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Manganese is an important alloying element in iron and steel. Adding the appropriate amount of manganese can enhance the properties of steel. The manganese content directly influences steel quality in the converter steelmaking process. Too little manganese results in insufficient hardness and strength of steel products, whereas excessive manganese leads to increased embrittlement and production costs. Therefore, determining the appropriate amount of manganese is crucial for improving steel quality and reducing smelting costs. The quantity of manganese added during converter steelmaking primarily depends on the predicted final manganese content. However, this content is influenced by various factors, such as the oxidation reaction process and the addition of other alloying elements. These factors exhibit nonlinear effects on the manganese content, and the factors are highly interconnected, making accurate prediction of manganese content at the end point challenging. In response to the challenges posed by noise and strong coupling in predicting manganese content at the end point of converter steelmaking, a research framework was developed to address these issues and facilitate accurate predictions. Key influencing factors in the smelting process were identified through Pearson correlation coefficient analysis and mechanistic analysis. Subsequently, the relationship between these influencing factors and end-point manganese content was modeled using the long short-term memory network (LSTM). To mitigate the effects of high-frequency noise in nonlinear and nonstationary sequences, singular spectral analysis (SSA) was employed during the prediction process. This led to the development of a method known as SSA−LSTM for predicting end-point manganese content. The effects of different test sets and the number of neurons on the prediction results were investigated using converter steelmaking production data from Hebei Jingye Iron & Steel Co., Ltd. The proposed method achieved minimal prediction error when the test set comprised 10% of the data and the number of neurons was set to 85. At these parameters, the mean absolute error of the prediction method for end-point manganese was 1.19%, with a root-mean-square error of 1.48%. These results demonstrate that the proposed method effectively addresses issues related to large noise and nonlinear data. Moreover, compared with existing time series prediction methods, the proposed method, particularly after SSA treatment, showed reduced prediction errors. This validates the effectiveness of the method and provides a basis for accurate alloy addition in actual production processes.

Abstract: Given the threat of fossil fuel depletion, it is essential to proactively strive for carbon neutrality and promote clean, low-carbon and efficient energy use. This study used ERA5 reanalysis data to assess wind energy resources in the Pacific Northwest region. By analyzing key indicators such as wind power density, effective wind speed occurrence, and energy level occurrence, climate statistics and Empirical Orthogonal Function analysis (EOF) were used to examine the spatial distribution and long-term trend of offshore wind energy resources in the Northwest Pacific. The results suggest that there are abundant wind energy resources in this region, which are beneficial for the development of offshore wind energy. The rich areas are the East China Sea, Taiwan islands and reefs in the South China Sea and east of Japan, with prevailing wind power density (500 ∼ 2500 W/m2) and effective wind speed occurrence (80–90%) and energy level occurrence (60% ∼ 90%). Offshore wind energy resources in the Pacific Northwest are more abundant in fall and winter than in summer. The time coefficient of the first mode shows that the offshore wind energy in the Northwest Pacific has no obvious change trend, and the wind energy resources are relatively stable.

Abstract Background Myopia is a major health issue around the world. Myopia in children has increased significantly during the COVID-19 pandemic in China, but reports are scarce on the prevalence of myopia following the pandemic. This study collected vision screening data of school children in China for five consecutive years to observe the changes in myopia after the pandemic and compare the observed prevalence of myopia before and after the pandemic. Methods A school-based vision screening study used stratified samplings to collect the vision screening data in school children aged 6–13 from 45 primary schools in Hangzhou. Vision screening data including uncorrected visual acuity(UCVA) and spherical equivalent refraction(SER). Calculating the mean of SER and the prevalence of myopia and hyperopia from 2019 to 2023. Results A total of 79,068 screening results (158,136 eyes) were included in the analysis. A substantial myopic shift (approximately -0.30 diopters [D] on average) was found in 2020 and 2021 compared with 2019 in all age groups and a substantial myopic shift (approximately 0.4 D on average) was found in 2022 compared with 2021. A slight myopic shift (approximately -0.14 D on average) was found in 2023 compared with 2022. The prevalence of myopia in all age groups was the highest for five years in 2020 or 2021, which was 31.3% for 6-year-olds, 43.0% for 7-year-olds, and 53.7% for 8-year-olds. A positive change in the prevalence rate of myopia was found at 6 years old (0.59%, 0.12%, 0.36%, 0.25%, p

Abstract Background Porcine epidemic diarrhea virus (PEDV) mainly causes acute and severe porcine epidemic diarrhea (PED), and is highly fatal in neonatal piglets. No reliable therapeutics against the infection exist, which poses a major global health issue for piglets. Luteolin is a flavonoid with anti-viral activity toward several viruses. Results We evaluated anti-viral effects of luteolin in PEDV-infected Vero and IPEC-J2 cells, and identified IC50 values of 23.87 µM and 68.5 µM, respectively. And found PEDV internalization, replication and release were significantly reduced upon luteolin treatment. As luteolin could bind to human ACE2 and SARS-CoV-2 main protease (Mpro) to contribute viral entry, we first identified that luteolin shares the same core binding site on pACE2 with PEDV-S by molecular docking and exhibited positive pACE2 binding with an affinity constant of 71.6 µM at dose-dependent increases by surface plasmon resonance (SPR) assay. However, pACE2 was incapable of binding to PEDV-S1. Therefore, luteolin inhibited PEDV internalization independent of PEDV-S binding to pACE2. Moreover, luteolin was firmly embedded in the groove of active pocket of Mpro in a three-dimensional docking model, and fluorescence resonance energy transfer (FRET) assays confirmed that luteolin inhibited PEDV Mpro activity. In addition, we also observed PEDV-induced pro-inflammatory cytokine inhibition and Nrf2-induced HO-1 expression. Finally, a drug resistant mutant was isolated after 10 cell culture passages concomitant with increasing luteolin concentrations, with reduced PEDV susceptibility to luteolin identified at passage 10. Conclusions Our results push forward that anti-PEDV mechanisms and resistant-PEDV properties for luteolin, which may be used to combat PED.

ABSTRACT Background Rearrangements of the histone‐lysine‐N‐methyltransferase (KMT2A), previously referred to as mixed‐lineage leukemia (MLL), are among the most common chromosomal abnormalities in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), involving numerous different fusion partners. KMT2A‐rearranged (KMT2A‐r) leukemia is characterized by a rapid onset, aggressive progression, and significantly worse prognosis compared to non‐KMT2A‐r leukemias. Even with contemporary chemotherapeutic treatments and hematopoietic stem cell transplantations (HSCT), patients with KMT2A‐r leukemia typically experience poor outcomes and limited responses to these therapies. Objectives This review aims to consolidate recent studies on the general gene characteristics and associated mechanisms of KMT2A‐r acute leukemia, as well as the cytogenetics, immunophenotype, clinical presentation, and risk stratification of both KMT2A‐r‐AML and KMT2A‐r‐ALL. Particularly, the treatment targets in KMT2A‐r acute leukemia are examined. Methods A comprehensive review was carried out by systematically synthesizing existing literature on PubMed, using the combination of the keywords ‘KMT2A‐rearranged acute leukemia’, ‘lymphoblastic leukemia’, ‘myeloid leukemia’, and ‘therapy’. The available studies were screened for selection based on quality and relevance. Conclusions Studies indicate that KMT2A rearrangements are present in over 70% of infant leukemia cases, approximately 10% of adult AML cases, and numerous instances of secondary acute leukemias, making it a disease of critical concern to clinicians and researchers alike. The future of KMT2A‐r acute leukemia research is characterized by an expanding knowledge of the disease's biology, with an emphasis on personalized therapies, immunotherapies, genomic advancements, and innovative therapeutic combinations. The overarching aim is to enhance patient outcomes, lessen the disease burden, and elevate the quality of life for those affected. Ongoing research and clinical trials in this area continue to offer promising opportunities for refining treatment strategies and improving patient prognosis.

