A topical VAEGAN-IHMM approach for automatic story segmentation.

Feature representations with rich topic information can greatly improve the performance of story segmentation tasks. VAEGAN offers distinct advantages in feature learning by combining variational autoencoder (VAE) and generative adversarial network (GAN), which not only captures intricate data representations through VAE's probabilistic encoding and decoding mechanism but also enhances feature diversity and quality via GAN's adversarial training. To better learn topical domain representation, we used a topical classifier to supervise the training process of VAEGAN. Based on the learned feature, a segmentor splits the document into shorter ones with different topics. Hidden Markov model (HMM) is a popular approach for story segmentation, in which stories are viewed as instances of topics (hidden states). The number of states has to be set manually but it is often unknown in real scenarios. To solve this problem, we proposed an infinite HMM (IHMM) approach which utilized an HDP prior on transition matrices over countably infinite state spaces to automatically infer the state's number from the data. Given a running text, a Blocked Gibbis sampler labeled the states with topic classes. The position where the topic changes was a story boundary. Experimental results on the TDT2 corpus demonstrated that the proposed topical VAEGAN-IHMM approach was significantly better than the traditional HMM method in story segmentation tasks and achieved state-of-the-art performance.

Substantial Underestimation of Fine-Mode Aerosol Loading from Wildfires and Its Radiative Effects in Current Satellite-Based Retrievals over the United States.

Wildfires generate abundant smoke primarily composed of fine-mode aerosols. However, accurately measuring the fine-mode aerosol optical depth (fAOD) is highly uncertain in most existing satellite-based aerosol products. Deep learning offers promise for inferring fAOD, but little has been done using multiangle satellite data. We developed an innovative angle-dependent deep-learning model (ADLM) that accounts for angular diversity in dual-angle observations. The model captures aerosol properties observed from dual angles in the contiguous United States and explores the potential of Greenhouse gases Observing Satellite-2's (GOSAT-2) measurements to retrieve fAOD at a 460 m spatial resolution. The ADLM demonstrates a strong performance through rigorous validation against ground-based data, revealing small biases. By comparison, the official fAOD product from the Moderate Resolution Imaging Spectroradiometer (MODIS), the Visible Infrared Imaging Radiometer Suite (VIIRS), and the Multiangle Imaging Spectroradiometer (MISR) during wildfire events is underestimated by more than 40% over western USA. This leads to significant differences in estimates of aerosol radiative forcing (ARF) from wildfires. The ADLM shows more than 20% stronger ARF than the MODIS, VIIRS, and MISR estimates, highlighting a greater impact of wildfire fAOD on Earth's energy balance.

Development and validation of an integrated system for lung cancer screening and post-screening pulmonary nodules management: a proof-of-concept study (ASCEND-LUNG).

