ULDNA: integrating unsupervised multi-source language models with LSTM-attention network for high-accuracy protein-DNA binding site prediction.

Efficient and accurate recognition of protein-DNA interactions is vital for understanding the molecular mechanisms of related biological processes and further guiding drug discovery. Although the current experimental protocols are the most precise way to determine protein-DNA binding sites, they tend to be labor-intensive and time-consuming. There is an immediate need to design efficient computational approaches for predicting DNA-binding sites. Here, we proposed ULDNA, a new deep-learning model, to deduce DNA-binding sites from protein sequences. This model leverages an LSTM-attention architecture, embedded with three unsupervised language models that are pre-trained on large-scale sequences from multiple database sources. To prove its effectiveness, ULDNA was tested on 229 protein chains with experimental annotation of DNA-binding sites. Results from computational experiments revealed that ULDNA significantly improves the accuracy of DNA-binding site prediction in comparison with 17 state-of-the-art methods. In-depth data analyses showed that the major strength of ULDNA stems from employing three transformer language models. Specifically, these language models capture complementary feature embeddings with evolution diversity, in which the complex DNA-binding patterns are buried. Meanwhile, the specially crafted LSTM-attention network effectively decodes evolution diversity-based embeddings as DNA-binding results at the residue level. Our findings demonstrated a new pipeline for predicting DNA-binding sites on a large scale with high accuracy from protein sequence alone.

scFseCluster: a feature selection-enhanced clustering for single-cell RNA-seq data.

Single-cell RNA sequencing (scRNA-seq) enables researchers to reveal previously unknown cell heterogeneity and functional diversity, which is impossible with bulk RNA sequencing. Clustering approaches are widely used for analyzing scRNA-seq data and identifying cell types and states. In the past few years, various advanced computational strategies emerged. However, the low generalization and high computational cost are the main bottlenecks of existing methods. In this study, we established a novel computational framework, scFseCluster, for scRNA-seq clustering analysis. scFseCluster incorporates a metaheuristic algorithm (Feature Selection based on Quantum Squirrel Search Algorithm) to extract the optimal gene set, which largely guarantees the performance of cell clustering. We conducted simulation experiments in several aspects to verify the performance of the proposed approach. scFseCluster performed very well on eight benchmark scRNA-seq datasets because of the optimal gene sets obtained using the Feature Selection based on Quantum Squirrel Search Algorithm. The comparative study demonstrated the significant advantages of scFseCluster over seven State-of-the-Art algorithms. In addition, our analysis shows that feature selection on high-variable genes can significantly improve clustering performance. In conclusion, our study demonstrates that scFseCluster is a highly versatile tool for enhancing scRNA-seq data clustering analysis.

HNSPPI: a hybrid computational model combing network and sequence information for predicting protein-protein interaction.

Most life activities in organisms are regulated through protein complexes, which are mainly controlled via Protein-Protein Interactions (PPIs). Discovering new interactions between proteins and revealing their biological functions are of great significance for understanding the molecular mechanisms of biological processes and identifying the potential targets in drug discovery. Current experimental methods only capture stable protein interactions, which lead to limited coverage. In addition, expensive cost and time consuming are also the obvious shortcomings. In recent years, various computational methods have been successfully developed for predicting PPIs based only on protein homology, primary sequences of protein or gene ontology information. Computational efficiency and data complexity are still the main bottlenecks for the algorithm generalization. In this study, we proposed a novel computational framework, HNSPPI, to predict PPIs. As a hybrid supervised learning model, HNSPPI comprehensively characterizes the intrinsic relationship between two proteins by integrating amino acid sequence information and connection properties of PPI network. The experimental results show that HNSPPI works very well on six benchmark datasets. Moreover, the comparison analysis proved that our model significantly outperforms other five existing algorithms. Finally, we used the HNSPPI model to explore the SARS-CoV-2-Human interaction system and found several potential regulations. In summary, HNSPPI is a promising model for predicting new protein interactions from known PPI data.

Automated CT Pancreas Segmentation for Acute Pancreatitis Patients by combining a Novel Object Detection Approach and U-Net.