ABSTRACT: During poultry immunization, antibiotics are typically added to inactivated oil-adjuvant avian influenza (AI) vaccines. Here, we evaluated the effects of adding ceftiofur, a third-generation cephalosporin, to an AI vaccine on vaccine stability and structure and on chick growth, immune efficacy, blood concentrations, biochemical and immunological indices, and gut microbiota. The results demonstrated that neither aqueous ceftiofur sodium nor ceftiofur hydrochloride oil emulsion formed a stable mixture with the vaccine. Adding ceftiofur formulations, particularly ceftiofur hydrochloride, at >4% significantly destabilized the vaccine's water-in-oil structures. Adding ceftiofur also increased vaccine malabsorption at the injection site; specifically, adding ceftiofur hydrochloride reduced H5N8 and H7N9 antibody titers after the first immunization (P < 0.05) and H7N9 antibody titers after the second immunization (P < 0.01). Serum drug concentrations did not differ significantly between the groups with ceftiofur sodium and hydrochloride addition. Ceftiofur addition increased postvaccination chick weight loss; compared with the vaccine alone, ceftiofur sodium–vaccine mixture increased chick weight significantly (P < 0.05). Ceftiofur addition also increased stress indices and reduced antioxidant capacity significantly (P < 0.05 or P < 0.01). Vaccination-related immune stress reduced gut microbiota diversity in chicks; ceftiofur addition reversed this change. AI vaccine immunization significantly reduced the relative abundance of Lactobacillus and Muribaculaceae but significantly increased that of Bacteroides and Eubacterium coprostanoligenes group. Ceftiofur addition restored the gut microbiota structure; in particular, ceftiofur hydrochloride addition significantly increased the abundance of the harmful gut microbes Escherichia-Shigella and Enterococcus, whereas ceftiofur sodium addition significantly reduced it. The changes in gut microbiota led to alterations in metabolic pathways related to membrane transport, amino acids, and carbohydrates. In conclusion, adding ceftiofur to the AI vaccine had positive effects on chick growth and gut microbiota modulation; however, different antibiotic concentrations and formulations may disrupt vaccine structure, possibly affecting vaccine safety and immunization efficacy. Thus, the addition of antibiotics to oil-adjuvant vaccines is associated with a risk of immunization failure and should be applied to poultry with caution.

Dent disease is a rare disease with proximal renal tubular dysfunction, and is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and chronic kidney disease. Renal failure slowly progresses and end-stage renal disease may develop in the late decades of life. We report a case of a 15-year-old boy who was diagnosed with Dent disease 1 with a CLCN5 truncating mutation. The patient presented with arthralgia and rickets at the onset of Dent disease and he was diagnosed with end-stage renal disease at the age of 15 years. His only symptoms were arthralgia and rickets during the disease course. The findings in this case suggest that patients with arthralgia and rickets could have a rare cause such as Dent disease.

BackgroundAtrial fibrillation (AF) is the most common cardiac arrhythmia, significantly increasing the risk of death and stroke. The left atrial appendage (LAA) plays a crucial role in the development of AF. Reduced left atrial appendage emptying velocity (LAAEV) is an important indicator of nonvalvular AF, associated with thrombosis and recurrence after catheter ablation. This study aims to identify factors influencing LAAEV and construct a predictive model for LAAEV in nonvalvular AF patients.MethodsThis retrospective cohort study included 1,048 nonvalvular AF patients hospitalized at the Second Hospital of Hebei Medical University from January 1, 2015, to December 31, 2021. Patients underwent transthoracic and transesophageal echocardiography and had complete laboratory data. Statistical analyses included binary logistic regression and multiple linear regression to identify independent predictors of reduced LAAEV and construct a predictive model.ResultsPatients were divided into two groups: reduced LAAEV (

Modern food is evolving in the direction of green, healthy, and convenient products, and developing natural products with health benefits is an important direction for the food industry. Chlorella is rich in nutrients, such as carotene and fatty acids, which provide it with a variety of health benefits, and therefore widely used in the food industry as a health or functional food. This study reviews the research progress and specific applications of Chlorella in health, functional, and other foods, and expounds on the bottlenecks faced in the use of Chlorella in food industry. This review provides a theoretical basis for the research, utilisation, and production of new food materials involving Chlorella.

Abstract An approximation scheme that combines approximate solutions with error estimators to accelerate the adaptive h‐refinement of the RWG‐based method of moments (MoM) with the electric field integral equation (EFIE) is presented. The scheme is effectively implemented by using the near‐field matrix to solve the approximate solution. Several conventional error estimators incorporated with the scheme are investigated. Compared to using the full MoM system, it significantly reduces the computational cost while maintaining the refinement effect. Numerical results indicate that the scheme could accelerate the adaptive refinement, yielding significant reductions in computational time and memory requirements.

BackgroundAbnormal brain activation patterns in patients with knee osteoarthritis (KOA) at rest have been revealed, but it is unclear how brain activation patterns change during movement. This study aimed to investigate the alterations in brain activation patterns in KOA patients during knee isokinetic movement, and the correlation between cortical activity changes and pain severity and dysfunction.MethodsEighteen patients with KOA and 18 healthy controls (HC) were recruited, and to performed the knee isokinetic test with three speeds. Functional near-infrared spectroscopy (fNIRS) was used to detect the cerebral cortex hemodynamics changes of primary somatosensory (S1), primary motor (M1) and somatosensory association cortex (SAC) in the region of interest (ROI) during movement. Then, we evaluated potential correlations between M1, S1 and SAC values and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and visual analog scale (VAS) scores.ResultsThe results showed that peak torque of knee extension in KOA patients was significantly smaller than that in HC. For HC, unilateral knee movement activated bilateral ROIs. The contralateral activation was dominant, showing the phenomenon of high contralateral activation. For KOA patients, there were no statistical difference in the activation level between the left and right of the cerebral cortex, with both sides showing lower activation levels compared to HC. Further analysis found that the contralateral M1, S1, and SAC of the affected knee in KOA patients were significantly lower than those in HC, while no difference was found on the ipsilateral side. Moreover, during isokinetic movement at 180°/s, VAS score in KOA patients was negatively correlated with the activation level of the contralateral S1 and M1 values, and WOMAC was negatively correlated with the activation level of the contralateral M1 value.ConclusionContralateral activation of the sensorimotor cortex exists during unilateral knee movement, but in KOA patients, this contralateral cortical activation is suppressed. Furthermore, the clinical pain and dysfunction in KOA patients are associated with activation levels of specific brain regions. These findings can provide a better understanding of KOA brain science and are expected to contribute to the development of central intervention for the disease.

Abstract CRISPR/Cas12a‐based combinational screening has shown remarkable potential for identifying genetic interactions. Here, we describe an innovative method for combinational genetic screening with rapid construction of a dual‐CRISPR RNA (crRNA) library using gene splicing through overlap extension PCR (SOE PCR) and the adoption of CeCas12a, which we previously identified with strict PAM recognition and low off‐targeting to guarantee fidelity and efficiency. The custom‐pooled SOE crRNA array (SOCA) library for double‐knockout screening could be conveniently constructed in the laboratory for widespread use, and the CeCas12a‐mediated high‐fidelity screen displayed good performance even under a negative selection screen. By designing a SOCA dual‐crRNA library that covered most of the kinase and metabolism‐associated gene targets of FDA‐approved drugs implicated in hepatocellular carcinoma (HCC) tumourigenesis, novel cross‐talk between the two gene sets was negatively selected to inhibit HCC cell growth in vitro and in vivo and was validated using virtual double‐knockdown screening based on TCGA databases. Thus, this rapid, efficient and high‐fidelity double‐knockout screening system is promising for systemically identifying potential genetic interactions between multiple gene sets or combinations of FDA‐ approved drugs for clinical translational medicine in the future.

