Structural characterization and anti-oxidative activity for a glycopeptide from Ganoderma lucidum fruiting body.

A water-soluble glycopeptide (named GL-PWQ3) with a molecular weight (Mw) of 2.40 × 104 g/mol was isolated from Ganoderma lucidum fruiting body by hot water extraction, membrane ultrafiltration, and gel column chromatography, which mainly consisted of glucose and galactose. Based on the methylation, FT-IR, 1D, and 2D NMR analysis, the polysaccharide portion of GL-PWQ3 was identified as a glucogalactan, which was comprised of unsubstituted (1,6-α-Galp, 1,6-ß-Glcp, 1,4-ß-Glcp) and monosubstituted (1,2,6-α-Galp and 1,3,6-ß-Glcp) in the backbone and possible branches that at the O-3 position of 1,3-Glcp and T-Glcp, and the O-2 position of T-Fucp, T-Manp or T-Glcp. The chain conformational study by SEC-MALLS-RI and AFM revealed that GL-PWQ3 was identified as a highly branched polysaccharide with a polydispersity index of 1.25, and might have compact sphere structures caused by stacked multiple chains. Moreover, the GL-PWQ3 shows strong anti-oxidative activity in NRK-52E cells. This study provides a theoretical basis for further elucidating the structure-functionality relationships of GL-PWQ3 and its potential application as a natural antioxidant in pharmacotherapy as well as functional food additives.

OsGA3ox genes regulate rice fertility and plant height by synthesizing diverse active GA.

Gibberellin (GA) is an important hormone, which is involved in regulating various growth and development. GA biosynthesis pathway and synthetase have been basically clarified. Gibberellin 3ß hydroxylase (GA3ox) is the key enzyme for the synthesis of various active GA. There are two GA3ox genes (OsGA3ox1 and OsGA3ox2) in rice, and their physiological functions have been preliminarily studied. However, it is not clear how they work together to synthesize active GA to regulate rice development. In this study, the knockout mutants ga3ox1 and ga3ox2 were obtained by CRISPR/Cas9 technology. The pollen fertility of ga3ox1 decreased significantly, while the plant height of ga3ox2 decreased significantly. It shows that OsGA3ox1 is necessary for normal pollen development, while OsGA3ox2 is necessary for stem and leaf elongation. Tissue expression analysis showed that OsGA3ox1 was mainly expressed in unopened flowers, while OsGA3ox2 was mainly expressed in unexpanded leaves. The GA in different tissues of wild type (WT), and two ga3ox mutants were detected. It was found that pollen fertility is most closely related to the content of GA7, and plant height is most closely related to the content of GA1. It was found that OsGA3ox1 catalyzes GA9 to GA7 in flowers, which is closely related to pollen fertility; OsGA3ox2 catalyzes the GA20 to GA1 in unexpanded leaves, thereby regulating plant height; OsGA3ox1 catalyzes the GA19 to GA20 in roots, regulating the generation of GA3. OsGA3ox1 and OsGA3ox2 respond to developmental and environmental signals, and cooperate to synthesize endogenous GA in different tissues to regulate rice development. This study provides a reference for clarifying its role in GA biosynthesis pathway and further understanding the function of OsGA3ox.

First report of Fusarium falciforme causing root rot of pomegranate (Punica granatum L.) in China.

