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Abstract Early cancer detection by cell-free DNA faces multiple challenges: low fraction of tumor cell-free DNA, molecular heterogeneity of cancer, and sample sizes that are not sufficient to reflect diverse patient populations. Here, we develop a cancer detection approach to address these challenges. It consists of an assay, cfMethyl-Seq, for cost-effective sequencing of the cell-free DNA methylome (with > 12-fold enrichment over whole genome bisulfite sequencing in CpG islands), and a computational method to extract methylation information and diagnose patients. Applying our approach to 408 colon, liver, lung, and stomach cancer patients and controls, at 97.9% specificity we achieve 80.7% and 74.5% sensitivity in detecting all-stage and early-stage cancer, and 89.1% and 85.0% accuracy for locating tissue-of-origin of all-stage and early-stage cancer, respectively. Our approach cost-effectively retains methylome profiles of cancer abnormalities, allowing us to learn new features and expand to other cancer types as training cohorts grow.

Soil heavy metal(loid)s contamination caused by rapid urbanization and industrialization seriously affects human health and hinders the global sustainable development goals (SDGs). Currently, there is a lack of comprehensive human health risk assessment (HHRA) studies for multiple land use types at the regional scale. We propose a practical risk assessment framework that integrates empirical Bayesian kriging (EBK), pollution level analyses, and modified HHRA modeling. The concentrations of copper industry-related metals (Cu, Ni, Cd, As, and Hg) in 332 topsoil samples from the south bank of the Yangtze River in Tongling were investigated. Obvious enrichment of Cu, Cd, As, and Hg was detected, and the average concentration of Cu was 5.24 times higher than the background values. The distribution of heavy metal(loid) pollution was typically high in the south and east, and low in the north and west. The mean errors of interpolation for Cu, Ni, and Hg were 0.84, 1.29, and 0, respectively, and the root mean square errors of interpolation for Cd and As were 1.29 and 0.86, respectively. Non-carcinogenic risks of soil heavy metal(loid)s were assessed as acceptable throughout the studied area. The hazard index decreased in the order As (0.448) > Ni (0.0729) > Cd (0.0136) > Hg (9.04 ×10−4) > Cu (6.41 ×10−4). Nevertheless, the carcinogenic risks of Ni, Cd, and As in 70–80% of the administrative units (AUs) were between 10−6 to 10−4, considered an unacceptable level. Exposure through the oral ingestion route accounted for 88.0–99.2% of the total three exposure routes. It is worth noting that four AUs were considered to be the priority control units, and Ni and As were identified as the priority control soil heavy metal(loid)s. This case demonstrates the feasibility and scientific validity of the new EBK-HHRA framework, which confirms that EBK can effectively predict the spatial distribution patterns of soil heavy metal(loid)s and that modified HHRA models are conducive to risk integration at the regional scale. The EBK-HHRA approach is generic and provides substantial support for risk source identification and risk management of soil heavy metal(loid)s contamination at the regional scale.

Background: Lymphovascular invasion (LVI) is an invasive biologic behavior that affects the treatment and prognosis of patients with early-stage lung cancer. This study aimed to identify LVI diagnostic and prognostic biomarkers using deep learning-powered 3D segmentation with artificial intelligence (AI) technology. Methods: Between January 2016 and October 2021, we enrolled patients with clinical T1 stage non-small cell lung cancer (NSCLC). We used commercially available AI software (Dr. Wise system, Deep-wise Corporation, China) to extract quantitative AI features of pulmonary nodules automatically. Dimensionality reduction was achieved through least absolute shrinkage and selection operator regression; subsequently, the AI score was calculated.Then, the univariate and multivariate analysis was further performed on the AI score and patient baseline parameters. Results: Among 175 enrolled patients, 22 tested positive for LVI at pathology review. Based on the multivariate logistic regression results, we incorporated the AI score, carcinoembryonic antigen, spiculation, and pleural indentation into the nomogram for predicting LVI. The nomogram showed good discrimination (C-index = 0.915 [95% confidence interval: 0.89–0.94]); moreover, calibration of the nomogram revealed good predictive ability (Brier score = 0.072). Kaplan–Meier analysis revealed that relapse-free survival and overall survival were significantly higher among patients with a low-risk AI score and without LVI than those among patients with a high-risk AI score (p = 0.008 and p = 0.002, respectively) and with LVI (p = 0.013 and p = 0.008, respectively). Conclusions: Our findings indicate that a high-risk AI score is a diagnostic biomarker for LVI in patients with clinical T1 stage NSCLC; accordingly, it can serve as a prognostic biomarker for these patients.