Objectives: Compromised hepatic fatty acid oxidation (FAO) has been observed in human MASH patients and animal models of MASLD/MASH. It remains poorly understood how and when the hepatic FAO pathway is suppressed during the progression of MASLD towards MASH. Hepatic ChREBP⍺ is a classical lipogenic transcription factor that responds to the intake of dietary sugars. Methods: We examined its role in regulating hepatocyte fatty acid oxidation (FAO) and the impact of hepatic Chrebpa deficiency on sensitivity to diet-induced MASLD/MASH in mice. Results: We discovered that hepatocyte ChREBP⍺ is both necessary and sufficient to maintain FAO in a cell-autonomous manner independently of its DNA-binding activity. Supplementation of synthetic PPAR⍺/δ agonist is sufficient to restore FAO in Chrebp−/− primary mouse hepatocytes. Hepatic ChREBP⍺ was decreased in mouse models of diet-induced MAFSLD/MASH and in patients with MASH. Hepatocyte-specific Chrebp⍺ knockout impaired FAO, aggravated liver steatosis and inflammation, leading to early-onset fibrosis in response to diet-induced MASH. Conversely, liver overexpression of ChREBP⍺-WT or its non-lipogenic mutant enhanced FAO, reduced lipid deposition, and alleviated liver injury, inflammation, and fibrosis. RNA-seq analysis identified the CYP450 epoxygenase (CYP2C50) pathway of arachidonic acid metabolism as a novel target of ChREBP⍺. Over-expression of CYP2C50 partially restores hepatic FAO in primary hepatocytes with Chrebp⍺ deficiency and attenuates preexisting MASH in the livers of hepatocyte-specific Chrebp⍺-deleted mice. Conclusions: Our findings support the protective role of hepatocyte ChREBPa against diet-induced MASLD/MASH in mouse models in part via promoting CYP2C50-driven FAO.

Cold-in place recycling (CIR) is a promising technology for the rehabilitation of asphalt pavements. However, the CIR asphalt pavement constructed in the field often has high air voids due to the presence of moisture during construction, and the moisture susceptibility of the pavement is crucial in determining its service life. Therefore, the objective of this research was to assess the laboratory performance of CIR asphalt mixes under freeze-thaw conditions (The mix prior to being subjected to freezing and thawing is labeled as ''dry condition'', while the mix that was placed in a refrigerator at –18 °C for 16 h and then transferred to a distilled water bath at 60 °C for 24 h is referred to as ''post-freeze-thaw'') and forecast in-situ pavement performance through pavement mechanistic-empirical design (PMED). Moisture susceptibility was evaluated by preparing CIR asphalt mixtures under dry condition and freeze-thaw conditions. The Disk-Shaped Compact Tension (DCT) test was utilized to approximate the low-temperature characteristics of the CIR mixture, while the rutting resistance properties were assessed using the Hamburg wheel tracking device (HWDT). The dynamic modulus test was used to assess the elastic deformation characteristics. The asphalt was extracted from the loose material, and the viscoelasticity properties were analyzed using the Dynamic Shear Rheometer (DSR) test and Asphalt Binder Cracking Device (ABCD) test, respectively. Based on the M-E inputs, the projected pavement deterioration was determined through calculations. The outcomes indicated that the dynamic modulus of the asphalt mixture after the freeze-thaw cycle dropped by 11–42 % under varying temperatures and frequencies. The number of wheel passes for the dry condition CIR asphalt mixture was 8.4 % higher than that of the post-freeze-thaw CIR asphalt mixture. The fracture energy dropped by 6 % after freeze-thaw conditions. The emulsion asphalt used in the RAP (reclaimed asphalt pavement) made the binder softer, the fatigue and low-temperature cracking resistance of the material was enhanced, and decreased its resistance to rutting. the results of the M-E pavement design demonstrated that the freeze-thaw condition increased rutting, cracking, and IRI (International Roughness Index) distress. In conclusion, the application of CIR technology in the project enhanced the performance of the asphalt pavement with regard to its resistance to cracking and fatigue. As a result, CIR pavement may be suitable for use in low-traffic road.

Abstract Resident memory T (Trm) cells which are specifically located in non-lymphoid tissues showed distinct phenotypes and functions compared to circulating memory T cells and were vital for the initiation of robust immune response within tissues. However, the heterogeneity in the transcriptional features, development pathways, and cancer response of Trm cells in the small intestine was not demonstrated. Here, we integrated scRNA-seq and scTCR-seq data pan-tissue T cells to explore the heterogeneity of Trm cells and their development pathways. Trm were enriched in tissue-specific immune response and those in the DUO specially interacted with B cells via TNF and MHC-I signatures. T cell lineage analyses demonstrated that Trm might be derived from the T_CD4/CD8 subset within the same organ or migrated from spleen and mesenteric lymph nodes. We compared the immune repertoire of Trm among organs and implied that clonotypes in both DUO and ILE were less expanded and hydrophilic TRB CDR3s were enriched in the DUO. We further demonstrated that Trm in the intestine infiltrated the colorectal cancer and several effector molecules were highly expressed. Finally, the TCGA dataset of colorectal cancer implied that the infiltration of Trm from the DUO and the ILE was beneficial for overall survival and the response to immune checkpoint blockade.

Text sentiment analysis is an important task in natural language processing and has always been a hot research topic. However, in low-resource regions such as South Asia, where languages like Bengali are widely used, the research interest is relatively low compared to high-resource regions due to limited computational resources, flexible word order, and high inflectional nature of the language. With the development of quantum technology, quantum machine learning models leverage the superposition property of qubits to enhance model expressiveness and achieve faster computation compared to classical systems. To promote the development of quantum machine learning in low-resource language domains, we propose a quantum–classical hybrid architecture. This architecture utilizes a pretrained multilingual bidirectional encoder representations from transformer (BERT) model to obtain vector representations of words and combines the proposed batch upload quantum recurrent neural network (BUQRNN) and parameter nonshared batch upload quantum recurrent neural network (PN-BUQRNN) as feature extraction models for sentiment analysis in Bengali. Our numerical results demonstrate that the proposed BUQRNN structure achieves a maximum accuracy improvement of 0.993% in Bengali text classification tasks while reducing average model complexity by 12%. The PN-BUQRNN structure surpasses the BUQRNN structure once again and outperforms classical architectures in certain tasks.

The CRISPR-associated endonuclease Cas12a has become a powerful genome-editing tool in biomedical research due to its ease of use and low off-targeting. However, the size of Cas12a severely limits clinical applications such as adeno-associated virus (AAV)-based gene therapy. Here, we characterized a novel compact Cas12a ortholog, termed EbCas12a, from the metagenome-assembled genome of a currently unclassified Erysipelotrichia. It has the PAM sequence of 5'-TTTV-3' (V = A, G, C) and the smallest size of approximately 3.47 kb among the Cas12a orthologs reported so far. In addition, enhanced EbCas12a (enEbCas12a) was also designed to have comparable editing efficiency with higher specificity to AsCas12a and LbCas12a in mammalian cells at multiple target sites. Based on the compact enEbCas12a, an all-in-one AAV delivery system with crRNA for Cas12a was developed for both in vitro and in vivo applications. Overall, the novel smallest high-fidelity enEbCas12a, this first case of the all-in-one AAV delivery for Cas12a could greatly boost future gene therapy and scientific research.

Synthesis of 3/4-methyltetrahydrophthalic anhydride was carried out by the Diels-Alder reaction in a continuous flow capillary reactor. The efficient liquid–liquid reaction of pentadiene with molten maleic anhydride provided a theoretical basis for replacing the conventional batch reaction process. Different inner diameter sizes of the channel tubes were adjusted in the range of 0.50 ∼ 2.00 mm to find the optimal size to match the strong exothermic reaction. Under the capillary channel size of 0.8 mm, the conversion rate of C5 and MA reached 100 % when nC5: nMA = 1.08:1 at 65 °C for 8 min. The D-A reaction process is accompanied by the autopolymerization of diolefin in the batch reactor. Our results showed that choosing a continuous flow capillary reactor of appropriate size can directly improve the selectivity of the reaction and the quality of the product. The accurate reaction rate constant and activation energy were obtained by establishing a kinetic model, and the effects of temperature, reaction time and pipe diameter were designed using Comsol software.