Pomegranate (Punica granatum L.) is a deciduous shrub or small tree that is native to Iran and Afghanistan. It is also a commercially important fruit tree in China and worldwide. In the summer of 2022, a serious root rot disease occurred in some pomegranate orchards in Xichuan County(32º42´ N, 111º48´ E), Henan Province, China, with an incidence of ~30%. Symptoms included leaf yellowing and wilting, root browning and rotting, and stem-base cracking, eventually leading to defoliation and death. To isolate the causal agent, small pieces (5×5 mm) of diseased root from six trees were surface-sterilized by dipping in 2% NaClO for 8 min followed by 70% ethanol for 15 s, rinsed five times with sterile water, and plated on potato dextrose agar (PDA), then incubated at 28°C in the dark for 5 days. Fifteen pure fungal isolates with the same morphological characteristics were obtained from 24 pieces of roots. All isolates produced white fluffy mycelia. Microconidia were hyaline, oval or reniform, with zero to one septa and dimensions of 7.1 to 19.9 (average 14.5 )× 3.8 to 8.0 (average 5.6) µm (n = 100). Macroconidia were sickle-shaped, one to four septate, and 20.1 to 40.8 (average 26.5) × 4.8 to 8.6 (average 6.5) µm (n = 100). Chlamydospores were spherical, single, in pairs or chains, and 5.6 to 9.8 (average 6.8) µm in diameter (n = 100). Based on the above characteristics, the pathogens were identified as Fusarium sp. (Leslie and Summerell 2006). Genomic DNA was extracted from mycelia of two representative isolates Fs1 and Fs3. The internal transcribed spacer (ITS), translation elongation factor 1-alpha (TEF-1α) and RNA polymerase II second largest subunit (RPB2) sequences were PCR amplified using primer pairs of ITS1/ITS4, EF1/EF2, and RPB2-5f2/RPB2-7cr, RPB2-7cf/RPB2-11ar (O'Donnell et al., 2022), respectively. BLAST analysis showed that the ITS, TEF-1α and RPB2 sequences of isolates Fs1(GenBank accession nos. OK001765, OQ921726 and OQ928396) and Fs3 (GenBank accession nos. OK001771, OQ921727 and OQ928397) showed 99%-100% identity with multiple GenBank sequences of Fusarium falciforme (KY617066, MN064683, KF255514, OQ933361, KY556711 and ON331935). A phylogenetic tree based on concatenated sequences of ITS, TEF-1α and RPB2 using maximum-likelihood analysis revealed that both isolates Fs1 and Fs3 were in the same clade with F. falciforme strains. Based on the morphological and molecular characteristics, the isolates were identified as members of F. falciforme. For pathogenicity testing, conidial suspensions (1×108 spores /mL) of isolates Fs1 and Fs3 were poured onto the roots of healthy pomegranate that had been planted in pots two months previously. Ten plants were inoculated for each isolate. Control plants were drenched with sterile water. After 3 months, inoculated plants developed leaf yellowing and wilting accompanied by root browning and rotting, much like symptoms observed in field plants. The same fungi re-isolated from the experimental plants were confirmed to be F. falciforme by morphology and sequence analysis. This is the first report of F. falciforme causing root rot on pomegranate. F. falciforme is a ubiquitous soil-borne pathogen that causes root rot on multiple plants around the world (Xu F., et al. 2022; Qiu R., et al. 2023). The results of pathogen identification are essential precursors to development of effective control of the disease.

Perceived uncertainty stress and its predictors among residents in China during the COVID-19 pandemic.

The prevalence of and risk factors for uncertainty stress among residents during the COVID-19 pandemic remain unclear. An online cross-sectional survey was conducted to explore and identify the risk factors for high perceived uncertainty stress among the general public in China during the COVID-19 outbreak. Information about the respondents' socioeconomic characteristics, knowledge of and attitudes towards COVID-19, perceived uncertainty stress, social capital, anxiety, and depressive symptoms was collected and analysed. Among the 1205 respondents, 45.3% (546) reported a high level of uncertainty stress. Multiple linear regression analysis indicated that anxiety (ß=3.871,P<0.001) and depression symptoms (ß=2.458, P<0.001), family residence (in towns or rural areas) (ß=0.947, P<0.001), lack of support for local epidemic control strategies (ß=1.253, P<0.001), worry about the pandemic (ß=1.191, P<0.001), and symptoms of weakness among family members (ß=1.525, P=0.002) were positively associated with perceived uncertainty stress. Cognitive social capital (ß=-0.883, P<0.001) and social networks (ß=-0.726, P<0.001) were negatively, but social participation (ß=0.714, P<0.001) was positively associated with perceived uncertainty stress. Our findings identify factors associated with a higher level of uncertainty stress and should be helpful in the consideration of effective policies and interventions for uncertainty stress during the initial phases of public health emergencies.

Ganoderic acid alleviates chemotherapy-induced fatigue in mice bearing colon tumor.

