Minimal residual disease profiling predicts pathological complete response in esophageal squamous cell carcinoma.

Accurate presurgical prediction of pathological complete response (pCR) can guide treatment decisions, potentially avoiding unnecessary surgeries and improving the quality of life for cancer patients. We developed a minimal residual disease (MRD) profiling approach with enhanced sensitivity and specificity for detecting minimal tumor DNA from cell-free DNA (cfDNA). The approach was validated in two independent esophageal squamous cell carcinoma (ESCC) cohorts. In a cohort undergoing neoadjuvant, surgical, and adjuvant therapy (NAT cohort), presurgical MRD status precisely predicted pCR. All MRD-negative cases (10/10) were confirmed as pCR by pathological evaluation on the resected tissues. In contrast, MRD-positive cases included all the 27 non-pCR cases and only one pCR case (10/10 vs 1/28, P < 0.0001, Fisher's exact test). In a definitive radiotherapy cohort (dRT cohort), post-dRT MRD status was closely correlated with patient prognosis. All MRD-negative patients (25/25) remained progression-free during the follow-up period, while 23 of the 26 MRD-positive patients experienced disease progression (25/25 vs 3/26, P < 0.0001, Fisher's exact test; progression-free survival, P < 0.0001, log-rank test). The MRD profiling approach effectively predicted the ESCC patients who would achieve pCR with surgery and those likely to remain progression-free without surgery. This suggests that the cancer cells in these MRD-negative patients have been effectively eliminated and they could be suitable candidates for a watch-and-wait strategy, potentially avoiding unnecessary surgery.

New Insights into the Genetic Basis of Lysine Accumulation in Rice Revealed by Multi-Model GWAS.

Lysine is an essential amino acid that cannot be synthesized in humans. Rice is a global staple food for humans but has a rather low lysine content. Identification of the quantitative trait nucleotides (QTNs) and genes underlying lysine content is crucial to increase lysine accumulation. In this study, five grain and three leaf lysine content datasets and 4,630,367 single nucleotide polymorphisms (SNPs) of 387 rice accessions were used to perform a genome-wide association study (GWAS) by ten statistical models. A total of 248 and 71 common QTNs associated with grain/leaf lysine content were identified. The accuracy of genomic selection/prediction RR-BLUP models was up to 0.85, and the significant correlation between the number of favorable alleles per accession and lysine content was up to 0.71, which validated the reliability and additive effects of these QTNs. Several key genes were uncovered for fine-tuning lysine accumulation. Additionally, 20 and 30 QTN-by-environment interactions (QEIs) were detected in grains/leaves. The QEI-sf0111954416 candidate gene LOC_Os01g21380 putatively accounted for gene-by-environment interaction was identified in grains. These findings suggested the application of multi-model GWAS facilitates a better understanding of lysine accumulation in rice. The identified QTNs and genes hold the potential for lysine-rich rice with a normal phenotype.

KIAA1429 regulates lung adenocarcinoma proliferation and metastasis through the PI3K/AKT pathway by modulating ARHGAP30 expression.

BACKGROUND: Alterations in epigenetic factors are recognized as key contributors to the emergence of human cancer. The active and reversible alteration of N6-methyladenosine (m6A) RNA is crucial for controlling gene activity and determining cellular destiny. Even with these insights, the triggering of KIAA1429 (also called VIRMA) and its role in lung adenocarcinoma (LUAD) is mostly unclear. As a result, the objective of this study was to elucidate how KIAA1429 contributes to cancer development in LUAD. METHODS: This study utilized multiple methods for investigation, encompassing the in vitro functional examination of KIAA1429 in lung adenocarcinoma cells, transcriptome sequencing, methylation RNA immunoprecipitation sequencing (MeRIP-seq), as well as RNA stability tests to ascertain the half-life and stability of the target genes. RESULTS: The results indicated that modifying the expression of KIAA1429 regulated the proliferation and metastasis of LUAD. By employing transcriptome sequencing alongside MeRIP-seq analysis, the research pinpointed genes affected by m6A alterations triggered by KIAA1429. In a more detailed manner, it was discovered that KIAA1429 plays a regulatory role in the expression of ARHGAP30. Suppressing KIAA1429 results in reduced m6A levels in the mRNA of the target gene ARHGAP30, boosting its stability and expression, thus inhibiting tumor proliferation and metastasis. CONCLUSION: This study revealed the activation mechanism and pivotal function of KIAA1429 in LUAD tumor development, paving the way for molecular-based interventions for LUAD.

