Drug repurposing of histone deacetylase inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene a4 hydrolase and blocking LTB4 biosynthesis

OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a potential strategy for the treatment of ALI or IPF,we identified potent inhibitors of Leukotriene A4 hydrolase(LTA4H),a key enzyme in the biosynthesis of LTB4.METHODS In this study,we identified two known histone deacetylase(HDAC)inhibitors,suberanilohydroxamic acid(SAHA)and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide(M344),as effective inhibitors of LTA4H using enzymatic assay,thermofluor assay,and X-ray crystallographic investigation.We next tested the effect of SAHA and M344 on endogenous LTB4 biosynthesis in neutrophils by ELISA and neutrophil migration by transwell migration assay.A murine experimental model of ALI was induced by lipopolysaccharide(LPS)inhalation.Histopathological analysis of lung tissue using H&E staining revealed the serious pulmonary damage caused by LPS treatment and the effect of the SAHA.We next examined m RNA and protein levels of pro-inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid using q RT-PCR and ELISA to further investigate the underlying mechanisms of anti-inflammatory activities by SAHA.We also investigated the effects of SAHA and M344 on a murine experimental model of bleomycin(BLM)-induced IPF model.RESULTS The results of enzymatic assay and X-ray crystallography showed that both SAHA and M344 bind to LTA4H,significantly decrease LTB4 levels in neutrophil,and markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose.CONCLUSION Collectively,SAHA and M344 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.

The X-linked mental retardation gene PHF8 is a histone demethylase involved in neuronal differentiation

Recent studies have identified mutations in PHF8, an X-linked gene encoding a JmjC domain-containing protein, as a causal factor for X-linked mental retardation （XLMR） and cleft lip/cleft palate. However, the underlying mechanism is unknown. Here we show that PHF8 is a histone demethylase and coactivator for retinoic acid receptor （RAR）. Although activities for both H3K4me3/2/1 and H3K9me2/1 demethylation were detected in cellularbased assays, reeombinant PHF8 exhibited only H3K9me2/1 demethylase activity in vitro, suggesting that PHF8 is an H3K9me2/1 demethylase whose specificity may be modulated in vivo. Importantly, a mutant PHF8 （phenylalanine at position 279 to serine） identified in the XLMR patients is defective in enzymatie activity, indicating that the loss of histone demethylase activity is causally linked with the onset of disease. In addition, we show that PHF8 binds specifically to H3K4me3/2 peptides via an N-terminal PHD finger domain. Consistent with a role for PHF8 in neuronal differentiation, knockdown of PHF8 in mouse embryonic carcinoma P19 cells impairs RA-induced neuronal differentiation, whereas overexpression of the wild-type but not the F279S mutant PHF8 drives PI9 cells toward neuronal differentiation. Furthermore, we show that PHF8 interacts with RAR~ and functions as a coactivator for RARa. Taken together, our results suggest that histone methylation modulated by PHF8 plays a critical role in neuronal differentiation.

AOF1 is a histone H3K4 demethylase possessing demethylase activity-independent repression function

LSD1 （KDM1 under the new nomenclature） was the first identified lysine-specific histone demethylase belonging to the flavin-dependent amine oxidase family. Here, we report that AOF1 （KDM1B under the new nomenclature）, a mammalian protein related to LSD1, also possesses histone demethylase activity with specificity for H3K4mel and H3K4me2. Like LSD1, the highly conserved SWIRM domain is required for its enzymatic activity. However, AOF1 differs from LSD1 in several aspects. First, AOF1 does not appear to form stable protein complexes containing histone deacetylases. Second, AOF1 is found to localize to chromosomes during the mitotic phase of the cell cycle, whereas LSD1 does not. Third, AOF1 represses transcription when tethered to DNA and this repression activity is independent of its demethylase activity. Structural and functional analyses identified its unique N-terminal Zf-CW domain as essential for the demethylase activity-independent repression function. Collectively, our study identifies AOF1 as the second histone demethylase in the family of flavin-dependent amine oxidases and reveals a demethylase-independent repression function of AOF1.

The Challenge and promise of rare disease diagnosis in China

Rare diseases are chronic and serious,featuring early onset at birth or in childhood,rapid deterioration and high mortality rate,which creates a burden on society and public health systems.Of the known rare diseases,80 percent are genetic in origin,and half of those affected worldwide are children.In China,the rare disease patients are over 10 million,and70 percent of the patients are children(Song et al.,2012;Liu et al.,2010).