The clustered regularly interspaced short palindromic repeat (CRISPR)-Cas12a system is a powerful tool in gene editing; however, crRNA-DNA mismatches might induce unwanted cleavage events, especially at the distal end of the PAM. To minimize this limitation, we engineered a hyper fidelity AsCas12a variant carrying the mutations S186A/R301A/T315A/Q1014A/K414A (termed HyperFi-As) by modifying amino acid residues interacting with the target DNA and crRNA strand. HyperFi-As retains on-target activities comparable to wild-type AsCas12a (AsCas12aWT) in human cells. We demonstrated that HyperFi-As has dramatically reduced off-target effects in human cells, and HyperFi-As possessed notably a lower tolerance to mismatch at the position of the PAM-distal region compared with the wild type. Further, a modified single-molecule DNA unzipping assay at proper constant force was applied to evaluate the stability and transient stages of the CRISPR/Cas ribonucleoprotein (RNP) complex. Multiple states were sensitively detected during the disassembly of the DNA-Cas12a-crRNA complexes. On off-target DNA substrates, the HyperFi-As-crRNA was harder to maintain the R-loop complex state compared to the AsCas12aWT, which could explain exactly why the HyperFi-As has low off-targeting effects in human cells. Our findings provide a novel version of AsCas12a variant with low off-target effects, especially capable of dealing with the high off-targeting in the distal region from the PAM. An insight into how the AsCas12a variant behaves at off-target sites was also revealed at the single-molecule level and the unzipping assay to evaluate multiple states of CRISPR/Cas RNP complexes might be greatly helpful for a deep understanding of how CRISPR/Cas behaves and how to engineer it in future.

Cellular immunotherapy is a crucial aspect of current tumor immunotherapy, though it presents several challenges such as immune cell dysfunction, limited recognition of neoantigens, and inadequate lymphocyte infiltration into the tumor microenvironment. This study proposes a novel approach utilizing a combination of dendritic cell (DC)-based cellular immunotherapy and a photothermal nanoadjuvant black phosphorus (BP) nanoparticles to overcome these challenges. A new platform called PLGA@BP-R848, which consists of modifying poly-(lactic-co-glycolic acid) (PLGA) onto BP nanosheets loading the immune adjuvant R848. The PLGA@BP-R848 nanoparticles demonstrated exceptional drug delivery and release capabilities, as well as a photothermal effect, biocompatibility, and the ability to activate the mitochondrial apoptotic pathway Blc-2-Bax-Cytochrome c-caspase-3 and inhibit the PI3K-AKT-mTOR signaling pathway. In a hepatocellular carcinoma mouse model, the binding of PLGA@BP-R848 nanoparticles and dendritic cells primed with GPC3 peptides, successfully induced a systemic anti-tumor immune response. PLGA@BP-R848 nanoparticles bolster immune cell infiltration into tumors and induce cancer cell apoptosis. The synergistic therapy involving dendritic cells and photothermal nanoadjuvant effectively suppressed tumor growth, and facilitated the formation of tertiary lymphatic structures (TLS) in tumors. This study presents a novel approach in using photothermal nanoadjuvants to advance antitumor effect of cellular immunotherapy, such as DCs therapy.

Abstract Biosynthesis drives the cell volume increase during T cell activation. However, the contribution of cell volume regulation in TCR signaling during T lymphoblast formation and its underlying mechanisms remain unclear. Here we show that cell volume regulation is required for optimal T cell activation. Inhibition of VRACs (volume-regulated anion channels) and deletion of leucine-rich repeat-containing protein 8A (LRRC8A) channel components impair T cell activation and function, particularly under weak TCR stimulation. Additionally, LRRC8A has distinct influences on mRNA transcriptional profiles, indicating the prominent effects of cell volume regulation for T cell functions. Moreover, cell volume regulation via LRRC8A controls T cell-mediated antiviral immunity and shapes the TCR repertoire in the thymus. Mechanistically, LRRC8A governs stringent cell volume increase via regulated volume decrease (RVD) during T cell blast formation to keep the TCR signaling molecules at an adequate density. Together, our results show a further layer of T cell activation regulation that LRRC8A functions as a cell volume controlling “valve” to facilitate T cell activation.

Abstract Objective To explore the effect of acute normovolemic hemodilution (ANH) on the anesthetic effect, plasma concentration, and postoperative recovery quality in elderly patients undergoing spinal surgery. Methods A total of 60 cases of elderly patients aged 65 to 75 years who underwent elective multilevel spinal surgery were assigned randomly into the ANH group (n = 30) and control group (n = 30). Hemodynamic and blood gas analysis indexes were observed and recorded before ANH (T1), after ANH (T2), immediately after postoperative autologous blood transfusion (T3), 10 min (T4), 20 min (T5), 30 min (T6), 40 min (T7), and 50 min (T8) after the transfusion, and at the end of the transfusion (i.e., 60 min; T9). At T3 ~ 9, bispectral index (BIS) and train-of-four (TOF) stimulation were recorded and the plasma propofol/cisatracurium concentration was determined. The extubation time and recovery quality were recorded. Results The ANH group presented a lower MAP value and a higher SVV value at T2, and shorter extubation and orientation recovery time (P 0.05). Conclusion During orthopedic surgery, the plasma concentration of elderly patients is increased after autologous blood transfusion of ANH, and the depth of anesthesia and muscle relaxant effect are strengthened, thus leading to delayed recovery of respiratory function and extubation.

Given the diversity of medical images, traditional image segmentation models face the issue of domain shift. Unsupervised domain adaptation (UDA) methods have emerged as a pivotal strategy for cross modality analysis. These methods typically utilize generative adversarial networks (GANs) for both image-level and feature-level domain adaptation through the transformation and reconstruction of images, assuming the features between domains are well-aligned. However, this assumption falters with significant gaps between different medical image modalities, such as MRI and CT. These gaps hinder the effective training of segmentation networks with cross-modality images and can lead to misleading training guidance and instability. To address these challenges, this paper introduces a novel approach comprising a cross-modality feature alignment sub-network and a cross pseudo supervised dual-stream segmentation sub-network. These components work together to bridge domain discrepancies more effectively and ensure a stable training environment. The feature alignment sub-network is designed for the bidirectional alignment of features between the source and target domains, incorporating a self-attention module to aid in learning structurally consistent and relevant information. The segmentation sub-network leverages an enhanced cross-pseudo-supervised loss to harmonize the output of the two segmentation networks, assessing pseudo-distances between domains to improve the pseudo-label quality and thus enhancing the overall learning efficiency of the framework. This method’s success is demonstrated by notable advancements in segmentation precision across target domains for abdomen and brain tasks.

Abstract Background There is no standard recommendation for IgA nephropathy treatment in children. Methods This is a retrospective study. From 2012 to 2020, newly diagnosed primary IgAN followed up for at least 1 year were enrolled. The correlation of MESTC scores and clinical index including proteinuria, gross hematuria and renal dysfunction was analyzed. Treatment and clinical response of 6 month, 1year and 3 year at follow up were also analyzed. Complete renal remission was calculated with Kaplan-Meier analysis. Results The median follow up was 36 months, from 12 months to 87months in 40 IgAN children. Angiotensin-converting enzyme inhibitor (ACEI) was applied to all patients. 30% received ACEI alone; 15% received glucocorticoids; 37.5% received glucocorticoids plus cyclophosphamide, 17.5% received glucocorticoids plus mycophenolate mofetil. Individuals with diffuse mesangial hypercellularity (M1) were more likely to have nephrotic range proteinuria compared to patients with M0 (80% vs. 20%, P

Abstract Robot cloud service platform is a combination of cloud computing and robotics, providing intelligent cloud services for many robots. However, to select a cloud service that satisfys the robot’s requirements from the massive services with different QoS indicator in the cloud platform is an NP hard problem. In this paper, based on the cost model between the cloud platform, cloud services and cloud service robotics, we propose a two-stage service selection strategy, namely, candidate services selection stage according to the specific QoS requirements of service robots and final cost optimization stage. Additionally, with respect to optimizing the final cost for the model, we propose a Dynamic Vector Hybrid Genetic Algorithm (DVHGA) that is integrated with local and global search process as well as a three-phase parameter updating policy. Specifically, inspired by momentum optimization in deep learning, dynamic vector is integrated with DVHGA to modify the weights of QoS and ensure the reasonable allocation of resources. Moreover, we suggest a linear evaluation method for the service robots and the cloud platform concerning time and final cost at the same time, which could be expected to be used in the real application environment. Finally, the empirical results demonstrate that the proposed DVHGA outperforms other benchmark algorithms, i.e., DABC, ESWOA, GA, PGA and GA-PSO, in convergence rate, total final cost and evaluation score.

