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Genome-wide association analysis is a powerful tool to identify genomic loci underlying complex traits. However, the application in natural populations comes with challenges, especially power loss due to population stratification. Here, we introduce a bivariate analysis approach to a GWAS dataset ofArabidopsis thaliana. We demonstrate the efficiency of double-phenotype analysisto uncover hidden genetic loci masked by population structure via a series of simulations. In real data analysis, acommon allele, strongly confounded with population structure, is discovered to be associated with late flowering and slow maturation of the plant. The discovered genetic effect on flowering time is further replicated in independent datasets. Using Mendelian randomization analysis based on summary statistics from our GWAS and expression QTL scans, we predicted and replicated a candidate geneAT1G11560that potentially causes this association. Further analysis indicates that this locusis co-selected with flowering-time-related genes. The discovered pleiotropic genotypephenotype map provides new insights into understanding the genetic correlation of complex traits.

To evaluate the efficacy and safety of stereotactic body radiotherapy (SBRT) in treating spinal metastases. Two reviewers performed independent literature searches of the PubMed database, searching literatures of the efficacy and safety of SBRT in metastatic spinal diseases. A total of 67 studies were included in the review. Regarding SBRT for de novo spinal metastases, the 1- and 2-year local control (LC) rates were 51-100% and 56-96%, respectively. The local failure rate was 10.5-47.5%, with most studies reporting a local failure rate of 30%. The 1- and 2-year overall survival (OS) rates were 25.7-80% and 25-60.7%, respectively. The pain relief rate was 41.6-100%. In the postoperative scenario, the LC rate was 70-100%, and the local failure rate was 11.7-33%. Regarding the reirradiated setting, the 1-year LC rate was 71-83%, the local failure rate was 6.0-25.5%, and the 1-year OS rate was 28-68%. The pain relief rate was approximately 35.7-77%. Between studies on single- and multi-fraction SBRT, the 1- and 2-year LC rates with single-fraction SBRT were 71-95% and 70-96%, respectively; the 1- and 2-year OS rates with single-fraction SBRT were 43.5-46% and 43.5-49%, respectively. For the management of spinal metastases, it appears that regardless of the clinical scenario in which SBRT is applied, a high rate of LC is achieved, particularly with single-fraction SBRT, regardless of histology. Additionally, spinal SBRT can establish durable pain palliation with acceptable toxicities.

Background Secondary lymphedema is a common condition that affects patients with malignant tumors. Conservative treatments fail to provide lasting relief because they do not address the underlying pathological accumulation of excessive fat. Our aim is to clarify the molecular mechanisms of abnormal adipogenic differentiation in lymphedema adipose tissue. Methods We compared the proliferation and adipogenesis potential of adipose-derived mesenchymal stem cells (ASCs) from the lymphedema adipose tissue from liposuction specimens of 10 patients with extremity lymphedema with that of ASCs from adipose tissue from the normal upper abdomen of the same patients. Transcriptome analysis were performed to identify the differences between the two kinds of ASCs. Cyclin-dependent kinase 1 (CDK1) inhibitors were used to treat the abnormal ASCs in lymphedema adipose tissue. Results Our results demonstrate that significant functional and transcriptomic differences exist between the two kinds of ASCs. Up-regulated genes were mainly involved in cell proliferation and division while down-regulated genes were mainly associated with immune responses and inflammatory as well as osteogenic and myogenic differentiation. Furthermore, we find that the excessive proliferation and adipogenesis of ASCs from lymphedema adipose tissue returned to the normal phenotype by CDK1 inhibitors. ASCs from lymphedema adipose tissues have higher immunosuppressive effect and the cytokines related to immunosuppressive was significantly up-regulated. Conclusions In conclusion, lymphedema-associated ASCs had more rapid proliferation and a higher adipogenic differentiation capacity. CDK1 may be a key driver of proliferation and adipogenic differentiation in these cells, which might expound the accumulation of adipose tissue extensively observed in secondary lymphedema. ASCs from lymphedema adipose tissues showed immunomodulation dysfunction and immunomodulation may play an important role in the pathogenesis of lymphedema.

