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Abstract Despite advancements in chemotherapy and the availability of novel therapies, the outcome of adult patients with B-cell acute lymphoblastic leukemia (B-ALL) remains unsatisfactory. Therefore, it is necessary to understand the molecular mechanisms underlying the progression of B-ALL. Brahma-related gene 1 (BRG1) is a poor prognostic factor for multiple cancers. Here, the expression of BRG1 was found to be higher in patients with B-ALL, irrespective of the molecular subtype, than in healthy individuals, and its overexpression was associated with a poor prognosis. Upregulation of BRG1 accelerated cell cycle progression into the S phase, resulting in increased cell proliferation, whereas its downregulation facilitated the apoptosis of B-ALL cells. Mechanistically, BRG1 occupies the transcriptional activation site of PPP2R1A, thereby inhibiting its expression and activating the PI3K/AKT signaling pathway to regulate the proto-oncogenes c-Myc and BCL-2. Consistently, silencing of BRG1 and administration of PFI-3 (a specific inhibitor targeting BRG1) significantly inhibited the progression of leukemia and effectively prolonged survival in cell-derived xenograft mouse models of B-ALL. Altogether, this study demonstrates that BRG1-induced overactivation of the PPP2R1A/PI3K/AKT signaling pathway plays an important role in promoting the progression of B-ALL. Therefore, targeting BRG1 represents a promising strategy for the treatment of B-ALL in adults.

Abstract In order to evaluate the beneficiation plant environment in a more scientific and reasonable way, this paper took the workshop environment of the beneficiation plant as the research object. This paper divided the beneficiation plant into 7 evaluation units according to its functions. The evaluation indices are dust, noise, light environment, microclimate, benzene, toluene and xylene. This paper combines the G1 method and the entropy weight method to evaluate the weight of each evaluation index, the element extension model of the concentrator working environment is established by the element analysis method, and the matter element analysis method is used to establish an evaluation index system of a beneficiation plant in East China. The results show that the evaluation level of the breaking workshop and the auxiliary facilities are unqualified, the auxiliary facility is qualified, the culling workshop, culled yard and accessory building are medium, the screening workshop and grinding workshop are good.

Abstract To evaluate the success of pulpotomy in treating immature permanent teeth with irreversible pulpitis. This case series included patients with irreversible pulpitis admitted to the Department of Oral Medicine at the author’s Hospital between 2015 and 2020. The pulpotomies were carried out by clinicians with > 5 years of working experience. The follow-up findings and radiographic images were reviewed by two attending dentists. This study included 49 teeth from 48 children (25 boys and 23 girls). The follow-up was 23.3 ± 6.8 months (from 12 to 40 months). The success rate of pulpotomy was 85.7% (42/49). Pulpotomy failed in seven teeth (14.3%). The treatment success rate for traumatic crown fracture was lower than for dental caries and dens evaginatus (P 0.05). Pulpotomy might be successfully used to treat immature permanent teeth with irreversible pulpitis in young patients mainly caused by caries and a fractured tubercle of dens evaginatus.

BackgroundTumor microenvironment (TME) represents the key factor inducing leukemia development. As stromal cells within the leukemia microenvironment, Bone Marrow Mesenchymal Stem Cells (BM-MSCs) can trigger leukemia progression under certain conditions. As a critical transcription factor, nuclear factor erythroid related factor 2 (Nrf2) can modulate antioxidant response and antioxidant enzyme gene expression, and prevent various oxidative changes. We previously identified a novel mechanism by which Nrf2 promotes leukemia resistance, providing a potential therapeutic target for the treatment of drug-resistant/refractory leukemias. However, the role of Nrf2 in BM-MSCs from B-cell acute lymphoblastic leukemia (B-ALL) patients has not been clearly reported. The present work focused on investigating the effect of Nrf2 overexpression within MSCs on leukemia cell invasion, extramedullary infiltration and proliferation as well as its downstream pathway.MethodsThrough clinical sample detection, in vitro cell experiments and in vivo animal experiments, the role of Nrf2 within MSCs within adult B-ALL cell migration and invasion and its potential molecular mechanism was explored through transcriptome sequencing analysis, RT-PCR, Western blot, cell migration, cell invasion, lentivirus transfection and other experiments.ResultsNrf2 was highly expressed in BM-MSCs from patients with B-ALL as well as in BM-MSCs co-cultured with leukemia cells. Overexpression of Nrf2 within MSCs significantly promoted leukemia cell migration, invasion and proliferation. The extramedullary organ infiltration rate in B-ALL model mice receiving the combined infusion of both cell types dramatically increased relative to that of leukemia cells alone, accompanied by the significantly shortened survival time. Mechanism study found that Nrf2 overexpression within MSCs promoted PI3K-AKT/ERK1/2 phosphorylation in the downstream pathway by activating SDF-1/CXCR4 axis, ultimately leading to extramedullary infiltration of leukemia cells.ConclusionHigh Nrf2 expression with in MSCs enhances leukemia cell invasion and migration, which then accelerates infiltration in leukemic extramedullary organs. Targeting Nrf2 or inhibiting its downstream signal molecules may be the effective interventions for B-ALL patients treatment.