Summary: Nanobody, referred to the variable domain of heavy-chain-only antibodies, has several advantages such as small size and feasible Escherichia coli expression, making them promising for scientific research and therapies. Conventional nanobody screening and expression methods often suffer from the need for subcloning into expression vectors and amplification-induced diversity loss. Here, we developed an integrated method for simultaneous screening and expression. Nanobody libraries were cloned and secretly expressed in the culture medium. Target-specific nanobodies were isolated through 1–3 rounds of dilution and regrowth following the Poisson distribution. This ensured no dismissal of positive clones, with populations of positive clones increasing over 10-fold in each dilution round. Ultimately, we isolated 5 nanobodies against death domain receptor 5 and 5 against Pyrococcus furiosus DNA polymerase directly from their immunized libraries. Notably, our approach enables nanobody screening without specialized instruments, demonstrating broad applicability in routine monoclonal nanobody production for diverse biomedical applications.

Single drought index such as Precipitation Condition Index (PCI), Temperature Condition Index (TCI), Evapotranspiration Condition Index (ETCI) and so on, has a limited capability to indicate drought state. It has been proved that the composite drought index proposed by integrating multiple single drought indices can indicate and predict drought state more efficiently and accurately. This paper presents the Precipitation Temperature Evapotranspiration Drought Index (PTEDI) combining the PCI, TCI and ETCI. The three-dimensional Euclidean PCI-TCI-ETCI space is built, and the PTEDI is defined as the magnitude of the vector in the PCI-TCI-ETCI space. To verify the rationality and effectiveness of the PTEDI as a desired drought index in the Huang-Huai-Hai Plain, it is compared with the PCI, TCI, ETCI and PCACDI (Principal Component Analysis Combined Drought Index), and is evaluated with the Drought Affected/Disaster Area (DAA/DDA) and Net Primary Productivity (NPP). The results indicate that the PTEDI outperforms the PCI, TCI, ETCI and PCACDI, and is highly correlated with the Standardized Precipitation Index (SPI-1) (R = 0.61), Soil Moisture Condition Index (SMCI) (R= 0.56), and NPP (R = 0.56). The time series of the PTEDI and four indices (SPI-1, SMCI, Crop Water Stress Index (CWSI) and Temperature Vegetation Drought Index (TVDI)) exhibits good spatial consistency. The PTEDI has a negative correlation with the DAA/DDA (R < −0.6). Furthermore, to illustrate the applicability of the PTEDI, the drought spatiotemporal variation is analyzed by taking it as a drought index. At the monthly scale, moderate drought occurs most frequently in March and July. At the annual scale, the PTEDI fluctuates between 0.34 and 0.60 without obvious periodicity, and the study area is mainly characterized by mild drought. Moreover, the drought evolution is analyzed by using the timing analysis methods. In conclusion, the PTEDI can be applied to monitor drought effectively.

Objective The purpose of this study was to describe the clinicopathological characteristics and prognosis of primary small cell carcinoma of the breast (PSCCB) and compare PSCCB with breast invasive ductal carcinoma (IDC).Design A retrospective cohort study.Setting Data of patients with PSCCB and breast IDC were identified from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2016.Participants Eighty-three patients with PSCCB and 410 699 patients with breast IDC were enrolled in the present cohort study.Materials and methods Patients with PSCCB and breast IDC were identified from the SEER database between 2004 and 2016. The clinicopathological characteristics and survival of patients with PSCCB and IDC were compared. Propensity score matching (PSM) analysis was performed to adjust for differences in baseline characteristics when comparing overall survival (OS) and cancer-specific survival (CSS). Moreover, OS-/CSS-specific nomograms were established to predict the prognosis of PSCCB.Results Compared with IDC, PSCCB was significantly correlated with older age, male, higher pathological grade, higher TNM (tumour, node, metastases) stage, a higher proportion of triple-negative breast cancer, a lower proportion of ER/PR positivity and significantly worse clinical outcome. The median OS and CSS of patients with PSCCB were 23.0 m (95%CI 13.0 to 56.0) and 28.0 m (95%CI 18.0 to 66.0), respectively. The 5-year OS and CSS rates in the PSCCB group were 36.1% and 42.4%, respectively. In the matched cohort after PSM analysis, patients with PSCCB had significantly worse OS and CSS than IDC patients. Multivariate Cox regression analysis demonstrated that T stage and administration of chemotherapy were independent prognostic factors for both OS and CSS in patients with PSCCB. The C-index for OS-/CSS-specific nomogram was 0.75 (95%CI 0.66 to 0.85)/0.79 (95%CI 0.69 to 0.89), respectively. The calibration curve in the ROC analysis indicated that the predicted value was consistent with the actual observation value. Decision curve analysis suggested that the nomogram model has a significant positive net benefit from the risk of death and are better than the traditional TNM staging system.Conclusion PSCCB has distinct clinicopathological characteristics, and patients with PSCCB have significantly worse clinical outcomes than those with IDC.

IntroductionSeagrasses play a key role in biodiversity maintenance, sediment stabilization, and carbon reduction. Due to the significant decline of seagrass populations worldwide, many projects to restore seagrass by transplantation have been undertaken in recent decades. However, effective restoration technologies required to rapidly restore seagrass on Hainan Island are yet to be developed.MethodsIn this study, an experiment was carried out to investigate methods for alleviating continuous degradation of seagrass beds on Hainan Island. Seagrass were transplanted by “single-plant-fixed-distance transplantation” method, survival rate, shoot formation rate, coverage and shoot density of transplanting plants were monitored for 23 months.ResultsOver 67% of T. hemprichii and 90% of E. acoroides were still alive, shoot density were over 11 shoots/m2 and 15 shoots/m2 respectively after almost two years, E. acoroides was more likely to survive than T. hemprichii both in Gaolong Bay and Xincun lagoon. Because of the damage to below-ground tissues, the survival rate, shoot formation rate, coverage and shoot density decreased during the first one year after transplantation, then increased gradually.DiscussionWe considered transplantation established successfully of T. hemprichii and E. acoroides in the new site was about 12 months. In addition, T. hemprichii was suitable for transplanted in Xincun lagoon, and E. acoroides was suitable for transplanted in Gaolong bay. The results demonstrated that the growth of transplanted seagrass was greatly affected by suspend solids and DIN. The results of this study may provide data support and scientific basis for seagrass transplantation in South China.

