, P = 0.039). The Cox regression analysis indicated that elevated eosinophil count was correlated with better therapeutic efficacy for DMD patients [hazard ratio (HR) = 2.218, 95%CI: 1.154–3.924, P = 0.016]. Conclusion Eosinophil count in peripheral blood was correlated with the severity of DMD. It could indicate the therapeutic efficacy and prognosis of DMD patients to a certain extent. Eosinophils may be a potentially valuable biomarker or therapeutic target for DMD.

Lipases, crucial catalysts in biochemical synthesis, find extensive applications across industries such as food, medicine, and cosmetics. The efficiency of lipase-catalyzed reactions is significantly influenced by the choice of solvents. Polar organic solvents often result in a decrease, or even loss, of lipase activity. Conversely, nonpolar organic solvents induce excessive rigidity in lipases, thereby affecting their activity. While the advent of new solvents like ionic liquids and deep eutectic solvents has somewhat improved the activity and stability of lipases, it fails to address the fundamental issue of lipases’ poor solvent tolerance. Hence, the rational design of lipases for enhanced solvent tolerance can significantly boost their industrial performance. This review provides a comprehensive summary of the structural characteristics and properties of lipases in various solvent systems and emphasizes various strategies of protein engineering for non-aqueous media to improve lipases’ solvent tolerance. This study provides a theoretical foundation for further enhancing the solvent tolerance and industrial properties of lipases.

The atmospheric boundary layer is a key region for human activities and the interaction of various layers and is an important channel for the transportation of momentum, heat, and various substances between the free atmosphere and the surface, which has a significant impact on the development of weather and climate change. During the Second Tibetan Plateau Scientific Expedition and Research Program (STEP) in June 2022, utilizing the comprehensive stereoscopic observation experiment of the “Plateau Low Vortex Network”, this study analyzed the variation characteristics and influencing factors of the atmospheric boundary layer height (ABLH) at three stations with different underlying surface types on the Qinghai–Tibet Plateau (QTP): Qumalai Station (grassland), Southeast Tibet Observation and Research Station for the Alpine Environment (SETORS, forest), and Sieshan Station (cropland). The analysis utilized sounding observation data, microwave radiometer data, and ERA5 reanalysis data. The results revealed that the temperature differences between the sounding observation data and microwave radiometer data were minor at the three stations, with a notable temperature inversion phenomenon observed at Sieshan Station. Regarding water vapor density, the differences between the sounding observation data and microwave radiometer data were relatively small at Sieshan Station. The relative humidity increased with height at Sieshan Station, whereas it increased and then decreased with height at SETORS and Qumalai Station. The ABLH at all sites reached its maximum value around noon, approximately 1500 m, and exhibited mostly convective boundary layer (CBL) characteristics. During the night, the ABLH mostly showed a stable boundary layer (SBL) pattern, with heights around 250 m. In summer, latent heat flux (LE) and sensible heat flux (H) in the eastern plateau were generally lower than those in the western plateau except at 20:00, where they were higher. Vertical velocity (w) in the eastern plateau was greater than in the western plateau. Among Sieshan Station and SETORS, LE, and H had the most significant impact on ABLH, while at Qumalai Station, ABLH was more influenced by surface long-wave radiation (Rlu). These four influencing factors showed a positive correlation with ABLH. The impact of different underlying surface types on ABLH primarily manifests in surface temperature variations, solar radiation intensity, vegetation cover, and terrain. Grasslands typically exhibit a larger range of ABLH variations, while the ABLH in forests and mountainous cropland areas is relatively stable.

