A Novel Frameshift Variant of the ELF4 Gene in a Patient with Autoinflammatory Disease: Clinical Features, Transcriptomic Profiling and Functional Studies.

We described the diagnosis and treatment of a patient with autoinflammatory disease, named "Deficiency in ELF4, X-linked (DEX)". A novel ELF4 variant was discovered and its pathogenic mechanism was elucidated. The data about clinical, laboratory and endoscopic features, treatment, and follow-up of a patient with DEX were analyzed. Whole exome sequencing and Sanger sequencing were performed to identify potential pathogenic variants. The mRNA and protein levels of ELF4 were analyzed by qPCR and Western blotting, respectively. The association of ELF4 frameshift variant with nonsense-mediated mRNA decay (NMD) in the pathogenesis DEX was examined. Moreover, RNA-seq was performed to identify the key molecular events triggered by ELF4 variant. The relationship between ELF4 and IFN-ß activity was validated using a dual-luciferase reporter assay and a ChIP-qPCR assay. An 11-year-old boy presented with a Behçet's-like phenotype. The laboratory abnormality was the most obvious in elevated inflammatory indicators. Endoscopy revealed multiple ileocecal ulcers. Intestinal histopathology showed inflammatory cell infiltrations. The patient was treated with long-term immunosuppressant and TNF-α blocker (adalimumab), which reaped an excellent response over 16 months of follow-up. Genetic analysis identified a maternal hemizygote frameshift variant (c.1022del, p.Q341Rfs*30) in ELF4 gene in the proband. The novel variant decreased the mRNA level of ELF4 via the NMD pathway. Mechanistically, insufficient expression of ELF4 disturbed the immune system, leading to immunological disorders and pathogen susceptibility, and disrupted ELF4-activating IFN-ß responses. This analysis detailed the clinical characteristics of a Chinese patient with DEX who harbored a novel ELF4 frameshift variant. For the first time, we used patient-derived cells and carried out transcriptomic analysis to delve into the mechanism of ELF4 variant in DEX.

Vagus nerve stimulation (VNS) preventing postoperative cognitive dysfunction (POCD): two potential mechanisms in cognitive function.

Postoperative cognitive dysfunction (POCD) impacts a significant number of patients annually, frequently impairing their cognitive abilities and resulting in unfavorable clinical outcomes. Aimed at addressing cognitive impairment, vagus nerve stimulation (VNS) is a therapeutic approach, which was used in many mental disordered diseases, through the modulation of vagus nerve activity. In POCD model, the enhancement of cognition function provided by VNS was shown, demonstrating VNS effect on cognition in POCD. In the present study, we primarily concentrates on elucidating the role of the VNS improving the cognitive function in POCD, via two potential mechanisms: the inflammatory microenvironment and epigenetics. This study provided a theoretical support for the feasibility that VNS can be a potential method to enhance cognition function in POCD.

Motion detection and direction recognition in a photonic spiking neural network consisting of VCSELs-SA.

Motion detection and direction recognition are two important fundamental visual functions among the many cognitive functions performed by the human visual system. The retina and visual cortex are indispensable for composing the visual nervous system. The retina is responsible for transmitting electrical signals converted from light signals to the visual cortex of the brain. We propose a photonic spiking neural network (SNN) based on vertical-cavity surface-emitting lasers with an embedding saturable absorber (VCSELs-SA) with temporal integration effects, and demonstrate that the motion detection and direction recognition tasks can be solved by mimicking the visual nervous system. Simulation results reveal that the proposed photonic SNN with a modified supervised algorithm combining the tempotron and the STDP rule can correctly detect the motion and recognize the direction angles, and is robust to time jitter and the current difference between VCSEL-SAs. The proposed approach adopts a low-power photonic neuromorphic system for real-time information processing, which provides theoretical support for the large-scale application of hardware photonic SNN in the future.

A comparative-descriptive analysis of clinical characteristics in 2019-coronavirus-infected children and adults.

