Memristor-based circuit design of BiLSTM network.

The bidirectional long short-term memory (BiLSTM) network involves significant amount of parameter computations. This paper proposes the memristor-based bidirectional long short-term memory (MBiLSTM) network, with its capability of in-memory computing and parallel computing, can accelerates the parameter computations speed. The MBiLSTM network circuit is composed of normalization circuit, two memristor-based long short-term memory (LSTM) circuits, memristor-based resnet circuit, memristor-based dense circuitand winner-take-all (WTA) circuit. The voltage signals are scaled to the setting range by normalization circuit, memristor-based LSTM circuit is responsible for extracting features from the dataset, memristor-based resnet circuit can enhance the overall performance of the network, memristor-based dense circuit ensures that the final outputs dimension matches the dimension of the target signals, WTA circuit outputs the maximum voltage of memristor-based dense circuit. The effectiveness of the MBiLSTM network is validated through gait recognition experiment and handwritten digit recognition experiment. The stability, robustness and potential errors in the manufacturing process of memristance are analyzed.

Old concepts, new tricks: How peptide vaccines are reshaping cancer immunotherapy?

Over the past few decades, research on cancer immunotherapy has firmly established immune cells as key players in effective cancer treatment. Peptide vaccines directly targeting immune cells have demonstrated immense potential due to their specificity and applicability. However, developing peptide vaccines to generate tumor-reactive T cells remains challenging, primarily due to suboptimal immunogenicity and overcoming the immunosuppressive tumor microenvironment (TME). In this review, we discuss various elements of effective peptide vaccines, including antigen selection, peptide epitope optimization, vaccine adjuvants, and the combination of multiple immunotherapies, in addition to recent advances in tumor neoantigens as well as epitopes bound by non-classical human leukocyte antigen (HLA) molecules, to increase the understanding of cancer peptide vaccines and provide multiple references for the design of subsequent T cell-based peptide vaccines.

The effects of dabrafenib and/or trametinib treatment in Braf V600-mutant glioma: a systematic review and meta-analysis.

This study aimed to evaluate the effects of dabrafenib and/or trametinib therapy in BRAF v600-mutant glioma treatment. PubMed, the Cochrane Library, EMBASE and Web of Science were searched from inception to Sep 2023. Inclusion criteria were designed based on the PICO principle to select relevant articles. Search keywords included 'dabrafenib', 'trametinib', 'glioma' and other related keywords. Outcomes included overall survival (OS), progression-free survival (PFS), adverse events (AEs), and death events. Methodological index for non-randomized studies (MINORS) was used to assess the methodological quality. Stata 14.0 was selected to perform the Cochrane Q and I2 statistics to test the heterogeneity among all studies. As for publication bias assessment and sensitivity analysis, the funnel plot, Egger regression test, Begg test, and trim and fill method were selected. Including 8 studies for meta-analysis. The pooled results of the single-arm trials showed that the median PFS and median OS after treatment were 6.10 months and 22.73 months, respectively. Notably, this study found a high incidence of AEs and death events of 50% and 43% after treatment. All the above findings were statistically significant. Also, this study statistically supported the advantage of disease response improvement after the combination therapy in BRAF v600-mutant glioma patients, which were shown as a pooled rate of PR (30%), a pooled rate of CR (18%), and a pooled rate of ORR (39%). And the AE rate was lower in the monotherapy group (AE: 25%) than in the combination treatment group (AE: 60%). Sensitivity analysis indicated that all the results were robust. Based on current literature outcomes, dabrafenib and/or trametinib may lead to the median PFS of 6.10 months and median OS as 22.73 months for BRAF v600-mutant glioma patients, and the safety of monotherapy is better than that of combination therapy. This conclusion needs to be treated with caution and further verified.

Circular RNA circ_001621 acts as a tumor promoter in lung cancer by regulating the miR-199a-3p/GREM1 axis.

