Copper-Catalyzed Asymmetric [3 + 2] Cycloaddition of N-2,2,2-Trifluoroethylisatin Ketimines to Access Three Classes of Polyfunctionalized Spiro-Pyrrolidine-Oxindole Motifs.

A facile copper-catalyzed [3 + 2] cycloaddition of N-2,2,2-trifluoroethylisatin ketimines with various electron-deficient alkenes to access structurally polyfunctionalized spiro-pyrrolidine-oxindole motifs has been developed. Under the catalytic system, the N-2,2,2-trifluoroethylisatin ketimines could be utilized to react with a series of exocyclic alkenes, including 2-acylamino acrylates, 3-methylene-ß-lactams, and sterically hindered cycloalkenes represented by cyclobutenone, to obtain a variety of densely functionalized spiro-pyrrolidine frameworks bearing an α-amino acid ester, ß-lactam, and cyclobutanone, respectively, in generally good yields with excellent diastereo- and enantioselectivities.

[Profiles of Antibiotic Resistance Genes in the Coastal Aquatic Environment of Xiamen City].

The coastal areas and the adjacent islands are the hotspots of human economic and social activities, including urbanization, industrialization, and agricultural practices, which have profound impacts on the ecological environment of the coastal environment. Antibiotic resistance genes （ARGs）, as emerging contaminants, have become hot topics in water ecological security and public concern. However, the profiles of antibiotic resistome in the costal water remain largely unknown, impeding resistome risk assessment associated with coastal environments. In this study, the high-throughput quantitative PCR technique was used to investigate the abundance and distribution of ARGs in the coastal environment of Xiamen City. Combined with the 16S rDNA gene amplicon sequencing method, the structure and composition of the microbial community in a water environment were investigated, and the influencing factors and associated mechanism of ARGs in seawater were deeply explained. The results of this study showed that a total of 187 ARGs were detected in the coastal water environment, and the abundance level was up to 1.29×1010 copies·L-1. Multidrug resistance, aminoglycosides, and ß lactamase resistance genes were the three main classes of antibiotic resistance genes in the water environment of the Xiamen coastal zone. On the whole, the profile of ARGs was of high abundance, great diversity, and common co-existence, and the coastal water environment was an important hot area and reservoir for antibiotic resistance genes. Twenty-two microbes, including Nautella, Candidatus, Tenacibaculum, Rubripirellula, and Woeseia, were potential carriers of the corresponding 16 antibiotic resistance genes. The mobile genetic elements （MGEs） and microbial community structure accounted for 93.9% of the variation in environmental resistance genes in water. Therefore, microbial community and its mobile genetic elements were the most important driving forces for the occurrence and evolution of ARGs in coastal waters. Based on the results, it is implied that the environmental antibiotic resistance genes in the waters near Xiamen Island have potential risks to water ecological security and human health and highlight the necessity for comprehensive surveillance of ARGs associated with microbial contamination in the coastal aquatic environment.

Land use/cover drive functional patterns of bacterial communities in sediments of a subtropical river, China.

The bacterial community in sediment serves as an important indicator for assessing the environmental health of river ecosystems. However, the response of bacterial community structure and function in river basin sediment to different land use/cover changes has not been widely studied. To characterize changes in the structure, composition, and function of bacterial communities under different types of land use/cover, we studied the bacterial communities and physicochemical properties of the surface sediments of rivers. Surface sediment in cropland and built-up areas was moderately polluted with cadmium and had high nitrogen and phosphorus levels, which disrupted the stability of bacterial communities. Significant differences in the α-diversity of bacterial communities were observed among different types of land use/cover. Bacterial α-diversity and energy sources were greater in woodlands than in cropland and built-up areas. The functional patterns of bacterial communities were shown that phosphorus levels and abundances of pathogenic bacteria and parasites were higher in cropland than in the other land use/cover types; Urban activities have resulted in the loss of the denitrification function and the accumulation of nitrogen in built-up areas, and bacteria in forested and agricultural areas play an important role in nitrogen degradation. Differences in heavy metal and nutrient inputs driven by land use/cover result in variation in the composition, structure, and function of bacterial communities.

Clinical-Inspired Framework for Automatic Kidney Stone Recognition and Analysis on Transverse CT Images.