Acute respiratory disease caused by 2019 novel coronavirus (2019-nCoV) has rapidly spread throughout China. Children and adults show a different clinical course. The purpose of the current study is to comparatively analyze the clinical characteristics of 2019-nCoV infection in children and adults and to explore the possible causes for the discrepancies present. The medical records of 25 adults and 7 children confirmed cases of 2019-2019-nCoV acute respiratory diseases were reviewed retrospectively. All children were family clusters. The total adult patients were differentiated into the local residents of Wuhan, a history of travel to Wuhan and direct contact with people from Wuhan. The numbers were 14 (56%), 10 (40%), and 1 (4%), respectively. The median incubation period of children and adults was 5 days (ranged, 3-12 days) and 4 days (ranged, 2-12 days), respectively. Diarrhoea and/or vomiting (57.1%) were demic by World Health Organiza more common in children, whereas for adults it was myalgia or fatigue (52%). On admission, the percentage of children having pneumonia (5%, 71.4%) was roughly the same as adults (20%, 80%). A total of 20% of adults had leucopoenia, but leukocytosis was more frequently in children (28.6%, P=.014). A higher number of children had elevated creatine kinase isoenzyme (57.1% vs 4%, P=.004). Antiviral therapy was given to all adult patients but to none of the children. In summary, knowledge of these differences between children and adults will not only be helpful for the clinical diagnosis of 2019-nCoV disease, but also for a future discussion on age-specific coronavirus infection.

A PPO Promoter from Betalain-Producing Red Swiss Chard, Directs Petiole- and Root-Preferential Expression of Foreign Gene in Anthocyanins-Producing Plants.

A 1670 bp 5'-flanking region of the polyphenol oxidase (PPO) gene was isolated from red Swiss chard, a betalain-producing plant. This region, named promoter BvcPPOP, and its 5'-truncated versions were fused with the GUS gene and introduced into Arabidopsis, an anthocyanins-producing plant. GUS histochemical staining and quantitative analysis of transgenic plants at the vegetative and reproductive stages showed that BvcPPOP could direct GUS gene expression in vegetative organs with root- and petiole-preference, but not in reproductive organs including inflorescences shoot, inflorescences leaf, flower, pod and seed. This promoter was regulated by developmental stages in its driving strength, but not in expression pattern. It was also regulated by the abiotic stressors tested, positively by salicylic acid (SA) and methyl jasmonate (MeJA) but negatively by abscisic acid (ABA), gibberellin (GA), NaCl and OH(-). Its four 5'-truncated versions varied in the driving strength, but not obviously in expression pattern, and even the shortest version (-225 to +22) retained the root- and petiole- preference. This promoter is, to our knowledge, the first PPO promoter cloned and functionally elucidated from the betalain-producing plant, and thus provides not only a useful tool for expressing gene(s) of agricultural interest in vegetative organs, but also a clue to clarify the function of metabolism-specific PPO in betalain biosynthesis.

[Genotype, environment and their interactions of major bioactive components in 2-year licorice (Glycyrrhiza uralensis) population].

OBJECTIVE: This study aimed at analyzing the effect of genotype (G), environment (E) and their interactions (G x E) on the major bioactive components of 2-year licorice (Glycyrrhiza uralensis) population, in order to provide a theoretical basis for the licorice breeding with high content of bioactive components and quality improvement. METHOD: Four genotype licorice populations were transplanted under four different environments by using complete randomized block design with three replicates, and four major bioactive components, including glycyrrhizin (GL), total saponins (TS), liquiritin (LQ) and total flavonoids (TF) were determined by UV and by HPLC. RESULT: The major bioactive components of licorice were influenced by genotype and environment, and the genotype had more effect on all of the bioactive components. The contents of GL and LQ were codetermined by genotype and environment factors. CONCLUSION: There exist different selective effects on different growth region for quality breeding in cultivated population of licorice.

Meta-Analysis of Anesthetic Efficacy and Safety of Propofol in Craniotomy Patients.

