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Abstract Background Premature ovarian insufficiency (POI) is an important cause of female infertility and seriously impacts the physical and psychological health of patients. Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSCs-Exs, H-Exs) have exhibited protective effects on ovarian function with unclear mechanisms. Methods A comprehensive analysis of the Gene Expression Omnibus (GEO) database were used to identify POI-associated circRNAs and miRNAs. The relationship between HucMSC-derived exosomal circBRCA1/miR-642a-5p/FOXO1 axis and POI was examined by RT-qPCR, Western blotting, reactive oxygen species (ROS) staining, senescence-associated β-gal (SA-β-gal) staining, JC-1 staining, TEM, oxygen consumption rate (OCR) measurements and ATP assay in vivo and in vitro. RT-qPCR detected the expression of circBRCA1 in GCs and serum of patients with normal ovarian reserve function (n = 50) and patients with POI (n = 50); then, the correlation of circBRCA1 with ovarian reserve function indexes was analyzed. Results Herein, we found that circBRCA1 was decreased in the serum and ovarian granulosa cells (GCs) of patients with POI and was associated with decreased ovarian reserve. H-Exs improved the disorder of the estrous cycles and reproductive hormone levels, reduced the number of atretic follicles, and alleviated the apoptosis and senescence of GCs in rats with POI. Moreover, H-Exs mitigated mitochondrial damage and reversed the reduced circBRCA1 expression induced by oxidative stress in GCs. Mechanistically, FTO served as an eraser to increase the stability and expression of circBRCA1 by mediating the m6A demethylation of circBRCA1, and exosomal circBRCA1 sponged miR-642a-5p to block its interaction with FOXO1. CircBRCA1 insufficiency aggravated mitochondrial dysfunction, mimicking FTO or FOXO1 depletion effects, which was counteracted by miR-642a-5p inhibition. Conclusion H-Exs secreted circBRCA1 regulated by m6A modification, directly sponged miR-642a-5p to upregulate FOXO1, resisted oxidative stress injuries in GCs and protected ovarian function in rats with POI. Exosomal circBRCA1 supplementation may be a general prospect for the prevention and treatment of POI. Graphical Abstract

Abstract The water evaporation rate of 3D solar evaporator heavily relies on the water transport height of the evaporator. In this work, a 3D solar evaporator featuring a soil capillary‐like structure is designed by surface coating native balsa wood using potassium hydroxide activated carbon (KAC). This KAC‐coated wood evaporator can transport water up to 32 cm, surpassing that of native wood by ≈8 times. Moreover, under 1 kW m−2 solar radiation without wind, the KAC‐coated wood evaporator exhibits a remarkable water evaporation rate of 25.3 kg m−2 h−1, ranking among the highest compared with other reported evaporators. The exceptional water transport capabilities of the KAC‐coated wood should be attributed to the black and hydrophilic KAC film, which creates a porous network resembling a soil capillary structure to facilitate efficient water transport. In the porous network of coated KAC film, the small internal pores play a pivotal role in achieving rapid capillary condensation, while the larger interstitial channels store condensed water, further promoting water transport up more and micropore capillary condensation. Moreover, this innovative design demonstrates efficacy in retarding phenol from wastewater through absorption onto the coated KAC film, thus presenting a new avenue for high‐efficiency clean water production.

IntroductionPrimary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin’s lymphoma that affects brain parenchyma, eyes, cerebrospinal fluid, and spinal cord. Diagnosing PCNSL can be challenging because imaging studies often show similar patterns as other brain tumors, and stereotactic brain lesion biopsy conformation is invasive and not always possible. This study aimed to validate a previous proteomic profiling (PMID: 32610669) of cerebrospinal fluid (CSF) and develop a CSF-based proteomic panel for accurate PCNSL diagnosis and differentiation.MethodsCSF samples were collected from patients of 30 PCNSL, 30 other brain tumors, and 31 tumor-free/benign controls. Liquid chromatography tandem-mass spectrometry targeted proteomics analysis was used to establish CSF-based proteomic panels.ResultsFinal proteomic panels were selected and optimized to diagnose PCNSL from tumor-free controls or other brain tumor lesions with an area under the curve (AUC) of 0.873 (95%CI: 0.723-0.948) and 0.937 (95%CI: 0.807- 0.985), respectively. Pathways analysis showed diagnosis panel features were significantly enriched in pathways related to extracellular matrices-receptor interaction, focal adhesion, and PI3K-Akt signaling, while prion disease, mineral absorption and HIF-1 signaling were significantly enriched with differentiation panel features.DiscussionThis study suggests an accurate clinical test panel for PCNSL diagnosis and differentiation with CSF-based proteomic signatures, which may help overcome the challenges of current diagnostic methods and improve patient outcomes.

Updates in whole genome sequencing technologies have revealed various RNA modifications in cancer, among which RNA methylation is a frequent posttranscriptional modification. RNA methylation is essential for regulating biological processes such as RNA transcription, splicing, structure, stability, and translation. Its dysfunction is strongly associated with the development of human malignancies. Research advances with respect to the regulatory role of RNA modifications in ovarian cancer include N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G). Numerous studies have demonstrated that epigenetic modifications of RNA can influence the progression and metastasis of ovarian cancer and may provide excellent targets for cancer therapy. This review highlights advances in research on RNA methylation modifications and ovarian cancer prognosis, carcinogenesis, and resistance, which could provide a theoretical foundation for designing therapeutic strategies for ovarian cancer based on RNA methylation modifications.

The present study was designed to investigate the protective effects of pectin extracted from Premna microphylla Turcz leaves (PTP) against high-fat-diet (HFD)-induced lipid metabolism disorders and gut microbiota dysbiosis in obese mice. PTP was made using the acid extraction method, and it was found to be an acidic pectin that had relative mole percentages of 32.1%, 29.2%, and 26.2% for galacturonic acid, arabinose, and galactose, respectively. The administration of PTP in C57BL/6J mice inhibited the HFD-induced abnormal weight gain, visceral obesity, and dyslipidemia, and also improved insulin sensitivity, as revealed by the improved insulin tolerance and the decreased glucose levels during an insulin sensitivity test. These effects were linked to increased energy expenditure, as demonstrated by the upregulation of thermogenesis-related protein UCP1 expression in the brown adipose tissue (BAT) of PTP-treated mice. 16S rRNA gene sequencing revealed that PTP dramatically improved the HFD-induced gut dysbiosis by lowering the ratio of Firmicutes to Bacteroidetes and the quantity of potentially harmful bacteria. These findings may provide a theoretical basis for us to understand the functions and usages of PTP in alleviating obesity.

Abstract Diatom is a common single‐cell microalgae with large species and huge biomass. Diatom biosilica (DB), the shell of diatom, is a natural inorganic material with a micro‐nanoporous structure. Its unique hierarchical porous structure gives it great application potential in drug delivery, hemostat materials, and biosensors, etc. However, the structural diversity of DB determines its different biological functions. Screening hundreds of thousands of diatom species for structural features of DB that meet application requirements is like looking for a needle in a seaway. And the chemical modification methods lack effective means to control the micro‐nanoporous structure of DB. The formation of DB is a typical biomineralization process, and its structural characteristics are affected by external environmental conditions, genes, and other factors. This allows to manipulate the micro‐nanostructure of DB through biological regulation method, thereby transforming the screening mode of the structure function of DB from a needle in a seaway to biofabrication mode. This review focuses on the formation, biological modification, functional activity of DB structure, and its application in biomaterials field, providing regulatory strategies and research idea of DB from the perspective of biofabrication. It will also maximize the possibility of using DB as biological materials.