Acute pancreatitis is an inflammatory disorder of the pancreas. Medical imaging, such as computed tomography (CT), has been widely used to detect volume changes in the pancreas for acute pancreatitis diagnosis. Many pancreas segmentation methods have been proposed but no methods for pancreas segmentation from acute pancreatitis patients. The segmentation of an inflamed pancreas is more challenging than the normal pancreas due to the following two reasons. 1) The inflamed pancreas invades surrounding organs and causes blurry boundaries. 2) The inflamed pancreas has higher shape, size, and location variability than the normal pancreas. To overcome these challenges, we propose an automated CT pancreas segmentation approach for acute pancreatitis patients by combining a novel object detection approach and U-Net. Our approach includes a detector and a segmenter. Specifically, we develop an FCN-guided region proposal network (RPN) detector to localize the pancreatitis regions. The detector first uses a fully convolutional network (FCN) to reduce the background interference of medical images and generates a fixed feature map containing the acute pancreatitis regions. Then the RPN is employed on the feature map to precisely localize the acute pancreatitis regions. After obtaining the location of pancreatitis, the U-Net segmenter is used on the cropped image according to the bounding box. The proposed approach is validated using a collected clinical dataset with 89 abdominal contrast-enhanced 3D CT scans from acute pancreatitis patients. Compared with other start-of-the-art approaches for normal pancreas segmentation, our method achieves better performance on both localization and segmentation in acute pancreatitis patients.

A Novel Feature Selection Strategy Based on Salp Swarm Algorithm for Plant Disease Detection.

Deep learning has been widely used for plant disease recognition in smart agriculture and has proven to be a powerful tool for image classification and pattern recognition. However, it has limited interpretability for deep features. With the transfer of expert knowledge, handcrafted features provide a new way for personalized diagnosis of plant diseases. However, irrelevant and redundant features lead to high dimensionality. In this study, we proposed a swarm intelligence algorithm for feature selection [salp swarm algorithm for feature selection (SSAFS)] in image-based plant disease detection. SSAFS is employed to determine the ideal combination of handcrafted features to maximize classification success while minimizing the number of features. To verify the effectiveness of the developed SSAFS algorithm, we conducted experimental studies using SSAFS and 5 metaheuristic algorithms. Several evaluation metrics were used to evaluate and analyze the performance of these methods on 4 datasets from the UCI machine learning repository and 6 plant phenomics datasets from PlantVillage. Experimental results and statistical analyses validated the outstanding performance of SSAFS compared to existing state-of-the-art algorithms, confirming the superiority of SSAFS in exploring the feature space and identifying the most valuable features for diseased plant image classification. This computational tool will allow us to explore an optimal combination of handcrafted features to improve plant disease recognition accuracy and processing time.

Deep Transfer Learning for Cross-Species Plant Disease Diagnosis Adapting Mixed Subdomains.

A deep transfer learning framework adapting mixed subdomains is proposed for cross-species plant disease diagnosis. Most existing deep transfer learning studies focus on knowledge transfer between highly correlated domains. These methods may fail to deal with domains that are poorly correlated. In this study, mixed domain images were generated from source and target image groups for improving the correlation between the mixed domain (training dataset) and the target domain (testing dataset). A subdomain alignment mechanism is employed to transfer knowledge from the mixed domain to the target domain. The proposed framework captures the fine-grained information more effectively. Extensive experiments were conducted and prove that the proposed method produces a more effective result compared with existing deep transfer learning technologies for poorly related subdomains.

ROR activation by Nobiletin enhances antitumor efficacy via suppression of IκB/NF-κB signaling in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by poor response to standard therapies and therefore unfavorable clinical outcomes. Better understanding of TNBC and new therapeutic strategies are urgently needed. ROR nuclear receptors are multifunctional transcription factors with important roles in circadian pathways and other processes including immunity and tumorigenesis. Nobiletin (NOB) is a natural compound known to display anticancer effects, and our previous studies showed that NOB activates RORs to enhance circadian rhythms and promote physiological fitness in mice. Here, we identified several TNBC cell lines being sensitive to NOB, by itself or in combination. Cell and xenograft experiments showed that NOB significantly inhibited TNBC cell proliferation and motility in vitro and in vivo. ROR loss- and gain-of-function studies showed concordant effects of the NOB-ROR axis on MDA-MB-231 cell growth. Mechanistically, we found that NOB activates ROR binding to the ROR response elements (RRE) of the IκBα promoter, and NOB strongly inhibited p65 nuclear translocation. Consistent with transcriptomic analysis indicating cancer and NF-κB signaling as major pathways altered by NOB, p65-inducible expression abolished NOB effects, illustrating a requisite role of NF-κB suppression mediating the anti-TNBC effect of NOB. Finally, in vivo mouse xenograft studies showed that NOB enhanced the antitumor efficacy in mammary fat pad implanted TNBC, as a single agent or in combination with the chemotherapy agent Docetaxel. Together, our study highlights an anti-TNBC mechanism of ROR-NOB via suppression of NF-κB signaling, suggesting novel preventive and chemotherapeutic strategies against this devastating disease.