In order to investigate the effects of temperature on the quality of Procambarus clarkiii during waterless preservation, the changes in survival rates, muscle flesh quality, and physiological indicators of Procambarus clarkiii were analyzed under different waterless storage temperatures. The results showed that the survival rates of Procambarus clarkii in those of 4~16 ℃ groups were 80%~90% after 72 h of waterless preservation, the 24 ℃ group dropped to 40%, and the 32 °C group had reached zero. The moisture content, water-holding capacity, muscle hardness, and elasticity of muscle decreased significantly with the increase in temperature and time (P

ObjectiveThis study aimed to evaluate the effects of self-help mindfulness-based cognitive therapy (MBCT-SH) on mindfulness, symptom change, and suicidal ideation in patients with depression.MethodsFor this randomized controlled study, 97 patients were randomly assigned to either the MBCT-SH (n = 48) or control (n = 49) group. The Five Facet Mindfulness Questionnaire (FFMQ), Hamilton Depression Rating Scale (HAMD-24), and Suicide Attitude Questionnaire (SAQ) were used to assess mindfulness, depression symptoms, and suicidal ideation, respectively, at baseline (T0), intervention week 4 (T1), intervention week 8 (T2), and 3-month follow-up (T3). The groups were also compared on treatment costs and readmission rates at a 6-month follow-up.ResultsIn the MBCT-SH group, 46 of 48 participants (96%) completed the eight-week program. At T0, there were no statistically significant between-group differences in demographics, clinical characteristics, FFMQ, HAMD-24, or SAQ. Nor were there statistically significant differences on the HAMD-24 or SAQ between the MBCT-SH and control groups at T1 (p = 0.18 and p = 0.59, respectively), while mindfulness was significantly higher in the MBCT-SH group (t = 2.383, p = 0.019). At T2, there were significant between-group differences on the FFMQ, HAMD-24, and SAQ, all of which remained significant at T3. At the 6-month follow-up, per capita treatment costs were 5,298 RMB lower in the MBCT-SH group compared with the control group, while their readmission rates (6.1% and 4.2%, respectively) did not differ significantly.ConclusionThese findings support the feasibility and effectiveness of MBCT-SH among patients with depression.Clinical trial registrationhttp://www.chictr.org.cn, ChiCTR2300077850.

ABSTRACTMetal oxide nanorods exhibit promising potential as reinforcement fillers in various polymer matrices, but their application in the Multi Jet Fusion (MJF) technique is rarely reported. In this work, surface-modified zinc oxide nanorods (SMZnO) were synthesized and incorporated into polyamide 12 (PA12) powder to enhance the mechanical properties of the MJF-printed parts. Compared to ZnO, SMZnO exhibited better dispersion, resulting in markedly enhanced mechanical performances. The ultimate tensile strength and the Young's modulus of the MJF-printed SMZnO/PA12 nanocomposites were 62.02 MPa and 2.28 GPa in the X orientation and 64.07 MPa and 2.34 GPa in the Y orientation, equivalent to 27.85%, 59.44%, 29.12%, and 54.97% increments, respectively. The flexural strength and modulus demonstrated similar improvements in the X and Y orientations, confirming the uniform mechanical enhancement effect of homogenously distributed SMZnO. This work provides a novel and facile approach for the additive manufacturing of polymeric nanocomposites with superior mechanical performance.

Background: Hypertension and hyperlipidemia are considered risk factors for Alzheimer’s disease (AD) and other related dementias. Clinically approved medications typically prescribed to manage these conditions have shown an association with reduced risk of developing AD and could be explored as potential repurposed therapeutics. Objective: We aimed to explore the effects of the pharmacological treatment with angiotensin-converting enzyme inhibitors (ACEI) and statins (STAT) on AD-related neuropathology and the potential benefits of their concurrent use. Methods: We investigated the effect of ACEI, STAT or combination of both by exploring the transcriptomic, proteomic and tau pathology profiles after treatment in both human patients and in P301S transgenic mice (PS19) modeling tauopathies and AD. We performed bioinformatic analysis of enriched pathways after treatment. Results: Proteomics and transcriptomics analysis revealed proteins and genes whose expression is significantly changed in subjects receiving treatment with ACEI, STAT or combined drugs. In mice, treatment with the ACEI lisinopril significantly decreased brain levels of total tau (Tau) and phosphorylated tau (pTau)-181, while the STAT atorvastatin significantly reduced the levels of pTau-396. The combined therapy with lisinopril and atorvastatin significantly decreased Tau. Moreover, brain levels of lisinopril were negatively correlated with Tau. Among the others, CD200, ADAM22, BCAN and NCAM1 were significantly affected by treatments in both human subjects and transgenic mice. Conclusions: Our findings provide significant information that may guide future investigation of the potential use of ACEI, STAT, or the combination of the two drug classes as repurposed therapies or preventive strategies for AD and other neurodegenerative diseases.