Summary: Background: Immunotherapy has revolutionized the treatment of cancer. However, microsatellite stable (MSS) metastatic colorectal cancer (mCRC) shows a low response to PD-1 inhibitors. Antiangiogenic therapy can enhance anti-PD-1 efficacy, but it still cannot meet clinical needs. Increasing evidence supported a close relationship between gut microbiome and anti-PD-1 efficacy. This study aimed to explore the efficacy and safety of the combination of fecal microbiota transplantation (FMT) and tislelizumab and fruquintinib in refractory MSS mCRC. Methods: In the phase II trial, MSS mCRC patients were administered FMT plus tislelizumab and fruquintinib as a third-line or above treatment. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR), clinical benefit rate (CBR), safety and quality of life. Feces and peripheral blood were collected for exploratory biomarker analysis. This study is registered with Chictr.org.cn, identifier ChiCTR2100046768. Findings: From May 10, 2021 to January 17, 2022, 20 patients were enrolled. Median follow-up was 13.7 months. Median PFS was 9.6 months (95% CI 4.1–15.1). Median OS was 13.7 months (95% CI 9.3–17.7). Median DoR was 8.1 months (95% CI 1.7–10.6). ORR was 20% (95% CI 5.7–43.7). DCR was 95% (95% CI 75.1–99.9). CBR was 60% (95% CI 36.1–80.9). Nineteen patients (95%) experienced at least one treatment-related adverse event (TRAE). Six patients (30%) had grade 3–4 TRAEs, with the most common being albuminuria (10%), urine occult blood (10%), fecal occult blood (10%), hypertension (5%), hyperglycemia (5%), liver dysfunction (5%), hand-foot skin reaction (5%), and hypothyroidism (5%). No treatment-related deaths occurred. Responders had a high-abundance of Proteobacteria and Lachnospiraceae family and a low-abundance of Actinobacteriota and Bifidobacterium. The treatment did not change the structure of peripheral blood TCR repertoire. However, the expanded TCRs exhibited the characteristics of antigen-driven responses in responders. Interpretation: FMT plus tislelizumab and fruquintinib as third-line or above treatment showed improved survival and manageable safety in refractory MSS mCRC, suggesting a valuable new treatment option for this patient population. Funding: This study was supported by the National Natural Science Foundation of China (82102954 to Wensi Zhao) and the Special Project of Central Government for Local Science and Technology Development of Hubei Province (ZYYD2020000169 to Yongshun Chen).

Abstract Service robot cloud platform is effective method to improve the intelligence of robots. An efficient cloud service scheduling algorithm is the basis of ensuring service quality and platform concurrency. In this paper, Hierarchy Genetic Algorithm of robot service(RHGA) is presented to solve the scheduling problem with the crucial constraints. Firstly, the limitations and attributes of the cloud service robots and cloud services are presented and boiled down to an important optimization goal. Secondly, three factors (i.e. evolutionary factor, hunting factor and parent similarity) are integrated with RHGA to promote the efficiency of small-scale service invocations and improve the performance of large-scale service invocations on the platform. Finally, a series of experiments are conducted on several service scheduling algorithms, including four traditional efficient algorithms and two state-of-art algorithms. The experimental results demonstrate that the RHGA can enhance the performance on small-scale service scheduling and ensure its excellent ability in large-scale service scheduling. Moreover, the empirical studies also prove that our proposal has a better performance in service scheduling completion time and cost-savings with comparison to other methods.

During deep-sea mining, heavy metal pollutants can cause contamination in the marine environment. In this paper, the multiphasic coupling model is established to describe the heavy metal migration process during deep-sea mining, which takes the effects of the convection–diffusion, adsorption–desorption, and sedimentation–resuspension of heavy metals in the aquatic environment into full consideration. Due to the advantages of the Lattice Boltzmann method, it is adopted to numerically solve the multiphasic coupling model and achieve the simulation of the heavy metal migration process during deep-sea mining. In addition, taking cadmium as an example, the concentration variations are discussed and analyzed in detail. Based on the established model and Lattice Boltzmann method, the concentration distribution of heavy metals can be accurately described to provide the reasonable bases for the evaluation of marine environmental protection.

Phosphoglycerate kinase 1 (PGK1) serves as a pivotal enzyme in the cellular glycolysis pathway, facilitating adenosine-triphosphate (ATP) production in tumor cells and driving the Warburg effect. PGK1 generates ATP through the reversible phosphorylation reaction of 1,3-bisphosphoglycerate (1,3-BPG) to Mg-adenosine-5′-diphosphate (Mg-ADP). In addition to its role in regulating cellular metabolism, PGK1 plays a pivotal role in autophagy induction, regulation of the tricarboxylic acid cycle (TCA), and various mechanisms including tumor cell drug resistance, and so on. Given its multifaceted functions within cells, the involvement of PGK1 in many types of cancer, including breast cancer, astrocytoma, metastatic colon cancer, and pancreatic ductal adenocarcinoma, is intricate. Notably, PGK1 can function as an intracellular protein kinase to coordinate tumor growth, migration, and invasion via posttranslational modifications (PTMs). Furthermore, elevated expression levels of PGK1 have been observed in cancer tissues, indicating its association with unfavorable treatment outcomes and prognosis. This review provides a comprehensive summary of PGK1’s expression pattern, structural features, functional properties, involvement in PTMs, and interaction with tumors. Additionally highlighted are the prospects for developing and applying related inhibitors that confirm the indispensable value of PGK1 in tumor progression.

The prognosis of renal pelvis cancer is poor and therapeutic options are limited, especially for patients with advanced disease. In this report, we present a case of advanced renal pelvis carcinoma in a male patient in his 60s, characterized by an activating mutation in ERBB2 . Clinical evaluation resulted in a pathological diagnosis of renal pelvis carcinoma with liver metastasis. Immunohistochemistry staining results suggested that CK, P63, and PAX8 were positively expressed, while Sy, CK7, CK20, S100, PAX8, and HEP1 were negatively expressed. Furthermore, next-generation sequencing results showed an activating mutation in the ERBB2 gene. The patient initially received a trastuzumab-based combination therapy, which led to a significant reduction in ERBB2 mutation frequency and a stable condition after three treatment cycles. However, following continuous treatment for 4 months, the patient developed drug resistance that resulted in disease relapse. Subsequently, the patient received apatinib treatment, but the therapeutic response was not satisfactory. The patient’s condition underwent rapid deterioration and he ultimately succumbed to the disease. This case underscores the potential benefit of trastuzumab for treating ERBB2 -mutated advanced renal pelvis cancer, but further highlights that overcoming drug resistance remains a crucial challenge for long-term efficacy.

BackgroundAlthough there are many freezing protocols available, the optimal freezing dose is still not determined. We aimed to evaluate the effectiveness and safety of different freeze strategies of CBA in the treatment of AF.MethodsPubMed, Cochrane Library, Web of Science, and Embase were searched up to 1st December 2022. Studies comparing the outcomes between single-shot technique and standard technique of cryoablation were included. Subgroup analysis identified potential determinants for single-shot technique procedure.ResultsOur search resulted in 3407 records after deduplication. A total of 17 qualified studies met our inclusion criteria. Compared with standard technique, single-shot technique of cryoablation has a comparable rate of freedom from AF/AT(RR 1.00; P = 0.968), a trend for lower rate of procedure complications (RR 0.80; P = 0.069), a lower rate in transient phrenic paralysis (t-PNP) (RR 0.67; P = 0.038), a similar rate in persistent phrenic paralysis (per-PNP) (RR 1.15; P = 0.645), as well as a comparable procedure parameters. Importantly, potentially significant treatment covariable interactions in procedure complications were found in freeze strategy subgroup, male proportion subgroup and age subgroup, including single-shot freeze (RR 1.02; P = 0.915) and TTI-guided (RR 0.63; P = 0.007) with interaction P = 0.051, high male proportion (RR 0.54; P = 0.005) and a low male proportion (RR 0.94; P = 0.759) with interaction P = 0.074, as well as age ≥ 65 (RR0.91; P = 0.642) and age 60% (RR 0.89; P = 0.549) and HT ≤ 60% (RR 0. 46; P

Thermal conductivity, one of critical properties for composite materials, constitutes an indispensable part of high-efficient materials design. However, a quantitative model to describe the thermal conductivity of two-phase composites has yet to be developed. In this work, we proposed an effective evaluation framework of a microstructure-based thermal conductivity model with key inputs from CALPHAD-type approach. Two-phase WC-Ni composites with Ni–W solid-solution matrix were used as the target system to validate this framework combined with key thermal conductivity measurements. Calculated thermal conductivities agree well with experimental results within the experimental error of 10%. Applying this well-established framework, thermal conductivities depending on wide ranges of temperature, WC grain size (dWC), and phase constitution are predicted, suggesting some unique features. The thermal conductivity becomes less dependent on dWC when dWC is >3 μm. Additionally, the thermal conductivity of nano-sized WC-Ni shows a quite different temperature-dependent variation tendency in contrast to that of micron-sized WC-Ni. These correlations are found and quantitatively described in the present work. Furthermore, the thermal conductivity for WC-Ni carbide rolls is predicted by the established framework, demonstrating a high accuracy. The present work is expected to guide the design of composite materials with desirable thermal properties efficiently.