How is work-family conflict linked to nurse-assessed patient safety among intensive care unit nurses? A serial multiple mediation analysis.

AIM: The aim of this study was to test whether rumination and negative affectivity mediate the relationship between work-family conflict and nurse-assessed patient safety among intensive care unit nurses. BACKGROUND: Most intensive care unit nurses experience work-family conflicts that jeopardise patient safety. Although prior studies have explored the effect of work-family conflict on patient safety, few have investigated whether work-family conflict is associated with patient safety through rumination and negative affectivity among intensive care unit nurses. DESIGN: Cross-sectional study. METHODS: This study included 209 intensive care unit nurses from five general hospitals. The Work-Family Conflict Scale, the Ruminative Response Scale, the Positive and Negative Affect Schedule-Negative Affectivity, and three items indicating nurses' perception of overall patient safety were used to gather data. Associations between work-family conflict, rumination, negative affectivity, and nurse-assessed patient safety were assessed using correlation and serial multiple mediation analysis. RESULTS: Work-family conflict, rumination, negative affectivity, and nurse-assessed patient safety were significantly correlated (p < 0.01). Work-family conflict can have not only a direct negative impact on the nurse-assessed patient safety (effect = -0.0234; standard error [SE] = 0.0116; 95% confidence interval [CI]: lower limit [LL] = -0.0464, upper limit [UL] = -0.0005) but also an indirect impact on nurse-assessed patient safety through three paths: the independent mediating role of rumination (effect = -0.0118; SE = 0.0063; 95% CI: LL = -0.0251, UL = -0.0006), the independent mediating role of negative affectivity (effect = -0.0055; SE = 0.0039; 95% CI: LL = -0.0153, UL = -0.0001), and the chain-mediating role of rumination and negative affectivity (effect = -0.0078; SE = 0.0031; 95% CI: LL = -0.0152, UL = -0.0027). CONCLUSION: Our findings indicated that work-family conflict could influence nurse-assessed patient safety through increasing rumination and negative affectivity among intensive care unit nurses. Based on the results, interventions aimed at decreasing work-family conflict would be beneficial for intensive care unit nurses' emotional stability and patient safety.

HLA-A+ tertiary lymphoid structures with reactivated tumor infiltrating lymphocytes are associated with a positive immunotherapy response in esophageal squamous cell carcinoma.

BACKGROUND: Immune checkpoint blockade (ICB) therapy provides remarkable clinical benefits for multiple cancer types. However, the overall response rate to ICB therapy remains low in esophageal squamous cell carcinoma (ESCC). This study aimed to identify biomarkers of ICB therapy for ESCC and interrogate its potential clinical relevance. METHODS: We investigated gene expression in 42 treatment-naïve ESCC tumor tissues and identified differentially expressed genes, tumor-infiltrating lymphocytes and immune-related genes signatures associated with differential immunotherapy responses. We systematically assessed the tumor microenvironment using the NanoString GeoMx digital spatial profiler, single-cell RNA-seq and multiplex immunohistochemistry in ESCC. Finally, we evaluated the associations between HLA-A-positive tertiary lymphoid structures (TLSs) and patients' responses to ICB in 60 ESCC patients. RESULTS: Tumor infiltrating B lymphocytes and several immune-related gene signatures, such as the antigen presenting machinery (APM) signature, are significantly elevated in ICB treatment responders. Multiplex immunohistochemistry identified the presence of HLA-A+ TLSs and showed that TLS-resident cells increasingly express HLA-A as TLSs mature. Most TLS-resident HLA-A+ cells are tumor-infiltrating T (TIL-T) or tumor-infiltrating B (TIL-B) lymphocytes. Digital spatial profiling of spatially distinct TIL-T lymphocytes and single-cell RNA-seq data from 60 ESCC tumor tissues revealed that CXCL13-expressing exhausted TIL-Ts inside TLSs are reactivated with elevated expression of the APM signature as TLSs mature. Finally, we demonstrated that HLA-A+ TLSs and their major cellular components, TIL-Ts and TIL-Bs, are associated with a clinical benefit from ICB treatment for ESCC. CONCLUSIONS: HLA-A+ TLSs are present in ESCC tumor tissues. TLS-resident TIL-Ts with elevated expression of the APM signature may be reactivated. HLA-A+ TLSs and their major cellular components, TIL-Ts and TIL-Bs, may serve as biomarkers for ICB-treated ESCC patients.