Introduction: Investigating how circular RNAs (circRNAs) function during tumorigenesis may help uncover novel diagnostic markers for cancer treatment. The oncogenic role of circ_001621 has been verified in osteosarcoma, but its role in lung cancer has yet to be reported. This research is the first to investigate the circ_001621 expression and regulatory mechanism in lung cancer. Material and methods: RT-qPCR was performed to assess the circ_001621 expression levels in lung cancer cells and tissues. The influence of circ_001621 on the viability, invasive ability, and apoptosis of lung cancer cells was investigated through CCK-8, transwell, and caspase-3 activity experiments, respectively. A xenograft nude mouse model was designed to evaluate how circ_001621 functions in vivo. The RIP and luciferase reporter experiments confirmed the binding among circRNA, miRNA, and mRNA. Results: Circ_001621 was dramatically upregulated in lung cancer tissues and cells. Silencing circ_001621 in lung cancer cells reduced their viability and invasive ability but stimulated apoptosis. The nude mice experiment demonstrated that circ_001621 downregulation considerably stunted tumor growth in vivo. Additionally, circ_001621 could sponge miR-199a-3p. The inhibitor of miR-199a-3p improved the viability and invasion of cells while inhibiting apoptosis. Moreover, it offset the impact of circ_001621 on lung cancer cells. MiR-199a-3p was observed to target GREM1, and the downregulation of GREM1 could counteract miR-199a-3p-induced effects on lung cancer cells. Conclusions: The circ_001621/miR-199a-3p/GREM1 axis exhibits an association with the development of lung cancer, suggesting its potential as a future therapeutic target for the disease.

Nanotechnology as a new strategy for the diagnosis and treatment of gliomas.

Glioma is the most common malignant tumor of the central nervous system (CNS), and is characterized by high aggressiveness and a high recurrence rate. Currently, the main treatments for gliomas include surgical resection, temozolomide chemotherapy and radiotherapy. However, the prognosis of glioma patients after active standardized treatment is still poor, especially for glioblastoma (GBM); the median survival is still only 14.6 months, and the 5-year survival rate is only 4-5%. The current challenges in glioma treatment include difficulty in complete surgical resection, poor blood‒brain barrier (BBB) drug permeability, therapeutic resistance, and difficulty in tumor-specific targeting. In recent years, the rapid development of nanotechnology has provided new directions for diagnosing and treating gliomas. Nanoparticles (NPs) are characterized by excellent surface tunability, precise targeting, excellent biocompatibility, and high safety. In addition, NPs can be used for gene therapy, photodynamic therapy, and antiangiogenic therapy and can be combined with biomaterials for thermotherapy. In recent decades, breakthroughs in diagnosing and treating gliomas have been made with various functional NPs, and NPs are expected to become a new strategy for glioma diagnosis and treatment. In this paper, we review the main obstacles in the treatment of glioma and discuss the potential and challenges of the latest nanotechnology in the diagnosis and treatment of glioma.

Evaluation of cooling effect and road performance of warm mixed high viscosity porous asphalt mixture.

In order to study the effect of different warm mixing agents on the cooling and road performance of porous mixture bonded with High Viscosity Asphalt (HVA), the Superpave Gyratory Compactor (SGC) was proposed to conduct variable temperature compaction test on the warm mixed porous asphalt mixture. The relationship between the compaction difficulty coefficient and the temperature of the mixture was obtained by regression, and the mixing and compacting temperature and cooling effect of the warm mixed porous asphalt mixture were determined. Then, the influence of Evotherm M1 and EC120 warm mix agents on the performance of porous asphalt mixture was compared by rutting tests, beam bending tests, immersion Marshall tests, freeze-thaw splitting tests, and penetration strength tests. The results show that two types of warm mixing agents can reduce the mixing and rolling temperatures of the mixture by more than 10°C. The addition of warm mix agents will increase the high temperature stability, water stability, and shear resistance of porous asphalt mixtures. For the improvement effect of high temperature stability, EC120 warm mixing agent is greater than Evotherm M1 warm mixing agent, and for the improvement effect of water stability, Evotherm M1 warm mixing agent is greater than EC120 warm mixing agent. For shear resistance, the improvement effect of both is equivalent, with a penetration strength increase of about 3% to 4%. For low temperature performance, Evotherm M1 warm mixing agent improved the low temperature performance, while EC120 warm mixing agent showed the opposite effect.