Chemotherapy-related fatigue (CRF) is increasingly being recognized as one of the severe symptoms in patients undergoing chemotherapy, which not only largely reduces the quality of life in patients, but also diminishes their physical and social function. At present, there is no effective drug for preventing and treating CRF. Ganoderic acid (GA), isolated from traditional Chinese medicine Ganoderma lucidum, has shown a variety of pharmacological activities such as anti-tumor, anti-inflammation, immunoregulation, etc. In this study, we investigated whether GA possessed anti-fatigue activity against CRF. CT26 tumor-bearing mice were treated with 5-fluorouracil (5-FU, 30 mg/kg) and GA (50 mg/kg) alone or in combination for 18 days. Peripheral and central fatigue-related behaviors, energy metabolism and inflammatory factors were assessed. We demonstrated that co-administration of GA ameliorated 5-FU-induced peripheral muscle fatigue-like behavior via improving muscle quality and mitochondria function, increasing glycogen content and ATP production, reducing lactic acid content and LDH activity, and inhibiting p-AMPK, IL-6 and TNF-α expression in skeletal muscle. Co-administration of GA also retarded the 5-FU-induced central fatigue-like behavior accompanied by down-regulating the expression of IL-6, iNOS and COX2 in the hippocampus through inhibiting TLR4/Myd88/NF-κB pathway. These results suggest that GA could attenuate 5-FU-induced peripheral and central fatigue in tumor-bearing mice, which provides evidence for GA as a potential drug for treatment of CRF in clinic.

First Report of Neofusicoccum parvum Causing Leaf Spot on Geodorum eulophioides in China.

Geodorum eulophioides Schltr. is a critically endangered orchid listed in the International Union for Conservation of Nature (IUCN) Red List of threatened species. At present, only two natural populations were found in China. It has important scientific and ornamental values because of its uniqueness. During the summer of 2019, a black leaf spot disease occurred on G. eulophioides, in Yachang Orchid National Nature Reserve (E106°13'32″，N24°44'19″) in Guangxi province, China. More than 60% of leaves of these plants were infected. The disease symptoms initially appeared as small yellow circular spots, which enlarged into irregular brown spots (6 to 9 cm length and 3 to 5 cm width). In later stages of the disease development, the center of the spots became dark brown with a clear edge and surrounded by a yellow halo. In severe infections, the spots coalesced covering the entire leaf. Six symptomatic leaves were collected from three infected plants, surface sterilized in 75% ethanol for 15 s and 0.1% HgCl2 for 4 min, and subsequently washed three times with sterile water, then plated onto potato dextrose agar (PDA), and incubated at 28℃ for three days. Eighteen fungal cultures with similar morphological characteristics were obtained from the infected tissues. Colonies were initially white, then turned dark grey after nine days. To induce sporulation, isolates were grown on 2% water agar and incubated under UVA light at 28℃ for nine days. Three isolates were selected for morphological characterization. Conidia were hyaline, unicellular, nonseptate, ellipsoidal to fusiform, externally smooth, thin-walled, and ranged from 10.7 to 16.6 µm (avg. 13.8 µm) × 4.1 to 6.7 µm (avg. 5.1 µm) (n=50). The isolate DBL-1 was selected as a representative for molecular identification. Genomic DNA was extracted and used for PCR to amplify the rDNA internal transcribed spacer region (ITS), translation elongation factor 1-alpha gene (EF1-α), and beta-tubulin gene (TUB2), using the primer pairs ITS1/ITS4 (White et al., 1990), EF1-728F/EF1-986R（Alves et al. 2008；Carbone & Kohn, 1999）, and T1/T2 (O'Donnell et al., 1997), respectively. The obtained ITS sequence (GenBank Accession No. MN918440), EF1-α sequence (MN963815), and TUB2 sequence (MN963816) showed >99% homology with several GenBank sequences of Neofusicoccum parvum (JX513636, KU997497 for ITS, KU997261, MH252401 for EF1-α, and KJ841779, MK412882 for TUB2, respectively). Based on morphological characteristics of the asexual morph and maximum likelihood analyses of a combined rDNA-ITS, EF1-α and TUB2 gene sequences, was identified as N. parvum. Pathogenicity test was performed using isolate DBL-1 by inoculating 3 leaves of G. eulophioides plants. The test was repeated three times. Each leaf was wounded using a sterile needle, and a mycelial plug (6 mm diameter) harvested from the periphery of a 3-day-old colony grown on PDA was placed on each wound. Plants were then covered with plastic bags to maintain high relative humidity of 90% and kept at 28℃ in a greenhouse under natural daylight conditions. An equal number of leaves on the same plant were inoculated using sterile PDA plugs and served as mock inoculated controls. After three days, all the inoculated leaves showed black spot symptoms resembling those observed in the field, whereas controls remained symptomless. The fungus was re-isolated from the symptomatic leaves, thus completing Koch's postulates. N. parvum has been reported to cause leaf spot disease on Myristica fragrans (Jayakumar, et al., 2011), Ginkgo biloba (Mirhosseini, et al., 2014), Vitis heyneana (Wu, et al., 2015), and Hevea brasiliensis (Liu et al., 2017), respectively. To the best of our knowledge, this is the first report of N. parvum causing leaf spot disease on G. eulophioides in China. The disease control measures and in-situ conservation method need to be strengthened to protect this rare species.

