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Babesiosis is a malaria-like disease in humans and animals that is caused by Babesia species, which are tick-transmitted apicomplexan pathogens. Babesia duncani causes severe to lethal infection in humans, but despite the risk that this parasite poses as an emerging pathogen, little is known about its biology, metabolic requirements or pathogenesis. Unlike other apicomplexan parasites that infect red blood cells, B. duncani can be continuously cultured in vitro in human erythrocytes and can infect mice resulting in fulminant babesiosis and death. We report comprehensive, detailed molecular, genomic, transcriptomic and epigenetic analyses to gain insights into the biology of B. duncani. We completed the assembly, 3D structure and annotation of its nuclear genome, and analysed its transcriptomic and epigenetics profiles during its asexual life cycle stages in human erythrocytes. We used RNA-seq data to produce an atlas of parasite metabolism during its intraerythrocytic life cycle. Characterization of the B. duncani genome, epigenome and transcriptome identified classes of candidate virulence factors, antigens for diagnosis of active infection and several attractive drug targets. Furthermore, metabolic reconstitutions from genome annotation and in vitro efficacy studies identified antifolates, pyrimethamine and WR-99210 as potent inhibitors of B. duncani to establish a pipeline of small molecules that could be developed as effective therapies for the treatment of human babesiosis.

The Hi-C technique has enabled genome-wide mapping of chromatin interactions and investigated the organizational principles of the spatial structure of the genome. However, computational methods for studying Hi-C are still in the early stage.Pioneering models have been developed to reconstruct the 3D genome structures. But there is no consistent measuring result between the modeling methods, thereby imposing challenges for the users to interpret the organization of the 3D structures and to understand the genome functions. Moreover, 3D genome modeling becomes more complicated at higher resolution because of the sparsity and diversity in bulk Hi-C and the restrictions of computational resources. Furthermore, high-resolution Hi-C requires costly, deep sequencing; therefore, it has only been achieved for a limited number of cell types. Neural networks have been developed as a remedy to these problems at high resolution.In this work, we first reviewed the 3D structure modeling methods comprehensively. We developed a simulation method based on the 3D conformations from single-cell modeling and several evaluation metrics for measuring the similarity between structures. We profiled the performance of existing bulk Hi-C based 3D genome structure modeling methods using both simulated and real bulk Hi-C.Next, we proposed a novel method, GIST, for predicting 3D structures at a high resolution based on Auto-encoder with GAT. We convert the Hi-C into a heterogeneous graph, and GIST encodes the graph as a population of 3D conformations optimized by edge classification. We demonstrated that GIST produced chromosome structures consistent with FISH and outperformed existing 3D modeling methods. We illustrated the diversity of 3D structure predictions by evaluating the active and inactive X chromosome structures.Lastly, we proposed a novel method, EnHiC, for predicting high-resolution Hi-C from low-resolution input based on a generative adversarial network. Inspired by non-negative ma

The Hi-C technique has enabled genome-wide mapping of chromatin interactions and investigated the organizational principles of the spatial structure of the genome. However, computational methods for studying Hi-C are still in the early stage.Pioneering models have been developed to reconstruct the 3D genome structures. But there is no consistent measuring result between the modeling methods, thereby imposing challenges for the users to interpret the organization of the 3D structures and to understand the genome functions. Moreover, 3D genome modeling becomes more complicated at higher resolution because of the sparsity and diversity in bulk Hi-C and the restrictions of computational resources. Furthermore, high-resolution Hi-C requires costly, deep sequencing; therefore, it has only been achieved for a limited number of cell types. Neural networks have been developed as a remedy to these problems at high resolution.In this work, we first reviewed the 3D structure modeling methods comprehensively. We developed a simulation method based on the 3D conformations from single-cell modeling and several evaluation metrics for measuring the similarity between structures. We profiled the performance of existing bulk Hi-C based 3D genome structure modeling methods using both simulated and real bulk Hi-C.Next, we proposed a novel method, GIST, for predicting 3D structures at a high resolution based on Auto-encoder with GAT. We convert the Hi-C into a heterogeneous graph, and GIST encodes the graph as a population of 3D conformations optimized by edge classification. We demonstrated that GIST produced chromosome structures consistent with FISH and outperformed existing 3D modeling methods. We illustrated the diversity of 3D structure predictions by evaluating the active and inactive X chromosome structures.Lastly, we proposed a novel method, EnHiC, for predicting high-resolution Hi-C from low-resolution input based on a generative adversarial network. Inspired by non-negative ma

