TMEFF1 is a neuron-specific restriction factor for herpes simplex virus.

The brain is highly sensitive to damage caused by infection and inflammation1,2. Herpes simplex virus 1 (HSV-1) is a neurotropic virus and the cause of herpes simplex encephalitis3. It is unknown whether neuron-specific antiviral factors control virus replication to prevent infection and excessive inflammatory responses, hence protecting the brain. Here we identify TMEFF1 as an HSV-1 restriction factor using genome-wide CRISPR screening. TMEFF1 is expressed specifically in neurons of the central nervous system and is not regulated by type I interferon, the best-known innate antiviral system controlling virus infections. Depletion of TMEFF1 in stem-cell-derived human neurons led to elevated viral replication and neuronal death following HSV-1 infection. TMEFF1 blocked the HSV-1 replication cycle at the level of viral entry through interactions with nectin-1 and non-muscle myosin heavy chains IIA and IIB, which are core proteins in virus-cell binding and virus-cell fusion, respectively4-6. Notably, Tmeff1-/- mice exhibited increased susceptibility to HSV-1 infection in the brain but not in the periphery. Within the brain, elevated viral load was observed specifically in neurons. Our study identifies TMEFF1 as a neuron-specific restriction factor essential for prevention of HSV-1 replication in the central nervous system.

The role of macrophage-fibroblast interaction in lipopolysaccharide-induced pulmonary fibrosis: an acceleration in lung fibroblast aerobic glycolysis.

Recent evidence has shown that lipopolysaccharide (LPS)-induced aerobic glycolysis of lung fibroblasts is closely associated with the pathogenesis of septic pulmonary fibrosis. Nevertheless, the underlying mechanism remains poorly defined. In this study, we demonstrate that LPS promotes c-Jun N-terminal kinase (JNK) signaling pathway activation and endogenous tumor necrosis factor-α (TNF-α) secretion in pulmonary macrophages. This, in turn, could significantly promote aerobic glycolysis and increase lactate production in lung fibroblasts through 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) activation. Culturing human lung fibroblast MRC-5 cell line with TNF-α or endogenous TNF-α (cell supernatants of macrophages after LPS stimulation) both enhanced the aerobic glycolysis and increased lactate production. These effects could be prevented by treating macrophages with JNK pathway inhibitor, by administering TNF-α receptor 1 (TNFR1) siRNA, PFKFB3 inhibitor, or by silencing PFKFB3 with fibroblasts-specific shRNA. In addition, the inhibition of TNF-α secretion and PFKFB3 expression prevented LPS-induced pulmonary fibrosis in vivo. In conclusion, this study revealed that LPS-induced macrophage secretion of TNF-α could initiate fibroblast aerobic glycolysis and lactate production, implying that inflammation-metabolism interactions between lung macrophages and fibroblasts might play an essential role in LPS-induced pulmonary fibrosis.

Simultaneous gentamicin-mediated damage and Atoh1 overexpression promotes hair cell regeneration in the neonatal mouse utricle.

Loss of hair cells from vestibular epithelium results in balance dysfunction. The current therapeutic regimen for vestibular diseases is limited. Upon injury or Atoh1 overexpression, hair cell replacement occurs rapidly in the mammalian utricle, suggesting a promising approach to induce vestibular hair cell regeneration. In this study, we applied simultaneous gentamicin-mediated hair cell ablation and Atoh1 overexpression to induce neonatal utricular hair cell formation in vitro. We confirmed that type I hair cells were the primary targets of gentamicin. Furthermore, injury and Atoh1 overexpression promoted hair cell regeneration in a timely and efficient manner through robust viral transfection. Hair cells regenerated with type II characteristics in the striola and type I/II characteristics in non-sensory regions. Rare EdU+/myosin7a+ cells in sensory regions and robust EdU+/myosin7a+ signals in ectopic regions indicate that transdifferentiation of supporting cells in situ, and mitosis and differentiation of non-sensory epithelial cells in ectopic regions, are sources of regenerative hair cells. Distinct regeneration patterns in in situ and ectopic regions suggested robust plasticity of vestibular non-sensory epithelium, generating more developed hair cell subtypes and thus providing a promising stem cell-like source of hair cells. These findings suggest that simultaneously causing injury and overexpressing Atoh1 promotes hair cell regeneration efficacy and maturity, thus expanding the understanding of ectopic plasticity in neonatal vestibular organs.

