The art of finding the right drug target: emerging methods and strategies.

Drug targets are specific molecules in biological tissues and body fluids that interact with drugs. Drug target discovery is a key component of drug discovery and is essential for the development of new drugs in areas such as cancer therapy and precision medicine. Traditional in vitro or in vivo target discovery methods are time-consuming and labour-intensive, limiting the pace of drug discovery. With the development of modern discovery methods, the discovery and application of various emerging technologies have greatly improved the efficiency of drug discovery, shortened the cycle time and reduced the cost. This review provides a comprehensive overview of various emerging drug target discovery strategies, including computer-assisted approaches, drug affinity response target stability, multiomics analysis, gene editing, and NMD, and discusses the effectiveness and limitations of the various approaches, as well as their application in real cases. Through the review of the above related contents, a general overview of the development of novel drug targets and disease treatment strategies will be provided, and a theoretical basis will be provided for those who are engaged in pharmaceutical science research. Significance Statement Target-based drug discovery has been the main approach to drug discovery in the pharmaceutical industry for the past three decades. Traditional drug target discovery methods based on in vivo or in vitro validation are time-consuming and costly, greatly limiting the development of new drugs. Therefore, the development and selection of new methods in the drug target discovery process is crucial.

Plant serine/arginine-rich proteins: versatile players in RNA processing.

MAIN CONCLUSION: Serine/arginine-rich (SR) proteins participate in RNA processing by interacting with precursor mRNAs or other splicing factors to maintain plant growth and stress responses. Alternative splicing is an important mechanism involved in mRNA processing and regulation of gene expression at the posttranscriptional level, which is the main reason for the diversity of genes and proteins. The process of alternative splicing requires the participation of many specific splicing factors. The SR protein family is a splicing factor in eukaryotes. The vast majority of SR proteins' existence is an essential survival factor. Through its RS domain and other unique domains, SR proteins can interact with specific sequences of precursor mRNA or other splicing factors and cooperate to complete the correct selection of splicing sites or promote the formation of spliceosomes. They play essential roles in the composition and alternative splicing of precursor mRNAs, providing pivotal functions to maintain growth and stress responses in animals and plants. Although SR proteins have been identified in plants for three decades, their evolutionary trajectory, molecular function, and regulatory network remain largely unknown compared to their animal counterparts. This article reviews the current understanding of this gene family in eukaryotes and proposes potential key research priorities for future functional studies.

The Importance of a Genome-Wide Association Analysis in the Study of Alternative Splicing Mutations in Plants with a Special Focus on Maize.

Alternative splicing is an important mechanism for regulating gene expressions at the post-transcriptional level. In eukaryotes, the genes are transcribed in the nucleus to produce pre-mRNAs and alternative splicing can splice a pre-mRNA to eventually form multiple different mature mRNAs, greatly increasing the number of genes and protein diversity. Alternative splicing is involved in the regulation of various plant life activities, especially the response of plants to abiotic stresses and is also an important process of plant growth and development. This review aims to clarify the usefulness of a genome-wide association analysis in the study of alternatively spliced variants by summarizing the application of alternative splicing, genome-wide association analyses and genome-wide association analyses in alternative splicing, as well as summarizing the related research progress.

Intra-Sac Injection of Thrombin During Endovascular Aneurysm Repair to Remedy Type II Endoleak and Promote Sac Shrinkage.

PURPOSE: To evaluate the safety and effectiveness of intra-sac thrombin injection to remedy type II endoleaks (T2ELs) during endovascular aneurysm repair (EVAR). MATERIALS AND METHODS: 224 cases abdominal aortic aneurysm (AAA) were treated with EVAR. For the 52 cases of intra-operative type II endoleaks and 8 cases of ruptured AAAs, after the grafts were deployed, thrombin was injected into the aneurysm sac through a preset catheter. The occurrence of endoleaks post-EVAR were followed up with by Computed Tomography (CT) angiogram. The diameter and the volume of the aneurysm sac were also measured. Endpoints included incidence of T2ELs, AAA sac shrinkage and re-intervention rate and all-cause mortality. RESULTS: The overall technical success rate was 100%. Fifty-two patients were followed up with for 9-56 (median 24) months. No serious complications were observed during follow-up. The incidence of endoleak was 5.8% (3/52) during follow-up. The maximum diameter of the aneurysm decreased from 61.1 ± 14.2 mm to 53.7 ± 10.6 mm, 47.9 ± 8.3 mm and 43.7 ± 7.2 mm (87.9%, 78.4% and 71.5% of pre-EVAR) at the 6-month, 1-year and 2-year follow-up, respectively (P < .05). The volume of the aneurysm sac shrank from 236.2 ± 136.2 cm3 to 202.6 ± 114.1 cm3, 155.6 ± 68.4 cm3 and 129.7 ± 52.4 cm3 (85.8%, 65.9%, and 54.9% of pre-EVAR) at the 6-month, 1-year and 2-year follow-up, respectively (P < .05). The rate of various endoleaks was 5.8% (3/52) and the re-intervention rate was 1.9% (1/52) in this research. CONCLUSIONS: Clinical outcomes show that intra-sac injection of thrombin during EVAR is safe and may be effective in remedying small amount and low-velocity endoleaks and promoting shrinkage of the aneurysm sac.