Abstract Tumor-associated lncRNAs regulated by epigenetic modification switches mediate immune escape and chemoresistance in ovarian cancer (OC). However, the underlying mechanisms and concrete targets have not been systematically elucidated. Here, we discovered that methylation modifications played a significant role in regulating immune cell infiltration and sensitizing OC to chemotherapy by modulating immune-related lncRNAs (irlncRNAs), which represent tumor immune status. Through deep analysis of the TCGA database, a prognostic risk model incorporating four methylation-related lncRNAs (mrlncRNAs) and irlncRNAs was constructed. Twenty-one mrlncRNA/irlncRNA pairs were identified that were significantly related to the overall survival (OS) of OC patients. Subsequently, we selected four lncRNAs to construct a risk signature predictive of OS and indicative of OC immune infiltration, and verified the robustness of the risk signature in an internal validation set. The risk score was an independent prognostic factor for OC prognosis, which was demonstrated via multifactorial Cox regression analysis and nomogram. Moreover, risk scores were negatively related to the expression of CD274, CTLA4, ICOS, LAG3, PDCD1, and PDCD1LG2 and negatively correlated with CD8+, CD4+, and Treg tumor-infiltrating immune cells. In addition, a high-risk score was associated with a higher IC50 value for cisplatin, which was associated with a significantly worse clinical outcome. Next, a competing endogenous RNA (ceRNA) network and a signaling pathway controlling the infiltration of CD8+ T cells were explored based on the lncRNA model, which suggested a potential therapeutic target for immunotherapy. Overall, this study constructed a prognostic model by pairing mrlncRNAs and irlncRNAs and revealed the critical role of the FTO/RP5-991G20.1/hsa-miR-1976/MEIS1 signaling pathway in regulating immune function and enhancing anticancer therapy.

Abdominal aortic aneurysm (AAA) is a progressive aortic dilatation, causing ∼80% mortality upon rupture. Currently, there is no approved drug therapy for AAA. Surgical repairs are invasive and risky and thus not recommended to patients with small AAAs which, however, account for ∼90% of the newly diagnosed cases. It is therefore a compelling unmet clinical need to discover effective non-invasive strategies to prevent or slow down AAA progression. We contend that the first AAA drug therapy will only arise through discoveries of both effective drug targets and innovative delivery methods. There is substantial evidence that degenerative smooth muscle cells (SMCs) orchestrate AAA pathogenesis and progression. In this study, we made an exciting finding that PERK, the endoplasmic reticulum (ER) stress Protein Kinase R-like ER Kinase, is a potent driver of SMC degeneration and hence a potential therapeutic target. Indeed, local knockdown of PERK in elastase-challenged aorta significantly attenuated AAA lesions in vivo. In parallel, we also conceived a biomimetic nanocluster (NC) design uniquely tailored to AAA-targeting drug delivery. This NC demonstrated excellent AAA homing via a platelet-derived biomembrane coating; and when loaded with a selective PERK inhibitor (PERKi, GSK2656157), the NC therapy conferred remarkable benefits in both preventing aneurysm development and halting the progression of pre-existing aneurysmal lesions in two distinct rodent models of AAA. In summary, our current study not only establishes a new intervention target for mitigating SMC degeneration and aneurysmal pathogenesis, but also provides a powerful tool to facilitate the development of effective drug therapy of AAA.

International negotiations towards a legally binding instrument on the global plastic pollution have obtained wide-ranging attention from international community. It is revealed that Japan has taken a conservative but proactive stance during negotiations. This study overviews Japan’s current legal framework on the management of plastic pollution including land and the sea. On this basis, the paper then analyzes Japan’s stance in the negotiations to examine the issues that are of most concern to Japan in international cooperation towards ending plastic pollution. It will further analyze Japan’s views on the legally binding instrument’s framework, operational mechanism and key components from the perspective of international environmental law. And it will also summarize Japan’s specific claims and objectives in the negotiations, and provide an evaluation of Japan’s stance.

ABSTRACTIntroduction An effective salvage regimen for the reinduction of remission is lacking for refractory or relapsed primary central nervous system lymphoma (r/r PCNSL). This study aimed to evaluate the efficacy and safety of cytarabine plus temozolomide in treating r/r PCNSL and to explore the associated prognostic factors.Methods A single-center retrospective cohort study was conducted to assess the efficacy and safety of cytarabine and temozolomide (AT) in r/r PCNSL patients. KIR and HLA genotyping was performed on peripheral blood samples.Results Thirty PCNSL patients receiving an AT regimen (cytarabine 3 g/m2 for 2 days combined with temozolomide 150 mg/m2 for 5 days) in our institution were analyzed. The median age was 65 years (range 25–79 years). A total of 43.4% of patients (13/30) achieved an overall response within a median follow-up of 16 months (95% confidence interval [CI]: 11–23 months). The median PFS and OS of the cohort were 1.5 months (95% CI: 1–4 months) and 19.5 months (95% CI: 11 months to not calculable), respectively. Patients harboring KIR3DL1/HLA-B genotypes predicting low affinity had a higher response rate (p = 0.042) and longer median PFS (3 months) than those with KIR3DL1/HLA-B genotypes predicting high affinity (1 month) (p = 0.0047). Cox regression analysis indicated that KIR/HLA-B genotypes were independently associated with PFS (p = 0.043). However, KIR/HLA-B genotypes had no impact on the OS of the cohort. The toxicity of AT treatment was mild and manageable.Conclusion The AT regimen was well tolerated, and patients with specific KIR-HLA genotypes may benefit from this regimen.

Toosendanin (TSN), extracted from Melia. toosendan Sieb.et Zucc. and Melia. azedarach L., has been developed into an ascaris repellent in China. However, with the improvement of public health protection, the incidence of ascariasis has been reduced considerably, resulting in limited medical application of TSN. Therefore, it is questionable whether this old ascaris repellent can develop into a drug candidate. Modern studies have shown that TSN has strong pharmacological activities, including anti-tumor, anti-botulinum, anti-viral and anti-parasitic potentials. It also can regulate fat formation and improve inflammation. These researches indicate that TSN has great potential to be developed into a corresponding medical product. In order to better development and application of TSN, the availability, pharmacodynamics, pharmacokinetics and toxicology of TSN are summarized systematically. In addition, this review discusses shortcomings in the current researches and provides useful suggestions about how TSN developed into a drug candidate. Therefore, this paper illustrates the possibility of developing TSN as a medical product, aimed to provide directions for the clinical application and further research of TSN.