Mathematical reasoning recently has been shown as a hard challenge for neural systems. Abilities including expression translation, logical reasoning, and mathematics knowledge acquiring appear to be essential to overcome the challenge. This paper demonstrates that some abilities can be achieved through abductive combination with discrete systems that have been programmed with human knowledge. On a mathematical reasoning dataset, we adopt the recently proposed abductive learning framework, and propose the ABL-Sym algorithm that combines the Transformer neural models with a symbolic mathematics library. ABL-Sym shows 9.73% accuracy improvement on the interpolation tasks and 47.22% accuracy improvement on the extrapolation tasks, over the state-of-the-art approaches. Online demonstration: http://math.polixir.ai, Comment: Appeared in ICML 2020 Workshop on Bridge Between Perception and Reasoning: Graph Neural Networks & Beyond, Vienna, Austria, 2020. Code at https://agit.ai/Polixir/ABL-Sym | Video presentation available at https://slideslive.com/s/yangyang-hu-38188 | Online demonstration available at http://math.polixir.ai

Bin Hu,1 Jinxia Cao,1 Yangyang Hu,2 Zuoan Qin,3 Jun Wang1 1Department of Hematology, First People’s Hospital of Changde City, Changde, Hunan, People’s Republic of China; 2Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 3Department of Cardiovascular Medicine, First People’s Hospital of Changde City, Changde, Hunan, People’s Republic of ChinaCorrespondence: Jun WangDepartment of Hematology, First People’s Hospital of Changde City, 818 Renmin Road, Wuling District, Changde, 415000, Hunan, People’s Republic of ChinaTel +86-736-7788720Email xueyeke2020@sina.comPurpose: Studies regarding death risk factors of disseminated intravascular coagulation (DIC) patients were limited. We conducted this study to investigate whether red blood cell distribution width (RDW) was independently related to all-cause mortality of DIC patients.Methods: We used data from the Medical Information Mart for Intensive Care III version 1.4 (MIMIC-III v1.4). A total of 2098 patients with DIC were included. The main outcome was in-hospital all-cause mortality.Results: After adjusting for potential covariates, the in-hospital all-cause mortality was positively correlated with RDW. The hazard ratio (HR), 95% confidence intervals (CI), and P-value were 1.08, (1.05, 1.12), and P< 0.0001, respectively. The Kaplan–Meier curve found DIC patients with elevated RDW had a lower survival rate than patients with normal RDW (P< 0.0001). A nonlinear relationship between RDW and mortality was found with the inflection point 19.2%. When RDW < 19.2%, RDW was positively correlated with in-hospital all-cause mortality of DIC patients (HR (95% CI): 1.17 (1.11, 1.24), P< 0.0001). An elevation in RDW greater than 19.2% did not result in an additional increased risk of mortality (HR=0.97, 95% CI: 0.91– 1.04, P=0.4617).Conclusion: RDW is an independent predictor of all-c

Bin Hu,1 Jinxia Cao,1 Yangyang Hu,2 Zuoan Qin,3 Jun Wang1 1Department of Hematology, First People’s Hospital of Changde City, Changde, Hunan, People’s Republic of China; 2Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 3Department of Cardiovascular Medicine, First People’s Hospital of Changde City, Changde, Hunan, People’s Republic of ChinaCorrespondence: Jun WangDepartment of Hematology, First People’s Hospital of Changde City, 818 Renmin Road, Changde, 415000, Hunan, People’s Republic of ChinaTel +86 736-7788720Email xueyeke2020@sina.comPurpose: Studies regarding death risk factors of disseminated intravascular coagulation (DIC) patients were limited. Therefore, we conducted this study to investigate whether the serum anion gap (AG) was independently related to all-cause mortality of DIC patients.Methods: We used the data from Medical Information Mart for Intensive Care III version 1.4 (MIMIC-III v1.4). A total of 2,654 DIC patients were included. The main outcomes were in-hospital, 30-day, and 90-day all-cause mortality. The AG was measured upon ICU admission and its association with mortality was evaluated using the Cox proportional-hazards regression model. The generalized additive model and the smooth curve fitting were introduced to examine the non-linear association.Results: After adjusting for potential covariates, the in-hospital, 30-day, and 90-day all-cause mortality were positively correlated with AG. The hazard ratio (HR), confidence intervals (CI), and P were 1.05 (1.04– 1.07) < 0.0001, 1.06 (1.04– 1.07) < 0.0001, and 1.05 (1.03– 1.07) < 0.0001, respectively. We did not find an obvious non-linear relationship between AG and in-hospital, 30-day, and 90-day mortality, which indicated that the association between AG and all-cause mortality of DIC patients was nearly linear.Conclusion: Serum AG is positi