Hair cell uptake of gentamicin in the developing mouse utricle.

Intratympanic injection of gentamicin has proven to be an effective therapy for intractable vestibular dysfunction. However, most studies to date have focused on the cochlea, so little is known about the distribution and uptake of gentamicin by the counterpart of the auditory system, specifically vestibular hair cells (HCs). Here, with a combination of in vivo and in vitro approaches, we used a gentamicin-Texas Red (GTTR) conjugate to investigate the mechanisms of gentamicin vestibulotoxicity in the developing mammalian utricular HCs. In vivo, GTTR fluorescence was concentrated in the apical cytoplasm and the cellular membrane of neonatal utricular HCs, but scarce in the nucleus of HCs and supporting cells. Quantitative analysis showed the GTTR uptake by striolar HCs was significantly higher than that in the extrastriola. In addition, the GTTR fluorescence intensity in the striola was increased gradually from 1 to 8 days, peaking at 8-9 days postnatally. In vitro, utricle explants were incubated with GTTR and candidate uptake conduits, including mechanotransduction (MET) channels and endocytosis in the HC, were inhibited separately. GTTR uptake by HCs could be inhibited by quinine, a blocker of MET channels, under both normal and stressed conditions. Meanwhile, endocytic inhibition only reduced GTTR uptake in the CoCl2 hypoxia model. In sum, the maturation of MET channels mediated uptake of GTTR into vestibular HCs. Under stressed conditions, MET channels play a pronounced role, manifested by channel-dependent stress enhanced GTTR permeation, while endocytosis participates in GTTR entry in a more selective manner.

Canonical Wnt Signaling Pathway on Polarity Formation of Utricle Hair Cells.

As part of the inner ear, the vestibular system is responsible for sense of balance, which consists of three semicircular canals, the utricle, and the saccule. Increasing evidence has indicated that the noncanonical Wnt/PCP signaling pathway plays a significant role in the development of the polarity of the inner ear. However, the role of canonical Wnt signaling in the polarity of the vestibule is still not completely clear. In this study, we found that canonical Wnt pathway-related genes are expressed in the early stage of development of the utricle and change dynamically. We conditionally knocked out ß-catenin, a canonical Wnt signaling core protein, and found that the cilia orientation of hair cells was disordered with reduced number of hair cells in the utricle. Moreover, regulating the canonical Wnt pathway (Licl and IWP2) in vitro also affected hair cell polarity and indicated that Axin2 may be important in this process. In conclusion, our results not only confirm that the regulation of canonical Wnt signaling affects the number of hair cells in the utricle but also provide evidence for its role in polarity development.

The transcriptome characteristics of vestibular organs from delayed endolymphatic hydrops patients (Meniere's disease).

OBJECTIVES: To identify genes that are related to delayed endolymphatic hydrops (DEH) in patients by RNA-Seq analysis. DESIGN: Observational study. SETTING: Eye & ENT Hospital, Fudan University (Shanghai, China). PARTICIPANTS: We collected the entire vestibular system from four patients with DEH who underwent labyrinthectomy. Three control samples were collected from patients with acoustic neuroma or facial neuroma treated via the translabyrinthine approach. High-throughput RNA-Seq analysis was performed to investigate gene expression in the pathological vestibular system. MAIN OUTCOME MEASURES: Our bioinformatic analysis identified 17 genes that were upregulated and eight genes that were downregulated in patients with DEH compared with the controls. RESULTS: The altered gene expression profile suggested that DEH is closely related to neuropathy and autoimmune disease. In addition, many of the differentially regulated genes were involved in cell adhesion, suggesting a role of cell adhesion in DEH. Immunofluorescence analysis confirmed the expression of PMP2 and CLDN19 in the cytoplasm of hair cells and scattered expression of MPZ at cell junctions. The protein expression levels were higher in specimens from patients with Ménière's disease and DEH compared with controls. CONCLUSIONS: The protein expression profile of vestibular organs in patients with endolymphatic hydrops exhibited a degree of similarity to that of Ménière's disease. Endolymphatic hydrops is characterised by autoimmune abnormalities. DEH and Ménière's disease are likely to be different manifestations of the same disease, with disparate clinical symptoms. RNA-Seq is a useful analytical tool to characterise the vestibular pathology based on its transcriptome.

Concurrent Occurrence of Congenital Ossicular Anomaly and Localized Cholesteatoma: Series of 10 Cases.