Multi jet fusion (MJF), a powder-based additive manufacturing technology, is suitable for fabricating fibre-reinforced polymer composites. However, the types of reinforcement fibres applied in MJF are limited due to the incompatibility between the fibres and polymer. Herein, a simple and cost-effective surface modification method for Fe3O4-coated aramid fibres (Fe3O4@AF hybrids) is proposed to fabricate polyamide 12 (PA12) composites by MJF. The optimal fibre content for Fe3O4@AF/PA12 composites is 6 wt%, which resulted in 10.83% and 16.05% higher ultimate tensile strength and Young’s modulus, respectively, compared with AF/PA12. The addition of Fe3O4@AF hybrids also improved the flame retardancy of AF/PA12 by reducing the peak heat release rate (PHRR) and postponing the temperature at PHRR. This practical surface modification method can be potentially applied to other reinforcement fibres for fabricating functional polymer composites by other powder-based manufacturing technologies.

Multi Jet Fusion (MJF) has attracted extensive attention because of its ability to print support-free complex structures. However, the mechanical properties of MJF-printed polymer parts are still unsatisfactory for certain industrial requirements. Herein, by leveraging the fibre reinforcement effect and high specific strength of polyimide (PI) fibres, this work developed PI/polyamide 12 (PA12) composites with largely enhanced mechanical performance via MJF. Specifically, the tensile strength and modulus were increased by 43% and 42%, and the flexural strength and modulus were improved by 39% and 46%, respectively, compared to those of the neat PA12 parts. Furthermore, the incorporation of lightweight PI fibres endowed the composites with high specific tensile strength (67.60 kN·m/kg) and specific flexural strength (93.70 kN·m/kg), which are superior to those of MJF-printed PA12 composites reinforced with other fibres. This work provides new insights into enhancing the mechanical performance of lightweight parts printed by MJF and other powder-based techniques.

Study region: Guizhou Province, Southwest China Study focus: Karst slopes are highly heterogeneous, with a large number of rocks exposed on the surface. Empirical soil erosion models (such as the revised universal soil loss equation (RUSLE)) based on homogeneous soil areas have encountered significant challenges in their application to karst areas. Currently, a quantitative relationship between the exposed rock and soil erosion has not been systematically established, although the establishment of this relationship could provide opportunities for empirical soil erosion model optimisation in karst areas. In view of this, we combined a field natural rainfall test with an indoor simulated rainfall test and artificially simulated exposed rock to investigate rock exposure rate (RER) effects on soil loss and runoff processes on karst slopes and attempted to build a coupled RER and soil loss model. New hydrological insights for the region: As the RER increased, the runoff and sediment content decreased under both simulated and natural rainfall conditions. Soil loss decreased exponentially with an increase in RER under natural rainfall tests in the field. There was a relationship between the soil loss and the RER quadratic function under simulated rainfall tests indoors. The exponential relationship based on natural rainfall more accurately reflected karst slope soil erosion conditions. These results contribute to a deeper understanding of soil erosion mechanisms on slopes in karst areas and provide confidence in our subsequent introduction of soil erosion sensitivity-exposed rock relationships to optimise soil erosion models such as RUSLE.

Abstract Objective To determine the effect of dose calculation accuracy on inverse linear energy transfer (LET) optimization for intensity‐modulated proton therapy, and to determine whether adding more beams would improve the plan robustness to different dose calculation engines. Methods Two sets of intensity‐modulated proton therapy plans using two, four, six, and nine beams were created for 10 prostate cancer patients: one set was optimized with dose constraints (DoseOpt) using the pencil beam (PB) algorithm, and the other set was optimized with additional LET constraints (LETOpt) using the Monte Carlo (MC) algorithm. Dose distributions of DoseOpt plans were then recalculated using the MC algorithm, and the LETOpt plans were recalculated using the PB algorithm. Dosimetric indices of targets and critical organs were compared between the PB and MC algorithms for both sets of plans. Results For DoseOpt plans, dose differences between the PB and MC algorithms were minimal. However, the maximum dose differences in LETOpt plans were 11.11% and 15.85% in the dose covering 98% and 2% (D2) of the clinical target volume, respectively. Furthermore, the dose to 1 cc of the bladder differed by 11.42 Gy (relative biological effectiveness). Adding more beams reduced the discrepancy in target coverage, but the errors in D2 of the structure were increased with the number of beams. Conclusion High modulation of LET requires high dose calculation accuracy during the optimization and final dose calculation in the inverse treatment planning for intensity‐modulated proton therapy, and adding more beams did not improve the plan robustness to different dose calculation algorithms.