Background: In order to address the low compliance and dissatisfied specificity of low-dose computed tomography (LDCT), efficient and non-invasive approaches are needed to complement its limitations for lung cancer screening and management. The ASCEND-LUNG study is a prospective two-stage case-control study designed to evaluate the performance of a liquid biopsy-based comprehensive lung cancer screening and post-screening pulmonary nodules management system. Methods: We aimed to develop a comprehensive lung cancer system called Peking University Lung Cancer Screening and Management System (PKU-LCSMS) which comprises a lung cancer screening model to identify specific populations requiring LDCT and an artificial intelligence-aided (AI-aided) pulmonary nodules diagnostic model to classify pulmonary nodules following LDCT. A dataset of 465 participants (216 cancer, 47 benign, 202 non-cancer control) were used for the two models' development phase. For the lung cancer screening model development, cancer participants were randomly split at a ratio of 1:1 into the train and validation cohorts, and then non-cancer controls were age-matched to the cancer cases in a 1:1 ratio. Similarly, for the AI-aided pulmonary nodules model, cancer and benign participants were also randomly divided at a ratio of 2:1 into the train and validation cohorts. Subsequently, during the model validation phase, sensitivity and specificity were validated using an independent validation cohort consisting of 291 participants (140 cancer, 25 benign, 126 non-cancer control). Prospectively collected blood samples were analyzed for multi-omics including cell-free DNA (cfDNA) methylation, mutation, and serum protein. Computerized tomography (CT) images data was also obtained. Paired tissue samples were additionally analyzed for DNA methylation, DNA mutation, and messenger RNA (mRNA) expression to further explore the potential biological mechanisms. This study is registered with ClinicalTrials.gov, NCT04817046. Findings: Baseline blood samples were evaluated for the whole screening and diagnostic process. The cfDNA methylation-based lung cancer screening model exhibited the highest area under the curve (AUC) of 0.910 (95% CI, 0.869-0.950), followed by the protein model (0.891 [95% CI, 0.845-0.938]) and lastly the mutation model (0.577 [95% CI, 0.482-0.672]). Further, the final screening model, which incorporated cfDNA methylation and protein features, achieved an AUC of 0.963 (95% CI, 0.942-0.984). In the independent validation cohort, the multi-omics screening model showed a sensitivity of 99.2% (95% CI, 0.957-1.000) at a specificity of 56.3% (95% CI, 0.472-0.652). For the AI-aided pulmonary nodules diagnostic model, which incorporated cfDNA methylation and CT images features, it yielded a sensitivity of 81.1% (95% CI, 0.732-0.875), a specificity of 76.0% (95% CI, 0.549-0.906) in the independent validation cohort. Furthermore, four differentially methylated regions (DMRs) were shared in the lung cancer screening model and the AI-aided pulmonary nodules diagnostic model. Interpretation: We developed and validated a liquid biopsy-based comprehensive lung cancer screening and management system called PKU-LCSMS which combined a blood multi-omics based lung cancer screening model incorporating cfDNA methylation and protein features and an AI-aided pulmonary nodules diagnostic model integrating CT images and cfDNA methylation features in sequence to streamline the entire process of lung cancer screening and post-screening pulmonary nodules management. It might provide a promising applicable solution for lung cancer screening and management. Funding: This work was supported by Science, Science, Technology & Innovation Project of Xiongan New Area, Beijing Natural Science Foundation, CAMS Innovation Fund for Medical Sciences (CIFMS), Clinical Medicine Plus X-Young Scholars Project of Peking University, the Fundamental Research Funds for the Central Universities, Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, Peking University People's Hospital Research and Development Funds, National Key Research and Development Program of China, and the fundamental research funds for the central universities.

Prognostic factors in children and adolescents with differentiated thyroid cancer treated with total thyroidectomy and radioiodine therapy: a retrospective two-center study from China.

Purpose: This two-center study aimed to explore the main prognostic factors affecting the final disease status in children and adolescents with differentiated thyroid cancer (caDTC) following total thyroidectomy and radioiodine therapy (RAIT). Materials and methods: All caDTC patients from two centers in the period from 2004-2022 were retrospectively included. At the last follow-up, the patients' disease status was assessed and classified as an incomplete response (IR) or as an excellent or indeterminate response (EIDR). Then, the difference in preablation stimulated thyroglobulin (ps-Tg) levels between the two groups was compared, and the threshold for predicting IR was determined using receiver operating characteristic (ROC) analysis. Moreover, univariate and multivariate analyses were conducted to identify the factors influencing the patients' ultimate disease outcomes. Results: A total of 143 patients (98 females, 45 males; median age 16 years) were recruited. After a median follow-up of 42.9 months, 80 patients (55.9%) exhibited an EIDR, whereas 63 patients (44.1%) exhibited an IR. Patients with an IR had significantly greater ps-Tg levels than did those with an EIDR (median ps-Tg 79.2 ng/mL vs. 9.3 ng/mL, p<0.001). The ROC curve showed that ps-Tg ≥20 ng/mL was the most accurate for predicting IR at the last follow-up. According to multivariate analysis, only ps-Tg, T stage and the therapeutic response to initial RAIT were significantly associated with IR. Conclusion: In caDTC patients, the ps-Tg level, T stage, and response to initial RAIT are critical final outcome indicators.