Crystal structure of sulfonic peroxiredoxin Ahp1 in complex with thioredoxin Trx2 mimics a conformational intermediate during the catalytic cycle.

Peroxiredoxin (Prx) is a thiol-based peroxidase that eliminates reactive oxygen species to avoid oxidative damage. Alkyl hydroperoxide reductase Ahp1 is a novel and specific typical 2-cysteine Prx. Here, we present the crystal structure of sulfonic Ahp1 complexed with thioredoxin Trx2 at 2.12 Å resolution. This structure implies that the transient Ahp1-Trx2 complex during the catalytic cycle already have an ability to decompose the peroxides. Structural analysis reveals that the segment glutamine23-lysine32 juxtaposed to the resolving cysteine (CR) of Ahp1 moves inward to generate a compact structure upon peroxidatic cysteine (CP) overoxidation, resulting in the breakdown of several conserved hydrogen bonds formed by Ahp1-Trx2 complex interaction. Structural comparisons suggest that the structure of sulfonic Ahp1 represents a novel conformation of Ahp1, which can mimic a conformational intermediate between the reduced and oxidized forms. Therefore, this study may provide a new structural insight into the intermediate state in which the segment glutamine23-lysine32 juxtaposed to the cysteine31 (CR) undergoes a conformational change upon cysteine62 (CP) oxidation to prepare for the formation of an intermolecular CP-CR disulfide bond during Ahp1 catalytic cycle.

New structural insights into the recognition of undamaged splayed-arm DNA with a single pair of non-complementary nucleotides by human nucleotide excision repair protein XPA.

XPA (Xeroderma pigmentosum complementation group A) is a core scaffold protein that plays significant roles in DNA damage verification and recruiting downstream endonucleases in the nucleotide excision repair (NER) pathway. Here, we present the 2.81 Å resolution crystal structure of the DNA-binding domain (DBD) of human XPA in complex with an undamaged splayed-arm DNA substrate with a single pair of non-complementary nucleotides. The structure reveals that two XPA molecules bind to one splayed-arm DNA with a 10-bp duplex recognition motif in a non-sequence-specific manner. XPA molecules bind to both ends of the DNA duplex region with a characteristic ß-hairpin. A conserved tryptophan residue Trp175 packs against the last base pair of DNA duplex and stabilizes the conformation of the characteristic ß-hairpin. Upon DNA binding, the C-terminal last helix of XPA would shift towards the minor groove of the DNA substrate for better interaction. Notably, human XPA is able to bind to the undamaged DNA duplex without any kinks, and XPA-DNA binding does not bend the DNA substrate obviously. This study provides structural basis for the binding mechanism of XPA to the undamaged splayed-arm DNA with a single pair of non-complementary nucleotides.

Azithromycin as an add-on treatment for persistent uncontrolled asthma in adults: protocol of a systematic review and meta-analysis.