Dihydroartemisinin remodels tumor micro-environment and improves cancer immunotherapy through inhibiting cyclin-dependent kinases.

Cancer immunotherapies are ineffective in nonresponding patients due to absence of immune responses. Here, we identified that dihydroartemisinin (DHA) induced immunogenic cell death (ICD) in hepatocellular carcinoma (HCC), proved by release or surface expose of damage-associated molecular patterns and in vivo protective vaccine activity. Mechanistically, DHA can inhibit cyclin-dependent kinases (CDKs), leading to a buildup of intracellular reactive oxygen species (ROS), which induces immunogenic cell death. In both Hepa1-6 and H22 tumor bearing mice, DHA exerted anti-tumor activity through increasing tumor-infiltrating CD8+ T cells with expression of activation makers (CD25 and CD69), secretion of intracellular cytokines (IFN-γ and TNF-α) and activated dendritic cells expressing MHCⅡ, CD80 and CD86. In hepa1-6 tumor bearing mice, DHA decreased immunosuppressive myeloid-derived suppressor cells. Furthermore, DHA enhanced the anti-PD-1 antibody and chimeric antigen receptor (CAR) T cell-mediated tumor suppression through recruitment and activation of endogenous CD8+ T cells. Overall, we demonstrated that by inhibiting CDKs, DHA can remodel tumor micro-environment to amplify anti-tumor immune responses in HCC. These findings provide a promising therapy option for HCC patients.

High-fidelity CRISPR/Cas12a dual-crRNA screening reveals novel synergistic interactions in hepatocellular carcinoma.

 : 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.

Research progresses of imaging studies on preoperative prediction of microvascular invasion of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer, accounting for approximately 90% of liver cancer cases. It currently ranks as the fifth most prevalent cancer worldwide and represents the third leading cause of cancer-related mortality. As a malignant disease with surgical resection and ablative therapy being the sole curative options available, it is disheartening that most HCC patients who undergo liver resection experience relapse within five years. Microvascular invasion (MVI), defined as the presence of micrometastatic HCC emboli within liver vessels, serves as an important histopathological feature and indicative factor for both disease-free survival and overall survival in HCC patients. Therefore, achieving accurate preoperative noninvasive prediction of MVI holds vital significance in selecting appropriate clinical treatments and improving patient prognosis. Currently, there are no universally recognized criteria for preoperative diagnosis of MVI in clinical practice. Consequently, extensive research efforts have been directed towards preoperative imaging prediction of MVI to address this problem and the relative research progresses were reviewed in this article to summarize its current limitations and future research prospects.

Clinical application of dual-layer spectral CT multi-parameter feature to predict microvascular invasion in hepatocellular carcinoma.