Research on prediction of PPV in open-pit mine used RUN-XGBoost model.

The drill-blasting method is a commonly used mining technique in open-pit mines, and the peak particle velocity (PPV) caused by blasting vibrations is an important indicator for evaluating the rationality of blasting mining design parameters. To develop an effective PPV prediction model, a parameter self-optimizing RUN-XGBoost prediction model is implemented using the Runge-Kutta optimization algorithm (RUN) combined with extreme gradient boosting (XGBoost). The factors affecting the prediction of PPV, including maximum explosive (ME), total explosive (TE), blast center distance (BCD), blast hole depth (BHD), and height difference between the measurement location and the blast location (DH), are selected as the influencing indicators. 188 pieces of blasting operation data were measured at the RK open pit copper-cobalt mine. Then, the RUN-XGBoost prediction model for PPV is studied and compared with the Sadovsky empirical formula, traditional XGBoost model, PSO-XGBoost model, and some traditional machine learning models (Ridge, LASSO, SVM, and SVR) using R2, RMSE, VAF, MAE, and MBE as evaluation indicators for model prediction results. Finally, the Shapley Additive Explanations (SHAP) method is used to evaluate the contribution of different influencing indicators to the PPV prediction results. The results show that the RUN-XGBoost prediction model is significantly better than other machine learning models and the Sadovsky empirical formula in the prediction of PPV, further demonstrating that the RUN-XGBoost prediction model can handle the nonlinear features of multiple factors and provide a reliable, simple, and effective PPV prediction model, forming a rapid prediction and evaluation method for blasting vibrations in open-pit mining.

Improving tumor sensitivity by the introduction of an ester chain to triaryl derivatives targeting PD-1/PD-L1.

PD-1/PD-L1 pathway blockade is a promising immunotherapy for the treatment of cancer. In this manuscript, a series of triaryl compounds containing ester chains were designed and synthesized based on the pharmacophore studies of the lead BMS-1. After several SAR iterations, 22 showed the best biochemical activity binding to hPD-L1 with an IC50 of 1.21 nM in HTRF assay, and a KD value of 5.068 nM in SPR analysis. Cell-based experiments showed that 22 effectively promoted A549 cell death by restoring T-cell immune function. 22 showed significant in vivo antitumor activity in a 4T1 mouse model without obvious toxicity, with a TGI rate of 67.8 % (20 mg/kg, ip). Immunohistochemistry data indicated that 22 activates the immune activity in tumors. These results suggest that 22 is a promising compound for further development of PD-1/PD-L1 inhibitor for cancer therapy.

Progress in approved drugs from natural product resources.

Natural products (NPs) have consistently played a pivotal role in pharmaceutical research, exerting profound impacts on the treatment of human diseases. A significant proportion of approved molecular entity drugs are either directly derived from NPs or indirectly through modifications of NPs. This review presents an overview of NP drugs recently approved in China, the United States, and other countries, spanning various disease categories, including cancers, cardiovascular and cerebrovascular diseases, central nervous system disorders, and infectious diseases. The article provides a succinct introduction to the origin, activity, development process, approval details, and mechanism of action of these NP drugs.

Stereoselective Synthesis of ß, γ-Fused Bicyclic γ-Ureasultams via an Intramolecular Mannich and aza-Michael Addition Cascade.

A novel approach has been developed for the synthesis of bicyclic ß, γ-fused bicyclic γ-ureasultams containing two consecutive chiral centers through an intramolecular Mannich and aza-Michael addition cascade of alkenyl sulfamides. The straightforward practical procedure and readily available starting materials enable the synthesis of variously substituted ureasultams. In addition, bicyclic γ-ureasultams is a class of potential biotin analogues.

Light and matter co-confined multi-photon lithography.