The small molecule inhibitor of SARS-CoV-2 3CLpro EDP-235 prevents viral replication and transmission in vivo.

The COVID-19 pandemic has led to the deaths of millions of people and severe global economic impacts. Small molecule therapeutics have played an important role in the fight against SARS-CoV-2, the virus responsible for COVID-19, but their efficacy has been limited in scope and availability, with many people unable to access their benefits, and better options are needed. EDP-235 is specifically designed to inhibit the SARS-CoV-2 3CLpro, with potent nanomolar activity against all SARS-CoV-2 variants to date, as well as clinically relevant human and zoonotic coronaviruses. EDP-235 maintains potency against variants bearing mutations associated with nirmatrelvir resistance. Additionally, EDP-235 demonstrates a ≥ 500-fold selectivity index against multiple host proteases. In a male Syrian hamster model of COVID-19, EDP-235 suppresses SARS-CoV-2 replication and viral-induced hamster lung pathology. In a female ferret model, EDP-235 inhibits production of SARS-CoV-2 infectious virus and RNA at multiple anatomical sites. Furthermore, SARS-CoV-2 contact transmission does not occur when naïve ferrets are co-housed with infected, EDP-235-treated ferrets. Collectively, these results demonstrate that EDP-235 is a broad-spectrum coronavirus inhibitor with efficacy in animal models of primary infection and transmission.

Clinicopathological features affecting the efficacy in 131I ablation therapy of papillary thyroid carcinoma with lymph node metastasis.

Background: Lymph node metastasis is the major cause of increased recurrence and death in patients with papillary thyroid carcinoma (PTC). We evaluate the clinicopathologic factors affecting excellent response (ER) in patients with PTC with lymph node metastasis following operation and 131I ablation therapy. Methods: A total of 423 patients with PTC with lymph node metastasis who underwent thyroidectomy and postoperative 131I ablation therapy were enrolled. The relationship between clinicopathological factors affecting ER achievement was analyzed. Results: Multivariate analysis showed that the foci diameter (≤1 cm), unifocal, combination with Hashimoto's thyroiditis (HT), lymph node metastases rate (LR) (≤40%), no postoperative lymph node metastasis, low preablative stimulated thyroglobulin (ps-Tg) level (≤3.87 ng/mL), and the time of 131I ablation therapy (one time) were positively correlated with the ER achievement [odds ratio (OR): 1.744, 3.114, 3.920, 4.018, 2.074, 9.767, and 49.491, respectively; all p < 0.05]. The receiver operating characteristic (ROC) curves showed that the cutoff values of ps-Tg and LR were 4.625 ng/mL and 50.50%, respectively. The AUC of ROC of ps-Tg and LR for predicting ER achievement was 0.821 and 0.746, respectively. The Tg and the cumulative risk of non-ER elevated with the increase of LR, especially for the high-level ps-Tg (>4.625 ng/mL) group. Conclusion: The foci diameter and number, combination with HT, LR, and ps-Tg level are independent factors for ER. Ps-Tg level and LR are valid predictive factors for the efficacy of 131I therapy in patients with PTC. The predictive value of the cumulative risk of non-ER can be improved by the combination of ps-Tg and LR.

Sequential dual-locking strategy using photoactivated Pt(IV)-based metallo-nano prodrug for enhanced chemotherapy and photodynamic efficacy by triggering ferroptosis and macrophage polarization.