Alternative Splicing, An Overlooked Defense Frontier of Plants with Respect to Bacterial Infection.

Disease represents a major problem in sustainable agricultural development. Plants interact closely with various microorganisms during their development and in response to the prevailing environment. In particular, pathogenic microorganisms can cause plant diseases, affecting the fertility, yield, and longevity of plants. During the long coevolution of plants and their pathogens, plants have evolved both molecular pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) signaling networks in order to regulate host cells in response to pathogen infestation. Additionally, in the postgenomic era, alternative splicing (AS) has become uncovered as one of the major drivers of proteome diversity, and abnormal RNA splicing is closely associated with bacterial infections. Currently, the complexity of host-bacteria interactions is a much studied area of research that has shown steady progress over the past decade. Although the development of high-throughput sequencing technologies and their application in transcriptomes have revolutionized our understanding of AS, many mechanisms related to host-bacteria interactions remain still unclear. To this end, this review summarizes the changes observed in AS during host-bacteria interactions and outlines potential therapeutics for bacterial diseases based on existing studies. In doing so, we hope to provide guidelines for plant disease management in agriculture.

[Histological character of intimal hyperplasia post jugular vein grafts and the protective effect of lovastatin].

OBJECTIVE: To investigate the characteristics of intimal hyperplasia and lovastatin's effects on canine jugular venous prosthesis bypass grafting. METHODS: In the study, 12 adult mistus dogs were randomly divided into 2 groups: lovastatin group and control group. All the dogs were performed with jugular venous prosthesis bypass grafting (ePTFE, 6 mm in diameter, and 5 cm in length). Four weeks later, all the 12 specimens were harvested. The patency and mural thrombus of grafts were evaluated. The characteristics of intimal hyperplasia were described and measured by HE staining and endothelial nitric oxide synthase (eNOs) immunohistochemical method. The differences between the two groups were compared. RESULTS: Four weeks later, 3 grafts with complete occlusion were found in the two groups separately. Apparent intimal hyperplasia was observed in all the grafts. The neointima of proximal and distal part in lovastatin group were thinner than in control group respectively (proximal P=0.045, distal P=0.040). The endothelial cells were found in the surface of neointima. Newly born vessels could be found in the neointima and the new vessels were more in lovastatin group than in control group (proximal P=0.041, distal P=0.031). CONCLUSION: At the end of 4 weeks, the intimal hyperplasia with neovascularization was obviously near the anastomosis. Lovastatin showed the ability to inhibit the intimal hyperplasia and promote the neovascularization.

Genome-wide comparison and in silico analysis of splicing factor SYF2/NTC31/p29 in eukaryotes: Special focus on vertebrates.

The gene SYF2-an RNA splicing factor-can interact with Cyclin D-type binding protein 1 (GICP) in many biological processes, including splicing regulation, cell cycle regulation, and DNA damage repair. In our previous study we performed genome-wide identification and functional analysis of SYF2 in plant species. The phylogenetic relationships and expression profiles of SYF2 have not been systematically studied in animals, however. To this end, the gene structure, genes, and protein conserved motifs of 102 SYF2 homologous genes from 91 different animal species were systematically analyzed, along with conserved splicing sites in 45 representative vertebrate species. A differential comparative analysis of expression patterns in humans and mice was made. Molecular bioinformatics analysis of SYF2 showed the gene was conserved and functional in different animal species. In addition, expression pattern analysis found that SYF2 was highly expressed in hematopoietic stem cells, T cells, and lymphoid progenitor cells; in ovary, lung, and spleen; and in other cells and organs. This suggests that changes in SYF2 expression may be associated with disease development in these cells, tissues, or organs. In conclusion, our study analyzes the SYF2 disease resistance genes of different animal species through bioinformatics, reveals the relationship between the SYF2 genotype and the occurrence of certain diseases, and provides a theoretical basis for follow-up study of the relationship between the SYF2 gene and animal diseases.