IntroductionGranulocytic myeloid-derived suppressor cells (G-MDSCs) show fast recovery following allogeneic hematopoietic stem cell transplantation (allo-HSCT) constituting the major part of peripheral blood in the early phase. Although G-MDSCs mediate immune suppression through multiple mechanisms, they may also promote inflammation under specific conditions. MethodsG-MDSCs were isolated from 82 patients following allo-HSCT within 90 days after allo-HSCT, and their interactions with autologous CD3+ T-cells were examined. T-cell proliferation was assessed by flow cytometry following CFSE staining, while differentiation and interferon-γ secretion were characterized using chemokine receptor profiling and ELISpot assays, respectively. NK cell cytotoxicity was evaluated through co-culture with K562 cells. An aGVHD xenogeneic model in humanized mice was employed to study the in vivo effects of human leukocytes. Furthermore, transcriptional alterations in G-MDSCs were analyzed via RNA sequencing to investigate functional transitions.ResultsG-MDSCs promoted inflammation in the early-stage, by facilitating cytokine secretion and proliferation of T cells, as well as their differentiation into pro-inflammatory T helper subsets. At day 28, patients with a higher number of G-MDSCs exhibited an increased risk of developing grades II-IV aGvHD. Besides, adoptive transfer of G-MDSCs from patients at day 28 into humanized mice exacerbated aGvHD. However, at day 90, G-MDSCs led to immunosuppression, characterized by upregulated expression of indoleamine 2,3-dioxygenase gene and interleukin-10 secretion, coupled with the inhibition of T cell proliferation. Furthermore, transcriptional analysis of G-MDSCs at day 28 and day 90 revealed that 1445 genes were differentially expressed. These genes were associated with various pathways, revealing the molecular signatures of early post-transplant differentiation in G-MDSCs. In addition, genes linked to the endoplasmic reticulum stress were upregulated in patients without aGvHD. The acquisition of immunosuppressive function by G-MDSCs may depend on the activation of CXCL2 and DERL1 genes. ConclusionOur findings revealed the alteration in the immune characteristics of G-MDSCs within the first 90 days post-allo-HSCT. Moreover, the quantity of G-MDSCs at day 28 may serve as a predictive indicator for the development of aGvHD.

BackgroundCurrently, percutaneous transhepatic cholangial drainage (PTCD) and endoscopic retrograde cholangiopancreatography (ERCP) are commonly employed in clinical practice to alleviate malignant obstructive jaundice (MOJ). Nevertheless, there lacks a consensus regarding the superiority of either method in terms of efficacy and safety.AimTo conduct a systematic evaluation of the effectiveness and safety of PTCD and ERCP in treating MOJ, and to compare the therapeutic outcomes and safety profiles of these two procedures.MethodsCNKI, VIP, Wanfang, CBM, PubMed, Web of Science, Embase, The Cochrane Library, and other databases were searched for randomized controlled trials (RCTs) on the use of PTCD or ERCP for MOJ. The search period was from the establishment of the databases to July 2023. After quality assessment and data extraction from the included studies, Meta-analysis was performed using RevMan5.3 software.ResultsA total of 21 RCTs involving 1,693 patients were included. Meta-analysis revealed that there was no significant difference in the surgical success rate between the two groups for patients with low biliary obstruction (P=0.81). For patients with high biliary obstruction, the surgical success rate of the PTCD group was higher than that of the ERCP group (P < 0.0001), and the overall surgical success rate of the PTCD group was also higher than that of the ERCP group (P = 0.008). For patients with low biliary obstruction, the rate of jaundice relief (P < 0.00001) and the clinical efficacy (P = 0.0005) were better in the ERCP group, while for patients with high biliary obstruction, the rate of jaundice relief (P < 0.00001) and the clinical efficacy (P = 0.003) were better in the PTCD group. There was no significant difference in the overall jaundice remission rate and clinical efficacy between the two groups (P = 0.77, 0.53). There was no significant difference in the reduction of ALT, TBIL, and DBIL before and after surgery and the incidence of postoperative complications between the two groups (P > 0.05).ConclusionBoth PTCD and ERCP can efficiently alleviate biliary obstruction and enhance liver function. ERCP is effective in treating low biliary obstruction, while PTCD is more advantageous in treating high biliary obstruction.