Selective activation of Pt(IV) prodrugs within tumors has emerged as a promising strategy in tumor treatment. Although progress has been made with photo- and ultrasound-activated Pt(IV) prodrugs, concerns remain over the non-specific activation of photosensitizers (PS) and the potential for phototoxicity and chemical toxicity. In this study, a sequential dual-locked Pt(IV) nano-prodrug that can be activated by both the acidic tumor microenvironment and light was developed. The Pt(IV) prodrug was prepared by conjugating PS-locked Pt(IV) to a polymeric core, which was then chelated with metallo iron to lock its photoactivity and form a metallo-nano prodrug. Under acidic tumor microenvironment conditions, the metallo-nano prodrug undergoes dissociation of iron, triggering a reduction process in oxaliplatin under light irradiation, resulting in the activation of both chemotherapy and photodynamic therapy (PDT). Additionally, the prodrug could induce metallo-triggered ferroptosis and polarization of tumor-associated macrophages (TAM), thereby enhancing tumor inhibition. The dual-lock strategy employed in a nanoparticle delivery system represents an expansion in the application of platinum-based anticancer drugs, making it a promising new direction in cancer treatment.

Harnessing Electro-Descriptors for Mechanistic and Machine Learning Analysis of Photocatalytic Organic Reactions.

Photocatalysis has emerged as an effective tool for addressing the contemporary challenges in organic synthesis. However, the trial-and-error-based screening of feasible substrates and optimal reaction conditions remains time-consuming and potentially expensive in industrial practice. Here, we demonstrate an electrochemical-based data-acquisition approach that derives a simple set of redox-relevant electro-descriptors for effective mechanistic analysis and performance evaluation through machine learning (ML) in photocatalytic synthesis. These electro-descriptors correlate to the quantification of shifted charge transfer processes in response to the photoirradiation and enabled construction of reactivity diagram where high-yield reactive "hot zones" can reflect subtle changes of the reaction system. For the model reaction of photocatalytic deoxygenation reaction, the influence of varying carboxylic acids (substrate A, oxidation-intended) and alkenes (substrate B, reduction-intended) and varying reaction conditions on the reaction yield can be visualized, while mathematical analysis of the electro-descriptor patterns further revealed distinct mechanistic/kinetic impacts from different substrates and conditions. Additionally, in the application of ML algorithms, the experimentally derived electro-descriptors reflect an overall redox kinetic outcome contributed from vast reaction parameters, serving as a capable means to reduce the dimensionality in the case of complex multiparameter chemical space. As a result, utilization of electro-descriptors enabled efficient and robust quantitative evaluation of chemical reactivity, demonstrating promising potential of introducing operando-relevant experimental insights in the data-driven chemistry.

Ring Contraction of Saturated Cyclic Amines and Rearrangement of Acyclic Amines Through Their Corresponding Hydroxylamines.

Compared to modifications at the molecular periphery, skeletal adjustments present greater challenges. Within this context, skeletal rearrangement technology stands out for its significant advantages in rapidly achieving structural diversity. Yet, the development of this technology for ring contraction of saturated cyclic amines remains exceedingly rare. While most existing methods rely on specific substitution patterns to achieve ring contraction, there is a persistent demand for a more general strategy for substitution-free cyclic amines. To address this issue, we report a B(C6F5)3-catalyzed skeletal rearrangement of hydroxylamines with hydrosilanes. This methodology, when combined with the N-hydroxylation of amines, enables the regioselective ring contraction of cyclic amines and proves equally effective for rapid reorganization of acyclic amine skeletons. By this, the direct scaffold hopping of drug molecules and the strategic deletion of carbon atoms are achieved in a mild manner. Based on mechanistic experiments and density functional theory calculations, a possible mechanism for this process is proposed.

Quantifying the pollution changes and meteorological dependence of airborne trace elements coupling source apportionment and machine learning.