The stone recognition and analysis in CT images are significant for automatic kidney stone diagnosis. Although certain contributions have been made, existing methods overlook the promoting effect of clinical knowledge on model performance and clinical interpretation. Thus, it is attractive to establish methods for detecting and evaluating kidney stones originating from the practical diagnostic process. Inspired by this, a novel clinical-inspired framework is proposed to involve the diagnostic process of urologists for better analysis. The diagnostic process contains three main steps, the localization step, the identification step and the evaluation step. Three modules integrating the decision-making mode of urologists are designed to mimic the diagnosis process. The object attention module simulates the localization step to provide the position of kidneys by embedding weight feature factor and angle loss. The feature-driven discriminative module mimics the identification step to detect stones by extracting geometric and positional features. The analysis module based on the principle of clustering and graphic combination is a quantitative analysis strategy for simulating the evaluation step. This work constructed a clinical dataset collecting 27,885 transverse CT images with stones and/or clinical interference. Experiments on the dataset show that the object attention module outperforms the well-performing Yolov7 model by +1% mAP.5:.95, and the analysis module outperforms the well-performing AR-DBSCAN model and the formula method by +21.9% average cluster accuracy and -17.35% average error. Experiments demonstrate that the proposed framework is recently the most effective solution for recognizing and evaluating kidney stones.

The feasibility of using pathobiome strains as live biotherapeutic products for human use.

The evaluation of pathobiome strains should be conducted at the strain level, involving the identification of the functional genes, while considering the impact of ecological niche and drug interactions. The safety, efficacy, and quality management of live biotherapeutic products (LBPs), especially pathobiome strains, have certain peculiarities. Promising development methods include the recombinant LBP and active metabolites.

Antitumor activity of Z15-0-2, a bispecific nanobody targeting PD-1 and CTLA-4.

The combination of programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies has potential for enhancing clinical efficacy. We described the development and antitumor activity of Z15-0, a bispecific nanobody targeting both the PD-1 and CTLA-4 pathways simultaneously. We designed and optimized the mRNA sequence encoding Z15-0, referred to as Z15-0-2 and through a series of in vitro and in vivo experiments, we established that the optimized Z15-0-2 mRNA sequence significantly increased the expression of the bispecific nanobody. Administration of Z15-0-2 mRNA to tumor-bearing mice led to greater inhibition of tumor growth compared to controls. In aggregate, we introduced a novel bispecific nanobody and have re-engineered it to boost expression of mRNA, representing a new drug development paradigm.

Iron(II)-Catalyzed Radical [3 + 2] Cyclization of N-Aryl Cyclopropylamines for the Synthesis of Polyfunctionalized Cyclopentylamines.

A facile iron(II)-catalyzed radical [3 + 2] cyclization of N-aryl cyclopropylamines with various alkenes to access the structurally polyfunctionalized cyclopentylamine scaffolds has been developed. Using low-cost FeCl2·4H2O as catalyst, N-aryl cyclopropylamines could be utilized to react with a wide range of alkenes including exocyclic/acyclic terminal alkenes, cycloalkenes, alkenes from the natural-occurring compounds (Alantolactone, Costunolide), and known drugs (Ibuprofen, l-phenylalanine, Flurbiprofen) to obtain a variety of cyclopentylamines fused with different useful motifs in generally good yields and diastereoselectivities. The highlight of this protocol is also featured by no extra oxidant, no base, EtOH as the solvent, gram-scale synthesis, and further diverse transformations of the synthetic products. More importantly, an iron(II)-mediated hydrogen radical dissociation pathway was proposed based on the mechanism research experiments.

Phosphorus starvation response genes and function coupling: A mechanism to regulate phosphorus availability in a subtropical estuary.