Objective: To investigate the value of energy spectrum CT multi-parameter quantitative analysis in the differential diagnosis of lung squamous cell carcinoma and adenocarcinoma. Methods: Seventy-five patients with lung cancer who were confirmed by pathology and underwent energy spectrum CT scanning were collected, including 40 cases of squamous cell carcinoma and 35 cases of adenocarcinoma. We measured and compared the energy spectrum parameters of arterial phase and venous phase between the two groups. Results: The spectrum curve of adenocarcinoma (λ40～65 keV) in arterial and venous phase, effective atomic number, concentration of iodine (water) and standardized iodine concentration were greater than that of squamous carcinoma, the difference was statistically significant, the difference of water (iodine) concentration between the two groups of arterial phase held no statistical significance, the water (iodine) concentration of adenocarcinoma was lower than that of squamous cell carcinomas, the difference was statistically significant. The results of ROC curve analysis showed that the energy spectrum (λ40～65 keV) in the venous phase was of great value in the differentiation of squamous cell carcinoma and adenocarcinoma, with the AUC of 0.839, the sensitivity of 88.6% and the specificity of 72.5%. Conclusion: Adenocarcinoma and squamous cell carcinoma of lung show different energy spectrum CT parameters. It holds certain value to distinguish them, which can provide a new method for preoperative diagnosis.

ObjectiveThe standard treatment for stage II–III gastroesophageal junction adenocarcinoma (GEJA) remains controversial, and the role of radiotherapy (RT) in stage II–III GEJA is unclear. Herein, we aimed to evaluate the prognosis of different RT sequences and identify potential candidates to undergo neoadjuvant RT (NART) or adjuvant RT (ART).Materials and methodsIn total, we enrolled 3,492 patients with resectable stage II–III GEJA from the Surveillance, Epidemiology, and End Results (SEER) database, subsequently assigned to three categories: T1–2N+, T3–4N−, and T3–4N+. Survival curves were evaluated using the Kaplan–Meier method along with the log-rank test. We compared survival curves for NART, ART, and non-RT in the three categories. To further determine histological types impacting RT-associated survival, we proposed new categories by combining the tumor, node, and metastasis (TNM) stage with Lauren’s classification.ResultsART afforded a significant survival benefit in patients with T1–2N+ and T3–4N+ tumors. In addition, NART conferred a survival advantage in patients with T3–4N+ and T3–4 exhibiting the intestinal type. Notably, ART and NART were both valuable in patients with T3–4N+, although no significant differences between treatment regimens were noted.ConclusionsBoth NART and ART can prolong the survival of patients with stage II–III GEJA. Nevertheless, the selection of NART or ART requires a concrete analysis based on the patient’s condition.

It is possible to call single-nucleotide variant (SNV) in cell-free DNA (cfDNA), but the accuracy of detection is often affected by low tumour cfDNA content. Here, the authors develop a method, cfSNV, and show that it can be used even for medium-coverage whole exome sequencing of cfDNA.

In the context of today’s rapid economic development and increasingly strict ecological protection, interactions between humans and wildlife will intensify. Therefore, we need to identify the spatial distribution of such interactions and to take measures to mitigate possible negative interactions. Using the Three-Rivers Source Region as a case study, we combined species habitat suitability, species feeding habits, species conservation levels and human impact intensity to construct a “human-wildlife spatial interaction index” (HWSII) to evaluate the intensity of human-wildlife spatial interactions. The overall level of HWSII was relatively low in the Three-River Source Region. Higher potential human-wildlife interactions occurred in areas with roads and railways. Areas of relatively high interactions between carnivores and livestock were mainly located in the southern part of the study area, and those with relatively high interactions between herbivores and livestock appeared in the western and eastern parts. Managers in these areas should consider mitigation measures. Although developed for a specific region of China, the ‘human-wildlife spatial interaction index’ could have application in other areas of the world for setting a baseline reference to identify areas with the potential for high levels of human-wildlife interactions and pinpoint places where potential negative interactions can be mitigated.