Mask-free multi-photon lithography enables the fabrication of arbitrary nanostructures low cost and more accessible than conventional lithography. A major challenge for multi-photon lithography is to achieve ultra-high precision and desirable lateral resolution due to the inevitable optical diffraction barrier and proximity effect. Here, we show a strategy, light and matter co-confined multi-photon lithography, to overcome the issues via combining photo-inhibition and chemical quenchers. We deeply explore the quenching mechanism and photoinhibition mechanism for light and matter co-confined multiphoton lithography. Besides, mathematical modeling helps us better understand that the synergy of quencher and photo-inhibition can gain a narrowest distribution of free radicals. By using light and matter co-confined multiphoton lithography, we gain a 30 nm critical dimension and 100 nm lateral resolution, which further decrease the gap with conventional lithography.

Ultrasound-Assisted CRISPRi-Exosome for Epigenetic Modification of α-Synuclein Gene in a Mouse Model of Parkinson's Disease.

Currently, there is a lack of effective treatment for Parkinson's disease (PD). In PD patients, aberrant methylation of SNCA (α-synuclein gene) has been reported and may be a potential therapeutic target. In this study, we established an epigenetic regulation platform based on an exosomal CRISPR intervention system. With the assist of focused ultrasound (FUS) opening the blood-brain barrier, engineered exosomes carrying RVG (rabies viral glycoprotein) targeting peptide, sgRNA (single guide RNA), and dCas9-DNMT3A (named RVG-CRISPRi-Exo) were efficiently delivered into the brain lesions and induced specific methylation of SNCA. In vivo, FUS combined with RVG-CRISPRi-Exo significantly improved motor performance, balance coordination, and neurosensitivity in PD mice, greatly down-regulated the elevation of α-synuclein (α-syn) caused by modeling, rescued cell apoptosis, and alleviated the progression of PD in mice. [18F]-FP-DTBZ imaging suggested that the synaptic function of the nigrostriatal pathway could be restored, which was conducive to the control of motor behavior in PD mice. Pyrosequencing results showed that RVG-CRISPRi-Exo could methylate CpG at specific sites of SNCA, and this fine-tuned editing achieved good therapeutic effects in PD model mice. In vitro, RVG-CRISPRi-Exo down-regulated SNCA transcripts and α-syn expression and relieved neuronal cell damage. Collectively, our findings provide a proof-of-principle for the development of targeted brain nanodelivery based on engineered exosomes and provide insights into epigenetic regulation of brain diseases.

Construction of poly (ionic liquid)-derived gold/silver alloy@nitrogen-doped carbon shell and its application for ratiometric electrochemical detection of nitric oxide.

A nitrogen-doped carbon shell loaded with a gold and silver alloy (Au/Ag@NCS) was constructed for highly sensitive electrochemical detection of NO. The Au/Ag@NCS material was prepared by use of SiO2 particles as a template to polymerize imidazolium-based ionic liquids loaded with gold and silver salts, and subsequent carbonization treatment and template removal. The hollow structure of the carbon material acted as a carrier for electrochemical sensing, offering high specific surface area, large pore capacity, robust electron conductivity, and excellent mechanical stability. The inclusion of gold in the composite enhanced its catalytic and sensing capabilities, while silver oxidation was employed as a reference signal for accurate detection. By utilization of the Au/Ag@NCS-modified electrode, a wide detection range from 0.5 nM to 1.05 µM with a low detection limit of 0.32 nM was achieved for NO detection. The electrochemical sensor also exhibited high selectivity and excellent stability. The fabricated sensor was further utilized to explore the release of NO from breast cancer cells, revealing that the electrochemical platform could be regarded as an important method to study the daily tests of NO in clinical application.

Insight into the Storage Mechanism of Sandwich-Like Molybdenum Disulphide/Carbon Nanofibers Composite in Aluminum-Ion Batteries.