Phosphorus (P) plays an important role in regulating primary production in estuarine environments. However, knowledge of the P-functional gene composition of microbial communities and the mechanisms of microbial adaptation to changes in available P in estuaries remain limited. This study coupling 16 s rDNA and metagenomics sequencing was conducted to reveal the relationship between P cycling functional genes, microbial interactions, and P availability in the Jiulong River Estuary. The results showed that the relative abundance of P cycling functions genes was highest in winter, and lowest in summer. Spatially, the total relative abundance of P cycling functions genes was higher in the riverward than that in the seaward. P cycling functional microbial interactions and P cycling gene coupling were strongest in summer and in the seaward. Changes in both temperature and salinity had significant direct and indirect effects on P cycling function, and the influence of salinity on P cycling function was greater than that on the microbial community in the estuary. Salinity had significant direct negative effects on inorganic P-solubilization (IP), organic P-mineralization (OP), and P uptake and transport functions (PT). Whereas, salinity had a significant positive effect on P-starvation response regulation (PR) function. Thus, salinity and microbial communities regulate the soluble reactive phosphate concentrations in estuarine environments by strengthening internal coupling among P cycling functions, promoting PR function, and facilitating PT gene expression. PR is the most important predictors, PR, PT, and PR-PT together explained 38.56 % of the overall soluble reactive phosphorus (SRP) variation. Over 66 % of the explained SRP variations can be predicted by the PR, PT, and PR-PT functional genes. This finding improves the knowledge base of the microbial processes for P cycling and provides a foundation for eutrophication management strategies in the estuary.

Genome-wide identification of GATA transcription factors in tetraploid potato and expression analysis in differently colored potato flesh.

The GATA gene family belongs to a kind of transcriptional regulatory protein featuring a zinc finger motif, which is essential for plant growth and development. However, the identification of the GATA gene family in tetraploid potato is still not performed. In the present research, a total of 88 GATA genes in the tetraploid potato C88.v1 genome were identified by bioinformatics methods. These StGATA genes had an uneven distribution on 44 chromosomes, and the corresponding StGATA proteins were divided into four subfamilies (I-IV) based on phylogenetic analysis. The cis-elements of StGATA genes were identified, including multiple cis-elements related to light-responsive and hormone-responsive. The collinearity analysis indicates that segmental duplication is a key driving force for the expansion of GATA gene family in tetraploid potato, and that the GATA gene families of tetraploid potato and Arabidopsis share a closer evolutionary relationship than rice. The transcript profiling analysis showed that all 88 StGATA genes had tissue-specific expression, indicating that the StGATA gene family members participate in the development of multiple potato tissues. The RNA-seq analysis was also performed on the tuber flesh of two potato varieties with different color, and 18 differentially expressed GATA transcription factor genes were screened, of which eight genes were validated through qRT-PCR. In this study, we identified and characterized StGATA transcription factors in tetraploid potato for the first time, and screened differentially expressed genes in potato flesh with different color. It provides a theoretical basis for further understanding the StGATA gene family and its function in anthocyanin biosynthesis.

A multi-omics study reveals the therapeutic effect of Linderae Radix water extract on irritable bowel syndrome (IBS-D).

ETHNOPHARMACOLOGICAL RELEVANCE: Linderae Radix (Lindera aggregata (Sims) Kosterm) is a traditional Chinese medicine known for its capability to regulate qi and relieve pain, particularly in the context of gastrointestinal disorders. AIM OF THE STUDY: While our previous research has demonstrated the efficacy of the Linderae Radix water extract (LRWE) in the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D), the precise mechanisms remain elusive. This study aims to provide a comprehensive understanding of the therapeutic effects of LRWE on IBS-D through multi-omics techniques. MATERIALS AND METHODS: 16 S rRNA gene sequencing combined with LC-MS metabolomics was employed to investigate the effect of LRWE on the gut microbiota and metabolites of IBS-D rats. Spearman correlation analysis was performed on the gut microbiota and metabolites. RESULTS: LRWE administration significantly ameliorated IBS-D rats' symptoms, including diarrhea, visceral hypersensitivity, and low-grade intestinal inflammation. Gut microbiota analysis revealed that LRWE influenced the diversity of the gut microbiota in IBS-D rats by significantly reducing the relative abundance of Patescibacteria and Candidatus Saccharimonas, while increasing the relative abundance of Jeotgalicoccus. Serum metabolomic analysis identified 16 differential metabolites, associated with LRWE's positive effects on IBS-D symptoms, focusing on glyoxylate and dicarboxylic acid metabolism, and cysteine and methionine metabolism. Spearman analysis demonstrated a strong correlation between cecal microbiota composition and serum metabolite levels. CONCLUSIONS: This study elucidates that LRWE plays a crucial role in the comprehensive therapeutic approach to IBS-D by restoring the relative abundance of gut microbiota and addressing the disturbed metabolism of endogenous biomarkers. The identified bacteria and metabolites present potential therapeutic targets for IBS-D.