OBJECTIVE: This study aimed to investigate the feasibility of using dual-layer spectral CT multi-parameter feature to predict microvascular invasion of hepatocellular carcinoma. METHODS: This retrospective study enrolled 50 HCC patients who underwent multiphase contrast-enhanced spectral CT studies preoperatively. Combined clinical data, radiological features with spectral CT quantitative parameter were constructed to predict MVI. ROC was applied to identify potential predictors of MVI. The CT values obtained by simulating the conventional CT scans with 70 keV images were compared with those obtained with 40 keV images. RESULTS: 50 hepatocellular carcinomas were detected with 30 lesions (Group A) with microvascular invasion and 20 (Group B) without. There were significant differences in AFP,tumer size, IC, NIC,slope and effective atomic number in AP and ICrr in VP between Group A ((1000(10.875,1000),4.360±0.3105, 1.7750 (1.5350,1.8825) mg/ml, 0.1785 (0.1621,0.2124), 2.0362±0.2108,8.0960±0.1043,0.2830±0.0777) and Group B (4.750(3.325,20.425),3.190±0.2979,1.4700 (1.4500,1.5775) mg/ml, 0.1441 (0.1373,0.1490),1.8601±0.1595, 7.8105±0.7830 and 0.2228±0.0612) (all p < 0.05). Using 0.1586 as the threshold for NIC, one could obtain an area-under-curve (AUC) of 0.875 in ROC to differentiate between tumours with and without microvascular invasion. AUC was 0.625 with CT value at 70 keV and improved to 0.843 at 40 keV. CONCLUSION: Dual-layer spectral CT provides additional quantitative parameters than conventional CT to enhance the differentiation between hepatocellular carcinoma with and without microvascular invasion. Especially, the normalized iodine concentration (NIC) in arterial phase has the greatest potential application value in determining whether microvascular invasion exists, and can offer an important reference for clinical treatment plan and prognosis assessment.

Cost-Effective Whole Transcriptome Sequencing Landscape and Diagnostic Potential Biomarkers in Active Tuberculosis.

Tuberculosis (TB) is a prevalent and severe infectious disease that poses a significant threat to human health. However, it is frequently disregarded as there are not enough quick and accurate ways to diagnose tuberculosis. Here, we develop a strategy for tuberculosis detection to address the challenges, including an experimental strategy, namely, Double Adapter Directional Capture sequencing (DADCSeq), an easily operated and low-cost whole transcriptome sequencing method, and a computational method to identify hub differentially expressed genes as well as the diagnosis of TB based on whole transcriptome data using DADCSeq on peripheral blood mononuclear cells (PBMCs) from active TB and latent TB or healthy control. Applying our approach to create a robust and stable TB multi-mRNA risk probability model (TBMMRP) that can accurately distinguish active and latent TB patients, including active TB and healthy controls in clinical cohorts, this diagnostic biomarker was successfully validated by several independent cross-platform cohorts with favorable performance in differentiating active TB from latent TB or active TB from healthy controls and further demonstrated superior or similar diagnostic accuracy compared to previous diagnostic markers. Overall, we develop a low-cost and effective strategy for tuberculosis diagnosis; as the clinical cohort increases, we can expand to different disease kinds and learn new features through our disease diagnosis strategy.

Effects of different proportions of fruit tree branches on nicotine content and microbial diversity during composting of tobacco waste.

Adding fruit tree branches to the compost pile in appropriate proportions is one of the methods used to address the challenge of tobacco waste recycling. However, the effects of different proportions of fruit tree branches on nicotine concentration and microbial diversity during tobacco waste composting have not been reported. In this study, a composting system with tobacco waste, cow dung, and fruit tree branches was established in a laboratory fermenter to assess the impact of adding 10%, 20%, and 30% fruit tree branches on quantity changes. In addition, the relationships between nicotine degradation, compost properties, enzyme activities, and microbial diversities were determined using biochemical assay methods and high-throughput sequencing. The results showed that adding appropriate proportions of fruit branch segments affected changes in physical and chemical properties during composting and promoted tobacco waste compost maturity. Aerobic composting effectively degraded nicotine in tobacco waste. Increased proportions of fruit branch segments led to elevations in nicotine degradation rates and enzyme activities related to lignocellulose degradation. The addition of fruit branches influenced the relative abundance and species of dominant bacteria and fungi at the phylum and genus levels. However, it did not significantly affect the relative abundance of the main bacterial genera involved in nicotine degradation. Nevertheless, it reduced the sensitivity of enzyme activity to nicotine content within heaps, increasing reliance on total nitrogen changes. The results of this study provide a theoretical basis for the utilization of tobacco waste in composting systems and indicate that fruit tree branches can enhance nicotine degradation efficiency during tobacco waste composting.