Microalgae biofilm-based culture systems have wide applications in environmental engineering and biotechnology. Biofilm structure is critical for the transport of nutrients, gas, and signaling molecules in a microalgal biofilm. This work aims to understand the influence of cell surface energy (SE) on the microalgal biofilm structure. Three microalgae species were used as model cells in the study: Chlorella sp., Nannochloris oculata, and Chlorella pyrenoidosa. First, by mediating biofilm culture conditions, we obtained Chlorella sp. cells with SEs of 40.4 ± 1.5, 44.7 ± 1.0, and 62. 7 ± 1.2 mJ/m2, N. oculata cells with SEs of 47.7 ± 0.5, 41.1 ± 1.0, and 62.6 ± 1.2 mJ/m2, and C. pyrenoidosa cells with SEs of 64.0 ± 0.6, 62.1 ± 0.7, and 62.8 ± 0.6 mJ/m2. Then, based on the characterizations of biofilm structures, we found that cell SE can significantly affect the microalgae biofilm structure. When the cell SEs ranged from 40 to 50 mJ/m2, the microalgae cells formed heterogeneous biofilms with a large number of open voids, and the biofilm porosity was higher than 20%. Alternatively, when the cell SEs ranged from 50 to 65 mJ/m2, the cells formed a flat, homogeneous biofilm with the porosity lower than 20%. Finally, the influencing mechanism of cell SE on biofilm structure was interpreted based on the thermodynamic theory via analyzing the co-adhesion energy between cells. The study has important implications in understanding factors that influence the biofilm structures.

Congenital heart disease (CHD) is the most common cause of major birth defects, with a prevalence of 1%. Although an increasing number of studies reporting the etiology of CHD, the findings scattered throughout the literature are difficult to retrieve and utilize in research and clinical practice. We therefore developed CHDbase, an evidence-based knowledgebase with CHD-related genes and clinical manifestations manually curated from 1114 publications, linking 1124 susceptibility genes and 3591 variations to more than 300 CHD types and related syndromes. Metadata such as the information of each publication and the selected population and samples, the strategy of studies, and the major findings of study were integrated with each item of research record. We also integrated functional annotations through parsing ~50 databases/tools to facilitate the interpretation of these genes and variations in disease pathogenicity. We further prioritized the significance of these CHD-related genes with a gene interaction network approach, and extracted a core CHD sub-network with 163 genes. The clear genetic landscape of CHD enables the phenotype classification based on the shared genetic origin. Overall, CHDbase provides a comprehensive and freely available resource to study CHD susceptibility, supporting a wide range of users in the scientific and medical communities. CHDbase is accessible at http://chddb.fwgenetics.org/.

Anomalous pulmonary venous return (APVR) is a potentially lethal congenital heart disease. Elucidating the genetic etiology is crucial for understanding its pathogenesis and improving clinical practice, whereas its genetic basis remains largely unknown because of complex genetic etiology. We thus performed whole-exome sequencing for 144 APVR patients and 1636 healthy controls and report a comprehensive atlas of APVR-related rare genetic variants. Novel singleton, loss-of-function and deleterious missense variants (DVars) were enriched in patients, particularly for genes highly expressed in the developing human heart at the critical time point for pulmonary veins draining into the left atrium. Notably, PLXND1, encoding a receptor for semaphorins, represents a strong candidate gene of APVR (adjusted P = 1.1e-03, odds ratio: 10.9–69.3), accounting for 4.17% of APVR. We further validated this finding in an independent cohort consisting of 82 case–control pairs. In these two cohorts, eight DVars were identified in different patients, which convergently disrupt the GTPase-activating protein-related domain of PLXND1. All variant carriers displayed strikingly similar clinical features, in that all anomalous drainage of pulmonary vein(s) occurred on the right side and incorrectly connected to the right atrium, which may represent a novel subtype of APVR for molecular diagnosis. Studies in Plxnd1 knockout mice further revealed the effects of PLXND1 deficiency on severe heart and lung defects and cellular abnormalities related to APVR such as abnormal migration and vascular formation of vascular endothelial cells. These findings indicate the important role of PLXND1 in APVR pathogenesis, providing novel insights into the genetic etiology and molecular subtyping for APVR.