INTRODUCTION: Clinical management of asthma remains a public challenge. Despite standard treatment with inhaled corticosteroids (ICS) and long-acting beta-agonists (LABAs), asthma remains uncontrolled in a substantial number of chronic asthma patients who risk reduced lung function and severe exacerbations. Azithromycin could have add-on effects for these patients. This study is proposed to systematically evaluate the efficacy of azithromycin as an add-on treatment for adults with persistent uncontrolled symptomatic asthma. METHODS AND ANALYSIS: Two reviewers will perform a comprehensive search of PubMed, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL) and four Chinese electronic databases including China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), WanFang Data and VIP Database from inception to May 2019. Only randomised controlled trials will be included. There is no restriction on language or publication status. Combined oral azithromycin and an ICS or/and a LABA will be compared with standard treatment alone or with a placebo. The primary outcomes are the number or frequency of asthma exacerbations, changes in asthma symptoms and lung function. Secondary outcomes include the number or frequency of inhalations of beta-agonists with or without corticosteroids for rescue use, eosinophil counts in blood or sputum, adverse events and others. A meta-analysis will be attempted to provide an estimate of the pooled treatment effect. Otherwise, qualitative descriptions of individual studies will be given. ETHICS AND DISSEMINATION: Ethical approval is not required because no primary data will be collected. Study findings will be presented at scientific conferences or published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42019117272.

Discovery of supercritical carbon dioxide in a hydrothermal system.

Supercritical CO2 appearing as bubbles in hydrothermal vents was identified in the south part of the Okinawa Trough using in situ Raman spectroscopy. Significantly, the N2 peak in supercritical CO2 is much larger than those in seawater and vent fluids, indicating that supercritical CO2 enriches N2 from the surrounding environment. Considering that the partial pressures of CO2 and N2 in the Earth's proto-atmosphere were ~10-20 MPa, supercritical CO2 with high N2 was likely the dominant CO2 phase near the water-air interface in the early history of the Earth, which promoted the synthesis, pre-enrichment and preservation of amino acids and other organic matters that are essential to the origin of life.

An investigation of a family COVID-19 cluster / 上海预防医学

Objective To investigate epidemic characteristics of a family cluster of COVID-19, and to provide reference in improving the criteria for exclusion diagnosis and medical observation of close contacts. Methods Field epidemiological method was used to investigate the cases and close contacts of a family cluster of COVID-19 in Pudong New Area.Descriptive analysis was conducted on epidemiological data.Real-time fluorescence quantitative RT-PCR was used to detect 2019-nCoV nucleic acid in the respiratory tract specimens. Results There were two confirmed cases and one suspected case in the family cluster.The source of infection was Case 1 with a living history in Wuhan, Hubei Province.Case 2 and Case 3, as close contacts, received 14-day medical observation in a centralized isolation site.Case 2 showed symptoms 4 days after the onset of Case 1, and the diagnosis of COVID-19 was excluded after two negative nucleic acid tests during the isolation period.However, after the expiration of isolation, Case 2 was diagnosed positively for COVID-19 and Case 3 was suspected first and then excluded. Conclusion Daily close contact is critical for COVID-19 transmission and is the major cause of family clustering.Once the close contacts show symptoms, diagnosis should be made by combining the results of nucleic acid test, chest CT test, serological test, etc.We suggest to grade the risk of infection for close contacts, and to strengthen the standard of medical observation for close contacts with high risk of infection.

Structural characterization of the redefined DNA-binding domain of human XPA.

XPA (xeroderma pigmentosum complementation group A), a key scaffold protein in nucleotide excision repair (NER) pathway, is important in DNA damage verification and repair proteins recruitment. Earlier studies had mapped the minimal DNA-binding domain (MBD) of XPA to a region corresponding to residues 98-219. However, recent studies indicated that the region involving residues 98-239 is the redefined DNA-binding domain (DBD), which binds to DNA substrates with a much higher binding affinity than MBD and possesses a nearly identical binding affinity to the full-length XPA protein. However, the structure of the redefined DBD domain of XPA (XPA-DBD) remains to be investigated. Here, we present the crystal structure of XPA-DBD at 2.06 Šresolution. Structure of the C-terminal region of XPA has been extended by 21 residues (Arg211-Arg231) as compared with previously reported MBD structures. The structure reveals that the C-terminal extension (Arg211-Arg231) is folded as an α-helix with multiple basic residues. The positively charged surface formed in the last C-terminal helix suggests its critical role in DNA binding. Further structural analysis demonstrates that the last C-terminal region (Asp217-Thr239) of XPA-DBD might undergo a conformational change to directly bind to the DNA substrates. This study provides a structural basis for understanding the possible mechanism of enhanced DNA-binding affinity of XPA-DBD.