Regulatory emotional self-efficacy and self-compassion mediate anxiety, depression, body image distress and subjective well-being in women with polycystic ovary syndrome: A cross-sectional study.

AIMS: This study aims to investigate the mediating role of regulatory emotional self-efficacy and self-compassion in the relationship among anxiety, depression, body image distress and subjective well-being among women with polycystic ovary syndrome. DESIGN: A cross-sectional study. METHODS: The study recruited 510 women with polycystic ovary syndrome from a tertiary hospital affiliated with a university in Hunan Province, China. The study employed several tools to collect data, including the Generalized Anxiety Scale, the Patient Health Questionnaire-9, the Body Image States Scale, the Self-Compassion Scale, the Regulatory Emotional Self-Efficacy Scale and the Index of Well-being questionnaire. Data analysis was carried out using descriptive analysis, spearman correlation analysis, ordinary least squares regression and bootstrapping. RESULTS: The study's findings indicate that regulatory emotional self-efficacy and self-compassion both act as mediators in the connection between anxiety, depression, body image distress and subjective well-being among women with polycystic ovary syndrome. CONCLUSION: The study emphasizes the significance of regulatory emotional self-efficacy and self-compassion in promoting well-being among women with polycystic ovary syndrome. It also implies that interventions targeted at enhancing these factors could potentially enhance the subjective well-being of women affected by PCOS. IMPACT: Our study's primary contribution is to underscore the crucial mediating roles of regulatory emotional self-efficacy and self-compassion in the relationship among anxiety, depression, body image distress and subjective well-being. Our study indicates that clinical practitioners should prioritize improving the regulatory emotional self-efficacy and self-compassion of women with polycystic ovary syndrome, reducing their anxiety, depression and body image distress and improving their subjective well-being. REPORTING METHOD: This study was reported according to the Standards for Reporting Qualitative Research (SRQR). PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution outside of participation in the actual study for purposes of data collection.

A Biomimetic Fibrous Composite Scaffold with Nanotopography-Regulated Mineralization for Bone Defect Repair.

The effective regeneration of large bone defects via bone tissue engineering is challenging due to the difficulty in creating an osteogenic microenvironment. Inspired by the fibrillar architecture of the natural extracellular matrix, we developed a nanoscale bioengineering strategy to produce bone fibril-like composite scaffolds with enhanced osteogenic capability. To activate the surface for biofunctionalization, self-adaptive ridge-like nanolamellae were constructed on poly(ε-caprolactone) (PCL) electrospinning scaffolds via surface-directed epitaxial crystallization. This unique nanotopography with a markedly increased specific surface area offered abundant nucleation sites for Ca2+ recruitment, leading to a 5-fold greater deposition weight of hydroxyapatite than that of the pristine PCL scaffold under stimulated physiological conditions. Bone marrow mesenchymal stem cells (BMSCs) cultured on bone fibril-like scaffolds exhibited enhanced adhesion, proliferation, and osteogenic differentiation in vitro. In a rat calvarial defect model, the bone fibril-like scaffold significantly accelerated bone regeneration, as evidenced by micro-CT, histological histological and immunofluorescence staining. This work provides the way for recapitulating the osteogenic microenvironment in tissue-engineered scaffolds for bone repair.

Identification of extracellular matrix-related biomarkers in colon adenocarcinoma by bioinformatics and experimental validation.