Horizontal/interregional eco-compensation is an important policy to promote regional ecological and environmental cooperation and realize sustainable development for river basins. To solve these problems, a horizontal compensation framework based on integrated water rights (IWRs) transaction has been established. Taking the Yellow River basin as an example, the IWRs scheme realizes sustainable development, to a certain extent, improving the current issues of shortages, the low utilization efficiency of water resources, and weak water environmental carrying capacity. Evidence for this improvement includes: (1) an increased revenue of USD 244.71; (2) the water use efficiency in the middle and upper streams (Qinghai, Gansu, Ningxia, Neimenggu, Shanxi) and the overall river basin being obviously improved (the maximum improvement value is 0.1273 m3/USD); (3) the overload situation of water resource carrying status being relieved in some subareas (Ningxia, Neimenggu, Henan, Shandong) and improved in the whole basin (from 0.6366 to 0.6124); (3) the water environmental carrying rate (COD and NH4+-N) of the middle and upper streams (Qinghai, Gansu, Ningxia, Neimenggu, Shanxi) and the whole river basin obviously decreasing (with maximum decreasing values of 0.43 and 1.14, respectively).

FSHD is characterized by the misexpression of DUX4 in skeletal muscle. Although DUX4 upregulation is thought to be the pathogenic cause of FSHD, DUX4 is lowly expressed in patient samples, and analysis of the consequences of DUX4 expression has largely relied on artificial overexpression. To better understand the native expression profile of DUX4 and its targets, we performed bulk RNA-seq on a 6-day differentiation time-course in primary FSHD2 patient myoblasts. We identify a set of 54 genes upregulated in FSHD2 cells, termed FSHD-induced genes. Using single-cell and single-nucleus RNA-seq on myoblasts and differentiated myotubes, respectively, we captured, for the first time, DUX4 expressed at the single-nucleus level in a native state. We identified two populations of FSHD myotube nuclei based on low or high enrichment of DUX4 and FSHD-induced genes ("FSHD-Lo" and "FSHD Hi", respectively). FSHD-Hi myotube nuclei coexpress multiple DUX4 target genes including DUXA, LEUTX and ZSCAN4, and also upregulate cell cycle-related genes with significant enrichment of E2F target genes and p53 signaling activation. We found more FSHD-Hi nuclei than DUX4-positive nuclei, and confirmed with in situ RNA/protein detection that DUX4 transcribed in only one or two nuclei is sufficient for DUX4 protein to activate target genes across multiple nuclei within the same myotube. DUXA (the DUX4 paralog) is more widely expressed than DUX4, and depletion of DUXA suppressed the expression of LEUTX and ZSCAN4 in late, but not early, differentiation. The results suggest that the DUXA can take over the role of DUX4 to maintain target gene expression. These results provide a possible explanation as to why it is easier to detect DUX4 target genes than DUX4 itself in patient cells and raise the possibility of a self-sustaining network of gene dysregulation triggered by the limited DUX4 expression.