Chunlin Li,1,* Qi Wang,1,2,* Xiaohua Gu,3 Yingjie Kang,4 Yongxing Zhang,1 Yangyang Hu,5 Taixi Li,1 Hansong Jin,1 Guoying Deng,1 Qiugen Wang11Trauma Center, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201620, People’s Republic of China; 2Trauma Center, Shanghai General Hospital of Nanjing Medical University, Shanghai 200080, People’s Republic of China; 3Department of Orthopedics, Shanghai Seventh People’s Hospital, Shanghai, 200137, People’s Republic of China; 4Department of Radiology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People’s Republic of China; 5Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201620, People’s Republic of China*These authors contributed equally to this workBackground: Delay or failure of bone union is a significant clinical challenge all over the world, and it has been reported that bone marrow mesenchymal stem cells (BMSCs) offer a promising approach to accelerate bone fracture healing. Se can modulate the proliferation and differentiation of BMSCs. Se-treatment enhances the osteoblastic differentiation of BMSCs and inhibiting the differentiation and formation of mature osteoclasts. The purpose of this study was to assess the effects of porous Se@SiO2 nanocomposite on bone regeneration and the underlying biological mechanisms.Methods: We oxidized Se2-, to develop Se quantum dots, then we used the Se quantum dots to form a solid Se@SiO2 nanocomposite which was then coated with polyvinylpyrrolidone (PVP) and etched in hot water to synthesize porous Se@SiO2 nanocomposite. We used XRD pattern to assess the phase structure of the solid Se@SiO2 nanocomposite. The morphology of porous Se@SiO2 nanocomposite were evaluated by scanning electron microscope (S

Chunlin Li,1,* Qi Wang,1,2,* Xiaohua Gu,3 Yingjie Kang,4 Yongxing Zhang,1 Yangyang Hu,5 Taixi Li,1 Hansong Jin,1 Guoying Deng,1 Qiugen Wang11Trauma Center, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201620, People’s Republic of China; 2Trauma Center, Shanghai General Hospital of Nanjing Medical University, Shanghai 200080, People’s Republic of China; 3Department of Orthopedics, Shanghai Seventh People’s Hospital, Shanghai, 200137, People’s Republic of China; 4Department of Radiology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People’s Republic of China; 5Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201620, People’s Republic of China*These authors contributed equally to this workBackground: Delay or failure of bone union is a significant clinical challenge all over the world, and it has been reported that bone marrow mesenchymal stem cells (BMSCs) offer a promising approach to accelerate bone fracture healing. Se can modulate the proliferation and differentiation of BMSCs. Se-treatment enhances the osteoblastic differentiation of BMSCs and inhibiting the differentiation and formation of mature osteoclasts. The purpose of this study was to assess the effects of porous Se@SiO2 nanocomposite on bone regeneration and the underlying biological mechanisms.Methods: We oxidized Se2-, to develop Se quantum dots, then we used the Se quantum dots to form a solid Se@SiO2 nanocomposite which was then coated with polyvinylpyrrolidone (PVP) and etched in hot water to synthesize porous Se@SiO2 nanocomposite. We used XRD pattern to assess the phase structure of the solid Se@SiO2 nanocomposite. The morphology of porous Se@SiO2 nanocomposite were evaluated by scanning electron microscope (S

Kai Li,1,* Yongxing Zhang,2,* Mengting Chen,1 Yangyang Hu,1 Weiliang Jiang,1 Li Zhou,1 Sisi Li,1 Min Xu,1 Qinghua Zhao,2 Rong Wan1 1Department of Gastroenterology, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Department of Orthopaedics, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: To improve the antitumor efficacy of doxorubicin (DOX) and provide novel clinical treatment of gastric cancer, halloysite nanotubes (HNTs) loaded with DOX were encapsulated by soybean phospholipid (LIP) and the formed HNTs/DOX/LIP was systematically characterized via different techniques. The in vitro anticancer activity of HNTs/DOX/LIP was examined using an MTT assay. The antitumor efficacy and biocompatibility were monitored by measuring the tumor volume and assessing the blood routine and serum biochemistry using an ectopic implantation cancer model. The results show that when the concentration of HNTs was 3 mg/mL and the concentration of DOX was 1 mg/mL the optimal DOX loading efficiency was as high as 22.01%±0.43%. In vitro drug release behavior study demonstrated that HNTs/DOX/LIP shows a pH-responsive release property with fast drug release under acidic conditions (pH =5.4). MTT assays and in vivo experimental results revealed that HNTs/DOX/LIP exhibits a significantly higher inhibitory efficacy on the growth of mouse gastric cancer cells than free DOX at the same drug concentration. In addition, the life span of tumor-bearing mice in the HNTs/DOX/LIP-treated group was obviously prolonged compared with the control groups. Moreover, HNTs/DOX/LIP possessed excellent hemocompatibility as shown in the blood and histology studies. These findings indicated that the formed HNTs/DOX/LIP possesses higher