Abstract Adenosylcobalamin (AdoCbl), a biologically active form of vitamin B12 (coenzyme B12), is one of the most complex metal-containing natural compounds and an essential vitamin for animals. However, AdoCbl can only be de novo synthesized by prokaryotes, and its industrial manufacturing to date was limited to bacterial fermentation. Here, we report a method for the synthesis of AdoCbl based on a cell-free reaction system performing a cascade of catalytic reactions from 5-aminolevulinic acid (5-ALA), an inexpensive compound. More than 30 biocatalytic reactions are integrated and optimized to achieve the complete cell-free synthesis of AdoCbl, after overcoming feedback inhibition, the complicated detection, instability of intermediate products, as well as imbalance and competition of cofactors. In the end, this cell-free system produces 417.41 μg/L and 5.78 mg/L of AdoCbl using 5-ALA and the purified intermediate product hydrogenobyrate as substrates, respectively. The strategies of coordinating synthetic modules of complex cell-free system describe here will be generally useful for developing cell-free platforms to produce complex natural compounds with long and complicated biosynthetic pathways.

Abstract Purpose To evaluate the safety and the effectiveness of our novel penetrating keratoplasty for infectious keratitis. Methods Retrospective, noncomparative, interventional case series of patients with infectious keratitis who received the novel penetrating keratoplasty technique were analyzed. A prepared plastic sheet was located between the diseased cornea and iris-lens diaphragm. After the diseased lesions were removed, the graft was positioned on the plastic sheet and sutured to the recipient bed. The plastic sheet was pulled out from the anterior chamber before the all interrupted sutures were placed. The intra- and post-operative complications, the outcome of the graft and the number of corneal endothelial cells were analyzed. Results A total of 82 eyes of 82 patients was included. The mean follow-up period was 29 ± 16 months (range from 13 to 45 months). No intraocular content extrusion, simultaneous cataract extraction and suprachoroidal hemorrhage occurred. Direct contact between the infectious cornea and the graft was successfully avoided. Greater than expected endothelial cell reduction or complications were not found. Conclusions This modified technique effectively prevents the extrusion of intraocular contents while avoiding the direct contact with donor endothelium during the procedure. The occurrence rate of complications such as endothelial cell loss is not higher than the conventional methods.

Objective: Acute myeloid leukemia (AML) is a malignant hematologic cancer with poor prognosis. Emerging evidence suggests a close association between AML progression and hypoxia. The purpose of this study was to establish a new risk prognostic model for AML based on hypoxia-related genes, and to explore the mechanisms by which hypoxia-related genes affect the prognosis of AML based on tumor immune microenvironment (TIME) and drug resistance.Methods: The AML patient samples obtained from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database were classified into C1 and C2 based on hypoxia-related genes, followed by analysis utilizing Gene Ontology (GO), Kyoto Encyclopaedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA). Through univariate and LASSO Cox regression analysis, the hypoxia-related hub genes 26S proteasome non-ATPase regulatory subunit 11 (PSMD11) and 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) were identified to construct the model. AML patient samples were obtained from the TARGET and The Cancer Genome Atlas (TCGA) databases, serving as the training and the validation sets, and were stratified into high-risk and low-risk group according to the median risk score. The correlations between the model and TIME and anti-tumor drugs were analysed using CIBERSORT and Genomics of Drug Sensitivity in Cancer (GDSC) databases. The expressions of PSMD11/PSMD14 in clinical samples and AML sensitive and drug-resistant cell lines were detected by Western blot and real-time PCR.Results: The C1 group with high expression of hypoxia-related genes had lower overall survival (OS). Immune-related signaling pathways were different between C1/C2, and hypoxia was positively correlated with the activation of mammalian target of rapamycin (mTOR) signaling pathway. The model had good accuracy in both the training and the validation sets. The high-risk group exhibited lower OS and TIME activity, and was more sensitive to several anti-tumor drugs. PSMD11/PSMD14 were highly expressed in relapsed patients and AML drug-resistant cell lines.Conclusion: The established novel risk prognostic model and experiment results offer valuable insights for predicting AML prognosis and guiding drug selection. It also provides a fundamental framework for the mechanisms through which hypoxia impacts AML prognosis by modulating TIME and drug resistance.