Application of genome analysis strategies in the clinical testing for pediatric diseases

Next-generation sequencing (NGS) is being used in clinical testing.Government authorities in both China and the United States are overseeing the clinical application of NGS instruments and reagents.In addition,the US Association for Molecular Pathology and the College of American Pathologists have jointly released a guidance to standardize the analysis and interpretation of NGS data involved in clinical testing.At present,the analysis strategies and pipelines for NGS data related to the clinical detection of pediatric disease are similar to those used for adult diseases.However,for rare pediatric diseases without linkage to known genetic variants,it is currently difficult to detect the relevant pathogenic genes using NGS technology.Additionally,it is challenging to identify novel pathogenic genes of familial pediatric tumors.Therefore,characterization of the pathogenic genes associated with above diseases is important for the diagnosis and treatment of rare diseases in children.This article introduces the general pipelines for NGS data analyses of diseases and elucidates data analysis strategies for the pathogenic genes of rare pediatric diseases and familial pediatric tumors.

Landscape of global urban environmental resistome and its association with local socioeconomic and medical status

Antimicrobial resistance(AMR)poses a critical threat to global health and development,with environmental factors—particularly in urban areas—contributing significantly to the spread of antibiotic resistance genes(ARGs).However,most research to date has been conducted at a local level,leaving significant gaps in our understanding of the global status of antibiotic resistance in urban environments.To address this issue,we thoroughly analyzed a total of 86,213 ARGs detected within 4,728 metagenome samples,which were collected by the Meta SUB International Consortium involving diverse urban environments in 60 cities of 27 countries,utilizing a deep-learning based methodology.Our findings demonstrated the strong geographical specificity of urban environmental resistome,and their correlation with various local socioeconomic and medical conditions.We also identified distinctive evolutionary patterns of ARG-related biosynthetic gene clusters(BGCs)across different countries,and discovered that the urban environment represents a rich source of novel antibiotics.Our study provides a comprehensive overview of the global urban environmental resistome,and fills a significant gap in our knowledge of large-scale urban antibiotic resistome analysis.

Characterizing and annotating the genome using RNA-seq data

Bioinformatics methods for various RNA-seq data analyses are in fast evolution with the improvement of sequencing technologies. However, many challenges still exist in how to efficiently process the RNA-seq data to obtain accurate and comprehensive results. Here we reviewed the strategies for improving diverse transcriptomic studies and the annotation of genetic variants based on RNA-seq data. Mapping RNA-seq reads to the genome and transcriptome represent two distinct methods for quantifying the expression of genes/transcripts. Besides the known genes annotated in current databases, many novel genes/transcripts(especially those long noncoding RNAs) still can be identified on the reference genome using RNA-seq. Moreover, owing to the incompleteness of current reference genomes, some novel genes are missing from them. Genome-guided and de novo transcriptome reconstruction are two effective and complementary strategies for identifying those novel genes/transcripts on or beyond the reference genome. In addition, integrating the genes of distinct databases to conduct transcriptomics and genetics studies can improve the results of corresponding analyses.

HIV-1/AIDS vaccine development： are we in the darkness before the dawn？

The pandemic of human immunodeficiency virus type 1 （HIV-I） has been devastating for the last two decades in a number of developing countries and constituting a grand challenge to the public health. WHO/UNAIDS estimates that approximately 33.2 million people were living with HIV-1 infection by the end of 2007 and almost 2.5 million new infections occurred in 2007. An unprecedented scientific challenge for the AIDS vaccine community is how to develop an effective HIV vaccine that can block HIV transmission and consequently stop the continuing spread of HIV-1. The recent failure of Merck Phase II B trial alerted the HIV vaccine community that new vaccine strategies need to be more exclusively explored. In this review, we outline the basics of HIV vaccine and retrospect the history of the road to HIV vaccine in last two decades, and highlight the challenges we are currently facing and new strategies to develop HIV vaccines in this field.