OBJECTIVE: The objective of this study is to describe the clinical features, managements and outcomes of a rare coexistence of congenital ossicular anomaly and localized cholesteatoma. A literature review on these cases and each congenital disorder is also presented. METHODS: A retrospective chart review was performed on patients diagnosed with congenital ossicular anomaly with concurrent localized cholesteatoma from 2008 to 2017. Clinical data of these patients were collected. RESULTS: A total of 10 patients were identified. All patients presented with unilateral hearing loss. Pure-tone audiometry showed conductive hearing loss in all affected ears with an average air conduction (AC) threshold of 59 dB. High-resolution computed tomography scans of the temporal bone diagnosed ossicular anomaly for 90% (9/10); however, only 50% (5/10) had a diagnosis of localized cholesteatoma. A transcanal exploratory tympanotomy under the microscope was performed to discover whether the localized tiny-sized cholesteatoma around the ossicular chain did not have direct contact with the ossicular chain, which could be diagnosed as congenital cholesteatoma. We removed the localized cholesteatoma and reconstructed the ossicular chain in each patient. All localized cholesteatomas were found in the posterior-superior quadrant of the middle ear. Ossicular chain anomalies were associated with the incus and/or the stapes in all cases. Hearing improvement was achieved in each of the 6 patients who were followed up postoperatively, with an average AC threshold of 35 dB. The clinical features of congenital ossicular anomaly with concurrent congenital cholesteatoma were compared with those of each congenital disorder. The pathogenesis of each condition was also discussed. CONCLUSIONS: Congenital ossicular anomaly with concurrent congenital cholesteatoma is rare. It shares similar clinical features with congenital ossicular anomaly occurring alone, therefore awareness should be raised for a possible concurrent congenital cholesteatoma which was easy to miss in the diagnosis (50%) by the radiologist. A patient's hearing level can be improved by removal of the cholesteatoma and reconstruction of the ossicular chain. Localized cholesteatoma does not usually show residuals or recurrence.

Analysis of the Damage Mechanism Related to CO2 Laser Cochleostomy on Guinea Pig Cochlea.

Different types of lasers have been used in inner ear surgery. Therefore, it is of the utmost importance to avoid damage to the inner ear (e.g., hyperthermia and acoustic effects) caused by the use of such lasers. The aim of this study was to use a high powered fibre-enabled CO2 laser (10 W, 606 J/cm2) to perform cochleostomies on guinea pig cochlea and to investigate the possible laser-induced damage mechanisms. The temperature changes in the round window membrane, auditory evoked brainstem response, and morphological of the hair cells were measured and recorded before and after laser application. All of the outcomes differed in comparison with the control group. A rise in temperature and subsequent increased hearing loss were observed in animals that underwent surgery with a 10 W CO2 laser. These findings correlated with increased injury to the cochlear ultrastructure and a higher positive expression of E-cadherin and ß-catenin in the damaged organ of Corti. We assume that enhanced cell-cell adhesion and the activated ß-catenin-related canonical Wnt-signalling pathway may play a role in the protection of the cochlea to prevent further damage.

Pancytopenia as an early indicator for Stevens-Johnson syndrome complicated with hemophagocytic lymphohistiocytosis: a case report.

BACKGROUND: Stevens-Johnson syndrome (SJS) is a severe skin and mucosal bullous disease. When complicated with Hemophagocytic lymphohistiocytosis (HLH), the condition is especially life-threatening. CASE PRESENTATION: Here we report the case of a 4-year-old boy suffering from SJS with extensive erythema multiforme and bulla. Despite active intervention and supportive care, the boy experienced increased skin lesions and a higher fever. Meanwhile, decreases in white blood cell count and hemoglobin were observed. Hyperferritinemia, increased soluble CD25 level, decreased NK cell activity and hemophagocytosis in the boy's bone marrow confirmed the diagnosis of HLH. After high-dose intravenous immunoglobulin and methylprednisone pulse therapy, the boy was discharged in good condition. CONCLUSION: Simultaneous occurrence of HLH and SJS is very uncommon and the condition is life-threatening. Pancytopenia can be a precocious indicator and enables to start a prompt diagnosis and treatment.

Exploring Purification Methods of Exosomes from Different Biological Samples.