An endoplasmic reticulum stress-related signature featuring ASNS for predicting prognosis and immune landscape in prostate cancer.

Prostate cancer (PRAD) is one of the common malignant tumors of the urinary system. In order to predict the treatment results for PRAD patients, this study proposes to develop a risk profile based on endoplasmic reticulum stress (ERS). Based on the Memorial Sloan-Kettering Cancer Center (MSKCC) cohort and the Gene Expression Omnibus database (GSE70769), we verified the predictive signature. Using a random survival forest analysis, prognostically significant ERS-related genes were found. An ERS-related risk score (ERscore) was created using multivariable Cox analysis. In addition, the biological functions, genetic mutations and immune landscape related to ERscore are also studied to reveal the underlying mechanisms related to ERS in PRAD. We further explored the ERscore-related mechanisms by profiling a single-cell RNA sequencing (scRNA-seq) dataset (GSE137829) and explored the oncogenic role of ASNS in PRAD through in vitro experiments. The risk signature composed of eight ERS-related genes constructed in this study is an independent prognostic factor and validated in the MSKCC and GSE70769 data sets. The scRNA-seq data additionally revealed that several carcinogenic pathways were noticeably overactivated in the group with high ERS scores. As one of the prognostic genes, ASNS will significantly inhibit the proliferation, migration and invasion abilities of PRAD cells after its expression is interfered with. In conclusion, this study developed a novel risk-specific ERS-based clinical treatment strategy for patients with PRAD.

A comprehensive review of toxicity of coal fly ash and its leachate in the ecosystem.

Coal fly ash (CFA), a byproduct of coal combustion, is a hazardous industrial solid waste. Its excessive global production, coupled with improper disposal practices, insufficient utilization and limited awareness of its inherent hazards, poses a significant threat to both ecological environment and human health. Based on the physicochemical properties of CFA and its leachates, we elucidate the forms of CFA and potential pathways for its entry into the human body, as well as the leaching behavior, maximum tolerance and biological half-life of toxic elements present in CFA. Furthermore, we provide an overview of current strategies and methods for mitigating the leaching of these harmful elements from CFA. Moreover, we systemically summarize toxic effect of CFA on organisms across various tiers of complexity, analyze epidemiological findings concerning the human health implications resulting from CFA exposure, and delve into the biotoxicological mechanisms of CFA and its leachates at cellular and molecular levels. This review aims to enhance understanding of the potential toxicity of CFA, thereby promoting increased public awareness regarding the disposal and management of this industrial waste.

Multiple stable isotopic approaches for tracing nitrate contamination sources: Implications for nitrogen management in complex watersheds.

Nitrate (NO3-) contamination of surface water is a global environmental problem that has serious consequences for watershed ecosystems and endangers human health. It is crucial to identify influences of different sources of NO3-, especially the incoming water from upper reaches. A combination of hydrochemistry and multi-isotope tracers (δ11B, δ15N-NO3-, and δ18O-NO3-) were used to determine NO3- sources and their transformation the North Jiulong River (NJLR), Southeast China. The findings revealed that NO3-, which accounted for an average of 87.1% of dissolved inorganic nitrogen (DIN), was the main chemical form of nitrogen species. The integration of dual stable isotopes of NO3-, δ11B, and hydrochemistry showed that NO3- was primarily contributed by sewage, soil nitrogen (SN), and ammonium (NH4+) via precipitation or fertilizers. The contributions from the sewage and soil nitrate source were almost equivalent and much higher than those from other sources in the NJLR watershed. The contributions from diverse sources varied seasonally and spatially. Manure and sewage (M&S) were the leading sources in the summer and autumn, accounting for 60.9 ± 8.5% and 47.3 ± 7.9%, respectively. However, NO3- fertilizers were the predominant source in the spring and winter. The NO3- inflow from upper reaches was proposed as an additional end-member to identify its contribution in the midstream and downstream in this study. The contributions of NO3- from the upper reaches were significant sources in the midstream and downstream, accounting for 27.2 ± 17.8% and 42.9 ± 21.9%, respectively. The obvious decline in local NO3-contribution shares from midstream to downstream implied structural changes in pollutant sources and regional environmental responsibility. Therefore, tracing nitrate sources and quantifying their contributions is critical for clarifying environmental responsibilities for precise local nitrogen management in watersheds.