The disorder of mitochondrial functions plays a key role in oncogenesis. It is known that TSPO (18-kDa translocator protein) lies in a peculiar location at the interface between the mitochondria and the cytosol. TSPO is found in many types of tissues and is associated with multiple cellular processes, including apoptosis, cell proliferation and the regulation of mitochondria. However, the involvement of TSPO in hepatocellular carcinoma (HCC) remains unclear. In this study, we found that TSPO is upregulated in HCC tissue and is associated with poor differentiation and poor survival. Multivariate analyses showed that TSPO was an independent predictive factor for poor prognosis in HCC patients. For the first time, we provided evidence that TSPO knockdown suppressed HCC cell proliferation in vitro. Hence, TSPO knockdown-induced apoptosis by disturbing mitochondrial function by enhancing the formation of reactive oxygen species (ROS) and decreasing the mitochondrial membrane potential (ΔΨm). An assay exploring the underlying mechanism revealed that TSPO knockdown modulated apoptotic regulatory proteins by regulating the ERK signaling pathway. Through a functional assay and an in vivo mouse model, the anti-cancer effect of PK11195, a specific ligand of TSPO, on HCC was revealed. In summary, TSPO may potentially serve as a prognostic biomarker, and TSPO might be a potential therapeutic target for HCC.

Chemotherapy leads to significant side effects in patients, especially in the gut, resulting in various clinical manifestations and enhanced economic pressure. Until now, many of the underlying mechanisms remain poorly understood. Here, we used Drosophila melanogaster (fruit fly) as in vivo model to delineate the side effects and underlying mechanisms of Irinotecan (CPT-11). The results showed that administration of CPT-11 delayed larval development, induced imbalance of male to female ratio in offspring, shortened lifespan, impaired locomotor ability, changed metabolic capacity, induced ovarian atrophy, and increased excretion. Further, CPT-11 supplementation dramatically caused intestinal damages, including decreased intestinal length, increased crop size, disrupted gastrointestinal acid-based homeostasis, induced epithelial cell death, and damaged the ultrastructure and mitochondria structure of epithelial cells. The cross-comparative analysis between transcriptome and bioinformation results showed that CPT-11 induced intestinal damage mainly via regulating the Toll-like receptor signaling, NF-kappa B signaling, MAPK signaling, FoxO signaling, and PI3K-AKT signaling pathways. In addition, CPT-11 led to the intestinal damage by increasing ROS accumulation. These observations raise the prospects of using Drosophila as a model for the rapid and systemic evaluation of chemotherapy-induced side effects and high-throughput screening of the protective drugs.

Abstract Objective Purpose To observe the safety and effect of the C-pupilloplasty for the treatment of iris coloboma and traumatic iris defects. Methods A total of 21 cases (21 eyes) with iris coloboma or traumatic iris defects who underwent C-pupilloplasty (a single-pass three-throw technique) from Feb. 2016 to Mar. 2020 were analyzed retrospectively. Uncorrected visual acuity, refraction, corneal topographic keratometry and endothelial cell density were examined. Results All the patients were successfully treated, and a central and round pupil was restored. The mean follow-up duration was 8.76 ± 3.58 months (ranging from 2 to 14 months). All patients had round or round-like pupils with a diameter less than or equal to 3 mm after the C-pupilloplasty. Very slightly endothelial loss, negligible symptoms such as glare, distortion, dizziness and photophobia were observed. Conclusion We introduced a new technique of pupilloplasty (C-pupilloplasty) which could be a more straight forward and more effective treatment for iris coloboma and traumatic iris defect.