Aluminum-ion batteries (AIBs) have become a research hotspot in the field of energy storage due to their high energy density, safety, environmental friendliness, and low cost. However, the actual capacity of AIBs is much lower than the theoretical specific capacity, and their cycling stability is poor. The exploration of energy storage mechanisms may help in the design of stable electrode materials, thereby contributing to improving performance. In this work, molybdenum disulfide (MoS2) was selected as the host material for AIBs, and carbon nanofibers (CNFs) were used as the substrate to prepare a molybdenum disulfide/carbon nanofibers (MoS2/CNFs) electrode, exhibiting a residual reversible capacity of 53 mAh g-1 at 100 mA g-1 after 260 cycles. The energy storage mechanism was understood through a combination of electrochemical characterization and first-principles calculations. The purpose of this study is to investigate the diffusion behavior of ions in different channels in the host material and its potential energy storage mechanism. The computational analysis and experimental results indicate that the electrochemical behavior of the battery is determined by the ion transport mechanism between MoS2 layers. The insertion of ions leads to lattice distortion in the host material, significantly impacting its initial stability. CNFs, serving as a support material, not only reduce the agglomeration of MoS2 grown on its surface, but also effectively alleviate the volume expansion caused by the host material during charging and discharging cycles.

Deep learning on tertiary lymphoid structures in hematoxylin-eosin predicts cancer prognosis and immunotherapy response.

Tertiary lymphoid structures (TLSs) have been associated with favorable immunotherapy responses and prognosis in various cancers. Despite their significance, their quantification using multiplex immunohistochemistry (mIHC) staining of T and B lymphocytes remains labor-intensive, limiting its clinical utility. To address this challenge, we curated a dataset from matched mIHC and H&E whole-slide images (WSIs) and developed a deep learning model for automated segmentation of TLSs. The model achieved Dice coefficients of 0.91 on the internal test set and 0.866 on the external validation set, along with intersection over union (IoU) scores of 0.819 and 0.787, respectively. The TLS ratio, defined as the segmented TLS area over the total tissue area, correlated with B lymphocyte levels and the expression of CXCL13, a chemokine associated with TLS formation, in 6140 patients spanning 16 tumor types from The Cancer Genome Atlas (TCGA). The prognostic models for overall survival indicated that the inclusion of the TLS ratio with TNM staging significantly enhanced the models' discriminative ability, outperforming the traditional models that solely incorporated TNM staging, in 10 out of 15 TCGA tumor types. Furthermore, when applied to biopsied treatment-naïve tumor samples, higher TLS ratios predicted a positive immunotherapy response across multiple cohorts, including specific therapies for esophageal squamous cell carcinoma, non-small cell lung cancer, and stomach adenocarcinoma. In conclusion, our deep learning-based approach offers an automated and reproducible method for TLS segmentation and quantification, highlighting its potential in predicting immunotherapy response and informing cancer prognosis.

Two types of coumarins-specific enzymes complete the last missing steps in pyran- and furanocoumarins biosynthesis.

Pyran- and furanocoumarins are key representatives of tetrahydropyrans and tetrahydrofurans, respectively, exhibiting diverse physiological and medical bioactivities. However, the biosynthetic mechanisms for their core structures remain poorly understood. Here we combined multiomics analyses of biosynthetic enzymes in Peucedanum praeruptorum and in vitro functional verification and identified two types of key enzymes critical for pyran and furan ring biosynthesis in plants. These included three distinct P. praeruptorum prenyltransferases (PpPT1-3) responsible for the prenylation of the simple coumarin skeleton 7 into linear or angular precursors, and two novel CYP450 cyclases (PpDC and PpOC) crucial for the cyclization of the linear/angular precursors into either tetrahydropyran or tetrahydrofuran scaffolds. Biochemical analyses of cyclases indicated that acid/base-assisted epoxide ring opening contributed to the enzyme-catalyzed tetrahydropyran and tetrahydrofuran ring refactoring. The possible acid/base-assisted catalytic mechanisms of the identified cyclases were theoretically investigated and assessed using site-specific mutagenesis. We identified two possible acidic amino acids Glu303 in PpDC and Asp301 in PpOC as vital in the catalytic process. This study provides new enzymatic tools in the epoxide formation/epoxide-opening mediated cascade reaction and exemplifies how plants become chemically diverse in terms of enzyme function and catalytic process.

Uniform Nanoscale Ion-Selective Membrane Prepared by Precision Control of Solution Spreading and Evaporation.