The anesthetic effect and safety of propofol in craniotomy patients by meta-analysis is investigated. Relevant studies consistent with the anesthetic effect and safety of propofol in craniotomy patients are searched and screened from domestic and foreign literature databases such as Wanfang Medical Center, CNKI, VIP, and PubMed, and meta-analysis is performed by RevMan 5.2 software. Experimental results show that the recovery time, intracranial pressure, cerebral edema, partial cerebral oxygen pressure, glutamate, and MDA in the propofol group are better than those in the control group (P < 0.05), and the incidence of superoxide dismutase, TNF-α, and adr in the propofol group is better than that in the control group (P > 0.05). Intravenous anesthesia with propofol in patients with craniotomy has the advantage of rapid recovery, and this program can improve intracranial pressure, brain edema, and brain oxygen partial pressure and help to improve oxidative stress and inflammatory reaction.

Effect of plastic film mulching and film residues on phthalate esters concentrations in soil and plants, and its risk assessment.

The application of plastic film mulching can greatly improve dryland productivity, while the release of toxic phthalate esters (PAEs) from the plastic film has generated concern. This study investigated the effects of mulched plastic film and residual plastic film on the PAE concentrations in the soil-crop system and assessed the risks to people eating crop products. The PAEs concentration in the 0-25 cm soil layer of plastic mulched farmland was 0.45-0.81 mg/kg, while the average PAEs concentration of 0.37-0.73 mg/kg in non-mulched farmland decreased by 19%. The PAEs concentration in mulched soil reached the highest in July, being 0.80-0.84 mg/kg, while in the non-mulched soil, the PAEs also appeared and gradually decreased from May at 0.62-0.74 mg/kg to October, and the PAEs concentrations were almost the same in the mulched and non-mulched soils at the harvest time in October at 0.37-0.44 mg/kg. With the amounts of residual film in farmland increasing from 0 kg/ha to 2700 kg/ha (equivalent to the total amount of residual film after 60 years of continuous plastic film mulching), the PAEs concentrations were no significant changes, being 0.54-0.93 mg/kg. Maize (Zea mays L.) roots could absorb and accumulate PAEs, and the bio-concentration factor (BCF) was 1.6-2.3, and the average PAEs concentrations in stems, leaves, and grains were 79%-80% of those in roots at 0.77-1.47 mg/kg. For the ingestion of maize grains or potato (Solanum tuberosum L.) tubers grown in plastic film mulched farmland or farmland containing residual film of 450-2700 kg/ha, the hazard index (HI) were less than 1, the carcinogenic risks (CRs) were 2.5 × 10-7-2.2 × 10-6, and the estrogenic equivalences were 6.17-17.73 ng E2/kg. This study provides important data for the risk management of PAEs in farmlands.

Sulforaphane attenuates cisplatin-induced hearing loss by inhibiting histone deacetylase expression.

INTRODUCTION: Cruciferous vegetables are a rich source of sulforaphane (SFN), which acts as a natural HDAC inhibitor (HDACi). Our previous study found that HDACi could restore histone acetyltransferase/histone deacetylase (HAT/HDAC) balance in the cochlea and attenuate gentamicin-induced hearing loss in guinea pigs. Here, we investigated the protective effect of SFN on cisplatin-induced hearing loss (CIHL). METHODS: Thirty rats were randomly divided into 3 equal groups: the control group, cisplatin group, and SFN+cisplatin group. Rats were injected with SFN (30 mg/kg once a day) and cisplatin (7 mg/kg twice a day) for 7 days to investigate the protective role of SFN on CIHL. We observed auditory brainstem response (ABR) threshold shifts and immunostained cochlear basilar membranes of rats. For in vitro experiments, we treated HEI-OC1 cells and rat cochlear organotypic cultures with SFN (5, 10, and 15 µM) and cisplatin (10 µM). Immunofluorescence, cell viability, and protein analysis were performed to further analyze the protective mechanism of SFN on CIHL. RESULTS: SFN (30 mg/kg once a day) decreased cisplatin (7 mg/kg twice a day)-induced ABR threshold shifts and outer hair cell loss. CCK-8 assay showed that cisplatin (10 µM) reduced the viability of HEI-OC1 cells to 42%, and SFN had a dose-dependent protective effect. In cochlear organotypic cultures, we found that SFN (10 and 15 µM) increased cisplatin (10 µM)-induced myosin 7a+ cell count and restored ciliary morphology. SFN (5, 10, and 15 µM) reversed the cisplatin (10 µM)-induced increase in HDAC2, -4, and -5 and SFN (15 µM) reversed the cisplatin (10 µM)-induced decrease in H3-Ack9 [acetyl-histone H3 (Lys9)] protein expression in HEI-OC1 cells. Neither cisplatin nor cisplatin combined with SFN affected the expression of HDAC7, or HDAC9. CONCLUSION: SFN prevented disruption of the HAT/HDAC balance, protecting against CIHL in rats.