Evolution of the PB1 gene of human influenza A (H3N2) viruses circulating between 1968 and 2019.

One avian H3N2 influenza virus, providing its PB1 and HA segments, reassorted with one human H2N2 virus and caused a pandemic outbreak in 1968, killing over 1 million people. After its introduction to humanity, the pandemic H3N2 virus continued adapting to humans and has resulted in epidemic outbreaks every influenza season. To understand the functional roles of the originally avian PB1 gene in the circulating strains of human H3N2 influenza viruses, we analyzed the evolution of the PB1 gene in all human H3N2 isolates from 1968 to 2019. We found several specific residues dramatically changed around 2002-2009 and remained stable through to 2019. Then, we verified the functions of these PB1 mutations in the genetic background of the early pandemic virus, A/Hong Kong/1/1968(HK/68), as well as a recent seasonal strain, A/Jiangsu/34/2016 (JS/16). The PB1 V709I or PB1 V113A/K586R/D619N/V709I induced higher polymerase activity of HK/68 in human cells. And the four mutations acted cooperatively that had an increased replication capacity in vitro and in vivo at an early stage of infection. In contrast, the backward mutant, A113V/R586K/N619D/I709V, reduced polymerase activity in human cells. The PB1 I709V decreased viral replication in vitro, but this mutant only showed less effect on mice infection experiment, which suggested influenza A virus evolved in human host was not always consisted with highly replication efficiency and pathogenicity in other mammalian host. Overall, our results demonstrated that the identified PB1 mutations contributed to the viral evolution of human influenza A (H3N2) viruses.

Redox integration of signaling and metabolism in a head and neck cancer model of radiation resistance using COSMRO.

Redox metabolism is increasingly investigated in cancer as driving regulator of tumor progression, response to therapies and long-term patients' quality of life. Well-established cancer therapies, such as radiotherapy, either directly impact redox metabolism or have redox-dependent mechanisms of action defining their clinical efficacy. However, the ability to integrate redox information across signaling and metabolic networks to facilitate discovery and broader investigation of redox-regulated pathways in cancer remains a key unmet need limiting the advancement of new cancer therapies. To overcome this challenge, we developed a new constraint-based computational method (COSMro) and applied it to a Head and Neck Squamous Cell Cancer (HNSCC) model of radiation resistance. This novel integrative approach identified enhanced capacity for H2S production in radiation resistant cells and extracted a key relationship between intracellular redox state and cholesterol metabolism; experimental validation of this relationship highlights the importance of redox state in cellular metabolism and response to radiation.

Single-cell transcriptomics reveals heterogeneous progression and EGFR activation in pancreatic adenosquamous carcinoma.

Pancreatic adenosquamous carcinoma (PASC) - a rare pathological pancreatic cancer (PC) type - has a poor prognosis due to high malignancy. To examine the heterogeneity of PASC, we performed single-cell RNA sequencing (scRNA-seq) profiling with sample tissues from a healthy donor pancreas, an intraductal papillary mucinous neoplasm, and a patient with PASC. Of 9,887 individual cells, ten cell subpopulations were identified, including myeloid, immune, ductal, fibroblast, acinar, stellate, endothelial, and cancer cells. Cancer cells were divided into five clusters. Notably, cluster 1 exhibited stem-like phenotypes expressing UBE2C, ASPM, and TOP2A. We found that S100A2 is a potential biomarker for cancer cells. LGALS1, NPM1, RACK1, and PERP were upregulated from ductal to cancer cells. Furthermore, the copy number variations in ductal and cancer cells were greater than in the reference cells. The expression of EREG, FCGR2A, CCL4L2, and CTSC increased in myeloid cells from the normal pancreas to PASC. The gene sets expressed by cancer-associated fibroblasts were enriched in the immunosuppressive pathways. We demonstrate that EGFR-associated ligand-receptor pairs are activated in ductal-stromal cell communications. Hence, this study revealed the heterogeneous variations of ductal and stromal cells, defined cancer-associated signaling pathways, and deciphered intercellular interactions following PASC progression.

Multi-scale modeling for systematically understanding the key roles of microglia in AD development.