AIM: To investigate the efficacy of optimal pulse technology(OPT)in the treatment of demodex blepharitis and its influence on ocular surface function.METHODS: A retrospective study was conducted from February 2018 to October 2020. A total of 127 patients(254 eyes)with demodex blepharitis were assigned to the observation group and the control group according to the treatment method. The control group(63 patients, 126 eyes)were given conventional hot compress, eye cleansing and drug therapy. On this basis, the observation group(64 patients, 128 eyes)was treated with OPT. Both groups were given 6wk of continuous treatment. Demodex count, Marx's line scores, meibum character scores, ocular surface disease index(OSDI)scores, non-invasive tear break-up time(NIBUT), non-invasive tear meniscus height(NITMH)and lipid layer thickness(LLT)were compared between the two groups, and safety was evaluated.RESULTS: After 6wk of treatment, demodex count, Marx's line scores, meibum character scores and OSDI scores of the two groups decreased. NIBUT, NITMH and LLT increased. Meanwhile, demodex count, Marx's line scores, meibum character scores and OSDI scores of the observation group were significantly lower than those in the control group. NIBUT, NITMH and LLT were longer/larger than those in the control group(P

Peroxisome proliferator-activated receptor gamma (PPARG), a key transcription factor involved in lipid metabolism and glucose homeostasis, has been implicated in various types of cancer. However, its precise role in cancer remains unclear. In this study, we conducted a comprehensive pan-cancer analysis of PPARG expression using various types of cancer obtained from public databases. We observed significant heterogeneity in PPARG expression across different types of cancer. The association between PPARG expression and patient prognosis was investigated using Cox proportional hazards regression models and survival analysis. Clinical features and protein expression levels in the cohort showed that PPARG expression was strongly associated, suggesting its potential as a therapeutic target. We also evaluated the prognostic potential of PPARG by analyzing immune infiltration and genomic stability. We experimentally validated the potential of PPARG as a therapeutic target by analyzing drug sensitivity profiles, molecular docking simulations, and in vitro cell proliferation assays associated with PPARG expression. We identified common expression patterns of PPARG with other genes involved in key carcinogenic pathways. This provides deeper insights into the molecular mechanisms underlying its carcinogenic role. Additionally, functional enrichment analysis revealed significant enrichment of genes related to drug metabolism, cell proliferation, and immune response pathways associated with PPARG. Our findings highlight the importance of PPARG in the broader biology of cancer and suggest its potential as a diagnostic and therapeutic target for specific types of cancer. The results of our study provide strong support for the potential role of PPARG as a promising prognostic biomarker and immunotherapeutic target across various types of cancer.

High-voltage cascaded energy storage systems have become a major technical direction for the development of large-scale energy storage systems due to the advantages of large unit capacity, high overall efficiency, satisfactory economy, reliable safety, and easy access to grid dispatching. The loss characteristics analysis is the design basis of the water-cooling system of a high-voltage cascaded energy storage system, and its accurate calculation can determine the system’s safe and reliable operation of the system. This paper first introduces the four-quadrant operation principles of a cascaded H-bridge energy storage system, and analyzes the calculation method of the loss of the Integrated Gate-Commutated Thyristor based power module; On this basis, it studies the loss characteristics of the cascaded energy storage system and analyzes the influence of different modulation strategies and third harmonic injection on the loss characteristics of the energy storage system; Finally, this paper has completed the loss test for the engineering prototype module and compared the test results with theoretical calculation results to verify the accuracy of the loss calculation method of the high-voltage cascaded energy storage system.

Colorectal cancer is one of the malignant tumors with the highest mortality rate in the world. Survival rates vary significantly among patients at various stages of the disease. A biomarker capable of early diagnosis is required to facilitate the early detection and treatment of colorectal cancer. Human endogenous retroviruses (HERVs) are abnormally expressed in various diseases, including cancer, and have been involved in cancer development. Real-time quantitative PCR was used to detect the transcript levels of HERV-K(HML-2) gag, pol, and env in colorectal cancer to systematically investigate the connection between HERV-K(HML-2) and colorectal cancer. The results showed that HERV-K(HML-2) transcript expression was significantly higher than healthy controls and was consistent at the population and cell levels. We also used next-generation sequencing to identify and characterize HERV-K(HML-2) loci that were differentially expressed between colorectal cancer patients and healthy individuals. The analysis revealed that these loci were concentrated in immune response signaling pathways, implying that HERV-K impacts the tumor-associated immune response. Our results indicated that HERV-K might serve as a screening tumor marker and a target for tumor immunotherapy in colorectal cancer.