Reduction effects of solar radiation, mechanical tension, and soil burial on phthalate esters concentrations in plastic film and soils.

Phthalate esters (PAEs) are potentially dangerous chemicals in plastic film mulched fields; however, few studies have investigated how to reduce their concentrations in plastic film and soil. In this study, the effects of solar radiation, mechanical tension, and soil burial on PAEs concentrations in polyethylene (PE) film and degradable film were investigated, and the half-lives of di-n-butyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP) in soil also studied. PAEs concentrations in polyethylene films were about twice those in the degradable films; however, PAEs concentrations in all experimental films were similar after 1-year of field exposure. Mechanical tension had no effect on the PAEs concentrations of polyethylene films, but increased the detected concentrations of PAEs in degradable films by 34%-120%. After 4-years of burial, the PAEs concentrations in films decreased by 79.2%-98.0%, and mechanical tension promoted the reductions. However, there was little difference in PAEs concentrations between the buried soils with and without films, indicating the released PAEs reduced quickly in soil. Also, the half-lives of DBP and DEHP were 2.4-4.6 days and 18.5-41.4 days, respectively. Overall, the results presented herein provide reasonable approaches to reduce the concentrations of PAEs in plastic films and soils.

miR-125b Promotes Colorectal Cancer Migration and Invasion by Dual-Targeting CFTR and CGN.

Metastasis contributes to the poor prognosis of colorectal cancer, the causative factor of which is not fully understood. Previously, we found that miR-125b (Accession number: MIMAT0000423) contributed to cetuximab resistance in colorectal cancer (CRC). In this study, we identified a novel mechanism by which miR-125b enhances metastasis by targeting cystic fibrosis transmembrane conductance regulator (CFTR) and the tight junction-associated adaptor cingulin (CGN) in CRC. We found that miR-125b expression was upregulated in primary CRC tumors and metastatic sites compared with adjacent normal tissues. Overexpression of miR-125b in CRC cells enhanced migration capacity, while knockdown of miR-125b decreased migration and invasion. RNA-sequencing (RNA-seq) and dual-luciferase reporter assays identified CFTR and CGN as the target genes of miR-125b, and the inhibitory impact of CFTR and CGN on metastasis was further verified both in vitro and in vivo. Moreover, we found that miR-125b facilitated the epithelial-mesenchymal transition (EMT) process and the expression and secretion of urokinase plasminogen activator (uPA) by targeting CFTR and enhanced the Ras Homolog Family Member A (RhoA)/Rho Kinase (ROCK) pathway activity by targeting CGN. Together, these findings suggest miR-125b as a key functional molecule in CRC and a promising biomarker for the diagnosis and treatment of CRC.

Greater Biofilm Formation and Increased Biodegradation of Polyethylene Film by a Microbial Consortium of Arthrobacter sp. and Streptomyces sp.