Abstract Background The occurrence and development of gastric cancer are related to microorganisms, which can be used as potential biomarkers of gastric cancer. Objective To screen the microbiological markers of gastric cancer from the microorganisms of gastric juice. Methods Gastric juice samples were collected from 61 healthy people and 78 patients with gastric cancer (48 cases of early gastric cancer and 30 cases of advanced gastric cancer). The bacterial 16 S rRNA V1-V4 region of gastric juice samples was sequenced. The Shannon index, Simpson index, Ace index and Chao index were used to analyze the diversity of gastric juice samples. The RDP classifier Bayesian algorithm was used to analyze the community structure of 97% OTU representative sequences with similar levels. Linear discriminant analysis and ST-test were used to analyze the differences. Six machine learning algorithms, including the logistic regression algorithm, random forest algorithm, neural network algorithm, support vector machine algorithm, Catboost algorithm and gradient lifting tree algorithm, were used to construct risk prediction models for gastric cancer and advanced gastric cancer. Results The microbiota diversity and the abundance of bacteria was different in the healthy group, early gastric cancer and advanced gastric cancer (P

The molecular chaperone HSP90 plays an essential role in cancer occurrence and development. Therefore, it is an important target for the development of anticancer drugs. 1,3-Dibenzyl-2-aryl imidazolidine (8) is a previously reported inhibitor of HSP90; however, its anticancer activity is poor. In this work, chemical modification of 8 led to the discovery of 2,4-diarylimidazoles and 2,4-bis(benzyloxy)-5-arylpyrimidines as two types of novel HSP90 N-terminal inhibitors. 16l and 22k exhibited antiproliferative activity against multiple breast cancer cell lines with IC50 values at the low micromolar level. 16l and 22k induced significant degradation of the client proteins AKT and ERK and a lower level of the heat shock response in comparison with tanespimycin (17-AAG). 22k exhibited a strong affinity for the HSP90α N-terminus with an IC50 value of 0.21 μM. A molecular docking study revealed that 16l and 22k successfully bind to the geldanamycin binding site at the N-terminus of HSP90α.

Abstract Background Protein arginine methyltransferases (PRMTs) regulate protein biological activity by modulating arginine methylation in cancer and are increasingly recognized as potential drug targets. Inhibitors targeting PRMTs are currently in the early phases of clinical trials and more candidate drugs are needed. Flavokawain A (FKA), extracted from kava plant, has been recognized as a potential chemotherapy drug in bladder cancer (BC), but its action mechanism remains unclear. Methods We first determined the role of a type II PRMT, PRMT5, in BC tissue samples and performed cytological experiments. We then utilized bioinformatics tools, including computational simulation, virtual screening, molecular docking, and energy analysis, to identify the potential use of PRMT5 inhibitors for BC treatment. In vitro and in vivo co-IP and mutation assays were performed to elucidate the molecular mechanism of PRMT5 inhibitor. Pharmacology experiments like bio-layer interferometry, CETSA, and pull-down assays were further used to provide direct evidence of the complex binding process. Results Among PRMTs, PRMT5 was identified as a therapeutic target for BC. PRMT5 expression in BC was correlated with poor prognosis and manipulating its expression could affect cancer cell growth. Through screening and extensive experimental validation, we recognized that a natural product, FKA, was a small new inhibitor molecule for PRMT5. We noticed that the product could inhibit the action of BC, in vitro and in vivo, by inhibiting PRMT5. We further demonstrated that FKA blocks the symmetric arginine dimethylation of histone H2A and H4 by binding to Y304 and F580 of PRMT5. Conclusions In summary, our research strongly suggests that PRMT5 is a potential epigenetic therapeutic target in bladder cancer, and that FKA can be used as a targeted inhibitor of PRMT5 for the treatment of bladder cancer.

Abstract The integration of small-scale Photovoltaics (PV) systems (such as rooftop PVs) decreases the visibility of power systems, since the real demand load is masked. Most rooftop systems are behind the metre and cannot be measured by household smart meters. To overcome the challenges mentioned above, this paper proposes an online solar energy disaggregation system to decouple the solar energy generated by rooftop PV systems and the ground truth demand load from net measurements. A 1D Convolutional Neural Network (CNN) Bidirectional Long Short-Term Memory (BiLSTM) deep learning method is used as the core algorithm of the proposed system. The system takes a wide range of online information (Advanced Metering Infrastructure (AMI) data, meteorological data, satellite-driven irradiance, and temporal information) as inputs to evaluate PV generation, and the system also enables online and offline modes. The effectiveness of the proposed algorithm is evaluated by comparing it to baselines. The results show that the proposed method achieves good performance under different penetration rates and different feeder levels. Finally, a transfer learning process is introduced to verify that the proposed system has good robustness and can be applied to other feeders.

AIM: To assess the effect of 0.01% atropine eye drops on intraocular pressure (IOP) in myopic children. METHODS: A placebo-controlled, double-masked, randomized study. Totally 220 children aged 6 to 12y with myopia ranging from -1.00 to -6.00 D in both eyes were enrolled. Children were randomized in a 1:1 ratio to either 0.01% atropine eye drops or a placebo group using generated random numbers. All participants underwent the examination of IOP and cycloplegic refraction at baseline, 6 and 12mo. The change of IOP and the proportion of subjects with increased IOP in atropine and placebo groups were compared. RESULTS: Of 220 children, 117 were boys (53.2%). A total of 159 (72.3%) participants completed the follow-up at the 1-year study. At baseline, the mean IOP was 15.74 mm Hg (95%CI, 15.13 to 16.34 mm Hg) for the 0.01% atropine group and 15.59 mm Hg (95%CI, 15.00 to 16.19 mm Hg) for placebo group (mean difference, 0.14 mm Hg; P=0.743) after adjusting for central corneal thickness at baseline. At one year follow-up, the mean change of IOP was 0.16 mm Hg (95%CI, -0.43 to 0.76 mm Hg) for the 0.01% atropine group and -0.11 mm Hg (95%CI, -0.71 to 0.50 mm Hg) for placebo group (mean difference, 0.27 mm Hg; P=0.525) after adjusting for central corneal thickness. The 51.4% of children have increased IOP in the 0.01% atropine group, compared with 45.9% in the placebo group (P=0.511). CONCLUSION: The 0.01% atropine eye drops do not significantly affect the risk of elevated IOP. It is relatively safer to use in the studies that try to minimize myopia progression. However, a further long-duration study is required to be validated.

Van der Waals crystals allow for magnetism down to the monolayer limit, however, this magnetism, and frequently the material itself, is fragile. Ferrites, conversely, have robust material stability and magnetic order, but are three dimensional. Here the authors succeed in creating a single unit cell thickness of Cobalt Ferrite via chemical vapour deposition, with hard magnetic properties, and curie temperature exceeding room temperature.

Silicon is an abundant element on earth and is perfectly compatible with the well-established CMOS processing industry. Here, Sun et al. demonstrate multifunctional neuromorphic devices based on silicon nanosheet stacks, bringing silicon back as a potential material for neuromorphic devices.