During an investigation of Diatrypaceae from southern China, 10 xylariales-like taxa have been collected. Morphological and multi-gene analyses confirmed that these taxa reside in Diatrypaceae and represent eight novel taxa and two new records belonging to six genera (viz., Allocryptovalsa, Diatrype, Diatrypella, Paraeutypella, Peroneutypa, and Vasilyeva gen. nov.). Vasilyeva gen. nov. was proposed to accommodate Vasilyeva cinnamomi sp. nov. Among the other collections, seven new species were introduced (viz., Diatrype camelliae-japonicae sp. nov., Diatrype rubi sp. nov., Diatrypella guiyangensis sp. nov., Diatrypella fatsiae-japonicae sp. nov., Paraeutypella subguizhouensis sp. nov., Peroneutypa hainanensis sp. nov., and Peroneutypa qianensis sp. nov.), while two were reported as new records from China (Allocryptovalsa rabenhorstii and Diatrype enteroxantha). For Diatrypaceae, the traditional taxonomic approach based on morphology may not be applicable.

Three arecophila-like fungal samples were collected on dead culms of gramineous plants in China. Morphological studies of our new collections and the herbarium specimen of Arecophila gulubiicola (generic type) were conducted and the morphological affinity of our new collections with Arecophila was confirmed. Maximum likelihood and Bayesian analyses using combined ITS, LSU, rpb2 and β-tubulin data from our collections revealed the phylogeny of Cainiaceae. The monospecific genus Alishanica (type species Al. miscanthi), which had been accepted in Cainiaceae, is revisited and synonymised under Arecophila. Based on morphology and phylogeny, Arecophila australis sp. nov. and A. clypeata sp. nov. are introduced as new species, while A. miscanthi is a new record for China. All the new collections are illustrated and described.

Abstract The structure design and switching regulation of pulse groups in multi‐function radars (MFRs) are closely related to the work mode. The sequential extraction and recognition of MFR pulse group structure is a fundamental task to analysing and interpreting the work modes and behaviour intentions of an MFR. In this study, the temporal structure of MFR pulse group is expressed hierarchically, which is intensively modelled based on regular grammar. Besides, a corresponding hierarchical automaton is established to sequentially extract and recognise the MFR pulse group structure in pulse train. The hierarchical automaton used for pulse group recognition has a two‐layer structure. The bottom layer of the hierarchical automaton realises the sequential input of pulses and recognition of pulse subgroups, and the sequential input of pulse subgroups and recognition of pulse groups are realised at the top layer. The simulation results demonstrate that the proposed method performs satisfyingly in recognising the pulse group structure and is robust to not only pulse noises but also to the emitter number and pulse group scale.

Due to real-time fluctuations in wind farm output, large-scale renewable energy (RE) generation poses significant challenges to power system stability. To address this issue, this paper proposes a deep reinforcement learning (DRL)-based electric hydrogen hybrid storage (EHHS) strategy to mitigate wind power fluctuations (WPFs). First, a wavelet packet power decomposition algorithm based on variable frequency entropy improvement is proposed. This algorithm characterizes the energy characteristics of the original wind power in different frequency bands. Second, to minimize WPF and the comprehensive operating cost of EHHS, an optimization model for suppressing wind power in the integrated power and hydrogen system (IPHS) is constructed. Next, considering the real-time and stochastic characteristics of wind power, the wind power smoothing model is transformed into a Markov decision process. A modified proximal policy optimization (MPPO) based on wind power deviation is proposed for training and solving. Based on the DRL agent's real-time perception of wind power energy characteristics and the IPHS operation status, a WPF smoothing strategy is formulated. Finally, a numerical analysis based on a specific wind farm is conducted. The simulation results based on MATLAB R2021b show that the proposed strategy effectively suppresses WPF and demonstrates excellent convergence stability. The comprehensive performance of the MPPO is improved by 21.25% compared with the proximal policy optimization (PPO) and 42.52% compared with MPPO. [ABSTRACT FROM AUTHOR]

Drug resistance after long‐term use of Tyrosine kinase inhibitors (TKIs) has become an obstacle for prolonging the survival time of patients with clear cell renal cell carcinoma (ccRCC). Here, genome‐wide CRISPR‐based screening to reveal that HDAC8 is involved in decreasing the sensitivity of ccRCC cells to sunitinib is applied. Mechanically, HDAC8 deacetylated ETS1 at the K245 site to promote the interaction between ETS1 and HIF‐2α and enhance the transcriptional activity of the ETS1/HIF‐2α complex. However, the antitumor effect of inhibiting HDAC8 on sensitized TKI is not very satisfactory. Subsequently, inhibition of HDAC8 increased the expression of NEK1, and up‐regulated NEK1 phosphorylated ETS1 at the T241 site to promote the interaction between ETS1 and HIF‐2α by impeded acetylation at ETS1‐K245 site is showed. Moreover, TKI treatment increased the expression of HDAC8 by inhibiting STAT3 phosphorylation in ccRCC cells is also found. These 2 findings highlight a potential mechanism of acquired resistance to TKIs and HDAC8 inhibitors in ccRCC. Finally, HDAC8‐in‐PROTACs to optimize the effects of HDAC8 inhibitors through degrading HDAC8 and overcoming the resistance of ccRCC to TKIs are synthesized. Collectively, the results revealed HDAC8 as a potential therapeutic candidate for resistance to ccRCC‐targeted therapies. [ABSTRACT FROM AUTHOR]