Alzheimer's disease (AD) is the leading cause of age-related dementia, affecting over 5 million people in the United States. Unfortunately, current therapies are largely palliative and several potential drug candidates have failed in late-stage clinical trials. Studies suggest that microglia-mediated neuroinflammation might be responsible for the failures of various therapies. Microglia contribute to Aß clearance in the early stage of neurodegeneration and may contribute to AD development at the late stage by releasing pro-inflammatory cytokines. However, the activation profile and phenotypic changes of microglia during the development of AD are poorly understood. To systematically understand the key role of microglia in AD progression and predict the optimal therapeutic strategy in silico, we developed a 3D multi-scale model of AD (MSMAD) by integrating multi-level experimental data, to manipulate the neurodegeneration in a simulated system. Based on our analysis, we revealed that how TREM2-related signal transduction leads to an imbalance in the activation of different microglia phenotypes, thereby promoting AD development. Our MSMAD model also provides an optimal therapeutic strategy for improving the outcome of AD treatment.

Potential Pathogenic Genes Prioritization Based on Protein Domain Interaction Network Analysis.

Pathogenicity-related studies are of great importance in understanding the pathogenesis of complex diseases and improving the level of clinical medicine. This work proposed a bioinformatics scheme to analyze cancer-related gene mutations, and try to figure out potential genes associated with diseases from the protein domain-domain interaction network. Herein, five measures of the principle of centrality lethality had been adopted to implement potential correlation analysis, and prioritize the significance of genes. This method was further applied to KEGG pathway analysis by taking the malignant melanoma as an example. The experimental results show that 25 domains can be found, and 18 of them have high potential to be pathogenically important related to malignant melanoma. Finally, a web-based tool, named Human Cancer Related Domain Interaction Network Analyzer, is developed for potential pathogenic genes prioritization for 26 types of human cancers, and the analysis results can be visualized and downloaded online.

A Novel Computational Framework for Precision Diagnosis and Subtype Discovery of Plant With Lesion.

Plants are often attacked by various pathogens during their growth, which may cause environmental pollution, food shortages, or economic losses in a certain area. Integration of high throughput phenomics data and computer vision (CV) provides a great opportunity to realize plant disease diagnosis in the early stage and uncover the subtype or stage patterns in the disease progression. In this study, we proposed a novel computational framework for plant disease identification and subtype discovery through a deep-embedding image-clustering strategy, Weighted Distance Metric and the t-stochastic neighbor embedding algorithm (WDM-tSNE). To verify the effectiveness, we applied our method on four public datasets of images. The results demonstrated that the newly developed tool is capable of identifying the plant disease and further uncover the underlying subtypes associated with pathogenic resistance. In summary, the current framework provides great clustering performance for the root or leave images of diseased plants with pronounced disease spots or symptoms.

Inhibitory effect of selected hydrocolloids on 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) formation in chemical models and beef patties.

2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mutagen and a rodent carcinogen mainly formed in thermally processed muscle foods. Hydrocolloids are widely used as thickeners, gelling agents and stabilizers to improve food quality in the food industry. In this study, the inhibitory effects of eight hydrocolloids on the formation of PhIP were investigated in both chemical models and beef patties. 1% (w/w) of carboxymethylcellulose V, κ-carrageenan, alginic acid, and pectin significantly reduced PhIP formation by 53 %, 54 %, 48 %, and 47 %, respectively in chemical models. In fried beef patties, κ-carrageenan appeared to be most capable of inhibiting PhIP formation among the eight tested hydrocolloids. 1% (w/w) of κ-carrageenan caused a decreased formation of PhIP by 90 %. 1% (w/w) of κ-carrageenan also significantly reduced the formation of other heterocyclic aromatic amines including MeIQx and 4,8-DiMeIQx by 64 % and 48 %, respectively in fried beef patties. Further mechanism study showed that κ-carrageenan addition decreased the PhIP precursor creatinine residue and reduced the content of Maillard reaction intermediates including phenylacetaldehyde and aldol condensation product in the chemical model. κ-Carrageenan may inhibit PhIP formation via trapping both creatinine and phenylacetaldehyde. The structures of adducts formed between κ-carrageenan and creatinine and κ-carrageenan and phenylacetaldehyde merits further study.

Exploring and validating the clinical risk factors for pancreatic cancer in chronic pancreatitis patients using electronic medical records datasets: three cohorts comprising 2,960 patients.