Objective: Exosomes were extracted from a variety of biological samples using several different purification processes, and our goal was to determine which method and sample were the most effective for exosome extraction. Methods: We used ExoQuick-TC combined with ultrafiltration to separate and purify exosomes from the supernatant of gastric cancer cells, while we used the ExoQuick kit and ultracentrifugation to purify exosomes from human serum samples. Furthermore, exosomes were isolated and purified from human urine samples by diafiltration and from postparturition human breast milk samples by the filtration-polyethylene glycol precipitation method. The isolated exosomes were morphologically analyzed using a transmission electron microscope, the particle size was measured by NanoSight, and the protein content was analyzed by western blotting. Results: The isolated exosomes showed an obvious cup holder shape, with a clear outline and typical exosome morphological characteristics. The sizes of exosomes derived from gastric cancer cell supernatant, serum, urine, and milk were 65.8 ± 26.9 nm, 87.6 ± 50.9 nm, 197.5 ± 55.2 nm, and 184.1 ± 68.7 nm, respectively. Western blot results showed that CD9 and TSG101 on the exosomes were expressed to varying degrees based on the exosome source. Exosome abundance was higher in the serum, urine, and breast milk than in the supernatant. It is suggested that its exosomes can be extracted to obtain an excellent potential biological source of exosomes. Conclusion: In this study, the extraction and separation methods of foreign bodies from different biological samples were obtained, and it was found that human breast milk was a potential excellent material for administration because of its high abundance.

Influence of biofertilizer on heavy metal bioremediation and enzyme activities in the soil to revealing the potential for sustainable soil restoration.

Overuse of chemical fertilizer and pesticides in agricultural activity is frequently damaging to soil health and can accumulate heavy metals in the soil environment, causing harm to plants, humans, and the ecosystem. This study was done to evaluate the effectiveness of biofertilizers in reducing heavy metal levels in contaminated soil and enhancing the activity of soil enzymes that are crucial to plant growth and development. Two bacteria strains, Pseudomonas aeruginosa. and Bacillus firmus, were chosen to develop biofertilizers based on molasses. The pot experiment was setup using a completely randomized design with four treatments and five levels; Bacillus firmus and Pseudomonas aeruginosa were used separately, and they were combined for the biofertilizer dose (20, 40, 60, 80, and 100 mL). Utilizing contaminated soils taken from a greenhouse farm the effect of biofertilizer on heavy metal bioremediation and soil enzyme activity was examined. Methods of soil agrochemical analysis were used to determine the soil physiochemical properties and the concentrations of heavy metals Cu, Fe, Zn, Cd, Mo, Mn, were determined by inductively coupled plasma-mass spectrometry ICP-MS, following DTPA extraction methods. In results, soil pH decreased from 8.28 to 7.39, Ec increased from 0.91 to 1.12, organic matter increased from 18.88 to 20.63 g/kg, N increased gradually from 16.7 to 24.4 mg/kg, and K increased from 145.25 to 201.4 mg/kg. The effect of biofertilizer treatment on soil physiochemical characteristics was significantly positive. Application of biofertilizer significantly increased the heavy metal bioavailability and the activities of soil enzymes. Soil pH were positively correlated with soil Zn (0.99819*), APK (0.95869*) activity and negatively correlated with Fe (0.96759*) also statistically significant at (p < 0.05). The soil Cu positively correlated with Fe (0.99645*), Cd (0.97866*), ß.D.GLU (0.99769*) and negatively correlated with PAK (- 0.9624*). Soil ARY had positive correlation with soil Mn (0.99683*), Cd (0.95695*), and negative correlation with PAK (- 0.99424*) at (p < 0.05). Soil enzyme activities were negatively correlated to heavy metals at a significant level. Collectively, the study highlights the potential of biofertilizers as a sustainable and effective approach to enhance soil health and remediate heavy metal-contaminated soils in greenhouses.

Construction of fluorescent sensor array and three-dimensional microfluidic paper based analytical device for specific identification and visual determination of antibiotics in food.

For antibiotics misuse since the global outbreak of COVID 19, a novel strategy for discriminating and detecting antibiotics is proposed based on the graphene quantum dots with multi-doped heteroatoms including F, N and P (M-GQDs), which exhibit blue emission (419.0 nm) under the excitation of 336.0 nm. Specifically, the fluorescence of M-GQDs is quenched by tetracyclines (TCs) owing to inner filter effect (IFE) and enhanced by alkane-modified fluoroquinolones (AFQs), which is attributed to restricted conformational rotation based on π-π stacking, hydrogen-bonding and electrostatic interactions. Meanwhile, the electron-accepting property of oxazine ring in oxazine-modified fluoroquinolones (OFQs) increases emission peak at 498.0 nm and decreases emission peak at 419.0 nm as the color changes from blue to cyan. Moreover, a cascade system integrated with 3D microfluidic paper-based analytical device (3D-µPAD) is applied successfully for visually distinguishing three antibiotics, which shows great potential and versatility of M-GQDs for food safety monitoring.