Synergistic antibacterial attributes of copper-doped polydopamine nanoparticles: an insight into photothermal enhanced antibacterial efficacy.

Antibiotic-resistant bacteria and associated infectious diseases pose a grave threat to human health. The antibacterial activity of metal nanoparticles has been extensively utilized in several biomedical applications, showing that they can effectively inhibit the growth of various bacteria. In this research, copper-doped polydopamine nanoparticles (Cu@PDA NPs) were synthesized through an economical process employing deionized water and ethanol as a solvent. By harnessing the high photothermal conversion efficiency of polydopamine nanoparticles (PDA NPs) and the inherent antibacterial attributes of copper ions, we engineered nanoparticles with enhanced antibacterial characteristics. Cu@PDA NPs exhibited a rougher surface and a higher zeta potential in comparison to PDA NPs, and both demonstrated remarkable photothermal conversion efficiency. Comprehensive antibacterial evaluations substantiated the superior efficacy of Cu@PDA NPs attributable to their copper content. These readily prepared nano-antibacterial materials exhibit substantial potential in infection prevention and treatment, owing to their synergistic combination of photothermal and spectral antibacterial features.

Epithelioid Subtype Gastrointestinal Stromal Tumors of Stomach in an Endoscopic Biopsy: A Potential Diagnostic Pitfall.

Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract with a broad morphological spectrum. Although epithelioid GISTs account for 20% of GISTs, their morphological features may pose a diagnostic pitfall for pathologists due to their morphological similarities to poorly differentiated adenocarcinoma and lymphoma. Case Presentation: Herein, we report a 65-year-old male patient with gastric epithelioid GIST misdiagnosed as adenocarcinoma for four years. During this period, he was treated with chemotherapy combined with PD-L1 immunotherapy. The clinicians thought the treatments were effective. However, there was no significant change in tumor size. The patient's clinical symptoms did not improve significantly as well. Finally, an endoscopic biopsy was performed again and gastric epithelioid GIST was confirmed in our hospital through morphology, immunohistochemistry, and whole-genome sequencing. Conclusion: A broad morphological spectrum and diverse immunophenotypic changes of GISTs could represent a pitfall for pathologists. However, predisposed anatomical sites, morphology, and corresponding immunohistochemical markers are of great significance for the diagnosis of GISTs and the differential diagnosis from other diseases. On the other hand, clinicians should diagnose and comprehensively evaluate treatment effects based on the patient's clinical symptoms and relevant laboratory examinations, instead of over-reliance on pathological diagnosis.

Correction: The Cardiorespiratory fitness of children and adolescents in Tibet at altitudes over 3,500 meters.

[This corrects the article DOI: 10.1371/journal.pone.0256258.].

Reduced graphene oxide-persimmon tannin/Pt@Pd nanozyme-based cascade colorimetric sensor for detection of 1,5-anhydroglucitol.

1,5-anhydroglucitol (1,5-AG) is of considerable clinical relevance as a biochemical marker of glucose metabolism in the assessment and monitoring of diabetes. Herein, a simple colorimetric biosensor was constructed for the identification and detection of 1,5-AG by using pyranose oxidase (PROD) enzyme cascaded with reduced graphene oxide/persimmon tannin/Pt@Pd (RGO-PT/Pt@Pd NPs) nanozyme. The as-prepared RGO-PT/Pt@Pd NPs had excellent peroxidase-like activity and can be applied as a nanozyme. First, PROD enzyme reacts with the target 1,5-AG, decomposing 1,5-AG into 1,5-anhydrofuctose (1,5-AF) and H2O2. At this point, the highly catalytic RGO-PT/Pt@Pd NPs nanozyme produces a cascade with PROD enzyme which catalyzes the decomposition of H2O2 to produce O2. This in turn oxidizes the substrate 3,3',5,5'-tetramethylbenzidine (TMB) and produces a color change in the solution. Finally, the detection of 1,5-AG was achieved by measuring the absorption peak at 652 nm with an ultraviolet visible (UV-vis) spectrophotometer. Under optimal conditions, the linear operating range of the 1,5-AG enzyme cascade colorimetric sensor was 1.0-100.0 µg/mL, and the limit of detection (LOD) was 0.81 µg/mL. The proposed colorimetric biosensor was successfully applied to detect 1,5-AG in spiked human serum samples with the recoveries of 97.2-103.9% and RSDs of 1.94-4.48%. It provides a promising developmental assay for clinical detection of 1,5-AG.