The effect of drying temperature on the drying characteristics of tobacco was investigated with different water content. The isothermal drying characteristics and kinetics of three kinds of tobacco on the production line of a tobacco factory in Hubei were studied by halogen water analyzer. The drying characteristics of tobacco with different water content under isothermal conditions were evaluated by water loss characteristics, water diffusion coefficient, and activation energy. The results showed that the drying time of cut tobacco was reduced by increasing the drying temperature within a certain range. The water diffusion coefficient of cut tobacco decreased with the increase of temperature from 70 to 100 °C, and increased with the increase of initial water content. The activation energy of cut tobacco was related to the production process. The activation energy in the experiment was as follows: CT-2 > CT-3 > CT-1. Five drying models were used for non-linear fitting of the drying behavior of tobacco. The fitting degree of the Midilli model was the highest, reaching 0.9944. This data will be useful in the design of tobacco drying equipment.

Abstract Background Retinal fibrosis affects 40–70% of neovascular age-related macular degeneration patients. This study investigated the effect of ageing on subretinal fibrosis secondary to choroidal neovascularization and the mechanism of action. Methods Subretinal fibrosis was induced in young (2.5-month) and aged (15–16-month) C57BL/6J mice using the two-stage laser protocol. Five and 30 days later, eyes were collected and stained for CD45 and collagen-1 and observed by confocal microscopy. Fibrocytes (CD45+collagen-1+) were detected in the bone marrow (BM), blood and fibrotic lesions by flow cytometry and confocal microscopy, respectively. BM-derived macrophages (BMDMs) were cultured from young and aged mice with or without TGF-β1 (10 ng/mL) treatment. The expression of mesenchymal marker αSMA (Acta2), fibronectin (Fn1) and collagen-1 (Col1a1) was examined by qPCR and immunocytochemistry, whereas cytokine/chemokine production was measured using the Luminex multiplex cytokine assay. BM were transplanted from 22-month (Ly5.2) aged mice into 2.5-month (Ly5.1) young mice and vice versa. Six weeks later, subretinal fibrosis was induced in recipient mice and eyes were collected for evaluation of fibrotic lesion size. Results Under normal conditions, the number of circulating fibrocytes (CD45+collagen-1+) and the expression levels of Tgfb1, Col1a1, Acta2 and Fn1 in BMDMs were significantly higher in aged mice compared to young mice. Induction of subretinal fibrosis significantly increased the number of circulating fibrocytes, enhanced the expression of Col1a1, Acta2 and Fn1 and the production of soluble urokinase plasminogen activator surface receptor (suPAR) but decreased the production of CXCL10 in BMDMs. BMDMs from aged subretinal fibrosis mice produced significantly higher levels of VEGF, angiopoietin-2 and osteopontin than cells from young subretinal fibrosis mice. The subretinal fibrotic lesion in 15–16-month aged mice was 62% larger than that in 2.5-month young mice. The lesion in aged mice contained a significantly higher number of fibrocytes compared to that in young mice. The number of circulating fibrocytes positively correlated with the size of subretinal fibrotic lesion. Transplantation of BM from aged mice significantly increased subretinal fibrosis in young mice. Conclusions A retina–BM–blood–retina pathway of fibrocyte/macrophage recruitment exists during retinal injury. Ageing promotes subretinal fibrosis through higher numbers of circulating fibrocytes and profibrotic potential of BM-derived macrophages.