Background: Due to the poor prognosis and rising occurrence, there is a crucial need to improve the diagnosis of Primary Central Nervous System Lymphoma (PCNSL), which is a rare type of non-Hodgkin’s lymphoma. This study utilized targeted metabolomics of cerebrospinal fluid (CSF) to identify biomarker panels for the improved diagnosis or differential diagnosis of primary central nervous system lymphoma (PCNSL).Methods: In this study, a cohort of 68 individuals, including patients with primary central nervous system lymphoma (PCNSL), non-malignant disease controls, and patients with other brain tumors, was recruited. Their cerebrospinal fluid samples were analyzed using the Ultra-high performance liquid chromatography - tandem mass spectrometer (UHPLC-MS/MS) technique for targeted metabolomics analysis. Multivariate statistical analysis and logistic regression modeling were employed to identify biomarkers for both diagnosis (Dx) and differential diagnosis (Diff) purposes. The Dx and Diff models were further validated using a separate cohort of 34 subjects through logistic regression modeling.Results: A targeted analysis of 45 metabolites was conducted using UHPLC-MS/MS on cerebrospinal fluid (CSF) samples from a cohort of 68 individuals, including PCNSL patients, non-malignant disease controls, and patients with other brain tumors. Five metabolic features were identified as biomarkers for PCNSL diagnosis, while nine metabolic features were found to be biomarkers for differential diagnosis. Logistic regression modeling was employed to validate the Dx and Diff models using an independent cohort of 34 subjects. The logistic model demonstrated excellent performance, with an AUC of 0.83 for PCNSL vs. non-malignant disease controls and 0.86 for PCNSL vs. other brain tumor patients.Conclusion: Our study has successfully developed two logistic regression models utilizing metabolic markers in cerebrospinal fluid (CSF) for the diagnosis and differential diagnosis of PCNSL. These models provide valuable insights and hold promise for the future development of a non-invasive and reliable diagnostic tool for PCNSL.

Biologically active and nanoscale extracellular vesicles (EVs) participate in a variety of cellular physiological and pathological processes in a cell-free manner. Unlike cells, EVs not only do not cause acute immune rejection, but are much smaller and have a low risk of tumorigenicity or embolization. Because of their unique advantages, EVs show promise in applications in the diagnosis and treatment of reproductive disorders. As research broadens, engineering strategies for EVs have been developed, and engineering strategies for EVs have substantially improved their application potential while circumventing the defects of natural EVs, driving EVs toward clinical applications. In this paper, we will review the engineering strategies of EVs, as well as their regulatory effects and mechanisms on reproductive disorders (including premature ovarian insufficiency (POI), polycystic ovarian syndrome (PCOS), recurrent spontaneous abortion (RSA), intrauterine adhesion (IUA), and endometriosis (EMS)) and their application prospects. This work provides new ideas for the treatment of female reproductive disorders by engineering EVs.

Epigenetically switched, proliferative vascular smooth muscle cells (SMCs) form neointima, engendering stenotic diseases. Histone-3 lysine-27 trimethylation (H3K27me3) and acetylation (H3K27ac) marks are associated with gene repression and activation, respectively. The polycomb protein embryonic ectoderm development (EED) reads H3K27me3 and also enhances its deposition, hence is a canonical gene repressor. However, herein we found an unexpected role for EED in activating the bona fide pro-proliferative gene Ccnd1 (cyclinD1). EED overexpression in SMCs increased Ccnd1 mRNA, seemingly contradicting its gene-repressing function. However, consistently, EED co-immunoprecipitated with gene-activating H3K27ac reader BRD4, and they co-occupied at both mitogen-activated Ccnd1 and mitogen-repressed P57 (bona fide anti-proliferative gene), as indicated by chromatin immunoprecipitation qPCR. These results were abolished by an inhibitor of either the EED/H3K27me3 or BRD4/H3K27ac reader function. In accordance, elevating BRD4 increased H3K27me3. In vivo, while EED was upregulated in rat and human neointimal lesions, selective EED inhibition abated angioplasty-induced neointima and reduced cyclinD1 in rat carotid arteries. Thus, results uncover a previously unknown role for EED in Ccnd1 activation, likely via its cooperativity with BRD4 that enhances each other’s reader function; i.e., activating pro-proliferative Ccnd1 while repressing anti-proliferative P57. As such, this study confers mechanistic implications for the epigenetic intervention of neointimal pathology.

Deep learning (DL) exhibits commendable performance in hyperspectral image (HSI) classification because of its powerful feature expression ability. Siamese neural network further improves the performance of DL models by learning similarities within-class and differences between-class from sample pairs. However, there are still some limitations in siamese neural network. On the one hand, siamese neural network usually needs a large number of negative pair samples in the training process, leading to computing overhead. On the other hand, current models may lack interpretability because of complex network structure. To overcome the above limitations, we propose a spectral-spatial siamese neural network with bag-of-features (S3BoF) for HSI classification. First, we use a siamese neural network with 3-D and 2-D convolutions to extract the spectral-spatial features. Second, we introduce stop-gradient operation and prediction head structure to make the siamese neural network work without negative pair samples, thus reducing the computational burden. Third, a bag-of-features (BoF) learning module is introduced to enhance the model interpretability and feature representation. Finally, a symmetric loss and a cross entropy loss are respectively used for contrastive learning and classification. Experiments results on four common hyperspectral datasets indicated that S3BoF performs better than the other traditional and state-of-the-art deep learning HSI classification methods in terms of classification accuracy and generalization performance, with improvements in terms of OA around 1.40%–30.01%, 0.27%–8.65%, 0.37%–6.27%, 0.22%–6.64% for Indian Pines, University of Pavia, Salinas, and Yellow River Delta datasets, respectively, under 5% labeled samples per class.

Abstract Background Phospholipase D (PLD) is highly valuable in the food and medicine industries, where it is used to convert low-cost phosphatidylcholine into high-value phospholipids (PLs). Despite being overexpressed in Streptomyces, PLD production requires expensive thiostrepton feeding during fermentation, limiting its industrialization. To address this issue, we propose a new thiostrepton-free system. Results We developed a system using a combinatorial strategy containing the constitutive promoter kasOp* and PLD G215S mutation fused to a signal peptide sigcin of Streptoverticillium cinnamoneum pld. To find a candidate vector, we first expressed PLD using the integrative vector pSET152 and then built three autonomously replicating vectors by substituting Streptomyces replicons to increase PLD expression. According to our findings, replicon 3 with stability gene (sta) inserted had an ideal result. The retention rate of the plasmid pOJ260-rep3-pld* was 99% after five passages under non-resistance conditions. In addition, the strain SK-3 harboring plasmid pOJ260-rep3-pld* produced 62 U/mL (3.48 mg/g) of PLD, which further improved to 86.8 U/mL (7.51 mg/g) at 32 °C in the optimized medium, which is the highest activity achieved in the PLD secretory expression to date. Conclusions This is the first time that a thiostrepton-free PLD production system has been reported in Streptomyces. The new system produced stable PLD secretion and lays the groundwork for the production of PLs from fermentation stock. Meanwhile, in the Streptomyces expression system, we present a highly promising solution for producing other complex proteins.