Abstract Background Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder frequently associated with heterozygous loss-of-function mutations of Nipped-B-like (NIPBL), the human homolog of Drosophila Nipped-B. NIPBL loads cohesin onto chromatin. Cohesin mediates sister chromatid cohesion important for mitosis but is also increasingly recognized as a regulator of gene expression. In CdLS patient cells and animal models, expression changes of multiple genes with little or no sister chromatid cohesion defect suggests that disruption of gene regulation underlies this disorder. However, the effect of NIPBL haploinsufficiency on cohesin binding, and how this relates to the clinical presentation of CdLS, has not been fully investigated. Nipbl haploinsufficiency causes CdLS-like phenotype in mice. We examined genome-wide cohesin binding and its relationship to gene expression using mouse embryonic fibroblasts (MEFs) from Nipbl+/− mice that recapitulate the CdLS phenotype. Results We found a global decrease in cohesin binding, including at CCCTC-binding factor (CTCF) binding sites and repeat regions. Cohesin-bound genes were found to be enriched for histone H3 lysine 4 trimethylation (H3K4me3) at their promoters; were disproportionately downregulated in Nipbl mutant MEFs; and displayed evidence of reduced promoter-enhancer interaction. The results suggest that gene activation is the primary cohesin function sensitive to Nipbl reduction. Over 50% of significantly dysregulated transcripts in mutant MEFs come from cohesin target genes, including genes involved in adipogenesis that have been implicated in contributing to the CdLS phenotype. Conclusions Decreased cohesin binding at the gene regions is directly linked to disease-specific expression changes. Taken together, our Nipbl haploinsufficiency model allows us to analyze the dosage effect of cohesin loading on CdLS development.

The jobs–housing balance concerns the spatial relationship between the number of jobs and housing units within a given geographical area. Due to the separation of jobs and housing, spatial dislocations have occurred in large cities, which have resulted in a significant increase in commuting distance and time. These changes have ultimately led to an increase in pressure on urban traffic, and the formation of tidal traffic. In this study we introduce a multi-agent approach to examine the jobs–housing relationship under the maximum location utility of agents. The jobs/housing ratio measures the balance of the of jobs–housing relationship, as well as comparing and analyzing jobs–housing separation in Beijing by district, county, and street scales. An agent-based model was proposed to simulate spatial location selection behavior of agents by considering environmental and economical influences on residential decisions of individuals. Results show that the jobs–housing relationship imbalance in Beijing has been mainly aggravated due to rapid population growth in the 6th Ring Road. An imbalance in the jobs–housing relationship has arisen due to a mismatch with the number of households available compared to the number of jobs; the surrounding urban areas cannot provide the required volume of housing to accommodate the increase in workers. Six sets of experiments were established to examine resident agents and enterprise agents. Differences in resident agents’ income level had a greater impact on residential location decision-making, and housing price was the primary factor affecting the decision of residents to choose their residential location. The spatial distribution of jobs and housing in Beijing under the maximization of micro-agent location utility was obtained in this study. Results indicated that the imbalance in the jobs¬-housing relationship in central Beijing has improved and, compared with the initial distributions, the number of jobs–housing balance areas in Beijing has increased.

Mobility and spatial interaction data have become increasingly available due to the widespread adoption of location-aware technologies. Examples of mobile data include human daily activities, vehicle trajectories, and animal movements. In this study we focus on a special type of mobility data, i.e., origin–destination (OD) pairs, and propose a new adapted chord diagram plot to reveal the urban human travel spatial-temporal characteristics and patterns of a seven-day taxi trajectory data set collected in Beijing; this large scale data set includes approximately 88.5 million trips of anonymous customers. The spatial distribution patterns of the pick-up points (PUPs) and the drop-off points (DOPs) on weekdays and weekends are analyzed first. The maximum of the morning and the evening peaks are at 8:00–10:00 and 17:00–19:00. The morning peaks of taxis are delayed by 0.5–1 h compared with the commuting morning peaks. Second, travel demand, intensity, time, and distance on weekdays and weekends are analyzed to explore human mobility. The travel demand and high-intensity travel of residents in Beijing is mainly concentrated within the 6th Ring Road. The residents who travel long distances (>10 km) and for a long time (>60 min) mainly from outside the 6th Ring Road and the surrounding new towns of Beijing. The circular structure of the travel distance distribution also confirms the single-center urban structure of Beijing. Finally, a new adapted chord diagram plot is proposed to achieve the spatial-temporal scale visualization of taxi trajectory origin–destination (OD) flows. The method can characterize the volume, direction, and properties of OD flows in multiple spatial-temporal scales; it is implemented using a circular visualization package in R (circlize). Through the visualization experiment of taxi GPS trajectory data in Beijing, the results show that the proposed visualization technology is able to characterize the spatial-temporal patterns of trajectory OD flows in multiple spatial-temporal scales. These results are expected to enhance current urban mobility research and suggest some interesting avenues for future research.