Bacterial biofilms are formed by communities, which are encased in a matrix of extracellular polymeric substances (EPS). Notably, bacteria in biofilms display a set of ‘emergent properties’ that vary considerably from free-living bacterial cells. Biofilms help bacteria to survive under multiple stressful conditions such as providing immunity against antibiotics. Apart from the provision of multi-layered defense for enabling poor antibiotic absorption and adaptive persistor cells, biofilms utilize their extracellular components, e.g., extracellular DNA (eDNA), chemical-like catalase, various genes and their regulators to combat antibiotics. The response of biofilms depends on the type of antibiotic that comes into contact with biofilms. For example, excessive production of eDNA exerts resistance against cell wall and DNA targeting antibiotics and the release of antagonist chemicals neutralizes cell membrane inhibitors, whereas the induction of protein and folic acid antibiotics inside cells is lowered by mutating genes and their regulators. Here, we review the current state of knowledge of biofilm-based resistance to various antibiotic classes in bacteria and genes responsible for biofilm development, and the key role of quorum sensing in developing biofilms and antibiotic resistance is also discussed. In this review, we also highlight new and modified techniques such as CRISPR/Cas, nanotechnology and bacteriophage therapy. These technologies might be useful to eliminate pathogens residing in biofilms by combating biofilm-induced antibiotic resistance and making this world free of antibiotic resistance.

Smooth surface blasting control technology is aimed at blasting the rock body until it is left with a smooth surface and to protect it from damage; the current air spaced axial uncoupled charge and air spaced radial uncoupled continuous charge are effective charging structures for smooth surface blasting. Reserved air spacing can effectively reduce the blast wave and the peak pressure of the explosive gas, improving the quasi-static pressure of the explosive gas under the action of rock surface blasting with fracture seam quality. In order to ensure the effect of surface blasting, small-diameter light surface holes are more often used; with the development of drilling machinery, the use of large-diameter light blast holes with an oversized uncoupled coefficient of loading structure effectively improves the efficiency of the construction and at the same time achieves better blasting results. However, according to the bursting assumption of obtaining the theory of light surface blasting in the application of large uncoupling coefficient loading, light surface blasting has certain limitations. In this regard, the bursting theory explores the air spacing uncoupling charge in line with the multi-faceted exponential expansion of the critical uncoupling coefficient and is in accordance with the following: the requirements of light surface blasting and the field loading structure; the derivation of the quasi-static pressure on the wall of the gunhole under the action of large uncoupling, uncoupling coefficient, and the parameters of the spacing between the gunholes; the establishment of the axial uncoupling coefficient and the radial uncoupling coefficient-equivalent relationship between the uncoupling coefficient and the theoretical relationship between the selection of the spacing between the holes; the uncoupling coefficient and the selection of the theoretical relationship between the spacing between the holes. This study reveals the mechanism by which different parameters of surface blasting can achieve good results in engineering practices. A slope in Guizhou is an example of sample calculations and the application of two different charging structures applied to field loading, which have achieved good surface blasting results.

ABSTRACT Purpose: To observe the mechanism of prepared Radix Rehmanniainon combined with Radix Astragali in treating osteoporosis. Methods: Osteoporosis rat model was established by bilateral ovariectomy combined with low-calcium diet feeding. Bone mineral density was measured by bone densitometer. Bone metabolism markers in serum were detected by enzyme linked immunosorbent assay (ELISA), bone tissue structure was observed by hematoxylin-eosin staining, and the effect of prepared Radix Rehmanniainon combined with Radix Astragali on PI3K-AKT signaling pathway was investigated by immunohistochemistry and reverse transcription polymerase chain reaction. Results: Compared with the model group, the bone tissue structure and imbalance of bone metabolism were improved, and the bone mineral density was significantly increased in the prepared Radix Rehmanniainon combined with Radix Astragali groups. After intervention with prepared Radix Rehmanniainon combined with Radix Astragali, the positive expression of PIK3CA and Akt1 in rat bone tissue was enhanced, and the expression levels of Akt1 mRNA were significantly increased. Conclusions: Prepared Radix Rehmanniainon combined with Radix Astragali may treat osteoporosis by activating PI3K/AKT pathway.