BackgroundPrimary central nervous system lymphoma (PCNSL) is an aggressive extranodal non-Hodgkin lymphoma with a poor prognosis. We aimed to evaluate the prognostic impact of circulating NK cells in PCNSL.Materials and methodsPatients diagnosed with PCNSL who were treated at our institution between December 2018 and December 2019 were retrospectively screened. Patient variables including age, sex, Karnofsky performance status, diagnostic methods, location of lesions, lactate dehydrogenase, cerebrospinal fluids (CSF), and vitreous fluids involvement or not were documented. NK cell count and NK cell proportion (NK cell count/lymphocyte count) in the peripheral blood were evaluated by flow cytometry. Some patients underwent two consecutive NK cell tests before and three weeks after chemotherapy (before the next chemotherapy). The fold change in NK cell proportion and NK cell counts were calculated. CD56-positive NK cells in tumor tissue were assessed by immunohistochemistry. NK cell cytotoxicity assay was performed using flow cytometry.ResultsA total of 161 patients with PCNSL were included in this study. The median NK cell count of all NK cell tests was 197.73/μL (range 13.11–1889.90 cells/μL). The median proportion of NK cells was 14.11% (range 1.68–45.15%) for all. Responders had a higher median NK cell count (p165 cells/μL) appeared to have a longer median overall survival than those with a low NK cell count (p=0.0054). A high fold change in the proportion of NK cells (>0.1957; p=0.0367) or NK cell count (>0.1045; p=0.0356) was associated with longer progression-free survival. Circulating NK cells from newly-diagnosed PCNSL demonstrated an impaired cytotoxicity capacity compared to those from patients with PCNSL in complete remission or healthy donors.ConclusionOur study indicated that circulating NK cells had some impact on the outcome of PCNSL.

The application of chemotherapy drugs in tumor treatment has a long history, but the lack of selectivity of drugs often leads to serious side effects during chemotherapy. The natural anti-tumor ingredients derived from Chinese herbal medicine are attracting increased attention due to their diverse anti-tumor effects, abundant resources, and minimal side effects. An effective anti-tumor strategy may lie in the combination of these naturally derived anti-tumor ingredients with conventional chemotherapy drugs. This approach could potentially inhibit tumor growth and the development of drug resistance in tumor cells while reducing the adverse effects of chemotherapy drugs. This review provides a comprehensive overview of the combined therapy strategies integrating natural anti-tumor components from Chinese herbal medicine with chemotherapy drugs in current research. We primarily summarize various compounds in Chinese herbal medicine exhibiting natural anti-tumor activities and the relevant mechanisms in synergistic anti-tumor combination therapy. The focus of this paper is on underlining that this integrative approach, combining natural anti-tumor components of Chinese herbal medicine with chemotherapy drugs, presents a novel cancer treatment methodology, thereby providing new insights for future oncological research.

Essential oils (EOs), also called liquid gold, are known for their wide range of applications and biological activities. The modern use of EOs has received increasing attention for more than 60 years. The precious EOs have been refined from plant raw materials using a variety of methods. Since the extraction, separation, and purification methods determine the type, quantity, and stereochemical structure of EO molecules as well as the final yield and quality of EOs, the selection of an appropriate method is crucial. The traditional and emerging extraction methods (hydrodistillation, steam distillation, organic solvent extraction, etc.), as well as separation and purification methods (chromatography, macroporous resin, chemical reaction, etc.), of plant EOs and their main volatile compounds were shown. Our review focused on the principles, processes, characteristics, and applications of these methods, so as to better understand the preparation of pure plant EOs and further guide their large-scale use.

Phosphatidylserine (PS) is a new resource food, which has less content in nature and the difficulty of extraction. Phospholipase D (PLD) is the critical synthetase in enzymatic preparation of PS. This paper mainly introduces the characteristics of molecular structure of PLD and the catalytic mechanism and enzyme activity, and summarizes the current preparation methods of PS, focusing on the research progress and reaction system of enzymatic synthesis, and analyzes and prospects the selection of the reaction system for PS preparation. It is expected to provide reference for deepening the research of enzymatic preparation of PS, so as to promote the industrial production and application of new resource food PS.

Abstract Background Menaquinone-7 (MK-7), which is associated with complex and tightly regulated pathways and redox imbalances, is produced at low titres in Bacillus subtilis. Synthetic biology provides a rational engineering principle for the transcriptional optimisation of key enzymes and the artificial creation of cofactor regeneration systems without regulatory interference. This holds great promise for alleviating pathway bottlenecks and improving the efficiency of carbon and energy utilisation. Results We used a bottom-up synthetic biology approach for the synthetic redesign of central carbon and to improve the adaptability between material and energy metabolism in MK-7 synthesis pathways. First, the rate-limiting enzymes, 1-deoxyxylulose-5-phosphate synthase (DXS), isopentenyl-diphosphate delta-isomerase (Fni), 1-deoxyxylulose-5-phosphate reductase (DXR), isochorismate synthase (MenF), and 3-deoxy-7-phosphoheptulonate synthase (AroA) in the MK-7 pathway were sequentially overexpressed. Promoter engineering and fusion tags were used to overexpress the key enzyme MenA, and the titre of MK-7 was 39.01 mg/L. Finally, after stoichiometric calculation and optimisation of the cofactor regeneration pathway, we constructed two NADPH regeneration systems, enhanced the endogenous cofactor regeneration pathway, and introduced a heterologous NADH kinase (Pos5P) to increase the availability of NADPH for MK-7 biosynthesis. The strain expressing pos5P was more efficient in converting NADH to NADPH and had excellent MK-7 synthesis ability. Following three Design-Build-Test-Learn cycles, the titre of MK-7 after flask fermentation reached 53.07 mg/L, which was 4.52 times that of B. subtilis 168. Additionally, the artificially constructed cofactor regeneration system reduced the amount of NADH-dependent by-product lactate in the fermentation broth by 9.15%. This resulted in decreased energy loss and improved carbon conversion. Conclusions In summary, a "high-efficiency, low-carbon, cofactor-recycling" MK-7 synthetic strain was constructed, and the strategy used in this study can be generally applied for constructing high-efficiency synthesis platforms for other terpenoids, laying the foundation for the large-scale production of high-value MK-7 as well as terpenoids.

Cultivating intercultural competence is a long-term and staged process requiring the efforts of all counterparts in the education field from primary school up to university. Currently, most research on intercultural education in China focuses on the tertiary education context, and little attention has been paid to elementary education as well as primary school EFL teachers. Against this background, this study intends to investigate Chinese primary school EFL teachers' preparedness for intercultural foreign language teaching (IFLT), its influencing factors, and the support teachers need to implement IFLT. A convergent mixed method was used in this study. Data was collected through questionnaires and interviews, SPSS and the thematic analysis method were used to analyze the data. Via both quantitative and qualitative methods, this empirical study found that: 1. Primary school EFL teachers are not well prepared for IFLT; 2. Textbooks, the current evaluation system, teachers' lack of literacy in intercultural competence, insufficient teacher training on intercultural competence, and teachers' lack of time and energy are five major factors that constrain the implementation of IFLT; 3. Support from school administration, the construction of intercultural-related materials and resources, and practice-oriented teacher training are the three main support teachers need. Based on these findings, the role of textbooks, experience abroad and general materials on culture in promoting IFLT were discussed. At last, implications and future research directions were proposed.

Postoperative cognitive dysfunction (POCD) is a prevalent clinical entity following surgery and is characterized by declined neurocognitive function. Neuroinflammation mediated by microglia is the essential mechanism of POCD. Anesthetics are thought to be a major contributor to the development of POCD, as they promote microglial activation and induce neuroinflammation. However, this claim remains controversial. Anesthetics can exert both anti- and pro-inflammatory effects by modulating microglial activation, suggesting that anesthetics may play dual roles in the pathogenesis of POCD. Here, we review the mechanisms by which the commonly used anesthetics regulate microglial activation via inflammatory signaling pathways, showing both anti- and pro-inflammatory properties of anesthetics, and indicating how perioperative administration of anesthetics might either relieve or worsen POCD development. The potential for anesthetics to enhance cognitive performance based on their anti-inflammatory properties is further discussed, emphasizing that the beneficial effects of anesthetics vary depending on dose, exposure time, and patients’ characteristics. To minimize the incidence of POCD, we recommend considering these factors to select appropriate anesthetics.