Thymic hyperplasia with lymphoepithelial sialadenitis (LESA)-like features: a case report and literature review.

BACKGROUND: Thymic hyperplasia with lymphoepithelial sialadenitis-like features (LESA-like TH) is a rare form of thymic hyperplasia, characterized by a prominent expansion of the thymic medulla containing hyperplastic lymphoid follicles with germinal centers, while an almost total absence of thymic cortex. Since the first report in 2012, only a few cases of LESA-like TH have been reported in the literature to date. Due to the rarity of LESA-like TH and the tumor-like morphology, it is easy to be misdiagnosed as other common diseases of the thymus in routine practice, such as thymoma and lymphoma. CASE PRESENTATION: Herein, we present a case report of a 52-year-old Chinese female patient with LESA-like TH, without any discomforting symptoms. Computer-tomography imaging revealed a cystic solid mass in the anterior mediastinum, with well-defined boundaries and multiple internal septa. Histologically, prominent features were florid lymphoid follicles containing germinal centers, as well as hyperplasia of thymic epithelial cells and proliferation of Hassall bodies. However, the thymic cortex rich in immature T cells was almost completely absent. Furthermore, mature plasma cells, lymphoepithelial lesions, and cholesterol clefts were frequently seen. CONCLUSION: We made a diagnosis of LESA-like TH and performed a literature review to better understand the clinicopathological features of LESA-like TH and reduce misdiagnosis.

Matrix stiffness, endothelial dysfunction and atherosclerosis.

Atherosclerosis (AS) is the leading cause of the human cardiovascular diseases (CVDs). Endothelial dysfunction promotes the monocytes infiltration and inflammation that participate fundamentally in atherogenesis. Endothelial cells (EC) have been recognized as mechanosensitive cells and have different responses to distinct mechanical stimuli. Emerging evidence shows matrix stiffness-mediated EC dysfunction plays a vital role in vascular disease, but the underlying mechanisms are not yet completely understood. This article aims to summarize the effect of matrix stiffness on the pro-atherosclerotic characteristics of EC including morphology, rigidity, biological behavior and function as well as the related mechanical signal. The review also discusses and compares the contribution of matrix stiffness-mediated phagocytosis of macrophages and EC to AS progression. These advances in our understanding of the relationship between matrix stiffness and EC dysfunction open the avenues to improve the prevention and treatment of now-ubiquitous atherosclerotic diseases.

RGD peptide modified RBC membrane functionalized biomimetic nanoparticles for thrombolytic therapy.

In recent years, the fabrication of nano-drug delivery systems for targeted treatment of thrombus has become a research hotspot. In this study, we intend to construct a biomimetic nanomedicine for targeted thrombus treatment. The poly lactic-co-glycolic acid (PLGA) was selected as the nanocarrier material. Then, urokinase and perfluoro-n-pentane (PFP) were co-loaded into PLGA by the double emulsification solvent evaporation method to prepare phase change nanoparticles PPUNPs. Subsequently, the RGD peptide-modified red blood cell membrane (RBCM) was coated on the surface of PPUNPs to prepare a biomimetic nano-drug carrier (RGD-RBCM@PPUNPs). The as-prepared RGD-RBCM@PPUNPs possessed a "core-shell" structure, have good dispersibility, and inherited the membrane protein composition of RBCs. Under ultrasound stimulation, the loaded urokinase could be rapidly released. In vitro cell experiments showed that RGD-RBCM@PPUNPs had good hemocompatibility and cytocompatibility. Due to the coated RGD-RBC membrane, RGD-RBCM@PPUNPs could effectively inhibit the uptake of macrophages. In addition, RGD-RBCM@PPUNPs showed better thrombolytic function in vitro. Overall, the results suggested that this biomimetic nanomedicine provided a promising therapeutic strategy for the targeted therapy of thrombosis.