Abstract Deletions of chromosome 17p, where TP53 gene locates, are the most frequent chromosome alterations in human cancers and associated with poor outcomes in patients. Our previous work suggested that there were p53–independent mechanisms involved in chromosome 17p deletions-driven cancers. Here, we report that altered arachidonate metabolism, due to the deficiency of mouse Alox8 on chromosome 11B3 (homologous to human ALOX15B on chromosome 17p), contributes to the B cell malignancy. While the metabolites produced from lipoxygenase pathway reduced, chromosome 11B3 deletions or Alox8 loss, lead to upregulating its paralleling cyclooxygenase pathway, indicated by the increased levels of oncometabolite prostaglandin E2. Ectopic PGE2 prevented the apoptosis and differentiation of pre-B cells. Further studies revealed that Alox8 deficiency dramatically and specifically induced Cox-2(Ptgs2) gene expression. Repressing Cox-2 by its shRNAs impaired the tumorigenesis driven by Alox8 loss. And, in turn, tumor cells with Alox8 or 11B3 loss were sensitive to the COX-2 inhibitor celecoxib. This correlation between COX-2 upregulation and chromosome 17p deletions was consistent in human B-cell lymphomas. Hence, our studies reveal that the arachidonate metabolism abnormality with unbalanced ALOX and COX pathways underlies human cancers with 17p deletions and suggest new susceptibility for this disease.

Abstract Background The disruption of blood-brain barrier (BBB), predominantly made up by brain microvascular endothelial cells (BMECs), is one of the characteristics of Alzheimer’s disease (AD). Thus, improving BMEC function may be beneficial for AD treatment. Tanshinone IIA (Tan IIA) has been proved to ameliorate the cognitive dysfunction of AD. Herein, we explored how Tan IIA affected the function of BMECs in AD. Methods Aβ1–42-treated brain-derived endothelium cells.3 (bEnd.3 cells) was employed for in vitro experiments. And we performed molecular docking and qPCR to determine the targeting molecule of Tan IIA on Sirtuins family. The APPswe/PSdE9 (APP/PS1) mice were applied to perform the in vivo experiments. Following the behavioral tests, protein expression was determined through western blot and immunofluorescence. The activities of oxidative stress-related enzymes were analyzed by biochemically kits. Nissl staining and thioflavin T staining were conducted to reflect the neurodegeneration and Aβ deposition respectively. Results Molecular docking and qPCR results showed that Tan IIA mainly acted on Sirtuin1 (SIRT1) in Sirtuins family. The inhibitor of SIRT1 (EX527) was employed to further substantiate that Tan IIA could attenuate SIRT1-mediated endoplasmic reticulum stress (ER stress) in BMECs. Behavioral tests suggested that Tan IIA could improve the cognitive deficits in APP/PS1 mice. Tan IIA administration increased SIRT1 expression and alleviated ER stress in APP/PS1 mice. In addition, LRP1 expression was increased and RAGE expression was decreased after Tan IIA administration in both animals and cells. Conclusion Tan IIA could promote Aβ transportation by alleviating SIRT1-mediated ER stress in BMECs, which ameliorated cognitive deficits in APP/PS1 mice.

Morchella esculenta is a precious edible and medicinal fungus rich in protein, polysaccharides, polyphenols, amino acids, triterpenes, and other active components. In this study, MS-1 was isolated from the fruiting body of M. esculenta. Through conducting single-factor experiments and the response surface analysis of the culture conditions, the optimal culture components of an M. esculenta fermentation broth for extracellular polysaccharide production were determined, namely, 3.7% glucose, 2% yeast extract, and 0.15% sodium chloride. The polysaccharides MSF and MSL were extracted from the fruiting body of M. esculenta and the fermentation broth, respectively, and analyzed with gel permeation chromatography (GPC), monosaccharide composition, scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and in vivo and in vitro antioxidant and anti-inflammatory activity analyses. The research results show that the calculated MW of MSF is 2.34 × 105 Da, and the calculated MW of MSL is 1.40 × 105 Da. MSF is composed of three monosaccharides: D-galactose, D-glucose, and D-mannose (molar ratio of 4.34:90.22:5.45). MSL consists of five monosaccharides: D-arabinose, D-galactose, D-glucose, D-mannose, and glucuronic acid (molar ratio of 0.31:14.71:13.03:71.43:0.53). The in vitro antioxidant test results show that MSF and MSL both have significant antioxidant activities. Activity experiments on MSF and MSL in zebrafish showed that MSF and MSL have significant repair effects on the oxidative damage caused by metronidazole in zebrafish embryos, and there were significant changes in the transcriptional activity levels of the oxidative stress-related genes SOD, Keap1, and Nrf2. Therefore, the polysaccharides MSF and MSL from MS-1 can be used as important raw materials for functional foods and drugs.