The migratory cardiac neural crest cells (CNCCs) contribute greatly to cardiovascular development. A thorough understanding of the cell lineages, developmental chronology, and transcriptomic states of CNCC derivatives during normal development is essential for deciphering the pathogenesis of CNCC‐associated congenital anomalies. Here, we perform single‐cell transcriptomic sequencing of 34,131 CNCC‐derived cells in mouse hearts covering eight developmental stages between E10.5 and P7. We report the presence of CNCC‐derived mural cells that comprise pericytes and microvascular smooth muscle cells (mVSMCs). Furthermore, we identify the transition from the CNCC‐derived pericytes to mVSMCs and the key regulators over the transition. In addition, our data support that many CNCC derivatives had already committed or differentiated to a specific lineage when migrating into the heart. We explore the spatial distribution of some critical CNCC‐derived subpopulations with single‐molecule fluorescence in situ hybridization. Finally, we computationally reconstruct the differentiation path and regulatory dynamics of CNCC derivatives. Our study provides novel insights into the cell lineages, developmental chronology, and regulatory dynamics of CNCC derivatives during development., A single‐cell transcriptomic atlas of mouse cardiac neural crest cell (CNCC) derivatives reveals that many had already committed or differentiated to a specific lineage when migrating into the heart.

Background With the life expectance prolonging, more cancer patients occurred spinal metastases. To evaluate the impact of histologies on outcomes of spinal metastases treated with stereotactic body radiotherapy (SBRT) and identify the correlated prognostic factors. Methods The authors retrospectively reviewed the records of all patients who underwent SBRT with no prior radiation for spinal metastases between October 2015 and October 2020 at Sun Yat-sen University Cancer Center. Propensity score matching (PSM) was applied to balance the distribution of related baseline characteristics. The endpoints included overall survival (OS), local control (LC), pain relief, and time to pain relief. Results A total of 202 consecutive patients with 345 spinal metastases were treated with a median follow-up time of 16.02 months (range, 0.73–57.90 months). The 1- and 2-year OS rates were 57% and 50%, respectively. The median survival was 35.63 months. A higher Karnofsky Performance Scale (KPS) score at consult predicted for better OS (P = 0.020). The presence of pain at enrollment assessed by the Brief Pain Inventory (BPI) predicted for worse OS (P = 0.038). The 1-year LC rate was 92.0%. The pain relief rate was 76.30% (103/135 patients). Younger age was identified to be prognostic for better pain relief (P = 0.037). In the univariate and multivariate analysis, no variable was independently associated with time to pain relief. As for toxicity, no Grade ≥ 3 toxicity was observed. Conclusions SBRT is feasible and appears to be an effective treatment paradigm for patients with spinal metastases, with limited accepted toxicities.

Inter-domain routing system (IRS) is the key infrastructure of the Internet. It is of great significance to perceive and identify the security threats of IRS for the stable operation of the Internet. Security quantification is an important part of security threat perception. The existing methods are unable to construct accurate abnormal state quantitative models because of limited data. Therefore, only the similarity between the current state and the normal state of IRC can be considered, and the types of security threats cannot be distinguished. Aiming at the above problems, this paper proposes a security measurement method based on the abnormal state modeling. By analyzing the security indicators, when IRS suffering from security events and extracting the common characteristics of the abnormal state, a qualitative model of IRS's abnormal state is established. Thus, the similarity between the current state and the specific abnormal state has been taken into consideration in measuring the security of IRS. Experiments based on SMW-4 cable fault event and Malaysian route leak event show that the highest detection and classification precision of the former are both 100%, and the highest detection and classification precision of the latter is 96% and 95.8%, respectively, which proves that the measurement results can indicate the occurrence of security threats and their types.