The widespread use of polyethylene (PE) mulch films has led to a significant accumulation of plastic waste in agricultural soils. The biodegradation of plastic waste by microorganisms promises to provide a cost-effective and environmentally-friendly alternative for mitigating soil plastic pollution. A large number of microorganisms capable of degrading PE have been reported, but degradation may be further enhanced by the cooperative activity of multiple microbial species. Here, two novel strains of Arthrobacter sp. and Streptomyces sp. were isolated from agricultural soils and shown to grow with PE film as a sole carbon source. Arthrobacter sp. mainly grew in the suspension phase of the culture, and Streptomyces sp. formed substantial biofilms on the surface of the PE film, indicating that these strains were of different metabolic types and occupied different microenvironments with contrasting nutritional access. Individual strains were able to degrade the PE film to some extent in a 90-day inoculation experiment, as indicated by decreased hydrophobicity, increased carbonyl index and CO2 evolution, and the formation of biofilms on the film surface. However, a consortium of both strains had a much greater effect on these degradation properties. Together, these results provide new insights into the mechanisms of PE biodegradation by a microbial consortium composed of different types of microbes with possible metabolic complementarities.

5-methylcytosine promotes pathogenesis of bladder cancer through stabilizing mRNAs.

Although 5-methylcytosine (m5C) is a widespread modification in RNAs, its regulation and biological role in pathological conditions (such as cancer) remain unknown. Here, we provide the single-nucleotide resolution landscape of messenger RNA m5C modifications in human urothelial carcinoma of the bladder (UCB). We identify numerous oncogene RNAs with hypermethylated m5C sites causally linked to their upregulation in UCBs and further demonstrate YBX1 as an m5C 'reader' recognizing m5C-modified mRNAs through the indole ring of W65 in its cold-shock domain. YBX1 maintains the stability of its target mRNA by recruiting ELAVL1. Moreover, NSUN2 and YBX1 are demonstrated to drive UCB pathogenesis by targeting the m5C methylation site in the HDGF 3' untranslated region. Clinically, a high coexpression of NUSN2, YBX1 and HDGF predicts the poorest survival. Our findings reveal an unprecedented mechanism of RNA m5C-regulated oncogene activation, providing a potential therapeutic strategy for UCB.

Mechanisms of wheat (Triticum aestivum) grain storage proteins in response to nitrogen application and its impacts on processing quality.

Basis for the effects of nitrogen (N) on wheat grain storage proteins (GSPs) and on the establishment of processing quality are far from clear. The response of GSPs and processing quality parameters to four N levels of four common wheat cultivars were investigated at two sites over two growing seasons. Except gluten index (GI), processing quality parameters as well as GSPs quantities were remarkably improved by increasing N level. N level explained 4.2~59.2% and 10.4~80.0% variability in GSPs fractions and processing quality parameters, respectively. The amount of N remobilized from vegetative organs except spike was significantly increased when enhancing N application. GSPs fractions and processing quality parameters except GI were only highly and positively correlated with the amount of N remobilized from stem with sheath. N reassimilation in grain was remarkably strengthened by the elevated activity and expression level of glutamine synthetase. Transcriptome analysis showed the molecular mechanism of seeds in response to N levels during 10~35 days post anthesis. Collectively, we provided comprehensive understanding of N-responding mechanisms with respect to wheat processing quality from N source to GSPs biosynthesis at the agronomic, physiological and molecular levels, and screened candidate genes for quality breeding.

Linoleic acid isomerase gene FgLAI12 affects sensitivity to salicylic acid, mycelial growth and virulence of Fusarium graminearum.