Disease spectrum analysis of hospitalized children in China: A study of 18 tertiary children's hospitals

Importance: Morbidity and mortality of children are important indicators of the performance of the public health system in any country. In China, the children's disease spectrum has gradually changed in recent years. However, the gender- and age-specific disease spectrum for hospitalized children under 15 years old is still unclear. Objective: To explore the gender- and age-based distribution of diseases in hospitalized children under 15 years in China. Methods: Medical records home page data for 2016 to 2018 were collected from 18 tertiary children's hospitals in China. The gender- and age-specific disease spectrum was analyzed, using the tenth revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10). Results: The most common diseases were those of the respiratory system (25.7% of all 2232142 hospitalized children). The top three diseases for boys were diseases of the respiratory system (25.6%), diseases of the digestive system (11.4%) and certain conditions originating in the perinatal period (8.6%). The top three diseases for girls were diseases of the respiratory system (25.9%), certain conditions originating in the perinatal period (10.1%), and factors influencing health status and contact with health services (9.4%).The most common diseases for children under 1 year old were certain conditions originating in the perinatal period (38.1%). For all other age groups, the most common conditions were respiratory diseases (33.8% for those aged 1–3 years, 25.2% for those aged 4–6 years, and 12.2% for those aged 7–14 years). Interpretation: This study analyzed the medical records home pages of 18 children's hospitals to provide the first overview of the disease spectrum and its gender- and age-specific distribution among children in China.

Lack of correlation between aristolochic acid exposure and hepatocellular carcinoma

Besides upper tract urothelial cell carcinoma(UTUCs),a recent study published in Science Translational Medicine has indicated that liver cancer may be associated with the exposure of aristolochic acids and similar derivatives(collectively,AA).However,according to our research,this study needs more number of samples for further verification which should be sampled from a wider range of people.

Significant variations in alternative splicing patterns and expression profiles between human-mouse orthologs in early embryos

Human and mouse orthologs are expected to have similar biological functions; however, many discrepancies have also been reported. We systematically compared human and mouse orthologs in terms of alternative splicing patterns and expression profiles. Human-mouse orthologs are divergent in alternative splicing, as human orthologs could generally encode more isoforms than their mouse orthologs. In early embryos, exon skipping is far more common with human orthologs, whereas constitutive exons are more prevalent with mouse orthologs. This may correlate with divergence in expression of splicing regulators. Orthologous expression similarities are different in distinct embryonic stages, with the highest in morula. Expression differences for orthologous transcription factor genes could play an important role in orthologous expression discordance. We further detected largely orthologous divergence in differential expression between distinct embryonic stages. Collectively, our study uncovers significant orthologous divergence from multiple aspects, which may result in functional differences and dynamics between human-mouse orthologs during embryonic development.

Identifying and annotating human bifunctional RNAs reveals their versatile functions

Bifunctional RNAs that possess both protein-coding and noncoding functional properties were less explored and poorly understood. Here we systematically explored the characteristics and functions of such human bifunctional RNAs by integrating tandem mass spectrometry and RNA-seq data. We first constructed a pipeline to identify and annotate bifunctional RNAs,leading to the characterization of 132 high-confidence bifunctional RNAs. Our analyses indicate that bifunctional RNAs may be involved in human embryonic development and can be functional in diverse tissues. Moreover, bifunctional RNAs could interact with multiple miRNAs and RNA-binding proteins to exert their corresponding roles. Bifunctional RNAs may also function as competing endogenous RNAs to regulate the expression of many genes by competing for common targeting miRNAs. Finally,somatic mutations of diverse carcinomas may generate harmful effect on corresponding bifunctional RNAs. Collectively,our study not only provides the pipeline for identifying and annotating bifunctional RNAs but also reveals their important gene-regulatory functions.

Regulation of latency to lytic life cycle:multiple tricks by KSHV RTA

The herpesviruses are large enveloped DNA viruses that infect a wide spectrum hosts including human being.A key characteristic of all herpesviruses is their ability to establish life-time latency within the infected host and to periodically reactivate and enter the lytic replication to produce infectious virus progeny.During latency the 120–300 kb double-stranded DNA genomes of these viruses are maintained as multiple copies of circular episomes within the nuclei of the host cells.

Innovation for better health of children

The past decades have witnessed a rapid development in the pediatric field along with the development of medical sciences in China.However,the increasing demand for pediatric healthcare services still cannot be met owing to various reasons.The shortage of pediatric medical resources and the limited access to medical care for pediatric patients have long been the priorities of healthcare reform in China.