Airborne trace elements (TEs) present in atmospheric fine particulate matter (PM2.5) exert notable threats to human health and ecosystems. To explore the impact of meteorological conditions on shaping the pollution characteristics of TEs and the associated health risks, we quantified the variations in pollution characteristics and health risks of TEs due to meteorological impacts using weather normalization and health risk assessment models, and analyzed the source-specific contributions and potential sources of primary TEs affecting health risks using source apportionment approaches at four sites in Shandong Province from September to December 2021. Our results indicated that TEs experience dual effects from meteorological conditions, with a tendency towards higher TE concentrations and related health risks during polluted period, while the opposite occurred during clean period. The total non-carcinogenic and carcinogenic risks of TEs during polluted period increased approximately by factors of 0.53-1.74 and 0.44-1.92, respectively. Selenium (Se), manganese (Mn), and lead (Pb) were found to be the most meteorologically influenced TEs, while chromium (Cr) and manganese (Mn) were identified as the dominant TEs posing health risks. Enhanced emissions of multiple sources for Cr and Mn were found during polluted period. Depending on specific wind speeds, industrialized and urbanized centers, as well as nearby road dusts, could be key sources for TEs. This study suggested that attentions should be paid to not only the TEs from primary emissions but also the meteorology impact on TEs especially during pollution episodes to reduce health risks in the future.

Combination therapy using Cel-CSO/Taxol NPs for reversing drug resistance in breast cancer through inhibiting PI3K/AKT/NF-κB/HIF-1α pathway.

The resistance of malignant tumors to multiple drugs is a significant obstacle in cancer treatment and prognosis. Accordingly, we synthesized a celastrol (Cel) prodrug (Cel-CSO) by conjugating chitosan oligosaccharides (CSO) to Cel for reversing Taxol resistance in chemotherapy, followed by self-assembly with Taxol into a novel nanoplatform of Cel-CSO/Taxol nanoparticles (termed NPs). NPs showed a suitable size (about 153 nm), excellent stability and prolonged release of Cel and Taxol in a manner that depended on both pH and time. NPs effectively inhibited the overexpression of multidrug resistance-related protein P-gp, hypoxia inducible factor-1α (HIF-1α), and triggered the MCF-7/Taxol cell apoptosis through inhibiting the PI3K/AKT/NF-κB/HIF-1α pathway. In tumor-bearing mice, NPs exhibited significant curative effects in inducing apoptosis of MCF-7/Taxol tumors which showed a low expression level of P-gp, microtubule-related proteins TUBB3 and Tau. The results indicated that NPs may be a promising strategy to overcome drug resistance caused by P-gp, which improve the antitumor effects in drug-resistant breast cancer.

Early detection and stratification of colorectal cancer using plasma cell-free DNA fragmentomic profiling.

Timely accurate and cost-efficient detection of colorectal cancer (CRC) is of great clinical importance. This study aims to establish prediction models for detecting CRC using plasma cell-free DNA (cfDNA) fragmentomic features. Whole-genome sequencing (WGS) was performed on cfDNA from 620 participants, including healthy individuals, patients with benign colorectal diseases and CRC patients. Using WGS data, three machine learning methods were compared to build prediction models for the stratification of CRC patients. The optimal model to discriminate CRC patients of all stages from healthy individuals achieved a sensitivity of 92.31% and a specificity of 91.14%, while the model to separate early-stage CRC patients (stage 0-II) from healthy individuals achieved a sensitivity of 88.8% and a specificity of 96.2%. Additionally, the cfDNA fragmentation profiles reflected disease-specific genomic alterations in CRC. Overall, this study suggests that cfDNA fragmentation profiles may potentially become a noninvasive approach for the detection and stratification of CRC.

Assembly mechanism and stability of zooplankton communities affected by China's south-to-north water diversion project.