Fusarium graminearum is the major causal agent of fusarium head blight in wheat, a serious disease worldwide. Linoleic acid isomerase (LAI) catalyses the transformation of linoleic acid (LA) to conjugated linoleic acid (CLA), which is beneficial for human health. We characterised a cis-12 LAI gene of F. graminearum (FGSG_02668; FgLAI12), which was downregulated by salicylic acid (SA), a plant defence hormone. Disruption of FgLAI12 in F. graminearum resulted in decreased accumulation of cis-9,trans-11 CLA, enhanced sensitivity to SA, and increased accumulation of LA and SA in wheat spikes during infection. In addition, mycelial growth, accumulation of deoxynivalenol, and pathogenicity in wheat spikes were reduced. Re-introduction of a functional FgLAI12 gene into ΔFgLAI12 recovered the wild-type phenotype. Fluorescent microscopic analysis showed that FgLAI12 protein was usually expressed in the septa zone of conidia and the vacuole of hyphae, but was expressed in the cell membrane of hyphae in response to exogenous LA, which may be an element of LA metabolism during infection by F. graminearum. The cis-12 LAI enzyme encoded by FgLAI12 is critical for fungal response to SA, mycelial growth and virulence in wheat. The gene FgLAI12 is potentially valuable for biotechnological synthesis of cis-9,trans-11 CLA.

MicroRNA-7/NF-κB signaling regulatory feedback circuit regulates gastric carcinogenesis.

MicroRNAs play essential roles in gene expression regulation during carcinogenesis. Here, we investigated the role of miR-7 and the mechanism by which it is dysregulated in gastric cancer (GC). We used genome-wide screenings and identified RELA and FOS as novel targets of miR-7. Overexpression of miR-7 repressed RELA and FOS expression and prevented GC cell proliferation and tumorigenesis. These effects were clinically relevant, as low miR-7 expression was correlated with high RELA and FOS expression and poor survival in GC patients. Intriguingly, we found that miR-7 indirectly regulated RELA activation by targeting the IκB kinase IKKε. Furthermore, IKKε and RELA can repress miR-7 transcription, which forms a feedback circuit between miR-7 and nuclear factor κB (NF-κB) signaling. Additionally, we demonstrate that down-regulation of miR-7 may occur as a result of the aberrant activation of NF-κB signaling by Helicobacter pylori infection. These findings suggest that miR-7 may serve as an important regulator in GC development and progression.

[Discussion on necessity of introduction of qualitative research into clinical research of traditional Chinese medicine].

Currently, the model of the research evaluation system of traditional Chinese medicine (TCM) is set up through imitating that of western medicine. The application of quantitative research to TCM does promote the advance of modernization of TCM, which explore the part of TCM that can be measured in quantitative method. However, TCM has a background of profound philosophy and culture. The priority of TCM can not be expressed through quantitative research alone. On the contrary, qualitative research is more suitable to most research area of TCM. In TCM clinical research, the priority of TCM should be fully explored. It is very significant to set up the effectiveness evaluation system of TCM, especially by applying qualitative research to the diagnosis and the evaluation of treatment results and combining quantitative research.

Truncated cotton subtilase promoter directs guard cell-specific expression of foreign genes in tobacco and Arabidopsis.

A 993-bp regulatory region upstream of the translation start codon of subtilisin-like serine protease gene was isolated from Gossypium barbadense. This (T/A)AAAG-rich region, GbSLSP, and its 5'- and 3'-truncated versions were transferred into tobacco and Arabidopsis after fusing with GUS or GFP. Histochemical and quantitative GUS analysis and confocal GFP fluorescence scanning in the transgenic plants showed that the GbSLSP-driven GUS and GFP expressed preferentially in guard cells, whereas driven by GbSLSPF2 to GbSLSPF4, the 5'-truncated GbSLSP versions with progressively reduced Dof1 elements, both GUS and GFP expressed exclusively in guard cells, and the expression strength declined with (T/A)AAAG copy decrement. Deletion of 5'-untranslated region from GbSLSP markedly weakened the activity of GUS and GFP, while deletion from the strongest guard cell-specific promoter, GbSLSPF2, not only significantly decreased the expression strength, but also completely abolished the guard cell specificity. These results suggested both guard cell specificity and expression strength of the promoters be coordinately controlled by 5'-untranslated region and a cluster of at least 3 (T/A)AAAG elements within a region of about 100 bp relative to transcription start site. Our guard cell-specific promoters will enrich tools to manipulate gene expression in guard cells for scientific research and crop improvement.