Kai Li,1,* Yongxing Zhang,2,* Mengting Chen,1 Yangyang Hu,1 Weiliang Jiang,1 Li Zhou,1 Sisi Li,1 Min Xu,1 Qinghua Zhao,2 Rong Wan1 1Department of Gastroenterology, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Department of Orthopaedics, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: To improve the antitumor efficacy of doxorubicin (DOX) and provide novel clinical treatment of gastric cancer, halloysite nanotubes (HNTs) loaded with DOX were encapsulated by soybean phospholipid (LIP) and the formed HNTs/DOX/LIP was systematically characterized via different techniques. The in vitro anticancer activity of HNTs/DOX/LIP was examined using an MTT assay. The antitumor efficacy and biocompatibility were monitored by measuring the tumor volume and assessing the blood routine and serum biochemistry using an ectopic implantation cancer model. The results show that when the concentration of HNTs was 3 mg/mL and the concentration of DOX was 1 mg/mL the optimal DOX loading efficiency was as high as 22.01%±0.43%. In vitro drug release behavior study demonstrated that HNTs/DOX/LIP shows a pH-responsive release property with fast drug release under acidic conditions (pH =5.4). MTT assays and in vivo experimental results revealed that HNTs/DOX/LIP exhibits a significantly higher inhibitory efficacy on the growth of mouse gastric cancer cells than free DOX at the same drug concentration. In addition, the life span of tumor-bearing mice in the HNTs/DOX/LIP-treated group was obviously prolonged compared with the control groups. Moreover, HNTs/DOX/LIP possessed excellent hemocompatibility as shown in the blood and histology studies. These findings indicated that the formed HNTs/DOX/LIP possesses higher

Actin, nucleation-promoting factors (NPFs), and the actin-related protein 2/3 complex (Arp2/3) are key elements of the cellular actin polymerization machinery. With nuclear actin polymerization implicated in ever-expanding biological processes and the discovery of the nuclear import mechanisms of actin and NPFs, determining Arp2/3 nucleo-cytoplasmic shuttling mechanism is important for understanding the function of nuclear actin. A unique feature of alphabaculovirus infection of insect cells is the robust nuclear accumulation of Arp2/3, which induces actin polymerization in the nucleus to assist in virus replication. We found that Ac34, a viral late gene product encoded by the alphabaculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV), is involved in Arp2/3 nuclear accumulation during virus infection. Further assays revealed that the subcellular distribution of Arp2/3 under steady-state conditions is controlled by chromosomal maintenance 1 (CRM1)-dependent nuclear export. Upon AcMNPV infection, Ac34 inhibits CRM1 pathway and leads to Arp2/3 retention in the nucleus.

Meiwan Chen,1,‡ Ruie Chen,1,‡ Shengpeng Wang,1 Wen Tan,1 Yangyang Hu,1 Xinsheng Peng,2 Yitao Wang11State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China; 2School of Pharmaceutical Sciences, Guangdong Medical College, Dongguan, China‡These authors contributed equally to this workAbstract: Brucea javanica has demonstrated a variety of antitumoral, antimalarial, and anti-inflammatory properties. As a Chinese herbal medicine, Brucea javanica is mainly used in the treatment of lung and gastrointestinal cancers. Pharmacological research has identified the main antitumor components are tetracyclic triterpene quassinoids. However, most of these active components have poor water solubility and low bioavailability, which greatly limit their clinical application. Nanoparticulate delivery systems are urgently needed to improve the bioavailability of Brucea javanica. This paper mainly focuses on the chemical components in Brucea javanica and its pharmacological properties and nanoparticulate formulations, in an attempt to encourage further research on its active components and nanoparticulate drug delivery systems to expand its clinical applications. It is expected to improve the level of pharmaceutical research and provide a strong scientific foundation for further study on the medicinal properties of this plant.Keywords: Brucea javanica, chemical components, pharmacology, nanoparticulate delivery systems

Meiwan Chen,1,‡ Ruie Chen,1,‡ Shengpeng Wang,1 Wen Tan,1 Yangyang Hu,1 Xinsheng Peng,2 Yitao Wang11State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China; 2School of Pharmaceutical Sciences, Guangdong Medical College, Dongguan, China‡These authors contributed equally to this workAbstract: Brucea javanica has demonstrated a variety of antitumoral, antimalarial, and anti-inflammatory properties. As a Chinese herbal medicine, Brucea javanica is mainly used in the treatment of lung and gastrointestinal cancers. Pharmacological research has identified the main antitumor components are tetracyclic triterpene quassinoids. However, most of these active components have poor water solubility and low bioavailability, which greatly limit their clinical application. Nanoparticulate delivery systems are urgently needed to improve the bioavailability of Brucea javanica. This paper mainly focuses on the chemical components in Brucea javanica and its pharmacological properties and nanoparticulate formulations, in an attempt to encourage further research on its active components and nanoparticulate drug delivery systems to expand its clinical applications. It is expected to improve the level of pharmaceutical research and provide a strong scientific foundation for further study on the medicinal properties of this plant.Keywords: Brucea javanica, chemical components, pharmacology, nanoparticulate delivery systems