Abstract It is challenging to match the mutual interactions between implant and host because the biomaterials usually cannot actively adjust their performance to the changing microenvironment. Surface potential is one of the critical factors affecting the bioactivity of biomaterials, but it is difficult to be directly controlled in vivo. Magnetic stimulation has attracted much attention due to its deep penetrability, good reliability, and convenient operability. Here, titanium dioxide (TiO2) nanotubes and Terfenol‐D/P(VDF‐TrFE) composite film are prepared by anodic oxidation and solution casting methods on opposite sides of a titanium sheet, respectively. Terfenol‐D magnetostrictive microparticles deform under a magnetic field, generating surface potential on the P(VDF‐TrFE) piezoelectric matrix through magneto‐electric coupling. Correspondingly, equal opposite charges are induced on the surface of TiO2 nanotubes. Stem cells cultured on TiO2 nanotubes show that cell adhesion, proliferation, and differentiation abilities can be regulated by magnetic strength, which correlates with the absorption of charged proteins. Therefore, a cascade coupling of magnetic, mechanical, electric, biochemical, and cellular effects is established. This work demonstrates the feasibility of regulating the bioactivity of biomaterials in vivo through a magnetic field.

The use of asphalt emulsion chip seal and hot rubber chip seal as pavement preservation techniques has been gaining popularity. This study aims to compare the laboratory performance of asphalt emulsion and hot rubber asphalt used in chip seal applications. Interlayer shear strength (ISS) and interlayer tensile strength (ITS) tests were designed to evaluate the bond quality of the chip seal samples prepared for both materials. The sweep test was used to estimate the aggregate loss of the chip seal on the asphalt pavement. The universal testing machines were used to evaluate the deterioration of the ISS and ITS values under cyclic load conditions, while the tensile and shear bond properties of chip seals under wet-freeze conditions were evaluated using freeze-thaw cycles. Results showed while both materials experienced a decline in their ISS and ITS values following repeated cycles of load and freeze-thaw, the hot rubber chip seal demonstrated significantly higher ISS and ITS values than the asphalt emulsion chip seal (48–111% and 36–102%, respectively). Moreover, the hot rubber chip seal exhibited better performance in terms of aggregate retention and cohesive strength. The aggregate gradation would affect the aggregate retention and cohesive strength. Nonetheless, both treatments are deemed acceptable for pavement maintenance. The weak bond between hot rubber asphalt or asphalt emulsion and aggregate could be attributed to cyclic load and freeze-thaw conditions.

Ground tire rubber (GTR) usage in asphalt pavement with the dry process has gained more prominence in recent times. The objective of this work is to investigate the pavement performance of GTR-modified asphalt pavement and polymer-modified asphalt pavement on heavy volume of traffic conditions in Michigan's wet and freeze environment. A suite of laboratory tests was done to evaluate the pavement performance of GTR-modified and polymer-modified asphalt mixtures. To reveal the strain and stress relationship under different frequencies and temperatures, the dynamic modulus test was applied. The Hamburg wheel tracking device (HWTD) was used to assess the high-temperature deformation resistance. The disc-shaped compact tension (DCT) test was used to evaluate the low-temperature cracking characteristics. The characteristics of the asphalt binder were assessed by the dynamic shear rheometer (DSR) for high-temperature properties and the asphalt binder cracking device (ABCD) for low-temperature properties. After the construction, a field noise test was conducted. The experimental results stated that the polymer-modified asphalt mixture and GTR-modified asphalt mixture showed higher dynamic modulus and better ability to prevent cracking than the conventional asphalt mixture at low temperatures, as well as better permanent deformation and stripping resistance than the conventional asphalt mixture. The fracture energy of the GTR-modified hot mix asphalt (HMA) is 13–16 % larger than the polymer-modified HMA. The number of passes to the stripping point of GTR-modified was 510–518 % higher than the conventional HMA. When compared to the field core, the lab-compacted HMA offers superior pavement performance. The extracted asphalt binder test results show the GTR-modified asphalt has better rutting resistance and cracking resistance than polymer-modified asphalt, and the results in the noise test demonstrated that the rubber-modified asphalt pavement mitigated the noise level by 2–3 dB on the road at different vehicle speeds. Moreover, the pavement condition was noticeably enhanced after the reconstruction of the surface course. The total number of passenger tires to be used in this project is about 2270. To summarize, better rutting and cracking properties in asphalt pavement are shown by the project's utilization of rubber technology. And the GTR-modified HMA is comparable to polymer-modified HMA. Therefore, it may be appropriate to utilize rubber technology on high-traffic volume asphalt pavement in Michigan's wet and freeze climate.

Abstract In vivo imaging in the deep near‐infrared (NIR) spectral region, that is, beyond 800 nm, has become popular due to its penetration depth. While imaging of the neutral medium/tissue has been repeatedly showcased, imaging of the high‐acidic medium remains challenging partly because of the high‐lying HOMO orbital and hence a high pKa of the electron‐donating group of the NIR fluorophores. We devised a novel electron‐donating group (D6) with which we further synthesized ECJ. ECJ exhibits an absorption wavelength beyond 900 nm and is fluorescent. Its pKa was found to be lower than zero, rendering it suitable for bioimaging of a highly‐acidic medium. Its potential for practical applications was showcased in proof‐of‐concept in vivo imaging with a mouse model.

BackgroundThe risk and prognosis of young breast cancer (YBC) with liver metastases (YBCLM) remain unclear. Thus, this study aimed to determine the risk and prognostic factors in these patients and construct predictive nomogram models.MethodsThis population-based retrospective study was conducted using data of YBCLM patients from the Surveillance, Epidemiology, and End Results database between 2010 and 2019. Multivariate logistic and Cox regression analyses were used to identify independent risk and prognostic factors, which were used to construct the diagnostic and prognostic nomograms. The concordance index (C-index), calibration plot, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) were used to assess the performances of the established nomogram models. Propensity score matching (PSM) analysis was used to balance the baseline characteristics between the YBCLM patients and non-young patients with BCLM when comparing overall survival (OS) and cancer-specific survival (CSS).ResultsA total of 18,275 YBC were identified, of whom 400 had LM. T stage, N stage, molecular subtypes, and bone, lung, and brain metastases were independent risk factors for LM developing in YBC. The established diagnostic nomogram showed that bone metastases contributed the most risk of LM developing, with a C-index of 0.895 (95% confidence interval 0.877–0.913) for this nomogram model. YBCLM had better survival than non-young patients with BCLM in unmatched and matched cohorts after propensity score matching analysis. The multivariate Cox analysis demonstrated that molecular subtypes, surgery and bone, lung, and brain metastases were independently associated with OS and CSS, chemotherapy was an independent prognostic factor for OS, and marital status and T stage were independent prognostic factors for CSS. The C-indices for the OS- and CSS-specific nomograms were 0.728 (0.69–0.766) and 0.74 (0.696–0.778), respectively. The ROC analysis indicated that these models had excellent discriminatory power. The calibration curve also showed that the observed results were consistent with the predicted results. DCA showed that the developed nomogram models would be effective in clinical practice.ConclusionThe present study determined the risk and prognostic factors of YBCLM and further developed nomograms that can be used to effectively identify high-risk patients and predict survival outcomes.

Abstract Accumulating evidence shows HOOK1 disordered in human malignancies. However, the clinicopathological and biological significance of HOOK1 in renal cell carcinoma (RCC) remains rarely studied. In this study, the authors demonstrate that HOOK1 is downregulated in RCC samples with predicted poorer clinical prognosis. Mechanistically, HOOK1 inhibits tumor growth and metastasis via canonical TGF‐β/ALK5/p‐Smad3 and non‐canonical TGF‐β/MEK/ERK/c‐Myc pathway. At the same time, HOOK1 inhibits RCC angiogenesis and sunitinib resistance by promoting degradation of TNFSF13B through the ubiquitin‐proteasome pathway. In addition, HOOK1 is transcriptionally regulated by nuclear factor E2F3 in VHL dependent manner. Notably, an agonist of HOOK1, meletin, is screened and it shows antitumor activity more effectively when combined with sunitinib or nivolumab than it is used alone. The findings reveal a pivotal role of HOOK1 in anti‐cancer treatment, and identify a novel therapeutic strategy for renal cell carcinoma.