Sequencing XMET genes to promote genotype-guided risk assessment and precision medicine

High-throughput next generation sequencing (NGS) is a shotgun approach applied in a parallel fashion by which the genome is fragmented and sequenced through small pieces and then analyzed either by aligning to a known reference genome or by de novo assembly without reference genome.This technology has led researchers to conduct an explosion of sequencing related projects in multidisciplinary fields of science.However,due to the limitations of sequencing-based chemistry,length of sequencing reads and the complexity of genes,it is difficult to determine the sequences of some portions of the human genome,leaving gaps in genomic data that frustrate further analysis.Particularly,some complex genes are difficult to be accurately sequenced or mapped because they contain high GC-content and/or low complexity regions,and complicated pseudogenes,such as the genes encoding xenobiotic metabolizing enzymes and transporters (XMETs).The genetic variants in XMET genes are critical to predicate interindividual variability in drug efficacy,drug safety and susceptibility to environmental toxicity.We summarized and discussed challenges,wet-lab methods,and bioinformatics algorithms in sequencing "complex" XMET genes,which may provide insightful information in the application of NGS technology for implementation in toxicogenomics and pharmacogenomics.

Acidic domains differentially read histone H3 lysine 4 methylation status and are widely present in chromatin-associated proteins

Histone methylation is believed to provide binding sites for specific reader proteins, which translate histone code into biological function. Here we show that a family of acidic domain-containing proteins including nucleophosmin （NPM 1）, pp32, SET/TAF 113, nucleolin （NCL） and upstream binding factor （UBF） are novel H3K4me2-binding proteins. These proteins exhibit a unique pattern of interaction with methylated H3K4, as their binding is stimulated by H3K4me2 and inhibited by H3K4mel and H3K4me3. These proteins contain one or more acidic domains consisting mainly of aspartic and/or glutamic residues that are necessary for preferential binding of H3K4me2. Furthermore, we demonstrate that the acidic domain with sufficient length alone is capable of binding H3K4me2 in vitro and in vivo. NPM1, NCL and UBF require their acidic domains for association with and transcriptional activation ofrDNA genes. Interestingly, by defining acidic domain as a sequence with at least 20 acidic residues in 50 continuous amino acids, we identified 655 acidic domain-containing protein coding genes in the human genome and Gene Ontology （GO） analysis showed that many of the acidic domain proteins have chromatin-related functions. Our data suggest that acidic domain is a novel histone binding motif that can differentially read the status of H3K4 methylation and is broadly present in chromatin-associated proteins.

Towards efficiency in rare disease research： what is distinctive and important？

Characterized by their low prevalence, rare diseases are often chronically debilitating or life threatening. Despite their low prevalence, the aggregate number of individuals suffering from a rare disease is estimated to be nearly 400 million worldwide.Over the past decades, efforts from researchers, clinicians, and pharmaceutical industries have been focused on both the diagnosis and therapy of rare diseases. However, because of the lack of data and medical records for individual rare diseases and the high cost of orphan drug development, only limited progress has been achieved. In recent years, the rapid development of next-generation sequencing(NGS)-based technologies, as well as the popularity of precision medicine has facilitated a better understanding of rare diseases and their molecular etiology. As a result, molecular subclassification can be identified within each disease more clearly, significantly improving diagnostic accuracy. However, providing appropriate care for patients with rare diseases is still an enormous challenge. In this review, we provide a brief introduction to the challenges of rare disease research and make suggestions on where and how our efforts should be focused.

Dental pulp stem cells and BonelikeVR for bone regeneration in ovine model

Development of synthetic bone substitutes has arisen as a major research interest in the need to find an alternative to autologous bone grafts.Using an ovine model,the present pre-clinical study presents a synthetic bone graft(BonelikeVR)in combination with a cellular system as an alternative for the regeneration of non-critical defects.The association of biomaterials and cell-based therapies is a promising strategy for bone tissue engineering.Mesenchymal stem cells(MSCs)from human dental pulp have demonstrated both in vitro and in vivo to interact with diverse biomaterial systems and promote mineral deposition,aiming at the reconstruction of osseous defects.Moreover,these cells can be found and isolated from many species.Non-critical bone defects were treated with BonelikeVR with or without MSCs obtained from the human dental pulp.Results showed that BonelikeVR and MSCs treated defects showed improved bone regeneration compared with the defects treated with BonelikeVR alone.Also,it was observed that the biomaterial matrix was reabsorbed and gradually replaced by new bone during the healing process.We therefore propose this combination as an efficient binomial strategy that promotes bone growth and vascularization in non-critical bone defects.

Biological data processing based on bio-processor unit(BPU), a new concept for next generation computational biology

The revolution of biotechnology has pushed forward life sciences into the Big Data era.Particularly,high-throughput bio-techniques have greatly accelerated the integration of biology,computing and informatics,and hence substantially pushed forward the development of bioinformatics and computational biology.According to the latest report of data deposition within National Centre for Biotechnology Information（NCBI）,the genome sequencing projects have increased 49.94%.