Water diversion can effectively alleviate water resource shortages and improve water environmental conditions, while also causing unknown ecological consequences, in particular, the assembly mechanism of zooplankton communities in the affected areas will become more complex after long-term water transfer. Taking Nansi Lake, the second largest impounded lake along the eastern route of China's South to North Water Diversion Project (SNWDP), as an example, the composition and diversity of zooplankton communities in the lake area and estuaries during the water diversion period (WDP) and non-water diversion period (NWDP) were studied. The potential assembly process of zooplankton communities was further explored, and the stability of communities in different regions during different periods was compared. The related results indicated that the changes in water quality conditions induced by water diversion had a relatively weak impact on the zooplankton communities. In the assembly mechanism of zooplankton communities, stochastic process played a more important role during both WDP or NWDP, and the proportion of deterministic process was relatively higher during NWDP, which may be related to the greater role of total nitrogen (TN) in the assembly of the zooplankton communities. The network analysis and cohesion calculation results showed that the stability of the zooplankton communities in the lake area sites was higher than that in the estuary sites, and the stability during NWDP was higher than that during WDP. In sum, the stability of zooplankton communities displayed a degree of change affected by water diversion activities, but the community assembly was not significantly influenced by the water quality fluctuations after about relatively long-term water diversion. This study provides an in-depth understanding of the ecological effects of water diversion on the biological communities in the affected lake, which is beneficial to the management and regulation of long-term water diversion projects.

Neurotransmitter system gene variants as biomarkers for the therapeutic efficacy of rTMS and SSRIs in obsessive-compulsive disorder.

Purpose: This study aims to examine the potential influence of RS4680 (COMT), RS16965628 (SLC6A4), and RS1019385 (GRIN2B) polymorphisms on the therapeutic response to repetitive transcranial magnetic stimulation (rTMS) and selective serotonin reuptake inhibitors (SSRIs) in individuals with obsessive-compulsive disorder (OCD). Patients and methods: Thirty-six untreated outpatients diagnosed with OCD were recruited and allocated to active or sham rTMS groups for two weeks. The mean age of the participants was 31.61, with 17 males (47.22%) and 19 females (52.78%). Peripheral blood samples (5 mL) were collected from each participant using ethylenediaminetetraacetic acid (EDTA) vacuum tubes for genotyping purposes, clinical evaluation was taken place at baseline and second week. Results: The A allele of RS4680, C allele of RS16965628, and GG allele of RS1019385 were identified as potential bio-markers for predicting treatment response to OCD treatments (rTMS & SSRIs). Conclusion: Those genes may serve as bio-markers for the combined treatment of rTMS and SSRIs in OCD. The finding hold promise for further research and the potential implementation of precision treatment of OCD. Clinical trial registration: https://www.chictr.org.cn, identifier ChiCTR1900023641.

A heterogeneous tumor immune microenvironment of uncommon epidermal growth factor receptor mutant non-small cell lung cancer.

Common epidermal growth factor receptor (EGFR) mutations are usually not considered for immunotherapy in non-small cell lung cancer (NSCLC) due to poor efficacy. However, whether uncommon EGFR mutations are suitable for immunotherapy has not been thoroughly studied. Thus, we explored the tumor immune microenvironment (TME) features in uncommon EGFR mutant NSCLC. In this study, a total of 41 patients with EGFR mutations were included, the majority (85.4%) of whom were stage I. Among them, 22 patients harbored common mutations, while 19 patients presented with uncommon mutations. Compared with common mutations, uncommon mutations exhibited more infiltrating T cells and fewer M2 macrophages, upregulated expression of antigen processing and a presentation pathway. Unsupervised clustering based on the mIF profile identified two classes with heterogeneous TME in uncommon mutations. Class 1 featured the absence of PD-1+ cytotoxic T cell infiltration, and class 2 displayed a hotter TME because of the downregulated expression of hypoxia (p < 0.001), oxidative phosphorylation (p = 0.009), and transforming growth factor beta signaling (p = 0.01) pathways as well as increased expression of CTLA4 (p = 0.001) and PDCD1 (p = 0.004). The association of CTLA4 and PDCD1 with TME profiles was validated in a TCGA lung adenocarcinoma cohort with uncommon EGFR mutations. Our study reveals the distinct and heterogeneous TME features in uncommon EGFR mutant NSCLC.