BACKGROUND: Patients with chronic pancreatitis (CP) have an increased risk of developing pancreatic cancer (PC). The purpose of this study was to identify predictors of PC in CP patients. METHODS: Electronic medical records (EMRs) of CP patients from two cohorts were collected, and a logistic regression analysis was performed to investigate the risk factors for PC. Subsequently, we validated the value of the risk prediction model with the EMRs of a third cohort. RESULTS: The derivation cohort consisted of 2,545 CP patients, and among them, 14 patients developed PC 7 years after CP diagnosis. Cyst of the pancreas [COP; odds ratio (OR): 4.37, 95% confidence interval (CI): 1.11 to 18.40, P=0.033], loss of weight (LW; OR: 3.21, 95% CI: 0.76 to 12.91, P=0.096) and high platelet (PLT) count (OR: 1.01 per 1 increment, 95% CI: 1.00 to 1.01, P=0.042) were independent risk factors for PC among CP patients. A risk prediction equation was constructed as follows: ln[p/(1-p)] = -6.68 + 1.55COP + 1.23LW + 0.0046PLT. The areas under the receiver operating characteristic (ROC) curve of our risk score were 0.83 and 0.72 in the derivation and validation cohorts, respectively. A score >0.0128 and >0.0122 had the best balance between sensitivity and specificity in the derivation and validation cohorts, respectively. CONCLUSIONS: In CP patients, LW, COP and high PLT count were identified as novel predictors of PC. A risk prediction model based on these factors exhibited moderate predictive value for CP patients.

Detection and Recognition for Life State of Cell Cancer Using Two-Stage Cascade CNNs.

Cancer cell detection and its stages recognition of life cycle are an important step to analyze cellular dynamics in the automation of cell based-experiments. In this work, a two-stage hierarchical method is proposed to detect and recognize different life stages of bladder cells by using two cascade Convolutional Neural Networks (CNNs). Initially, a hybrid object proposal algorithm (called EdgeSelective) by combining EdgeBoxes and Selective Search is proposed to generate candidate object proposals instead of a single Selective Search method in Region-CNN (R-CNN), and it can exploit the advantages of different mechanisms for generating proposals so that each cell in the image can be fully contained by at least one proposed region during the detection process. Then, the obtained cells from the previous step are used to train and extract features by employing CNNs for the purpose of cell life stage recognition. Finally, a series of comparison experiments are implemented. The results show that the proposed method can obtain better performance than traditional methods either in the stage of cell detection or cell life stage recognition, and it encourages and suggests the application in the development of new anticancer drug and cytopathology analysis of cancer patients in the near future.

Systematically understanding the immunity leading to CRPC progression.

Prostate cancer (PCa) is the most commonly diagnosed malignancy and the second leading cause of cancer-related death in American men. Androgen deprivation therapy (ADT) has become a standard treatment strategy for advanced PCa. Although a majority of patients initially respond to ADT well, most of them will eventually develop castration-resistant PCa (CRPC). Previous studies suggest that ADT-induced changes in the immune microenvironment (mE) in PCa might be responsible for the failures of various therapies. However, the role of the immune system in CRPC development remains unclear. To systematically understand the immunity leading to CRPC progression and predict the optimal treatment strategy in silico, we developed a 3D Hybrid Multi-scale Model (HMSM), consisting of an ODE system and an agent-based model (ABM), to manipulate the tumor growth in a defined immune system. Based on our analysis, we revealed that the key factors (e.g. WNT5A, TRAIL, CSF1, etc.) mediated the activation of PC-Treg and PC-TAM interaction pathways, which induced the immunosuppression during CRPC progression. Our HMSM model also provided an optimal therapeutic strategy for improving the outcomes of PCa treatment.

The different responses of growth and photosynthesis to NH4+ enrichments between Gracilariopsis lemaneiformis and its epiphytic alga Ulva lactuca grown at elevated atmospheric CO2.

We investigated how elevated CO2 affects the responses of Gracilariopsis lemaneiformis and Ulva lactuca to NH4+ enrichments. All algae were incubated under four nutritional conditions (zero addition, 100, 500, and 2500 µM NH4+), and two CO2 levels (390 ppm and 1000 ppm). The growth, photosynthesis, and soluble protein contents of both species increased under the eutrophication condition (100 µM NH4+). However, the growth and carotenoid contents of the two species declined when NH4+ concentration increased. Under the super eutrophication condition (2500 µM NH4+), all indexes measured in G. lemaneiformis were suppressed, while the growth and photosynthesis in U. lactuca changed indistinctively, both compared with the control. Moreover, under the super eutrophication condition, elevated CO2 reduced the suppression in the growth of G. lemaneiformis, but decreased the growth of U. lactuca. Nonetheless, G. lemaneiformis displayed much lower growth rates than U. lactuca under the super eutrophication and elevated CO2 condition.