Many rapidly developing regions have begun to draw the attention of the world. Meanwhile, the energy and environmental issues associated with rapid economic growth have aroused widespread critical concern. Therefore, studying energy, economic, and environmental systems is of great importance. This study establishes a system dynamic model that covers multiple aspects of those systems, such as energy, economy, population, water pollution, air pollution, solid waste, and technology. The model designed here attempts to determine the impacts of socioeconomic development on the energy and environment of Tongzhou District in three scenarios: under current, planning, and sustainable conditions. The results reveal that energy shortages and water pollutions are very serious and are the key issues constraining future social and economic development. Solid waste emissions increase with population growth. The prediction results provide valuable insights into social advancement.

Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant muscular dystrophy in which no mutation of pathogenic gene(s) has been identified. Instead, the disease is, in most cases, genetically linked to a contraction in the number of 3.3 kb D4Z4 repeats on chromosome 4q. How contraction of the 4qter D4Z4 repeats causes muscular dystrophy is not understood. In addition, a smaller group of FSHD cases are not associated with D4Z4 repeat contraction (termed "phenotypic" FSHD), and their etiology remains undefined. We carried out chromatin immunoprecipitation analysis using D4Z4-specific PCR primers to examine the D4Z4 chromatin structure in normal and patient cells as well as in small interfering RNA (siRNA)-treated cells. We found that SUV39H1-mediated H3K9 trimethylation at D4Z4 seen in normal cells is lost in FSHD. Furthermore, the loss of this histone modification occurs not only at the contracted 4q D4Z4 allele, but also at the genetically intact D4Z4 alleles on both chromosomes 4q and 10q, providing the first evidence that the genetic change (contraction) of one 4qD4Z4 allele spreads its effect to other genomic regions. Importantly, this epigenetic change was also observed in the phenotypic FSHD cases with no D4Z4 contraction, but not in other types of muscular dystrophies tested. We found that HP1gamma and cohesin are co-recruited to D4Z4 in an H3K9me3-dependent and cell type-specific manner, which is disrupted in FSHD. The results indicate that cohesin plays an active role in HP1 recruitment and is involved in cell type-specific D4Z4 chromatin regulation. Taken together, we identified the loss of both histone H3K9 trimethylation and HP1gamma/cohesin binding at D4Z4 to be a faithful marker for the FSHD phenotype. Based on these results, we propose a new model in which the epigenetic change initiated at 4q D4Z4 spreads its effect to other genomic regions, which compromises muscle-specific gene regulation leading to FSHD pathogenesis.

Plasma cell-free DNA (cfDNA) is a noninvasive biomarker for cell death of all organs. Deciphering the tissue origin of cfDNA can reveal abnormal cell death because of dis- eases, which has great clinical potential in disease detection and monitoring. Despite the great promise, the sensitive and accurate quantification of tissue-derived cfDNA remains challenging to existing methods due to the limited characterization of tissue methylation and the reliance on unsupervised methods. To fully exploit the clinical potential of tissue-derived cfDNA, here we present one of the largest comprehensive and high- resolution methylation atlas based on 521 noncancer tissue samples spanning 29 major types of human tissues. We systematically identified fragment-level tissue-specific methylation patterns and extensively validated them in orthogonal datasets. Based on the rich tissue methylation atlas, we develop the first supervised tissue deconvolution approach, a deep-learning-powered model, cfSort, for sensitive and accurate tissue decon- volution in cfDNA. On the benchmarking data, cfSort showed superior sensitivity and accuracy compared to the existing methods. We further demonstrated the clinical util- ities of cfSort with two potential applications: aiding disease diagnosis and monitoring treatment side effects. The tissue-derived cfDNA fraction estimated from cfSort reflected the clinical outcomes of the patients. In summary, the tissue methylation atlas and cfSort enhanced the performance of tissue deconvolution in cfDNA, thus facilitating cfDNA-based disease detection and longitudinal treatment monitoring. [ABSTRACT FROM AUTHOR]