Identifying the spatio-seasonal pattern of hydrochemical evolution and surface water-groundwater interaction in a large urban river basin, Northwest China.

There is insufficient understanding of the spatio-temporal evolution of surface water-groundwater quality and hydraulic connection under both natural and human influences in urban river basins. To this end, this paper investigated the spatio-seasonal pattern of hydrochemical evolution and surface water-groundwater interaction in a typical urban river basin (Dahei River basin) based on isotopic and hydrochemical data of 132 water samples collected during three seasons (normal, wet and dry seasons). From the normal season to the wet season, surface water in the Dahei River basin was dominated by the impacts of evaporation and groundwater discharge processes. During this period, the precipitation and agricultural activities (canal irrigation) were frequent. Thus, groundwater was affected by irrigation infiltration of surface water and precipitation from high-altitude areas. From the wet season to the dry season, precipitation decreased and irrigation methods changed (canal irrigation → well irrigation). In this case, groundwater discharge had a stronger impact on surface water, and shallow groundwater was recharged by deep groundwater through the well irrigation. Under this hydrological pattern, the hydrochemical characteristics of surface water were mainly influenced by evaporation, human activities (agricultural irrigation and sewage treatment) and groundwater discharge. In contrast, the hydrochemical characteristics of groundwater were main influenced by water-rock interactions (dissolution of evaporites and silicates, and cation exchange) and human activities. This study contributed to a better understanding of the hydrochemical and hydrological processes in urban river basins and provided a theoretical basis for the sustainable management of water resources.

Evaluation of Molecular Residual Disease by a Fixed Panel in Resectable Colorectal Cancer.

Purpose: Molecular residual disease (MRD) is a promising biomarker in colorectal cancer (CRC) for prognosis and guiding treatment, while the whole-exome sequencing (WES) based tumor-informed assay is standard for evaluating MRD based on circulating tumor DNA (ctDNA). In this study, we assessed the feasibility of a fixed-panel for evaluating MRD in CRC. Materials and Methods: 75 patients with resectable stage I-III CRC were enrolled. Tumor tissues obtained by surgery, and pre-operative and post-operative day 7 blood samples were collected. The ctDNA was evaluated using the tumor-agnostic and tumor-informed fixed assays, as well as the WES-based and panel-based personalized assays in randomly selected patients. Results: The tumor-informed fixed assay had a higher pre-operative positive rate than the tumor-agnostic assay (73.3% vs 57.3%). The pre-op ctDNA status failed to predict disease-free survival (DFS) in either of the fixed assays, while the tumor-informed fixed assay-determined post-op ctDNA positivity was significantly associated with worse DFS (HR, 20.74, 95%CI 7.19-59.83; p<0.001), which was an independent predictor by multivariable analysis (HR, 28.57, 95%CI 7.10-114.9; p<0.001). Sub-cohort analysis indicated the WES-based personalized assay had the highest pre-operative positive rate (95.1%). The two personalized assays and the tumor-informed fixed assay demonstrated same results in post-op landmark (HR, 26.34, 95%CI, 6.01-115.57; p<0.001), outperforming the tumor-agnostic fixed panel (HR, 3.04, 95%CI, 0.94-9.89; p=0.052). Conclusion: Our study confirmed the prognostic value of the ctDNA positivity at post-op day 7 by the tumor-informed fixed panel. The tumor-informed fixed panel may be a cost-effective method to evaluate MRD, which warrants further studies in future.

Switching between the [2π+2σ] and Hetero-[4π+2σ] Cycloaddition Reactivity of Bicyclobutanes with Lewis Acid Catalysts Enables the Synthesis of Spirocycles and Bridged Heterocycles.