Involvement of Dmp1 in the Precise Regulation of Hair Bundle Formation in the Developing Cochlea.

Dentin matrix protein 1 (Dmp1) is a highly phosphorylated, extracellular matrix protein that is extensively expressed in bone and teeth but also found in soft tissues, including brain and muscle. However, the functions of Dmp1 in the mice cochlea are unknown. Our study showed that Dmp1 was expressed in auditory hair cells (HCs), with the role of Dmp1 in those cells identified using Dmp1 cKD mice. Immunostaining and scanning electron microscopy of the cochlea at P1 revealed that Dmp1 deficiency in mice resulted in an abnormal stereociliary bundle morphology and the mispositioning of the kinocilium. The following experiments further demonstrated that the cell-intrinsic polarity of HCs was affected without apparent effect on the tissue planer polarity, based on the observation that the asymmetric distribution of Vangl2 was unchanged whereas the Gαi3 expression domain was enlarged and Par6b expression was slightly altered. Then, the possible molecular mechanisms of Dmp1 involvement in inner ear development were explored via RNA-seq analysis. The study suggested that the Fgf23-Klotho endocrine axis may play a novel role in the inner ear and Dmp1 may regulate the kinocilium-stereocilia interaction via Fgf23-Klotho signaling. Together, our results proved the critical role of Dmp1 in the precise regulation of hair bundle morphogenesis in the early development of HCs.

Decolorization of Textile Azo Dye via Solid-State Fermented Wheat Bran by Lasiodiplodia sp. YZH1.

Textile dyes are one of the major water pollutants released into water in various ways, posing serious hazards for both aquatic organisms and human beings. Bioremediation is a significantly promising technique for dye decolorization. In the present study, the fungal strain Lasiodiplodia sp. was isolated from the fruiting bodies of Schizophyllum for the first time. The isolated fungal strain was examined for laccase enzyme production under solid-state fermentation conditions with wheat bran (WB) using ABTS and 2,6-Dimethoxyphenol (DMP) as substrates, then the fermented wheat bran (FWB) was evaluated as a biosorbent for Congo red dye adsorption from aqueous solutions in comparison with unfermented wheat bran. A Box-Behnken design was used to optimize the dye removal by FWB and to analyze the interaction effects between three factors: fermentation duration, pH, and dye concentration. Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and scanning electron microscopy (SEM) were applied to study the changes in the physical and chemical characteristics of wheat bran before and after fermentation. An additional experiment was conducted to investigate the ability of the Lasiodiplodia sp. YZH1 to remove Congo red in the dye-containing liquid culture. The results showed that laccase was produced throughout the cultivation, reaching peak activities of ∼6.2 and 22.3 U/mL for ABTS and DMP, respectively, on the fourth day of cultivation. FWB removed 89.8% of the dye (100 mg L-1) from the aqueous solution after 12 h of contact, whereas WB removed only 77.5%. Based on the Box-Behnken design results, FWB achieved 93.08% dye removal percentage under the conditions of 6 days of fermentation, pH 8.5, and 150 mg L-1 of the dye concentration after 24 h. The fungal strain removed 95.3% of 150 mg L-1 of the dye concentration after 8 days of inoculation in the dye-containing liquid culture. These findings indicate that this strain is a worthy candidate for dye removal from environmental effluents.

Changes in cytosolic Mg2+ levels can regulate the activity of the plasma membrane H+-ATPase in maize.