Measurement of viscosity of crude oil is critical for reservoir simulators. Computational modeling is a useful tool for correlation of crude oil viscosity to reservoir conditions such as pressure, temperature, and fluid compositions. In this work, multiple distinct models are applied to the available dataset to predict heavy-oil viscosity as function of a variety of process parameters and oil properties. The computational techniques utilized in this work are Decision Tree (DT), MLP, and GRNN which were utilized in estimation of heavy crude oil samples collected from middle eastern oil fields. For the estimation of viscosity, the firefly algorithm (FA) was employed to optimize the hyper-parameters of the machine learning models. The RMSE error rates for the final models of DT, MLP, and GRNN are 40.52, 25.08, and 30.83, respectively. Also, the R2-scores are 0.921, 0. 978, and 0.933, respectively. Based on this and other criteria, MLP is chosen as the best model for this study in estimating the values of crude oil viscosity.

The efficiently renewable bioethanol can help to alleviate energy crisis and environmental pollution. Genetically modified strains for efficient use of xylose and developing lignocellulosic hydrolysates play an essential role in facilitating cellulosic ethanol production. Here we present a promising strain GRE3OE via GRE3 overexpressed in a previously reported Saccharomyces cerevisiae strain WXY70. A comprehensive evaluation of the fermentation level of GRE3OE in alkaline-distilled sweet sorghum bagasse, sorghum straw and xylose mother liquor hydrolysate. Under simulated corn stover hydrolysate, GRE3OE produced 53.39 g/L ethanol within 48 h. GRE3OE produced about 0.498 g/g total sugar in sorghum straw hydrolysate solution. Moreover, GRE3OE consumed more xylose than WXY70 in the high-concentration xylose mother liquor. Taken together, GRE3OE could be a candidate strain for industrial ethanol development, which is due to its remarkable fermentation efficiency during different lignocellulosic hydrolysates.

BackgroundA successful pregnancy using in vitro fertilization and embryo transfer (IVF-ET) requires a receptive endometrium, good-quality embryos, and a synchronized embryo-endometrial dialogue. Although embryo quality and endometrial receptivity (ER) have been fully assessed to exclude substandard conditions, the probability of successful ET is relatively low. Currently, embryo-endometrial synchrony is considered to be a possible explanation, because delayed, advanced, or narrowed window of implantation (WOI) may lead to ET failure.ObjectiveThis study aims to establish a nomogram incorporating a series of ultrasonic ER markers on the day before implantation to assess the embryo-endometrial synchrony, which may contribute to the improvement of clinical pregnancy outcomes.MethodsTotally 583 women with 1135 complete IVF cycles were retrospectively analyzed. Among them, 357 women with 698 cycles and 226 women with 437 cycles were assigned to the training and validation cohorts, respectively. Ultrasonic ER markers obtained on the day before implantation were collected for analyses. In the training cohort, the screened correlates of clinical pregnancy failure were utilized to develop a nomogram for determining whether an infertile woman is suitable for the ET next day. This model was validated both in the training and validation cohorts.ResultsSpiral artery (SA) resistance index (RI), vascularisation index (VI), and flow index (FI) were independently associated with the ET failure (all P < 0.05). They were served as the components of the developed nomogram to visualize the likelihood of implantation failure in IVF-ET. This model was validated to present good discrimination and calibration, and obtained clinical net benefits both in the training and validation cohorts.ConclusionWe developed a nomogram that included SA-RI, VI, and FI on the day before implantation. It may assist physicians to identify patients with displaced WOI, thus avoiding meaningless ET prior to implantation.

During an investigation of Xylariaceae from 2019 to 2020, isolates representing eight Nemania (Xylariacese) species were collected from Yunnan, Guizhou and Hainan Provinces in China. Morphological and multi-gene phylogenetic analyses, based on combined ITS, α-actin, rpb2 and β-tubulin sequences, confirmed that six of them are new to science, viz. Nemania camelliae, N. changningensis, N. cyclobalanopsina, N. feicuiensis, N. lishuicola and N. rubi; one is a new record (N. caries) for China and one is a known species (N. diffusa). Morphological descriptions and illustrations of all species are detailed. In addition, the characteristics of Nemania are summarised and prevailing contradictions in generic concepts are discussed.