The issue of compatibility of sustainable development policies, institutional quality, and economic growth gains on importance as the world races towards achieving the 2030 Agenda for Sustainable Development. This paper aims to examine the relationship between sustainable development, institutional quality, and economic growth between the years 2012 and 2021 in 116 countries. The quantile regression method has been employed in this study to capture various relationship nexuses in different quantiles of growth. The common 15th, 25th, 50th, 75th and 95th quantiles have been selected. The official Sustainable Development Goals (SDG) Index is applied to proxy the holistic conceptualization and policy achievement of the United Nation’s SDGs. The findings show a negative relationship between sustainable development and economic growth, indicating that achieving sustainable development goals will harm the economic growth. Increasing negative coefficient values from lower to higher quantiles imply increasing opportunity cost of degrowth towards increasing sustainable development. Besides, institutional quality did not affect economic growth, either directly or indirectly. The study suggests the necessity to review the existing policies, institutional structures, and strategies to foster compatibility between sustainable development, institutional quality, and growth.

Low-grade appendiceal mucinous neoplasms (LAMNs) are rare appendiceal tumors that are primarily diagnosed using computed tomography(CT) enhancement and magnetic resonance imaging (MRI). Herein, we report the sonographic features, especially for contrast-enhanced ultrasound (CEUS), of a 70-year-old female with an unusual LAMN metastasizing to the peritoneum and spleen. The patient had a right pelvic mass 2 days prior to presentation. Two-dimensional (2D) ultrasound revealed a mixed cystic-solid mass in the right lower abdomen and spleen parenchyma; CEUS showed heterogeneous enhancement in both areas, suspected to be a mucinous mass. CT enhancement and MRI findings revealed concurrent findings. Histopathologically, LAMN lesions were confirmed in the appendix, spleen, and peritoneum of the specimens obtained during exploratory laparoscopy. No recurrences were reported at three years postoperatively. LAMN lesions may metastasize to abdominal organs, and imaging examinations are essential for diagnosis. This study presents major ultrasonography and CEUS findings for the diagnosis of LAMNs.

The incidence of extra-gonadal germ cell tumor is low. There are few reports about liver metastasis and multiple systemic metastasis of mediastinal germ cell tumor. Here, we report a case of a 42-year-old young man with mediastinal mass discovered by computed tomography, which was finally confirmed as mediastinal germ cell tumor after many pathological biopsies. After radiotherapy and chemotherapy, the mediastinal mass was stable, but a new mass appeared in the liver. Mediastinal mass remained stable after modification of treatment regimen, but multiple metastases were found throughout the body. He finally died after 8 months of treatment because of his poor health.

During recent years, evidence has emerged that immune privileged sites such as the CNS and the retina may be more integrated in the systemic response to infection than was previously believed. In line with this, it was recently shown that a systemic acute virus infection leads to infiltration of CD8 T cells in the brains of immunocompetent mice. In this study, we extend these findings to the neurological tissue of the eye, namely the retina. We show that an acute systemic virus infection in mice leads to a transient CD8 T cell infiltration in the retina that is not directed by virus infection inside the retina. CD8 T cells were found throughout the retinal tissue, and had a high expression of CXCR6 and CXCR3, as also reported for tissue residing CD8 T cells in the lung and liver. We also show that the pigment epithelium lining the retina expresses CXCL16 (the ligand for CXCR6) similar to epithelial cells of the lung. Thus, our results suggest that the retina undergoes immune surveillance during a systemic infection, and that this surveillance appears to be directed by mechanisms similar to those described for non-privileged tissues.