Background: Ambient ozone pollution is steadily increasing and becoming a major environmental risk factor contributing to the global disease burden. Although the association between short-term ozone exposure and mortality has been widely studied, results are mostly reported on deaths from non-accidental or total cardiopulmonary disease rather than a spectrum of causes. In particular, a knowledge gap still exists for the potential thresholds in mortality risks. Methods: This nationwide time-series study in China included 323 counties totaling 230,266,168 residents. Daily maximum 8-hour average was calculated as the ozone exposure metric. A two-stage statistical approach was adopted to assess ozone effects on 21 cause-specific deaths for 2013–2018. The subset approach and threshold approach were utilized to explore potential thresholds, and stratification analysis was used to evaluate population susceptibility. Results: On average, the annual mean ozone concentration was 93.4 μg/m3 across 323 counties. A 10-μg/m3 increase in lag 0–1 day of ozone was associated with increases of 0.12 % in mortality risk from non-accidental disease, 0.11 % from circulatory disease, 0.09 % from respiratory disease, 0.29 % from urinary system disease, and 0.20 % from nervous system disease. There may be a “safe” threshold in the ozone-mortality association, which may be between 60 and 100 μg/m3, and vary by cause of death. Women and older adults (especially those over 75) are more affected by short-term ozone exposure. Populations in North China had a higher risk of ozone-related circulatory mortality, while populations in South China had a higher risk of ozone-related respiratory mortality. Conclusions: National findings link short-term ozone exposure to premature death from circulatory, respiratory, neurological, and urinary diseases, and provide evidence for a potential “safe” threshold in the association of ozone and mortality. These findings have important implications for helping policymakers tighten the relevant air quality standards and developing early warning systems for public health protection in China.

Abstract Chemoresistance is a severe outcome among patients with epithelial ovarian cancer (EOC) that leads to a poor prognosis. YBX-1 has been shown to cause treatment failure and cancer progression in EOC. However, strategies that directly target YBX-1 are not yet conceivable. Here, we identified that SIAH1 which was downregulated in chemoresistant EOC samples and cell lines functioned as novel E3 ligases to trigger degradation of YBX-1 at cytoplasm by RING finger domain. Mechanistic studies show that YBX-1 was ubiquitinated by SIAH1 at lys304 that lead to the instability of its target m5C-modified mRNAs, thus sensitized EOC cells to cDDP. Overexpression of SIAH1 enhanced the antitumor efficacy of cisplatin in vitro and in vivo, which were partially impaired by ectopic expression of YBX-1 or depletion of YBX-1 ubiquitination. In summary, our data identify the SIAH1/YBX-1 interaction as a therapeutic target for overcoming EOC chemoresistance.

Convolutional neural network (CNN) has exhibited enormous potentials in hyperspectral image (HSI) classification owing to excellent locally modeling ability. Although excellent performance of CNN-based methods has been witnessed, there still have some limitations of their internal network backbone. On the one hand, modeling long-distance context dependencies is an inborn defect, which leads to receptive field limitation and insufficient feature capture in HSI. On the other hand, CNN-based methods usually need various sample distribution to train and cannot infer dynamically, which may not capture the inherent changes of HSI data well. To overcome the abovementioned issues, we propose a novel local transformer with spatial partition restore network (SPRLT-Net) for HSI classification. First, local transformer is introduced to obtain the spatial attention weights dynamically by measuring the similarity between related pixel pairs. Second, a spatial partition restore (SPR) module is designed to split the input patch into several overlapping continuous subpatches as sequential. With the obtained attention weights at hand, the SPR module restores the sequential to the original patch. Finally, a fully connected layer is used for classification. SPRLT-Net can capture global context dependencies, and the dynamical attention weights can adapt the inherent changes of HSI spatial pixels. Experimental results based on spatially disjoint samples and randomly selected samples of five benchmark datasets demonstrate that SPRLT-Net outperforms the other state-of-the-art methods in terms of classification accuracy, generalization performance, and computational complexity.

Abstract The screening of non-small cell lung cancer (NSCLC) tumors for anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements is important because of the dramatically favorable therapy response to ALK inhibitor. However, the exact mechanism of poor survival in ALK fusion lung cancer patients without receiving targeted therapy is unclear. In this study, total of 521 tumor specimens from Chinese patients with lung cancer were screened for ALK fusion by immunohistochemistry (IHC) and confirmed by fluorescence in situ hybridization (FISH). As results, there were no cases of coexisting EGFR and ALK mutations identified. Fourteen cases (2.7%) harbored ALK fusion, including eight solid adenocarcinomas with signet ring cell features, four acinar adenocarcinomas with cribriform pattern containing mucin, one adenosquamous carcinoma and one micropapillary adenocarcinoma with mucin. Six (42.9%) of fourteen patients with ALK-positive lung cancer had stage IV disease, and five ALK-positive patients treated with platinum-based chemotherapy had poor outcome (all patients were dead and the mean survival time was 12 months), compared to 72 months for patients with ALK inhibitor therapy. Furthermore, Five ALK-positive cases were analyzed by whole exome sequencing (WES) and via direct transcript counting using a digital probe-base (NanoString) to explore the driver genes. Deregulation of PI3K/AKT signaling pathway in ALK-positive lung cancer was demonstrated by WES analysis, and significantly increased mRNA of ALK, ROS1, MET, SPP1 and PI3K signaling pathway was identified by NanoString assay. The concordance between NanoString, IHC and FISH methodologies for detecting ALK fusion was 100%. Significant overexpression of SPP1 protein in ALK-positive lung cancer was confirmed by IHC compared to paired adjacent normal tissues and ALK-negative cancers. Thus we concluded that SPP1 overexpression is associated with poor outcomes for patients with ALK fusion lung cancer without receiving targeted therapy and PI3K/AKT/SPP1 pathway may become the promising targets in patients with aggressive lung cancer.

Abdominal aortic aneurysm (AAA) is a prevalent vascular disease with high mortality rates upon rupture. Despite its prevalence in elderly populations, there remain limited treatment options; invasive surgical repair, while risky, is the only therapeutic intervention with proven clinical benefits. Dietary factors have long been suggested to be closely associated with AAA risks, and dietary therapies recently emerged as promising avenues to achieve non-invasive management of a wide spectrum of diseases. However, the role of dietary therapies in AAA remains elusive. In this article, we will summarize the recent clinical and pre-clinical efforts in understanding the therapeutic and mechanistic implications of various dietary patterns and therapeutic approaches in AAA.

This study implies finding the linkages among financial inclusion, non-performing loans (NPLs), and economic growth. The study uses large panel data of 21 Organization for Economic Corporation and Development (OECD) countries for the dynamic panel estimation by using the Driscoll-Kraay standard errors with fixed effect. The results of the dynamic panel estimation technique revealed the existence of a long-run relationship among financial inclusion, NPLs, and economic growth. Financial inclusion contributes positively to economic growth by reducing NPLs. Furthermore, NPLs negatively impact financial inclusion as well as economic growth. The study presents important policy recommendations to control NPLs and boost the level of financial inclusion in the selected economies.