Ion-selective membrane has broad application in various fields, while the present solution-processed techniques can only prepare uniform membrane with microscale thickness. Herein, a high-quality polymer membrane with nanoscale thickness and uniformity is precisely prepared by controlling solution spreading and solvent evaporation stability/rate. With the arrayed capillaries, the stable spreading of polymer solution with volume of microliter induces the formation of solution film with micrometers thickness. Moreover, the fast increase of solution dynamic viscosity during solvent evaporation inhibits nonuniform Marangoni flow and capillary flow in solution film. Consequently, the uniform Nafion-Li membranes with ∼200 nm thickness are prepared, while their Li+ conductivity is 2 orders of magnitude higher than that of commercially Nafion-117 membrane. Taking lithium-sulfur battery as a model device, the cells (capacities of 8-10 mAh cm-2) can stably operate for 150 cycles at a S loading of 12 mg cm-2 and an electrolyte/sulfur ratio of ∼7.

Regioselective Olefination and Arylation of Arene-Tethered Diols Using the Easily Foldable Directing Groups.

Arene-tethered diols constitute a valuable class of structural motifs of drug and bioactive natural product molecules. In this study, a regioselective protocol for olefination and arylation of arene-tethered 1,2-diols and 1,3-diols has been developed using easily foldable acetal structures for attaching pyridine and nitrile directing groups. The method overcomes the steric hindrance effect of the short-chain diols and affords products in high yield and regioselectivity. This efficient cascaded catalysis has been successfully utilized in the syntheses of natural products such as peucedanol, decursinol, and marmesin.

Ratiometric electrochemical determination of hydroxyl radical based on graphite paper modified with metal-organic frameworks and impregnated with salicylic acid.

Hydroxyl radical (•OH) detection is pivotal in medicine, biochemistry and environmental chemistry. Yet, electrochemical method-specific detection is challenging because of hydroxyl radicals' high reactivity and short half-life. In this study, we aimed to modify the electrode surface with a specific recognition probe for •OH. To achieve this, we conducted a one-step hydrothermal process to fabricate a CoZnMOF bimetallic organic framework directly onto conductive graphite paper (Gp). Subsequently, we introduced salicylic acid (SA) and methylene blue (MB), which easily penetrated the pores of CoZnMOF. By selectively capturing •OH by SA and leveraging the electrochemical signal generated by the reaction product, we successfully developed an electrochemical sensor Gp/CoZnMOF/SA + MB. The prepared sensor exhibited a good linear relationship with •OH concentrations ranging from 1.25 to 1200 nM, with a detection limit of 0.2 nM. Additionally, the sensor demonstrated excellent reproducibility and accuracy due to the incorporation of an internal reference. It exhibited remarkable selectivity for •OH detection, unaffected by other electrochemically active substances. The establishment of this sensor provides a way to construct MOF-modified sensors for the selective detection of other reactive oxygen species (ROS), offering a valuable experimental basis for ROS-related disease research and environmental safety investigations.

Enhanced Fe(ii)/Fe(iii) cycle by boron enabled efficient Cr(vi) removal with microscale zero-valent iron.

Recently, researchers have been paying much attention to zero-valent iron (ZVI) in the field of pollution remediation. However, the depressed electron transport from the iron reservoir to the iron oxide shell limited the wide application of ZVI. This study was aimed at promoting the performance of microscale ZVI (mZVI) for hexavalent chromium (Cr(vi)) removal by accelerating iron cycle with the addition of boron powder. It was found that the addition of boron powder enhanced the Cr(vi) removal rate by 2.1 times, and the proportion of Cr(iii) generation after Cr(vi) removal process also increased, suggesting that boron could promote the reduction pathway of Cr(vi) to Cr(iii). By further comparing the Cr(vi) removal percentage of Fe(iii) with or without the boron powder, we found that boron powder could promote the percentage removal of Cr(vi) with Fe(iii) from 10.1% to 33.6%. Moreover, the presence of boron powder could decrease the potential gap values (ΔEp) between Fe(iii) reduction and Fe(ii) oxidation from 0.668 V to 0.556 V, further indicating that the added boron powder could act as an electron sacrificial agent to promote the reduction process of Fe(iii) to Fe(ii), and thus enhancing the reduction of Cr(vi) with Fe(ii). This study shed light on the promoted mechanism of Cr(vi) removal with boron powder and provided an environmentally friendly and efficient approach to enhance the reactivity of the mZVI powder, which would benefit the wide application of mZVI technology in the environmental remediation field.