The exploration of the complex chemical diversity of bicyclo[n.1.1]alkanes and their use as benzene bioisosteres has garnered significant attention over the past two decades. Regiodivergent syntheses of thiabicyclo[4.1.1]octanes (S-BCOs) and highly substituted bicyclo[2.1.1]hexanes (BCHs) using a Lewis acid-catalyzed formal cycloaddition of bicyclobutanes (BCBs) and 3-benzylideneindoline-2-thione derivatives have been established. The first hetero-(4+3) cycloaddition of BCBs, catalyzed by Zn(OTf)2, was achieved with a broad substrate scope under mild conditions. In contrast, the less electrophilic BCB ester undergoes a Sc(OTf)3-catalyzed [2π+2σ] reaction with 1,1,2-trisubstituted alkenes, yielding BCHs with a spirocyclic quaternary carbon center. Control experiments and preliminary theoretical calculations suggest that the diastereoselective [2π+2σ] product formation may involve a concerted cycloaddition between a zwitterionic intermediate and E-1,1,2-trisubstituted alkenes. Additionally, the hetero-(4+3) cycloaddition may involve a concerted nucleophilic ring-opening mechanism.

Divergent Synthesis of Sulfur-Containing Bridged Cyclobutanes by Lewis Acid Catalyzed Formal Cycloadditions of Pyridinium 1,4-Zwitterionic Thiolates and Bicyclobutanes.

Bridged cyclobutanes and sulfur heterocycles are currently under intense investigation as building blocks for pharmaceutical drug design. Two formal cycloaddition modes involving bicyclobutanes (BCBs) and pyridinium 1,4-zwitterionic thiolate derivatives were described to rapidly expand the chemical space of sulfur-containing bridged cyclobutanes. By using Ni(ClO4)2 as the catalyst, an uncommon higher-order (5+3) cycloaddition of BCBs with quinolinium 1,4-zwitterionic thiolate was achieved with broad substrate scope under mild reaction conditions. Furthermore, the first Lewis acid-catalyzed asymmetric polar (5+3) cycloaddition of BCB with pyridazinium 1,4-zwitterionic thiolate was accomplished. In contrast, pyridinium 1,4-zwitterionic thiolates undergo an Sc(OTf)3-catalyzed formal (3+3) reaction with BCBs to generate thia-norpinene products, which represent the initial instance of synthesizing 2-thiabicyclo[3.1.1]heptanes (thia-BCHeps) from BCBs. Moreover, we have successfully used this (3+3) protocol to rapidly prepare thia-BCHeps-substituted analogues of the bioactive molecule Pitofenone. Density functional theory (DFT) computations imply that kinetic factors govern the (5+3) cycloaddition reaction between BCB and quinolinium 1,4-zwitterionic thiolate, whereas the (3+3) reaction involving pyridinium 1,4-zwitterionic thiolates is under thermodynamic control.

Objective Quantification Technique and Widely Targeted Metabolomics-Based Analysis of the Effects of Different Saccharidation Processes on Preserved French Plums.

Vacuum saccharification significantly affected the flavor and color of preserved French plums. However, the correlation between color, flavor, and metabolites remains unclear. Metabolites contribute significantly to enhancing the taste and overall quality of preserved French plums. This study aimed to investigate the distinctive metabolites in samples from various stages of the processing of preserved French plums. The PCF4 exhibited the highest appearance, overall taste, and chroma. Furthermore, utilizing UPLC and ESI-Q TRAP-MS/MS, a comprehensive examination of the metabolome in the processing of preserved French plums was conducted. A total of 1776 metabolites were analyzed. Using WGCNA, we explored metabolites associated with sensory features through 10 modules. Based on this, building the correlation of modules and objective quantification metrics yielded three key modules. After screening for 151 differentiated metabolites, amino acids, and their derivatives, phenolic acids, flavonoids, organic acids, and other groups were identified as key differentiators. The response of differential metabolites to stress influenced the taste and color properties of preserved prunes. Based on these analyses, six important metabolic pathways were identified. This study identified changes in the sensory properties of sugar-stained preserved prunes and their association with metabolite composition, providing a scientific basis for future work to improve the quality of prune processing.