The prognosis of relapsed/refractory (R/R) primary central nervous system lymphoma (PCNSL) is dismal, and there are limited treatment options for these patients. This was a prospective single-arm phase II study of combined pemetrexed and lenalidomide for salvage treatment of R/R PCNSL. Patients with R/R PCNSL (n = 38) who had undergone two or more different therapeutic regimens and experienced disease progression or recurrence were enrolled. The primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Patients were followed up for a median of 18 (range, 1–36) months. ORR was 68.4%, with median PFS and OS of 6 and 18 months, respectively. Adverse events (AEs) included myelosuppression, fatigue, nausea, fever, infection, cardiac disease, and thrombogenesis. Commonly observed grade ≥ 3 AEs included neutropenia (5.3%), leukopenia (2.6%), thrombocytopenia (7.9%), and infection (2.6%). Elevated lactate dehydrogenase (LDH) levels (χ2 = 13.25; P = 0.0003) and bulky disease (P = 0.032; χ2 = 4.580) were associated with short PFS. Elevated serum LDH level (P = 0.011; χ2 = 6.560), abnormal lymphoma cells in the cerebrospinal fluid (CSF) [P = 0.011; χ2 = 6.445], and multiple lesions (P = 0.036; χ2 = 4.404) were significantly associated with poorer OS. Abnormal lymphoma cells in the CSF were an independent predictor of poor prognosis on multivariate analysis (P = 0.034; hazard ratio (HR) = 2.836; 95% confidence interval, 1.082–7.434). Our results indicate that pemetrexed plus lenalidomide is effective for heavily treated R/R PCNSL, with moderate toxicity. Trial registration: #ChiCTR1900028070.

Arbuscular mycorrhizal fungi (AMF) symbiosis has been shown to improve the ability to obtain nutrients and resist adverse environmental conditions. However, there are few studies on the functions of AMF in the absorption and accumulation of boron (B). Moreover, it is still unclear whether the root colonization rates of AMF are limited by B deficiency. In this study, Camellia oleifera seedlings were planted in normal and boron-deficient substrates, and the seedlings were inoculated with Funneliformis mosseae or left uninoculated. The growth and physiological indices of C. oleifera seedlings were determined. The results of this experiment indicate that AMF inoculation increased the plant biomass, B content, B accumulation, and antioxidant enzyme activity in both normal and boron-deficient C. oleifera seedlings. Furthermore, boron deficiency resulted in a decrease in the AMF root colonization efficiency and the inhibition of C. oleifera seedlings’ growth and physiological activity. These findings suggest that AMF inoculation could improve the resistance to B-deficiency stress. Additionally, the colonization efficiency of AMF was adversely affected by B deficiency; thus, AMF play a cooperative role with B in the growth and physiological functions of plants. The results provide a theoretical basis for taking measures to solve B-deficiency stress in C. oleifera and other plants’ cultivation.

Licorice is a traditional and versatile herbal medicine and food. Glabridin (Gla) is a kind of isoflavone extracted from the licorice root, which has anti-obesity, anti-atherosclerotic, and antioxidative effects. Alcoholic liver disease (ALD) is a widespread liver disease induced by chronic alcohol consumption. However, studies demonstrating the effect of Gla on ALD are rare. The research explored the positive effect of Gla in C57BL/6J mice fed by the Lieber–DeCarli ethanol mice diet and HepG2 cells treated with ethanol. Gla alleviated ethanol-induced liver injury, including reducing liver vacuolation and lipid accumulation. The serum levels of inflammatory cytokines were decreased in the Gla-treated mice. The reactive oxygen species and apoptosis levels were attenuated and antioxidant enzyme activity levels were restored in ethanol-induced mice by Gla treatment. In vitro, Gla reduced ethanol-induced cytotoxicity, nuclear factor kappa B (NF-κB) nuclear translocation, and enhanced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nuclear translocation. Anisomycin (an agonist of p38 MAPK) eliminated the positive role of Gla on ethanol-caused oxidative stress and inflammation. On the whole, Gla can alleviate alcoholic liver damage via the p38 MAPK/Nrf2/NF-κB pathway and may be used as a novel health product or drug to potentially alleviate ALD.

Bromodomain protein BRD4 reads histone acetylation (H3K27ac), an epigenomic mark of transcription enhancers. CCAAT enhancer binding protein delta (CEBPD) is a transcription factor typically studied in metabolism. While both are potent effectors and potential therapeutic targets, their relationship was previously unknown. Here we investigated their interplay in vascular smooth muscle cell (SMC) inflammation. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) revealed H3K27ac/BRD4 enrichment at Cebpd in injured rat carotid arteries. While genomic deletion of BRD4-associated enhancer in SMCs in vitro decreased Cebpd transcripts, BRD4 gene silencing also diminished Cebpd mRNA and protein, indicative of a BRD4 control over CEBPD expression. Bromodomain-1, but not bromodomain-2, accounted for this BRD4 function. Moreover, endogenous BRD4 protein co-immunoprecipitated with CEBPD, and both proteins co-immunoprecipitated the Cebpd promoter and enhancer DNA fragments. These co-immunoprecipitations (coIPs) were all abolished by the BRD4-bromodomain blocker JQ1, suggesting a BRD4/CEBPD /promoter/enhancer complex. While BRD4 and CEBPD were both upregulated upon tumor necrosis factor alpha (TNF-α) stimulation of SMC inflammation (increased interleukin [IL]-1b, IL-6, and MCP-1), they mediated this stimulation via preferentially elevated expression of platelet-derived growth factor receptor alpha (PDGFRα, versus PDGFRβ), as indicated by loss- and gain-of-function experiments. Taken together, our study unravels a hierarchical yet collaborative BRD4/CEBPD relationship, a previously unrecognized mechanism that prompts SMC inflammation and may underlie other pathophysiological processes as well.

Abstract With the rapid expansion of the RMB exchange rate’s floating range, the effects of the RMB exchange rate and global commodity price changes on China’s stock prices are likely to increase. This study uses both auto regressive distributed lag (ARDL) and nonlinear ARDL (NARDL) approaches to explore the symmetric and asymmetric effects of the RMB exchange rate and global commodity prices on China’s stock prices. Our findings show that without considering the critical variable of global commodity prices, there is no cointegration relationship between the RMB exchange rate and China’s stock prices, and the coefficient of the RMB exchange rate is not statistically significant. However, when we introduce global commodity prices into the NARDL model, the result shows that the RMB exchange rate has a negative effect on China’s stock prices, that there indeed exists a long-run cointegration relationship among the RMB exchange rate, global commodity prices, and stock prices in the NARDL model, and that global commodity price changes have an asymmetric effect on China’s stock prices in the long run. Specifically, China’s stock prices are more sensitive to increases than decreases in global commodity prices. Thus, increases in global commodity prices cause China’s stock prices to decline sharply. In contrast, the same magnitude of decline in global commodity prices induces a smaller increase in China’s stock prices.