Differential Expression Profiles and Functional Predication of Circular Ribonucleic Acid in Traumatic Spinal Cord Injury of Rats.

Recent studies indicate that circular ribonucleic acids (circRNAs) are involved in a variety of human diseases. The roles of circRNAs in traumatic spinal cord injury (SCI) remain unknown, however. We performed RNA-seq to analyze the circRNA expression profile in rat spinal cord after SCI and to investigate the relevant mechanisms. In all, 150 circRNAs were significantly differentially expressed in rat spinal cord after SCI by a fold-change ≥2 and p value ≤0.05. Among these, 99 circRNAs were upregulated, while 51 were downregulated. Gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway analyses, and circRNA/miocroRNA (miRNA) interaction networks were conducted to predict the potential roles of circRNAs in the process of SCI. In addition, the expression levels of six selected circRNAs were verified successfully by quantitative real-time polymerase chain reaction. Further study identified circRNA_07079 and circRNA_01282 as being associated with SCI, and they may participate in the pathophysiology of SCI through circRNA-targeted miRNA-messenger RNA axis. In summary, the results of our study revealed the expression profiles and potential functions of differentially expressed circRNAs in traumatic SCI in rats; this may provide new clues for studying the mechanisms underlying SCI and also present novel molecular targets for clinical therapy of SCI.

The redefined DNA-binding domain of human xeroderma pigmentosum complementation group A: production, crystallization and structure solution.

Human xeroderma pigmentosum complementation group A (XPA) is a scaffold protein that plays significant roles in DNA-damage verification and in recruiting downstream endonucleases to facilitate the repair of DNA lesions in nucleotide-excision repair. XPA98-219 (residues 98-219) has been identified as a DNA-binding domain and has been extensively studied in the last two decades. However, the most recent studies have redefined the DNA-binding domain as XPA98-239 (residues 98-239); it exerts a remarkably higher DNA-binding affinity than XPA98-219 and has a binding affinity that is quite similar to that of the full-length protein. Here, the production, crystallization and structure solution of human XPA98-239 are described. Crystals were obtained using a precipitant composed of 1.8 M ammonium citrate tribasic pH 7.0. Native X-ray diffraction data and zinc single-wavelength anomalous diffraction (SAD) data were collected to 1.93 and 2.06 Šresolution, respectively. The crystals belonged to space group P3, with unit-cell parameters a = 67.1, b = 67.1, c = 35.6 Å, γ = 120.0°. Crystal-content analysis showed the presence of one molecule in the asymmetric unit, corresponding to a Matthews coefficient of 2.65 Å3 Da-1 and a solvent content of 53.6%. The initial phases were solved and the structure model was automatically built by zinc SAD using the AutoSol program. The initial structure model covered 119 of 142 residues in the asymmetric unit, with an Rwork of 22.15% and an Rfree of 25.82%. Compared with a previously obtained truncated solution NMR structure of XPA (residues 98-210), a 19-residue C-terminal extension (residues 211-229, corresponding to 10 of the 20 extra C-terminal residues in the redefined domain for enhanced DNA binding) was contained in this initial model. Refinement of the atomic coordinates of XPA is ongoing.

2018 China guideline for diagnosis and treatment of senile osteoporosis / 中国实用内科杂志

According to the procedures for the development of evidence-based medicine guidelines, a multi-disciplinary guideline development working group was established, after three rounds of discussions by the consensus expert group, a new evidencebased guideline for diagnosis and treatment of senile osteoporosis in China(2018) was developed. The grading of recommendations assessment, development and evaluation(GRADE) system was used to rate the quality of evidence and the strength of recommendations. Recommendations were derived from evidence body, and at the same time considered the balance of benefits and harms as well as values and preferences of Chinese patients. The guideline development working group developed 15 recommendations for the diagnosis and treatment of senile osteoporosis. The guideline covered the screening for senile osteoporosis, risk assessment, diagnosis, basic treatment, multiple anti-osteoporosis drugs, therapeutic effect monitoring and evaluation of senile osteoporosis. This guideline aims to serve as a tool for clinicians and patients for best decisions-making in China.

Microarray expression profiling and co-expression network analysis of circulating LncRNAs and mRNAs associated with neurotoxicity induced by BPA.