Plant PM (plasma membrane) H+-ATPase, a major consumer of cellular ATP, is driven by the MgATP complex which may dissociate at low cytosolic Mg2+ activity. We investigated whether hydrolytic activity of PM H+-ATPase is inhibited at ATP concentrations exceeding the Mg2+ concentration. Activity in isolated maize PMs was measured at pH 6.5 in the presence of 5 mM Mg2+ (high) or 2 mM Mg2+ (low), whereas K+ was applied at concentrations of 155 mM (high) or 55 mM (low). In all experiments, with membrane vesicles either from roots or leaves, the enzyme activity decreased in the presence of Mg2+-free ATP. At inhibitory ATP concentrations, the activity was not influenced by the K+ concentration. The activity was restored after increasing the Mg2+ concentration. ATP inhibition also occurred at pH 7.5. Kinetic modelling shows that Mg2+-free ATP acted as a competitive inhibitor with a Ki in the range of the Km. Ki decreased by 75% at low K+ concentration. Ki was one order of magnitude lower at pH 7.5 compared with pH 6.5. The observed inhibition is consistent with a concept in which down-regulation of the cytosolic Mg2+ activity is involved in (phyto)hormonal stress responses.

Methods to Investigate Cell Polarity of Inner Ear.

Hair cells in cochlea and vestibular organs depend on the coordinated cell polarity to perform the normal auditory or balance function. The mouse inner ear is one of the ideal model to study planar cell polarity. In this chapter, we introduce a series of general experimental methods for studying planar cell polarity in the inner ear. The approaches presented here are also applicable to other organs with particular polarity phenotypes.

Network-Based Pharmacological Study on the Mechanism of Guishao-Liujun Decoction in the Treatment of Gastric Cancer.

Objective: The aim of the study was to use a network pharmacological method to examine the mechanism of Guishao-Liujun decoction against gastric cancer (GC). Methods: The traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) and the Traditional Chinese Medicine Integrated Database (TCMID) were used to obtain the chemical composition and targets of all the drugs of Guishao-Liujun decoction, and the targets of GC were screened using GeneCards and Online Mendelian Inheritance in Man (OMIM) databases. The obtained targets were imported into Cytoscape 3.7.2 software by using the R language to take the intersection for a Venn analysis to construct active ingredient target networks, and they were imported into the STRING database to construct protein-protein interaction (PPI) networks, with the BisoGenet plugin in Cytoscape 3.7.2 being used for analyzing network topology. On the potential target of Guishao-Liujun decoction for GC, gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed using the R-language bioconductor platform, and the outcomes were imported into Cytoscape 3.7.2 software to obtain the KEGG network map. The core targets were docked with the active components by the macromolecular docking software application AutoDock Vina. Results: A total of 243 chemical components and 1,448 disease targets including 127 intersecting targets were discovered. AKT1, TP53, and GO functional analysis were mainly associated with ubiquitination and oxidase reduction activity. In GC treatment, the KEGG analysis revealed that Guishao-Liujun decoction mainly acted through the tumor necrosis factor (TNF), interleukin 17 (IL-17), and cancer-related signaling pathways, with the best binding performance with TP53, as indicated by the outcomes of macromolecular docking. Conclusion: In the treatment of GC, Guishao-Liujun decoction works with a variety of components and targets, establishing the groundwork for further research into its mechanism of action.

Hoxa9/meis1-transgenic zebrafish develops acute myeloid leukaemia-like disease with rapid onset and high penetrance.

HOXA9 and MEIS1 are co-expressed in over 50% of acute myeloid leukaemia (AML) and play essential roles in leukaemogenesis, but the mechanisms involved are poorly understood. Diverse animal models offer valuable tools to recapitulate different aspects of AML and link in vitro studies to clinical trials. We generated a double transgenic zebrafish that enables hoxa9 overexpression in blood cells under the draculin (drl) regulatory element and an inducible expression of meis1 through a heat shock promoter. After induction, Tg(drl:hoxa9;hsp70:meis1) embryos developed a preleukaemic state with reduced myeloid and erythroid differentiation coupled with the poor production of haematopoietic stem cells and myeloid progenitors. Importantly, most adult Tg(drl:hoxa9;hsp70:meis1) fish at 3 months old showed abundant accumulations of immature myeloid precursors, interrupted differentiation and anaemia in the kidney marrow, and infiltration of myeloid precursors in peripheral blood, resembling human AML. Genome-wide transcriptional analysis also confirmed AML transformation by the transgene. Moreover, the dihydroorotate dehydrogenase (DHODH) inhibitor that reduces leukaemogenesis in mammals effectively restored haematopoiesis in Tg(drl:hoxa9;hsp70:meis1) embryos and improved their late survival. Thus, Tg(drl:hoxa9;hsp70:meis1) zebrafish is a rapid-onset high-penetrance AML-like disease model, which provides a novel tool to harness the unique advantages of zebrafish for mechanistic studies and drug screening against HOXA9/MEIS1 overexpressed high-risk AML.