Hyperspectral image (HSI) classification has recently been successfully explored by using deep learning (DL) methods. However, DL models rely heavily on a large number of labeled samples, which are laborious to obtain. Therefore, finding a way to efficiently embed DL models in limited labeled samples is a hot topic in the field of HSI classification. In this paper, an active learning-based siamese network (ALSN) is proposed to solve the limited labeled samples problem in HSI classification. First, we designed a dual learning-based siamese network (DLSN), which consists of a contrastive learning module and a classification module. Secondly, in view of the problem that active learning is difficult to effectively sample under the extremely limited labeling cost, we proposed an adversarial uncertainty-based active learning (AUAL) method to query valuable samples, and to promote DLSN to learn a more complete feature distribution by fine-tuning. Finally, an active learning architecture, based on inter-class uncertainty (ICUAL), is proposed to construct a lightweight sample pair training set, fully extracting the inter-class information of sample pairs and improving classification accuracy. Experiments on three generic HSI datasets strongly demonstrated the effectiveness of ALSN for HSI classification, with performance improvements over other related DL methods.

It has been reported that ascorbic acid inhibits non-alcoholic fatty liver disease partially by activating fatty acid β-oxidation. However, little is known about the mechanism of ascorbic acid-mediated lipid synthesis. Western blot, qRT-PCR and immunofluorescent staining were used to determine if ascorbic acid can regulate expression of liver X receptor α (LXRα) and AMP-activated protein kinase α (AMPKα), which are key regulators of lipogenic genes. In hepatocytes, ascorbic acid decreased cellular lipid accumulation. Mechanistically, ascorbic acid inhibited expression of the genes for lipid synthesis by reducing LXRα nuclear translocation and activating AMPKα. In vivo, administration of ascorbic acid decreased triglyceride levels in serum and liver as well as FFA levels in the liver. Taken together, AMPKα/LXRα-mediated reduction of lipid accumulation in the liver is a novel activity of ascorbic acid on lipid metabolism, suggesting that ascorbic acid is an effective and safe dietary supplement to ameliorate hypertriglyceridemia.

Deep learning (DL) have been intensively exploited for synthetic aperture radar (SAR) target classification, and we have witnessed exciting performances provided by previous studies. Multiview-based DL methods exhibited huge potentials for SAR target classification since they can generate adequate sample images from few raw images. In order to further improve the generalization performance of the multiview-based framework with limited training samples, we propose a novel multiview low-rank hybrid dilated network (MLHDN) for SAR target recognition. Firstly, we design a parameter-sharing hybrid dilated convolution (HDC) to learn multiview features. Secondly, a composite low-rank bilinear pooling (CLRBP) is proposed to fuse multiview features and to reduce their dimensions, yielding class-oriented and compacted feature vectors which are distinctive and representative for classification. Finally, a Softmax layer is used as a classifier. Accordingly, MLHDN encompasses fewer parameters compared to existing multiview-based DL methods. Experimental results demonstrate that MLHDN can achieve state-of-the-art performances on the moving and stationary target acquisition and recognition (MSTAR) datasets for SAR target classification, yielding an accuracy of 96.13% with only 10 training samples per class.

Background: Various potential effect of drugs on alleviating diseases by regulating intestinal microbiome as well as the pharmaceutical excipients on gut microbiota has been revealed. However, the interaction between them is rarely investigated. Methods: Histological analysis, immunohistochemistry analysis, enzyme-linked immunosorbent assay (ELISA) analysis, RT-qPCR, and 16S rRNA analysis were utilized to explore the effect mechanism of the five excipients including hydroxypropyl methylcellulose (HPMC) F4M, Eudragit (EU) S100, chitosan (CT), pectin (PT), and rheum officinale polysaccharide (DHP) on berberine (BBR) to cure UC. Results: The combined BBR with PT and DHP group exhibited better therapeutic efficacy of UC with significantly increased colon length, and decreased hematoxylin-eosin (H&E) scores than other groups. Furthermore, the expression of tight junction ZO-1 and occludin in colon tissue were upregulated, and claudin-2 was downregulated. Ultimately, the serum content of tumor necrosis (TNF)-α, interleukin (IL)-1β, and IL-6 was decreased. Moreover, the combined BBR with PT significantly promoted the restoration of gut microbiota. The relative abundance of Firmicutes and Lactobacillus was significantly increased by the supplement of PT and DHP, and the relative abundance of Proteobacteria was downregulated. Conclusions: Our study may provide a new perspective that the selection of pharmaceutical excipients could be a crucial factor affecting the drugs’ therapeutic efficiency outcome.

In both animals and higher plants, xanthine dehydrogenase is a highly conserved housekeeping enzyme in purine degradation where it oxidizes hypoxanthine to xanthine and xanthine to uric acid. Previous reports demonstrated that xanthine dehydrogenase played a vital role in N metabolism and stress response. Is xanthine dehydrogenase involved in regulating leaf senescence? A recessive early senescence mutant with excess sugar accumulation, ossac3, was isolated previously by screening the EMS-induced mutant library. Here, we show that xanthine dehydrogenase not only plays a role in N metabolism but also involved in regulating carbon metabolism in rice. Based on map-based cloning, OsSAC3 was identified, which encodes the xanthine dehydrogenase. OsSAC3 was constitutively expressed in all examined tissues and the OsSAC3 protein located in the cytoplasm. Transcriptional analysis revealed purine metabolism, chlorophyll metabolism, photosynthesis, sugar metabolism and redox balance were affected in the ossac3 mutant. Moreover, carbohydrate distribution was changed, leading to the accumulation of sucrose and starch in the leaves containing ossac3 on account of decreased expression of OsSWEET3a, OsSWEET6a and OsSWEET14 and oxidized inactivation of starch degradation enzymes in ossac3. These results indicated that OsSAC3 played a vital role in leaf senescence by regulating carbon metabolism in rice.

Tensor-based dimensionality reduction (DR) of hyperspectral images is a promising research topic. However, patch-based tensorization usually adopts a squared neighborhood with fixed window size, which may be inaccurate in modeling the local spatial information in a hyperspectral image scene. In this work, we propose a novel shape-adaptive tensor factorization (SATF) model for dimensionality reduction and classification of hyperspectral images. Firstly, shape-adaptive patch features are extracted to build fourth-order tensors. Secondly, multilinear singular value decomposition (MLSVD) is adopted for tensor factorization and latent features are extracted via mode-i tensor-matrix product. Finally, classification is conducted by using a sparse multinomial logistic regression (SMLR) model. Experimental results, conducted with two popular hyperspectral data sets collected over the Indian Pines and the University of Pavia, respectively, indicate that the proposed method outperforms the other traditional and tensor-based DR methods.