A growing body of evidence has shown bisphenol A (BPA), an estrogen-like industrial chemical, has adverse effects on the nervous system. In this study, we investigated the transcriptional behavior of long non-coding RNAs (lncRNAs) and mRNAs to provide the information to explore neurotoxic effects induced by BPA. By microarray expression profiling, we discovered 151 differentially expressed lncRNAs and 794 differentially expressed mRNAs in the BPA intervention group compared with the control group. Gene ontology analysis indicated the differentially expressed mRNAs were mainly involved in fundamental metabolic processes and physiological and pathological conditions, such as development, synaptic transmission, homeostasis, injury, and neuroinflammation responses. In the expression network of the BPA-induced group, a great number of nodes and connections were found in comparison to the control-derived network. We identified lncRNAs that were aberrantly expressed in the BPA group, among which, growth arrest specific 5 (GAS5) might participate in the BPA-induced neurotoxicity by regulating Jun, RAS, and other pathways indirectly through these differentially expressed genes. This study provides the first investigation of genome-wide lncRNA expression and correlation between lncRNA and mRNA expression in the BPA-induced neurotoxicity. Our results suggest that the elevated expression of lncRNAs is a major biomarker in the neurotoxicity induced by BPA.

Identification and Characterizations of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Scaffold Hopping- and 2D-Molecular Fingerprint-Based Similarity Search.

SET7, serving as the only histone methyltransferase that monomethylates 'Lys-4' of histone H3, has been proved to function as a key regulator in diverse biological processes, such as cell proliferation, transcriptional network regulation in embryonic stem cell, cell cycle control, protein stability, heart morphogenesis and development. What's more, SET7 is involved inthe pathogenesis of alopecia aerate, breast cancer, tumor and cancer progression, atherosclerosis in human carotid plaques, chronic renal diseases, diabetes, obesity, ovarian cancer, prostate cancer, hepatocellular carcinoma, and pulmonary fibrosis. Therefore, there is urgent need to develop novel SET7 inhibitors. In this paper, based on DC-S239 which has been previously reported in our group, we employed scaffold hopping- and 2D fingerprint-based similarity searches and identified DC-S285 as the new hit compound targeting SET7 (IC50 = 9.3 µM). Both radioactive tracing and NMR experiments validated the interactions between DC-S285 and SET7 followed by the second-round similarity search leading to the identification ofDC-S303 with the IC50 value of 1.1 µM. In cellular level, DC-S285 retarded tumor cell proliferation and showed selectivity against MCF7 (IC50 = 21.4 µM), Jurkat (IC50 = 2.2 µM), THP1 (IC50 = 3.5 µM), U937 (IC50 = 3.9 µM) cell lines. Docking calculations suggested that DC-S303 share similar binding mode with the parent compoundDC-S239. What's more, it presented good selectivity against other epigenetic targets, including SETD1B, SETD8, G9a, SMYD2 and EZH2. DC-S303 can serve as a drug-like scaffold which may need further optimization for drug development, and can be used as chemical probe to help the community to better understand the SET7 biology.

Super-strong dislocation-structured high-carbon martensite steel.

High-carbon martensite steels (with C > 0.5 wt.%) are very hard but at the same time as brittle as glass in as-quenched or low-temperature-tempered state. Such extreme brittleness, originating from a twin microstructure, has rendered these steels almost useless in martensite state. Therefore, for more than a century it has been a common knowledge that high-carbon martensitic steels are intrinsically brittle and thus are not expected to find any application in harsh loading conditions. Here we report that these brittle steels can be transformed into super-strong ones exhibiting a combination of ultrahigh strength and significant toughness, through a simple grain-refinement treatment, which refines the grain size to ~4 µm. As a result, an ultra-high tensile strength of 2.4~2.6 GPa, a significant elongation of 4~10% and a good fracture toughness (K1C) of 23.5~29.6 MPa m1/2 were obtained in high-carbon martensitic steels with 0.61-0.65 wt.% C. These properties are comparable with those of "the king of super-high-strength steels"-maraging steels, but achieved at merely 1/30~1/50 of the price. The drastic enhancement in mechanical properties is found to arise from a transition from the conventional twin microstructure to a dislocation one by grain refinement. Our finding may provide a new route to manufacturing super-strong steels in a simple and economic way.