Modification of nucleotides significantly increases the diversity of functional nucleic acids. As one of the most common modifications of RNAs, methylation of the 2′-hydroxyl-group of ribonucleotides (2′-O-methylation) has been found in various RNAs in eukaryotes. However, due to the lack of an efficient method for quantifying small RNA 3′ terminal 2′-O-methylation, it is difficult to monitor the dynamic change of 3′ terminal 2′-O-methylation during various biological processes. Capitalizing on the finding that 3′ terminal RNA 2′-O-methylation can inhibit the activity of poly(A) polymerase, an enzyme that can add the poly(A)-tail to RNA, we develop a method by which the 2′-O-methylation level of small RNAs, such as microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs), can be directly quantified based on the poly(A)-tailed RT-qPCR technique. With this method, we successfully determine the 2′-O-methylation level of miRNAs in Arabidopsis thaliana and mouse lung tissue, piRNA in human seminal plasma, and monitor the alteration of miRNA 2′-O-methylation in Drosophila Schneider 2 cells after knockdown of Drosophila methyltransferase protein Hua enhancer 1 (DmHen-1).

Capture the Flag (CTF) competitions become popular to engage people with the world of cybersecurity. In CTF-style cybersecurity training, judging trainees’ attack behavior in terms of attack time, methods, and consequences is the key to know trainee ability and thus to provide more targeted training. Previous work focuses on consequences and lacks judgment on attack methods, which cannot provide enough information for trainers to assess trainee ability. To solve this problem, we propose a model called Attack Action Graph (AAG) to help judge trainees’ behavior. By creating AAG, we characterize predictable and unpredictable attack methods and establish an association between attack methods and consequences. Then we update AAG based on feature detection technology to judge attack behavior. In the experiment based on a typical enterprise network, AAG helps us to achieve real-time judgment of all predicted attack behavior. We find that only 5% of the trainees have unpredicted attack behavior. After extracting the characteristics of unpredicted attack behavior and doing offline judgment, we find new attack methods and cheating behavior.

RationaleCardiac neural crest cells (CNCCs) contribute greatly to cardiovascular development. A thorough understanding of the cell lineages, transcriptomic states and regulatory networks of CNCC derivatives during normal development is essential for deciphering the pathogenesis of CNCC-associated congenital anomalies. However, the transcriptomic landscape of CNCC derivatives during development has not yet been examined at a single-cell resolution.ObjectiveWe sought to systematically characterize the cell lineages, define the developmental chronology and elucidate the transcriptomic dynamics of CNCC derivatives during embryonic and neonatal development.Methods and ResultsWe performed single-cell transcriptomic sequencing of 34,131 CNCC-derived cells in mouse hearts from eight developmental stages between E10.5 and P7. Through single-cell analyses and single-molecule fluorescencein situhybridization, we confirmed the presence of CNCC-derived mural cells. Furthermore, we found the transition from CNCC-derived pericytes to microvascular smooth muscle cells, and identified the genes that were significantly regulated during this transition through pseudo-temporal analysis. CNCC-derived neurons first appeared at E10.5, which was earlier than previously recognized. In addition, the CNCC derivatives switched from a proliferative to a quiescent state with the progression of development. Gradual loss of the neural crest molecular signature with development was also observed in the CNCC derivatives. Our data suggested that many CNCC-derivatives had already committed or differentiated to a specific lineage when migrating to the heart. Finally, we characterized some previously unknown subpopulations of CNCC derivatives during development. For example, we found thatPenk+ cells, which were mainly localized in outflow tract cushions, were all derived from CNCCs.ConclusionsOur study provides novel insights into the cell lineages, molecular signatures, developmental chronology and state change dynamics of CNCC derivatives during embryonic and neonatal development. Our dataset constitutes a valuable resource that will facilitate future efforts in exploring the role of CNCC derivatives in development and disease.

Cascading failures are a severe threat to inter-domain routing system, while little has been done to detect and report impacts. To address the problem, we analyze the process of cascading failure in the inter-domain routing system, and find that it is constructed by two stages as key nodes/links failure and related nodes/links cascading failure. The first stage is shorter as the onset time is seconds' level, while the second stage is longer as the onset time is at least one hour. Then a two-phase detection method FD-SP mechanism is put forward, the first stage of which adopts real-time detection methods to identify the initial failure nodes and links and the second stage uses DF2-CFM model to predict the damage range of cascade failure before true propagation. To validate FD-SP, it is applied to security events containing cascading failures and the results of FD-SP are compared with the datasets collected from RIPE during security events. Using the number of Update messages received by nodes as the metric, the maximum relative error is 1.69 and the average one is 0.92. As our prediction is a little large than reality, the false negative rate of FD-SP is low.