Summary: Cellular plasticity is fundamental in biology and disease. Vascular smooth muscle cell (SMC) dedifferentiation (loss of contractile proteins) initiates and perpetrates vascular pathologies such as restenosis. Contractile gene expression is governed by the master transcription factor, serum response factor (SRF). Unlike other histone deacetylases, histone deacetylase 6 (HDAC6) primarily resides in the cytosol. Whether HDAC6 regulates SRF nuclear activity was previously unknown in any cell type. This study found that selective inhibition of HDAC6 with tubastatin A preserved the contractile protein (alpha-smooth muscle actin) that was otherwise diminished by platelet-derived growth factor-BB. Tubastatin A also enhanced SRF transcriptional (luciferase) activity, and this effect was confirmed by HDAC6 knockdown. Interestingly, HDAC6 inhibition increased acetylation and total protein of myocardin-related transcription factor A (MRTF-A), a transcription co-activator known to translocate from the cytosol to the nucleus, thereby activating SRF. Consistently, HDAC6 co-immunoprecipitated with MRTF-A. In vivo studies showed that tubastatin A treatment of injured rat carotid arteries mitigated neointimal lesion, which is known to be formed largely by dedifferentiated SMCs. This report is the first to show HDAC6 regulation of the MRTF-A/SRF axis and SMC plasticity, thus opening a new perspective for interventions of vascular pathologies. Key Words: dedifferentiation, HDAC6, MRTF-A, SRF, vascular smooth muscle cell

Variations in the Raman spectra of pyrite were studied from 113 to 853 K at room pressure with a Linkam heating and freezing stage, and for 297–513 K and pressures up to 1.9 GPa with a hydrothermal diamond anvil cell. All observed frequencies decreased continuously with an increase in temperatures up to 653 K at ambient pressure. Hematite began to form at 653 K, all pyrite had transformed to hematite (H) at 688 K, and the hematite melted at 853 K. An increase in temperature at every initial pressure (group 1: 0.5 GPa, group 2: 1.1 GPa, group 3: 1.7 GPa, group 4: 1.9 GPa), showed no evidence for chemical reaction or pyrite decomposition. Two or three Raman modes were observed because of crystal orientation or temperature-induced fluorescence effects. The pressure groups showed a decreasing trend of frequency with gradual heating. The interaction of pressure and temperature led to a gradual decrease in Ag and Eg mode at a lower pressure (0.5 GPa and 1.1 GPa) than other pressure groups. Pressure and temperature effects are evident for groups 1 and 2; however, for groups 3 and 4, the temperature shows a larger effect than pressure and leads to a sharp decrease in Ag and Eg modes.

Correlation analysis is a routine method of biological data analysis. In the process of RNA-Seq analysis, differentially expressed genes could be identified by calculating the correlation coefficients in the comparison of gene expression vs. phenotype or gene expression vs. gene expression. However, due to the complicated genetic backgrounds of perennial fruit, the correlation coefficients between phenotypes and genes are usually not high in fruit quality studies. In this study, a cluster-based correlation analysis method (C-CorA) is presented for fruit RNA-Seq analysis. C-CorA is composed of two main parts: the clustering analysis and the correlation analysis. The algorithm is described and then integrated into the MATLAB code and the C# WPF project. The C-CorA method was applied to RNA-Seq datasets of loquat (Eriobotrya japonica) fruit stored or ripened under different conditions. Low temperature conditioning or heat treatment of loquat fruit can alleviate the extent of lignification that occurs because of postharvest storage under low temperatures (0 °C). The C-CorA method generated correlation coefficients and identified many candidate genes correlated with lignification, including EjCAD3 and EjCAD4 and transcription factors such as MYB (UN00328). C-CorA is an effective new method for the correlation analysis of various types of data with different dimensions and can be applied to RNA-Seq data for candidate gene detection in fruit quality studies.

Climate, land use and human activity have an impact on the Qingshui River in Chongli County. The Soil and Water Assessment Tool (SWAT) was used to separately analyze the contributions of climate, land use and direct human activity on the discharge variations. The results indicated that human activity had been the dominant factor for the discharge decrease, while climate and land use change had a positive influence on the discharge increase. The contributions of these three factors were −56.24%, 38.59% and 5.17%, respectively. Moreover, on the seasonal scale, the impact of those factors was consistent with their impact on the annual scale. Human activity was the main factor for discharge decrease in the summer, the contribution accounting for −77.13%. Due to the over-extraction of groundwater for irrigation and use in the mining industry, the discharge showed a decreasing tendency, which has the potential to place stress on sustainable water use in the future. The result of the study may contribute to the optimization of water resource allocation and management.

The pattern of bounding box representation and regression has long been dominant in CNN-based pedestrian detectors. Despite the method’s success, it cannot accurately represent location, and introduces unnecessary background information, while pedestrian features are mainly located in axis-line areas. Other object representations, such as corner-pairs, are not easy to obtain by regression because the corners are far from the axis-line and are greatly affected by background features. In this paper, we propose a novel detection pattern, named Axis-line Representation and Regression (ALR), for pedestrian detection in road scenes. Specifically, we design a 3-d axis-line representation for pedestrians and use it as the regression target during network training. A line-box transformation method is also proposed to fit the widely used box-annotations. Meanwhile, we explore the influence of deformable convolution base-offset on detection performance and propose a base-offset initialization strategy to further promote the gain brought by ALR. Notably, the proposed ALR pattern can be introduced into both anchor-based and anchor-free frameworks. We validate the effectiveness of ALR on the Caltech-USA and CityPersons datasets. Experimental results show that our approach outperforms the baseline significantly through simple modifications and achieves competitive accuracy with other methods without bells and whistles.

Spatio-temporal distribution and leachability of some trace elements (TE) were investigated in sediments of the Xiangjiang River, tributary of the Yangtze River. Based on data collected during 2015–2017, a literature review and geoaccumulation indexes, the pollution level was the highest for Cd, Sb and Hg (Igeo > 3). Over the period reviewed, the TE contamination level displayed almost no temporal variation but an obvious spatial distribution. The most upstream contamination hotspot (Cd > Cr > As, Cu, Pb, Zn > Hg, Sb) was the Songbai section. This hotspot did not spread further downstream. The second hotspot identified was the Zhuzhou–Xiangtan section, impacted by Cd > Hg, Pb, Zn > Cu, with the Zhuzhou area being particularly highly impacted by Pb and Zn. A 30-day leaching experimental protocol under aerobic and anaerobic conditions was carried out to access TE mobility. Low percentages of TE released were calculated, showing that the TE fate mostly depends on the stability of bearing phases under specific physicochemical and microbial conditions. In this case, the studied sediments can be an important sink for these TE. However, some environmental issues have to be considered as some leachate concentrations of contaminants (As, Cr, Cu and U) released into water exceed freshwater aquatic life criteria.

Background: Intimal hyperplasia is a common cause of many vasculopathies. There has been a recent surge of interest in the bromo and extra-terminal (BET) epigenetic “readers” including BRD4 since the serendipitous discovery of JQ1(+), an inhibitor specific to the seemingly undruggable BET bromodomains. The role of the BET family in the development of intimal hyperplasia is not known. Methods: We investigated the effect of BET inhibition on intimal hyperplasia using a rat balloon angioplasty model. Results: While BRD4 was dramatically up-regulated in the rat and human hyperplastic neointima, blocking BET bromodomains with JQ1(+) diminished neointima in rats. Knocking down BRD4 with siRNA, or treatment with JQ1(+) but not the inactive enantiomer JQ1(−), abrogated platelet-derived growth factor (PDGF-BB)-stimulated proliferation and migration of primary rat aortic smooth muscle cells. This inhibitory effect of JQ1(+) was reproducible in primary human aortic smooth muscle cells. In human aortic endothelial cells, JQ1(+) prevented cytokine-induced apoptosis and impairment of cell migration. Furthermore, either BRD4 siRNA or JQ1(+) but not JQ1(−), substantially down-regulated PDGF receptor-α which, in JQ1(+)-treated arteries versus vehicle control, was also reduced. Conclusions: Blocking BET bromodomains mitigates neointima formation, suggesting an epigenetic approach for effective prevention of intimal hyperplasia and associated vascular diseases.