Backgrounds: Extracellular matrix (ECM) is an important component of tumor microenvironment, and its abnormal expression promotes tumor formation, progression and metastasis. Methods: Weighted gene co-expression network analysis (WGCNA) was used to identify ECM-related hub genes based on The Cancer Genome Atlas (TCGA) colon adenocarcinoma (COAD) data. COAD clinical samples were used to verify the expression of potential biomarkers in tumor tissues, and siRNA was used to explore the role of potential biomarkers in cell proliferation and epithelial-mesenchymal transition (EMT). Results: Three potential biomarkers (LEP, NGF and PCOLCE2) related to prognosis of COAD patients were identified and used to construct ERGPI. Immunohistochemical analysis of clinical samples showed that the three potential biomarkers were highly expressed in tumor tissues of COAD patients. Knockdown of LEP, NGF or PCOLCE2 inhibited COAD cell proliferation and EMT. Dictamnine inhibited tumor cell growth by binding to these three potential biomarkers based on molecular docking and transplanted tumor model. Conclusion: The three biomarkers can provide new ideas for the diagnosis and targeted therapy of COAD patients.

Engineering of a compact, high-fidelity EbCas12a variant that can be packaged with its crRNA into an all-in-one AAV vector delivery system.

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.

Heterologous synthesis of ginsenoside F1 and its precursors in Nicotiana benthamiana.

Ginsenoside F1 has high medicinal values, which is a kind of rare triterpene saponin isolated from Panax plants. The extremely low content of ginsenoside F1 in herbs has limited its research and application in medical field. In this work, we constructed a pathway in tobacco for the biosynthesis of ginsenoside F1 by metabolic engineering. Four enzyme genes (PnDDS, CYP716A47, CYP716S1 and UGT71A56) isolated from Panax notoginseng were introduced into tobacco. Thus, a biosynthetic pathway for ginsenoside F1 synthesis was artificially constructed in tobacco cells; moreover, the four exogenous genes could be expressed in the roots, stems and leaves of transgenic plants. Consequently, ginsenoside F1 and its precursors were successfully synthesized in the transgenic tobacco, compared with Panax plants, the content of ginsenoside F1 in transgenic tobacco was doubled. In addition, accumulation of ginsenoside F1 and its precursors in transgenic tobacco shows organ specificity. Based on these results, a new approach was established to produce rare ginsenoside F1; meanwhile, such strategy could also be employed in plant hosts for the heterologous synthesis of other important or rare natural products.

Assessment of Left Ventricular Longitudinal Systolic Function Using Global Tissue Motion Annular Displacement in Patients with Chronic Severe Aortic Regurgitation.

Background: In patients with chronic aortic regurgitation (AR), the left ventricle (LV) develops compensatory mechanisms to sustain its function. LV global longitudinal strain (GLS) is a key means to detect subclinical LV dysfunction, even when LV ejection fraction (LVEF) remains within the normal range. Compared to GLS, Tissue motion annular displacement (TMAD) is a simpler strain-based method to assess LV systolic function. This study investigated the correlation among TMAD parameters, LVEF, and GLS, and determined the diagnostic value and threshold of TMAD parameters for left ventricular systolic dysfunction. Methods: A prospective study was conducted at a single center. The case and control groups consisted of patients with chronic severe AR and healthy volunteers, respectively. Speckle-tracking echocardiography (STE) was used to assess the GLS and TMAD parameters in the apical 4-chamber and apical 2-chamber. Subsets of participants were analyzed for inter- and intra-observer variability and analysis time. A correlation analysis was performed among the TMAD parameters, LVEF, and GLS. Receiver operating characteristic curves and the area under the curves (AUCs) were used to evaluate the predictive value of the TMAD parameters for LVEF <50% and GLS > -18%. Results: This study involved 96 patients with severe chronic AR and 45 healthy volunteers. Compared to GLS, TMAD demonstrated superior intra- and inter-observer consistency and shorter average analysis time. Biplane global Midpt% showed the highest correlation with GLS and LVEF among all the TMAD parameters, with r values of 0.81 and 0.74, respectively. Furthermore, global Midpt% had AUCs of 0.89 and 0.92 for predicting LVEF< 50% and GLS > -18%, respectively. Conclusion: The TMAD global Midpt% has the potential to replace GLS in clinical practice and find wide applications.