Background The increasing occurrence of radiation-induced second primary squamous cell carcinoma of the oral cavity (RISCCO) after radiotherapy for nasopharyngeal carcinoma (NPC) has become a noteworthy complication that can influence long-term survival. This study aimed to analyze the associations of clinicopathologic characteristics with prognostic factors among patients who developed RISCCO after radiotherapy for NPC. Methods A total of 41,446 NPC patients admitted to Sun Yat-sen University Cancer Center (SYSUCC) between August 1989 and January 2019 were reviewed. Among these patients, 88 RISCCO patients who satisfied the inclusion criteria were included in the study. Results During our study, the incidence of RISCCO after radiotherapy was 0.21% (88/41,446) among NPC patients at SYSUCC. The latency period ranged from 1.0 to 34.0 years (median, 9.0 years), and the latency of RISCCO was notably shorter for patients who received intensity-modulated radiation therapy than that for patients who received conventional radiotherapy using cobalt-60 or 6-MV X-rays (median, 4.0 years vs. 11.0 years, P = 0.013). The 1-, 3-, and 5-year overall survival (OS) rates for the entire cohort of 88 patients were 79.0%, 46.6%, and 35.2%, respectively. The 5-year OS rate for the 79 patients who received treatment was 45.7%, and the 5-year OS rate for the 9 patients who refused treatment was 0%. T classification and surgery were identified as independent prognostic factors associated with a high OS rate. Conclusions Surgery as the first-choice treatment may improve survival and prognosis. A long-term follow-up is needed for early detection of RISCCO in NPC patients.

Modification of nucleotides significantly increases the diversity of functional nucleic acids. As one of the most common modifications of RNAs, methylation of the 2′-hydroxyl-group of ribonucleotides (2′-O-methylation) has been found in various RNAs in eukaryotes. However, due to the lack of an efficient method for quantifying small RNA 3′ terminal 2′-O-methylation, it is difficult to monitor the dynamic change of 3′ terminal 2′-O-methylation during various biological processes. Capitalizing on the finding that 3′ terminal RNA 2′-O-methylation can inhibit the activity of poly(A) polymerase, an enzyme that can add the poly(A)-tail to RNA, we develop a method by which the 2′-O-methylation level of small RNAs, such as microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs), can be directly quantified based on the poly(A)-tailed RT-qPCR technique. With this method, we successfully determine the 2′-O-methylation level of miRNAs in Arabidopsis thaliana and mouse lung tissue, piRNA in human seminal plasma, and monitor the alteration of miRNA 2′-O-methylation in Drosophila Schneider 2 cells after knockdown of Drosophila methyltransferase protein Hua enhancer 1 (DmHen-1).

Time-domain CD equalization using finite impulse response (FIR) filter is now a common approach for coherent optical fiber communication systems. The complex weights of FIR taps are calculated from a truncated impulse response of the CD transfer function, and the modulus of the complex weights is constant. In our work, we take the limited bandwidth of a single channel signal into account and propose weighted FIRs to improve the performance of CD equalization. The key in weighted FIR filters is the selection and optimization of weighted functions. In order to present the performance of different types of weighted FIR filters, a square-root raised cosine FIR (SRRC-FIR) and a Gaussian FIR (GS-FIR) are investigated. The optimization of square-root raised cosine FIR and Gaussian FIR are made in term of the bit rate error (BER) of QPSK and 16QAM coherent detection signal. The results demonstrate that the optimized parameters of the weighted filters are independent of the modulation format, symbol rate and the length of transmission fiber. With the optimized weighted FIRs, the BER of CD equalization signal is decreased significantly. Although this paper has investigated two types of weighted FIR filters, i.e. SRRC-FIR filter and GS-FIR filter, the principle of weighted FIR can also be extended to other symmetric functions super Gaussian function, hyperbolic secant function and etc.