Interactions of Vallisneria natans and Iron-Oxidizing Bacteria Enhance Iron-Bound Phosphorus Formation in Eutrophic Lake Sediments.

Submerged macrophyte restoration and in situ phosphorus (P) passivation are effective methods for the control of internal P loading from sediments. This study explored the synergistic effects of Vallisneria natans and iron (Fe)-oxidizing bacteria (IOB) on internal P loading from eutrophic freshwater lake sediments by taking into account Fe-bound P (FeP) formation and associated bacterial community structures. Sediment samples were prepared in glass tanks under four treatments, namely no V. natans planting or IOB inoculation (control), planting V. natans without IOB inoculation (Va), planting V. natans with IOB inoculation (Va-IOB), and planting V. natans with autoclaved IOB inoculation (Va-IOB[A]). Compared with the control, all three treatments with V. natans (Va, Va-IOB, and Va-IOB[A]) had significantly decreased organic matter contents and increased redox potential in sediments (p < 0.05), at the rapid growth and mature stages of V. natans. Planting V. natans with and without IOB inoculation also decreased the total P (TP) and Fe-P concentrations in sediments. Conversely, Fe3+ concentrations, Fe3+/Fe2+ ratios, and the proportions of Fe-P in TP all increased in sediments planted with V. natans, especially under the Va-IOB treatment (p < 0.05). Furthermore, bacterial community diversity increased in sediments due to the presence of V. natans. The relative abundances of IOB (including Acidovorax and Chlorobium) increased from the transplanting to the rapid growth stage of V. natans and then decreased afterwards. In the later stages, the relative abundances of IOB and their ratios to Fe-reducing bacteria were the highest under the Va-IOB treatment. Accordingly, synergistic interactions between V. natans and IOB could enhance Fe-P formation and reduce TP concentrations in eutrophic lake sediments by altering sediment physicochemical properties and Fe oxidation-related bacterial community structures.

Analysis of cancer-promoting genes related to chemotherapy resistance in esophageal squamous cell carcinoma.

Background: According to histopathology, esophageal cancer can be divided into squamous cell carcinoma (SCC) and esophageal adenocarcinoma (adeno arcinoma). In China, 90% of esophageal cancer patients are squamous cell carcinoma. Cisplatin and fluaziridine are the main chemotherapy before and after surgery. Long-term drug treatment is often accompanied by the emergence of drug resistance of tumor cells. There are many mechanisms for the emergence of drug resistance of tumor cells, including the increase of drug efflux, the decrease of drug intake, the inhibition of cell apoptosis, and so on. This study aimed to investigate the key cancer-promoting genes related to chemotherapy resistance in esophageal squamous cell carcinoma (ESCC). Methods: Two datasets from the Gene Expression Omnibus (GEO) database (GSE86099 and GSE50224) were retrieved. We performed microRNA (miRNA) and messenger RNA (mRNA) expression analysis to identify differentially expressed genes (DEGs). The intersection of the downregulated miRNA targets and the upregulated mRNAs were used for Gene Ontology (GO) enrichment analysis, and survival risk was assessed using data from The Cancer Genome Atlas (TCGA). Results: There were 35 common genes, of which, based on GO enrichment, most were related to the cardiac muscle cell action. Four genes showed significant association with the estimated half-maximal inhibitory concentration (IC50) of paclitaxel: bone morphogenetic protein 1 (BMP1), dumbbell former 4 protein (DBF4), angiogenin (ANG), and MAP7 domain containing 2 (MAP7D2). Four risk factors (MP1, HIP1, ANG, and MAP7D2) were selected to generate a signature using least absolute shrinkage and selection operator (LASSO) regression. Protein-protein interaction (PPI) analysis showed guanine nucleotide-binding protein subunit beta 4 (GNB4), calcium voltage-gated channel auxiliary subunit beta 2 (CACNB2), and sodium voltage-gated channel alpha subunit 1 (SCN1A) were located at key positions of the network. Among potential risk genes, only the high expression of dedicator of cytokinesis 8 (DOCK8) was associated with poorer survival. Conclusions: The 35 oncogenes may be involved in mechanisms of chemotherapy resistance in ESCC, as well as the corresponding enrichment and regulatory network. The signature containing 4 key risk genes merits further investigation and may provide a deeper understanding of the molecular mechanisms in ESCC treatment failure.